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Corrected Protocol Update #2 01/15/2015 ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY _________________________________________ PROTOCOL UPDATE TO CALGB 40903 _________________________________________ PHASE II STUDY OF NEOADJUVANT LETROZOLE FOR POSTMENOPAUSAL WOMEN WITH ESTROGEN RECEPTOR POSITIVE DUCTAL CARCINOMA IN SITU (DCIS) An Alliance trial conducted by CALGB* and open only to CALGB, ACOSOG and NCCTG sites American College of Radiation Imaging Network Core Imaging Laboratory (ACRIN) prequalification for breast MRI acquisition is a requirement for institutions enrolling patients on this protocol Letrozole for this study will be supplied and distributed by the Division of Cancer Prevention (DCP) NCI X Update: Status Change: Eligibility changes Activation Therapy / Dose Modifications / Study Calendar changes Closure Informed Consent changes Suspension / temporary closure Scientific / Statistical Considerations changes Reactivation Data Submission / Forms changes X Editorial / Administrative changes Other : No IRB approval of this amendment is required. Please follow your local IRB guidelines. UPDATES TO PROTOCOL: • In keeping with new DCP PIO requirements, the name of the lead group on the title page of the protocol has been updated from “Cancer and Leukemia Group B” to “Alliance for Clinical Trials in Oncology.” • The NCTN participating groups have been added to the lower left of the protocol cover page. A replacement protocol document has been issued. ____________________________________________________________ ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL __________________________________________________________________________ Activation Date: 02/15/12 Includes Update #2 ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY CALGB 40903 PHASE II STUDY OF NEOADJUVANT LETROZOLE FOR POSTMENOPAUSAL WOMEN WITH ESTROGEN RECEPTOR POSITIVE DUCTAL CARCINOMA IN SITU (DCIS) An Alliance trial conducted by CALGB* and open only to CALGB, ACOSOG and NCCTG sites American College of Radiation Imaging Network Core Imaging Laboratory (ACRIN) prequalification for breast MRI acquisition is a requirement for institutions enrolling patients on this protocol Letrozole for this study will be supplied and distributed by the Division of Cancer Prevention (DCP) NCI. Study Chair E. Shelley Hwang, MD, MPH Duke University Medical Center Seeley G. Mudd Building, Suite # 465 10 Bryan Searle Drive Durham, NC 27710 Phone: 919-684-6849 Fax: 919-684-6044 [email protected] Study Co- Chair Maura Dickler, M.D. Tel: 646-888-4560 Fax: 646-888-4555 [email protected] Correlative Science Co-Chair Nancy DeMore, MD Tel: 919-966-5221 [email protected] Pathology Co-Chair Baljit Singh, M.D. Tel: 212-263-0136 [email protected] Correlative Science Co-Chair Matthew J. Ellis, M.B., Ph.D. Tel: 314-996-5569 [email protected] Imaging Co-Chair Nola Hylton, Ph.D. Tel: 415-476-8856 [email protected] Breast Committee Co-Chairs Clifford A. Hudis, M.D. Eric P. Winer, M.D. Tel: 646-888-4551 Tel: 617-632-3800 [email protected] [email protected] Surgery Committee Chair Leslie J. Kohman, M.D. Tel: 315-464-6304 [email protected] Faculty Statistician Donald A. Berry, Ph.D Tel: 713-794-4141 [email protected] PET Faculty Statistician Kouros Owzar, Ph.D Tel: 919-681-8505 [email protected] Staff Statistician Connie T. Cirrincione, M.S. Tel: 919-681-5404 [email protected] Correlative Science Staff Statistician Brandelyn Pitcher, M.S. Tel: 919-681-6887 [email protected] Data Coordinator Eleanor Leung, Ph,D Tel: 919-668-9380 [email protected] Protocol Coordinator Heather Becker Tel: 773-834-2546 [email protected] Participating Organization: ALLIANCE/ Alliance for Clinical Trials in Oncology Version Date: 12/15/14 1 01/15/2015 CALGB 40903 Study Contacts CALGB Central Office 230 West Monroe Street, Suite 2050 Chicago, IL 60606-4703 Tel: 773-702-9171 Fax: 312-345-0117 www.calgb.org Alliance Biorepository at Ohio State University The Ohio State University Innovation Centre 2001 Polaris Parkway Columbus, OH 43240 Tel: 614-293-7073 Fax: 614-293-7967 CALGB Statistical Center Hock Plaza 2424 Erwin Road, Suite 802 Durham, NC 27705 Tel: 919-668-9348 Data Operations Fax: 919-668-9348 Biostatistics Fax: 919-681-8028 CALGB Patient Registration Tel: 919-668-9396 Fax: 919-668-9397 CALGB 40903 Pharmacy Liaison Brenda Gebhart, RPh Missouri Baptist Medical Center Tel: 314-996-5012 Fax: 314-996-5172 [email protected] American College of Radiology Imaging Network MRI Core Laboratory 1818 Market Street, 16th Floor Philadelphia, PA 19103 Lisa Cimino, Imaging Specialist Tel: 215-574-3243 [email protected] Deborah Harbison, Project Manager Tel: 215-940-8914 [email protected] ACRIN TRIAD Support Tel: 215-940-8820 [email protected] CALGB 40903 Nursing Liaison Kathy J. Klinger, RN, MSN, NP-BC, AOCN Hematology Oncology Assoc. of Central New York Tel: 315-472-7504 [email protected] UCSF Breast MRI Research Laboratory Breast Imaging Research Group UCSF Dept. of Radiology & Biomedical Imaging 1600 Divisadero St. Suite C201, Box 1667 San Francisco, CA 94115 Sachiko Suzuki, Research Associate Tel: 415-885-3777 Fax: 415-885-3884 [email protected] In office Monday, Wednesday, Friday 9:00-5:00 PT For urgent matters, please contact Krysta Banfield Tel: 415-885-3762 [email protected] or Margarita Watkins Tel: 415-476-0734 margarita.watkins @ucsf.edu CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION To submit site registration documents: CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA 19103 Phone – 1-866-651-CTSU Fax – 215-569-0206 For patient enrollments: Submit study data directly to the Lead Cooperative Group unless otherwise specified in the protocol: CALGB Statistical Center Hock Plaza 2424 Erwin Road, Suite 802 Durham, NC 27705 Please refer to the patient enrollment section for instructions on using the OPEN system. Tel: 919-668-9350 Data Operations Fax: 919-668-9348 Teleform Fax: 919-416-4990 Sites should submit Teleforms via Fax or Mail. Do not submit study data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions. The study protocol and all related forms and documents must be downloaded from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must use the current form version and adhere to the instructions and submission schedule outlined in the protocol. CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. For patient eligibility or treatment-related questions contact the Study PI of the Coordinating Group. For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or email: CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and correspondence will be triaged to the appropriate CTSU representative. For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website https://www.ctsu.org The CTSU Web site is located at https://www.ctsu.org Version Date: 12/15/14 2 01/15/2015 CALGB 40903 PHASE II STUDY OF NEOADJUVANT LETROZOLE FOR POSTMENOPAUSAL WOMEN WITH ESTROGEN RECEPTOR POSITIVE DUCTAL CARCINOMA IN SITU (DCIS) Letrozole for this study will be supplied and distributed for this study by the Division of Cancer Prevention (DCP), NCI. Patient Eligibility Required Initial Laboratory Values Pathologic confirmation of DCIS rendered on core biopsy of the female breast, without invasive cancer. Microinvasion allowed. ANC ≥ 1,000/µl All patients must have a clip placed either, the time of the diagnostic biopsy or at the time of the baseline MRI prior to the start of treatment. Serum Creatinine < 1.7 mg/dL Patient should have diagnostic tissue available for correlative studies. Total Bilirubin < 2.0 mg/dL Platelet count ≥ 100,000/µl AST, ALT ≤ 2.5 x ULN Clinical stage Tis or T1mi N0 M0. Hormone receptor status ER and/or PgR positive (see Section 4.4). For patients < 55 years of age and one year or more of amenorrhea, serum estradiol level assay must be < 20 pg/ml Patient must be postmenopausal (see Section 4.5). No prior surgical excision of index breast for current DCIS Dx. Any exogenous hormone therapy must be completed 4 weeks prior to registration. No prior treatment with tamoxifen or raloxifene. No prior neoadjuvant/adjuvant therapy for current DCIS Dx. No contraindication to breast MRI. Calcifications must be measurable in at least one dimension with each lesion > 1cm and < 7cm on mammogram; DCIS must be visible on MRI based on central review. No palpable DCIS or adenopathy. Multifocal or bilateral disease allowed. Patients with osteoporosis must be receiving appropriate therapy or have declined therapy (see Section 4.9). > 18 years of age. ECOG (Zubrod) performance status 0-1. Patients must not be pregnant or nursing. Study Schema: CR, PR or SD 6 month research R continue MRI followed by Diagnostic core E 3 month letrozole x 3 surgery♦ biopsy G Letrozole Disease evaluation months ER+ DCIS I 2.5 mg/day by research MRI S x 3 months Baseline MRI T Radiographic Surgery with IV contrast E PD! R !Patients who are found to have radiographic progressive disease at month 3 will have the preoperative mammogram and be scheduled for surgery within 30 days of the second (month 3) MRI central review. ♦ For patients who have completed 6 months of letrozole the surgery must be performed within 30 days of the 6 month MRI. At month 3 or month 6, discontinue letrozole the day before surgery. Version Date: 12/15/14 3 01/15/2015 TABLE OF CONTENTS 1.0 INTRODUCTION ..................................................................................................................................5 2.0 OBJECTIVES ........................................................................................................................................8 3.0 ON-STUDY GUIDELINES ...................................................................................................................9 4.0 ELIGIBILITY CRITERIA ...................................................................................................................9 5.0 REGISTRATION .................................................................................................................................11 6.0 DATA AND SPECIMEN SUBMISSION ...........................................................................................16 7.0 REQUIRED DATA ..............................................................................................................................20 8.0 TREATMENT PLAN ..........................................................................................................................23 9.0 DOSE MODIFICATIONS ..................................................................................................................25 10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION ..........................................25 11.0 CORRELATIVE STUDIES..............................................................................................................25 12.0 ASSESSMENT OF QUALITY OF LIFE AND MUSCULOSKELETAL SYMPTOMS ASSOCIATED WITH NEOADJUVANT LETROZOLE FOR ER POSITIVE DCIS ...........................30 13.0 CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE ..............................................35 14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ...................................................37 15.0 STATISTICAL CONSIDERATIONS ............................................................................................37 16.0 EXPEDITED ADVERSE EVENT REPORTING ..........................................................................43 17.0 REFERENCES...................................................................................................................................46 18.0 MODEL CONSENT FORM: ...........................................................................................................51 APPENDIX I CALGB 40903 SITE IMAGING MANUAL ....................................................................64 Version Date: 12/15/14 4 01/15/2015 1.0 INTRODUCTION Ductal carcinoma in situ (DCIS) will be diagnosed in over 60,000 women in the United States this year [1]. The incidence of DCIS has risen almost 5-fold over the last 15 years, and now represents 2530% of all mammographically detected breast cancer [2]. The current treatment of DCIS is based on a presumption that DCIS is a non-obligate precursor of invasive breast cancer that does not itself demonstrate invasive potential. The goal of treatment is prevention of invasive cancer, which is accomplished through aggressive local control. One-third of women diagnosed with DCIS will undergo mastectomy; the rest will undergo some combination of surgery, radiation, and systemic hormonal therapy [3, 4]. In fact, despite the 99% survival rate from DCIS, the locoregional treatments for DCIS are not much different than those recommended for the invasive cancers these interventions are aimed to prevent. The Problem: Some fraction of DCIS has the potential to become invasive cancer. There is a paucity of natural history studies of observation alone, since DCIS is generally surgically resected upon diagnosis. The few retrospective reports of women who had biopsies that were assumed to be benign but on later review were found to have DCIS report a 20-50% risk of invasive cancer in the twenty years after biopsy [5-8]. Thus, non-surgical management for those who may never progress to invasive cancer could reasonable, provided that a low-risk subgroup of DCIS could be identified. One approach would be to treat women with ER-positive DCIS with preoperative endocrine therapy in order to reverse malignant changes. If successful, some women could avoid surgery for this disease. The aromatase inhibitors (AIs) are ideal candidates for use in such a setting. 1.1 The role of aromatase inhibitors in breast cancer treatment It has long been recognized that breast cancers are susceptible to hormonal manipulation. The mainstay of hormonal treatment for breast cancer has been tamoxifen. However, a new class of pharmacologic agents, the aromatase inhibitors (AIs), has emerged in the last decade as an effective alternative to tamoxifen in postmenopausal women. The AIs function by preventing peripheral conversion of testosterone to estradiol, thereby inhibiting estrogen-dependent tumor growth. There have now been several pivotal adjuvant trials comparing aromatase inhibitors to tamoxifen [9-12]. In aggregate, these studies show that AIs confer an improved DFS over tamoxifen, thus establishing AIs as important and effective adjuvant hormonal treatment for ERpositive postmenopausal breast cancers. Furthermore, they support a significant potential benefit of AIs in breast cancer prevention, providing up to 70% reduction in contralateral breast cancer in patients treated with an adjuvant AI. 1.2 Neoadjuvant studies of aromatase inhibitors in invasive breast cancer The role of AIs in the neoadjuvant setting has also been actively investigated. The IMPACT study compared neoadjuvant treatment of ER-positive tumors between three arms: anastrazole alone, tamoxifen alone, or the combination. After 3 months of preoperative treatment, a greater proportion of the AI group were candidates for breast conserving surgery (46% versus 22%, p=0.03), although no significant difference in objective response between anastrazole and tamoxifen was observed [13]. A similar comparison between neoadjuvant letrozole alone to tamoxifen alone in the P024 trial showed an increase in clinical response rate (complete response + partial response; OR 2.23; 95% CI 1.43-3.50) and the breast conservation rate in the letrozole group compared to the tamoxifen group [14]. Most recently, in a study evaluating the DCIS component in prospective randomized window trial of letrozole versus anastrozole for ERpositive postmenopausal invasive cancer, a significant drop in Ki67 was seen for both groups in the DCIS component of the tumor [15]. Version Date: 12/15/14 5 01/15/2015 1.3 Letrozole Letrozole is a highly selective non-steroidal competitive inhibitor of the aromatase enzyme system. It has been shown to effectively inhibit the conversion of androgens to estrogens both in vitro and in vivo [16]. Some data that suggest that it may be the most effective AI in the neoadjuvant setting [17, 18]. It is administered orally, has few adverse effects, and unlike tamoxifen, does not lead to an increase in endometrial cancer. At least one clinical study shows that neoadjuvant letrozole may be more effective than tamoxifen in Her2-positive invasive cancers [19]. Since approximately 50% of DCIS lesions are Her-2/neu positive, letrozole may be particularly suited for neoadjuvant studies in DCIS. Major side effects associated with letrozole therapy include musculoskeletal pain in 15-25% of patients [20] and fracture rate, which in one study was reported to be 8.6% versus 5.8% in the letrozole group compared to the tamoxifen treated group at 51 months [21] (see Section 10.1). 1.4 Radiographic evaluation of DCIS: Rationale for magnetic resonance imaging (MRI) assessment The follow-up for patients undergoing nonsurgical or preoperative treatment for breast cancer is predicated on the ability to detect tumor progression. Thus, one important consideration for the primary treatment for DCIS is whether the response to nonsurgical interventions can be assessed noninvasively. Up to 90% of intraductal cancers are nonpalpable and therefore, not evaluable on physical examination. Moreover, although up to 75% of all DCIS is detected by mammography, it has been well documented that the extent of DCIS cannot be accurately predicted with mammography alone [22, 23]. The problem of mammographically occult DCIS is further underscored by the fact that up to 68% of margins, determined to be negative on specimen radiography, still demonstrate residual disease on final pathology [24]. Since DCIS usually presents as calcifications without an associated density or mass, ultrasound is not useful in this setting and appears to consistently underestimate the presence or extent of disease [25]. It is unknown whether microcalcifications, often the sole mammographic abnormality, disappear if DCIS regresses. Therefore, any study evaluating response of DCIS to medical therapy cannot rely solely on mammographic or sonographic imaging. The ideal imaging modality with which to follow patients with DCIS must be able to: (1) accurately determine extent of DCIS, and (2) assess whether invasive cancer is present. Preliminary studies indicate that magnetic resonance imaging (MRI) may have the ability to do both, with greater accuracy than either mammography or ultrasound. One of the earliest studies of MRI for intraductal cancers was a retrospective review of 22 cases of DCIS in which MRI accurately predicted the extent of disease in 21 of 22 cases, compared with 14 of 19 patients accurately assessed by mammography [26]. In another small retrospective study from the University of California, San Francisco (UCSF), extent of DCIS was correctly predicted by MRI in 11 of 13 patients [27]. An important limitation of MRI for DCIS, however, is its poor performance in detecting lesions less than 5 mm in diameter [28]. Nevertheless, Kuhl and colleagues have reported in a prospective observational study, that MRI detected 92% of DCIS compared to only 56% detected by mammography [29]. Presently, magnetic resonance imaging is the most sensitive imaging tool available to evaluate both the extent of DCIS and the presence of associated occult invasive carcinoma. In the neoadjuvant setting both tumor size and tumor volume have been proposed as surrogate indicators of treatment response, as baseline pathologic tumor measurement is not possible since surgical excision is undertaken after preoperative treatment has been administered. Although reduction in maximal tumor diameter has been a well-described radiographic endpoint for both mammographic and sonographic measures, we and other have found that tumor diameter may have limited ability to detect response to therapy in the setting of patchy, heterogeneous response Version Date: 12/15/14 6 01/15/2015 rather than concentric tumor reduction. In the UCSF study of patients undergoing neoadjuvant therapy for invasive breast cancer, change in MRI tumor volume was superior to change in MRI tumor diameter, clinical examination, or number of positive nodes in predicting relapse-free survival [30]. Furthermore, MRI volume has been shown to be a more reproducible measure than maximum diameter, particularly for irregularly shaped lesions with heterogeneous treatment response [31]. 1.5 Preliminary results of neoadjuvant hormonal therapy for DCIS Boland and colleagues first presented data to suggest that estrogen withdrawal may result in detectable biologic changes in DCIS [32]. The researchers conducted a retrospective review of 108 patients with core-biopsy diagnosed DCIS. The women were divided into three groups: 27 women who stopped hormone replacement therapy (HRT) at diagnosis, 25 women who continued to take HRT up to surgery, and 56 women who were not taking HRT at diagnosis. Ki67, ER, PR, and Her2 were evaluated by IHC on both the core biopsy and surgical excision specimens. Discontinuation of HRT resulted in both decreased cell proliferation and reduced PR expression only in those patients with ER(+) disease. The investigators hypothesized that administration of endocrine treatment may result in a similar biologic effect on unresected DCIS; furthermore, the investigators were interested in whether a radiographic correlate to biological response could be demonstrated. Investigators at UCSF recently completed a single-arm pilot study of 23 postmenopausal women with a diagnosis of ER-positive pure DCIS by stereotactic core biopsy. Participants were enrolled in a trial of neoadjuvant letrozole administered for three months followed by definitive surgical excision. A placebo arm was not deemed to be acceptable, as the risk of DCIS progression with 3 months was unknown and thus potentially deleterious to the patient. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. MRI examinations were obtained at baseline and following 3 months of endocrine therapy. Study adherence was high, with no patients withdrawing from the study prior to the 3-month MRI evaluation. Volume measurements on DCIS lesions at baseline and following three months of endocrine therapy were based on the signal enhancement ratio (SER) defined by the relationship between the highest signal intensity (SI) at baseline, at the first timepoint after contrast injection, and at the second timepoint after contrast injection. SER is defined as: (SER)=(S1-S0)/(S2-S0), where S0, S1 and S2 are the pre-contrast, first post-contrast and second-post contrast signal intensities of the three time-point data acquisition. In the pilot study, there was no significant change in mammographic extent of DCIS. However, there was a significant reduction in the extent of MRI enhancement based on single maximum tumor diameter as well as on calculated tumor volume (volSER) measurements. This pilot study demonstrates that preoperative endocrine therapy results in change in MRI enhancement characteristics for DCIS. Pathologic findings included a decrease in Ki67 and duct distention, an increase in periductal sclerosis and scattered degenerated cells, as well as an increase in macrophage infiltrate [33]. Furthermore, two of the 22 cases treated with endocrine therapy demonstrated only ADH without residual DCIS in the post-treatment excision specimens. Importantly, two of the 23 patients had invasive ductal carcinoma in addition to DCIS in posttreatment excision specimens. One of the invasive carcinomas was HER2-positive, as was its associated DCIS. In both cases, the invasive tumors were hormone receptor-positive. The cases of invasive cancer were encountered early in the trial and most likely represented failure of MRI to detect invasive cancer. Recent data from UCSF suggests that baseline MRI in women with newly detected DCIS has a negative predictive value of 96% - 100% for invasive cancer (unpublished data), making inclusion of patients with extensive invasive cancer highly unlikely. Disease progression cannot be entirely excluded, although this is not likely as all patients remained on hormonal treatment for the duration of the study. Version Date: 12/15/14 7 01/15/2015 The neoadjuvant approach described in this pilot study provides a framework for evaluating the radiographic response of DCIS, based on change in MRI volume, to preoperative therapies. These findings support a rationale for an extended study to both confirm these findings and to determine whether baseline radiographic and biologic markers could predict which patients will respond best to such a neoadjuvant approach. 1.6 Trial design The proposed trial is a neoadjuvant study of 6 months of aromatase inhibitor therapy for ER(+) postmenopausal DCIS. The goal will be to determine whether preoperative aromatase inhibitor treatment for DCIS results in mammographic and MR-detectable radiographic regression or stabilization of disease. This study is designed to establish a foundation from which to plan novel, less aggressive treatment algorithms for patients with pre-invasive breast disease. 1.7 Inclusion of Women and Minorities Trial participation will not be limited by race or ethnicity, and patients of all ethnic backgrounds will be encouraged to participate. However, the trial will be limited to female patients only, as this is the predominant population undergoing mammographic screening. Accrual Targets Ethnic Category Hispanic or Latino Not Hispanic or Latino Ethnic category: Total of all subjects Females 11 95 106 (A1) Racial Category 2.0 3 pts/month Total 11 95 106 (C1) 1 3 11 + + + 0 0 0 = = = 1 3 11 1 + 0 = 1 90 106 (A2) + 0 0 (B2) = = 90 106 (C2) (A1=A2) Accrual Rate: = = = + American Indian or Alaskan native Asian Black or African American Native Hawaiian or other Pacific Islander White Racial Category: Total of all subjects Sex/Gender Males + 0 + 0 + 0 (B1) Total Expected Accrual: (B1=B2) 106 Min (C1=C2) 115 Max OBJECTIVES 2.1 Primary Objective To estimate the mean change in MRI tumor volume from pretreatment to completion of preoperative endocrine therapy in ER(+) DCIS, as well as to determine whether 3-month change in volume correlates with 6-month change. 2.2 Secondary Objectives 2.2.1 To assess radiographic-pathologic correlation between MRI findings and histopathology, including the prevalence of occult invasive cancer in patients undergoing neoadjuvant endocrine therapy for DCIS. Version Date: 12/15/14 8 01/15/2015 2.2.2 To compare changes in (1) MRI maximum lesion diameter and (2) mammographic extent at baseline and following treatment. These are two additional radiographic parameters which may also detect biological response to therapy. 2.2.3 To determine practice patterns of adjuvant hormonal and radiation therapy in patients who complete neoadjuvant letrozole therapy for DCIS. 2.2.4 To determine whether Ki67 is reduced with neoadjuvant letrozole treatment for DCIS, and to compare the reduction in proliferation between radiographic responders and non-responders. 2.2.5 To identify baseline IHC and expression biomarkers predictive of response to treatment, with response determined by extent of Ki67 reduction. Subsets showing the greatest reduction in Ki67 would be the most likely candidates for non-operative treatment in future studies. 2.2.6 To examine whether germline polymorphisms are associated with clinical endpoints, including treatment-related toxicity or efficacy outcomes, or with expression of biomarkers in serum or tumor. 2.2.7 To assess quality of life and musculoskeletal symptoms associated with neoadjuvant letrozole for ER positive DCIS. 3.0 ON-STUDY GUIDELINES Any postmenopausal patient referred to a surgeon at a participating institution with a new diagnosis of ER-positive DCIS or DCIS with micro invasion rendered on core biopsy will be eligible to participate in the study. All study participants must be amenable to delaying definitive surgery for DCIS for up to 6 months while remaining on letrozole. Although the following will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the following may seriously increase the risk to patients entering this protocol: 4.0 • Psychiatric illness, which would prevent the patient from giving informed consent. • Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. • Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for ≥ 3 years. This includes a previous diagnosis of breast cancer. ELIGIBILITY CRITERIA All questions regarding eligibility criteria should be directed to the CALGB Study Chair. Please note that the Study Chair cannot grant waivers to eligibility requirements. 4.1 Histologic documentation Pathologic confirmation of DCIS of the female breast without invasive cancer, with diagnosis rendered on core biopsy only, completed within 60 days before registration. Patients diagnosed with DCIS on the basis of surgical biopsy are not eligible for this study. Patients with microinvasion on diagnostic core biopsy, defined as tumor < 1mm in greatest dimension, will be allowed to participate. All patients must have a clip placed, either at the time of the diagnostic biopsy or at the time of the baseline MRI prior to the start of treatment. Version Date: 12/15/14 9 01/15/2015 4.2 Tissue samples Patient has diagnostic tissue available for correlative studies. 4.3 Clinical stage Tis or T1mi N0 M0 4.4 Hormone receptor status DCIS must express estrogen and/or progesterone receptor, as determined by immunohistochemical methods on the diagnostic pathology sample, according to the local institution’s standard protocol. Greater than or equal to 1% cells will be considered to be positive. 4.5 Menopausal status Patients must be postmenopausal defined as: • Age ≥ 55 years and one year or more of amenorrhea • Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml. • Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration). The use of GnRH analogs to achieve postmenopausal status is not allowed. 4.6 4.7 Prior treatment • No prior surgical excision in the index breast for current DCIS diagnosis of DCIS • Any exogenous hormone therapy must be completed 4 weeks prior to registration • Any patients with a history of tamoxifen or raloxifene use within two years of current DCIS diagnosis are not eligible • No prior neoadjuvant/adjuvant therapy for current DCIS diagnosis Contraindication to MRI No contraindications to breast MRI 4.8 Measurable disease Mammographic extent of calcifications must be accurately measurable in at least one dimension with each lesion > 1 cm and < 7cm. DCIS must be visible on MRI based on central review. Patients with palpable DCIS or adenopathy are not eligible to participate. Patients with multifocal or bilateral disease are eligible. 4.9 History of osteoporosis Women diagnosed with osteoporosis may participate in this trial provided they are receiving appropriate therapy or if they have declined therapy. 4.10 Age Patients ≥ 18 years of age 4.11 Performance status ECOG performance status 0 or 1 Version Date: 12/15/14 10 01/15/2015 4.12 Pregnancy/nursing status Not pregnant or nursing 4.13 Required initial laboratory values ANC Platelet count Serum creatinine Bilirubin AST/ALT Serum estradiol level assay (required for patients < 55 years of age and one year or more of amenorrhea) 5.0 ≥ 1,000/µl ≥ 100,000/µl ≤ 1.7 mg/dL ≤ 2.0 mg/dL < 2.5 x ULN < 20 pg/ml REGISTRATION 5.1 Registration requirements 5.1.1 Informed consent The patient must be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the multiple procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks and discomforts. If local guidelines and regulations permit the enrollment of persons not able to fulfill all of these requirements, the registering institution is responsible for complying with all local regulations and requirements for obtaining consent from these persons. Modification of the model consent form would be required for this purpose. Human protection committee approval of this protocol and a consent form is required. Registration must occur prior to the initiation of therapy. Registration to the optional companion studies will be performed at the time registration occurs to the treatment study. Registration to both the treatment study and the companion studies will not be completed if eligibility requirements are not met for the three trials. 5.1.2 American College of Radiation Imaging Network (ACRIN) prequalification for breast MRI acquisition Prior to enrolling the first patient, institutions must be prequalified by ACRIN to participate in the trial. The purpose of the qualification process is to help ensure that study imaging is of high quality and performed per the standardized MRI acquisition protocol (see Section 7.1). Suboptimal image quality and/or imaging not performed per the trial-standardized protocol can result in exclusion of the imaging exam(s) and/or the entire case from analysis. Therefore, routine QC and adherence to the image acquisition protocol are of great importance. Sites are encouraged to communicate with the MR team and initiate the prequalification process prior to IRB approval so as to avoid delays in site activation due to the qualification process. Requirements of the qualification process are summarized below; please refer to the CALGB 40903 Site Imaging Manual (see Appendix I and the CALGB and CTSU 40903 study pages of these web sites) for additional details and data submission instructions. • Protocol-Specific Applications (PSA) For each scanner to be used in the trial: Version Date: 12/15/14 11 01/15/2015 • MR Qualification Form (MRQF) • Acquisition/submission of two test scans acquired per the standardized imaging protocol (as provided in the CALGB 40903 Site Imaging Manual) In order to pass the qualification process the test scans must display good image quality and be compliant with the standardized MRI acquisition protocol. Please refer to the CALGB 40903 Site Imaging Manual for all image acquisition and submission instructions. 5.1.3 Investigator information Prior to the recruitment of a patient for this study, investigators must be registered members of the CALGB, NCCTG, or ACOSOG. Each investigator must have an NCI investigator number and must maintain an “active” investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the members’ section of the CTSU web site (www.ctsu.org) or by calling the PMB at 301-496-5725 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 5.1.4 Site registration requirements IRB Approval 5.1.4.1 Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU web site (https://www.ctsu.org/) by clicking on the Regulatory Tab. 5.1.4.2 In addition to submitting initial IRB approval documents, ongoing IRB approval documentation must be on file (no less than annually). If the necessary documentation is not submitted in advance of attempting patient registration, the registration will not be accepted and the patient may not be enrolled in the protocol until the situation is resolved. 5.1.4.3 When the study has been permanently closed to patient enrollment, submission of annual IRB approvals to the CTSU is no longer necessary. Regulatory Requirements 5.1.4.4 Requirements for CALGB-40903 site registration: • CTSU IRB Certification • CTSU IRB/Regulatory Approval Transmittal Sheet • ACRIN Prequalification 5.1.5 Patient enrollment All site staff will use OPEN to enroll patients to this study. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. Version Date: 12/15/14 12 01/15/2015 5.1.5.1 Prior to accessing OPEN site staff should verify the following: • All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility. • All patients have signed an authorization form (if applicable). appropriate consent form and HIPAA 5.1.5.2 Access requirements for OPEN • Site staff will need to be registered with CTEP and have a valid and active CTEPIAM account. This is the same account (user id and password) used for the CTSU members' web site. • To perform registrations, the site user must have been assigned the 'Registrar role on the relevant Group or CTSU roster. • To perform registrations on protocols for which you are a member of the Lead Group, you must have an equivalent 'Registrar' role on the Lead Group roster. Role assignments are handled through the Groups in which you are a member. • To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead Group registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data Administrators can manage CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU members' web site. This will allow them to assign staff the "Registrar" role. Note: The OPEN system will provide the registering site, the ACRIN Core Laboratory and the UCSF MRI Research Laboratory with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the OPEN tab of the CTSU members’ side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or [email protected]. 5.2 Registration to companion studies There are two substudies within CALGB 40903. These correlative science and pharmacogenomic studies must be offered to all patients enrolled on CALGB 40903 (although patients may opt to not participate). These substudies do not require separate IRB approval. The substudies are included within CALGB 40903: • Correlative Science Studies, CALGB 151008 (Section 11.1) • Pharmacogenomic Studies, CALGB 61105 (Section 11.3.3) If a patient answers “yes” to “My specimens may be used for the research described above.” question #2 in the model consent, they have consented to participate in the substudy described in Section 12.1. The patient should be registered within the OPEN system to CALGB 151008 at the same time she is registered to the treatment trial (40903). Samples should be submitted per Section 6.4. If a patient answers “yes” to “My specimen may be used for the genetic research described above.” question #3 in the model consent, they have consented to participate in the substudy described in Section 12.3.3. The patient should be registered to CALGB 61105 at the same time she is registered to the treatment trial (40903). Samples should be submitted per Section 6.4. Version Date: 12/15/14 13 01/15/2015 5.3 Surgical protocol quality assurance requirements 5.3.1 General guidelines The Surgical Quality Assurance Form (SQA-40903) will be completed by the Study Chair, E. Shelley Hwang MD, within 30 days after submission of the CALGB: 40903 Surgical Summary Form (C-2057), the surgical pathology and operative reports. This is a neoadjuvant protocol for ER-positive DCIS in postmenopausal women, with surgery a requirement following preoperative treatment with letrozole. Pathologic confirmation of DCIS without invasive cancer is required to confirm eligibility (see Section 4.1). For patients who have consented, 1 FFPE diagnostic tissue block and one 1 FFPE tissue block from surgical excision specimens must be submitted to the Alliance Biorepository at Ohio State University for correlative science studies. Breast MRI scans will be performed at baseline, at 3 months, and at 6 months. Patients will undergo definitive excision following 6 months of treatment with letrozole, with the exception of those patients who demonstrate radiographic progression of DCIS on the basis of MRI, as determined by the clinicians at the enrolling site at 3 months and confirmed by the UCSF Breast MRI Research Laboratory (Section 8.0), who will then undergo surgery at 3 months. Patients will continue to receive letrozole until the day prior to surgery. Based on clinical criteria including mammography, breast MRI, and patient preference, a lumpectomy or mastectomy will be performed for definitive excision, with the reason for choice of surgery documented on the CALGB 40903 Surgical Summary Form (C-2057). All patients must be excised to negative margins documented on the C-2057 form, defined as no ink on tumor. All patients with positive margins are recommended to undergo re-excision to clear the margins. The only exception will be those patients in whom the positive margin is the posterior margin, and the surgeon has documented that pectoralis fascia has been excised. It is expected that for some patients, this may require more than one re-excision. Sentinel lymph node biopsy/axillary lymph node dissection are controversial in the setting of DCIS. In the absence of clear treatment guidelines, the axilla may be managed based on the clinical judgment of the treating surgeon. Options for management of the axilla include the following: no surgery, sentinel node biopsy only, or axillary dissection if positive axillary nodes are identified. Choice for management of the axilla will be recorded on the C-2057 form. The choice for reconstruction in patients undergoing mastectomy will be left to the discretion of the patient and her treating physician. 5.3.2 Surgical quality assurance (procedure) Credentialing: Not applicable Lumpectomy, mastectomy and sentinel node biopsy are routinely performed procedures. All surgeons who routinely treat patients with breast cancer in their practice may enroll patients to this study, without a credentialing requirement. Definitions of deviations in protocol performance Major deviations • Inadequate surgery: Lumpectomy or mastectomy with positive margins (excluding posterior margin) without re-excision of margin • Positive posterior margin without documentation of excision of pectoralis muscle • Failure to perform surgery within 30 days of the 6-Month study visit, or within 30 days of the 3-month MRI central review for patients who have radiographic progression at 3 months Version Date: 12/15/14 14 01/15/2015 Minor deviations Failure to submit pathological specimens for patients who have consented to specimen submission for the in the correlative science study and central pathology review: • 1 FFPE tissue blocks from the original diagnostic specimen • 1 post letrozole FFPE surgical excision specimens • Failure to have patient continue on letrozole until the day prior to surgery Version Date: 12/15/14 15 01/15/2015 6.0 DATA AND SPECIMEN SUBMISSION 6.1 Data submission: Forms are required to be submitted to the CALGB Statistical Center, Data Operations in compliance with the Data Submission schedule below. There are three options for submitting forms that use the Teleform barcode and cornerstones: • the preferred method is to submit the forms electronically using the “Submit to CALGB” button located at the bottom of the last page of each form. Forms submitted electronically should not be submitted by fax or mail. • the forms may be faxed at 919-416-4990. Please note that the four cornerstones and the form id ("bitmap") must appear on the form. Copies must be 100% of the original form size. • the forms may be mailed to the CALGB Statistical Center, Data Operations, Hock Plaza, 2424 Erwin Rd, Suite 802, Durham, NC 27705. Please note that the four cornerstones and the form id (“bitmap”) must appear on the form. Copies must be 100% of the original form size. 6.1.1 For the most up-to-date data forms, please visit the CALGB website at www.calgb.org. Form C-2054 C-2059 Submission Schedule CALGB: 40903 Registration Work Sheet CALGB: 40903 Eligibility Checklist CALGB: 40903 On-Study Form CALGB: 40902 Mammogram Tracking Form (baseline) Submit within two weeks of registration C-2060 Reports* CALGB: 40903 MRI Tracking Form (baseline) Diagnostic Pathology report Mammogram report (baseline) MRI report (baseline) C-2055 S-078 C-2056 CALGB: 40903 Treatment Form CALGB: 4003 Medication Calendar CALGB: 40903 Adverse Event Form Submit at month 1 visit C-2060 CALGB: 40903 MRI Tracking Form (Month 3) and MRI report ** Submit within 2 days of month 3 MRI C-2055 S-078 C-2056 CALGB: 40903 Treatment Form CALGB 40903 Medication Calendar CALGB: 40903 Adverse Event Form Submit at month 3 visit C-2060 CALGB: 40903 MRI Tracking form (Month 6) and MRI report** Submit within 2 days of month 6 MRI C-2055 S-078 C-2056 CALGB: 40903 Treatment Form CALGB: 40903 Medication Calendar CALGB: 40903 Adverse Event Form Submit at month 6 C-2055 S-078 C-2059 Reports* CALGB: 40903 Treatment Form CALGB: 40903 Medication Calendar CALGB Mammogram Tracking Form Pre-surgery mammogram reports Submit at first post-op visit C-2057 CALGB: 40903 Surgical Summary Form Pathology and operative reports Submit within 4 weeks of last surgery C-2058 CALGB: 40903 Follow-up Form Submit at 6 months after last surgery, or at 6 months after completion of letrozole treatment for patients who do not proceed to surgery CALGB: 40903 Quality of Life Assessment Forms See Sections 6.2 an 12.0 Version Date: 12/15/14 16 01/15/2015 * Submit copies of all required reports to confirm eligibility and response to treatment. ** If clinical read is done locally, please submit mammogram and MRI reports to Alliance Statistical and Data Center – Duke (Fax: 919-668-9348 or 919-416-4990). This study will utilize the Common Terminology Criteria for Adverse Events version 4.0 for routine toxicity reporting on study forms. 6.1.2 Patient follow-up Follow patients who undergo surgery until post operative clinic visit that occurs at 6 months after completion of surgical resection. For patients who do not undergo surgery, follow until the clinic visit that occurs at 6 months after ending letrozole therapy. 6.2 Submission of quality of life measures Form CALGB: Brief Pain Inventory (Short Form) C-358 C-2030 C-2031 C-2032 C-2033 C-2088 C-650 CALGB: 40903 Beliefs about Medicine Questionnaire (BMQModified) CALGB 40903 Morisky Medication Taking ScaleModified (MMAS) CALGB: 40903 Managing Medication Side Effects Self-Efficacy CALGB: 40903 Menopause Specific QOL Questionnaire Menqol CALGB: 40903-AIMS 2 Arthritis Impact Measurement Form (Abbreviated) CALGB: FACT-G Scale Baseline Month 1 Month 3 Month 6 X X X X X X X X X X X X X X X X X X X X X X X X X x Final visit (Six months post completion of final surgical resection or end of letrozole)* X For patients who have agreed to participate, baseline forms (a total of 5 forms) should be completed after consent has been signed, but prior to initiation of letrozole therapy. At the month 1, 3 and 6 visits the C-2030 (BMQ) and C-2031 (MMAS) forms will also be administered (total of 7 forms). Only patients who continue to receive letrozole therapy for the second 3 months will complete the month 6 QOL questionnaires. *The C-650 (FACT-G) will be completed at the final visit: 6.3 • Six months after completion of final surgical resection. • For patients who do not undergo surgery, after the last dose of letrozole. Submission of digital mammogram and MRI scan images Digital mammograms and MRI scans will be uploaded to the ACRIN Imaging Core Laboratory within 1-2 business days of image acquisition for central review and archiving. MRI image data will subsequently be sent by ACRIN to University of California San Francisco Breast MRI Version Date: 12/15/14 17 01/15/2015 Research Laboratory for central review and quantitative analysis. See Section 7.2 for image submission instructions. 6.4 Specimen submission for correlative studies: All participating institutions must offer the correlative biomarker (CALGB 151008) and genomic studies (CALGB 61105) to all patients enrolled on this study, although patient participation is optional. The studies are described in Section 12.0 of the protocol. Patients must be registered to these studies in order to log samples into BioMS (see Section 5.2). Sample Submission Table: Sample Type Tissue (151008) Blood (61105) Pre-treatment 1 FFPE tissue block from diagnostic specimen 20 ml peripheral whole venous blood collected in an EDTA lavender top tube(s) At Surgery 1 FFPE tissue block from surgical excision specimens Ship To OSU OSU Instructions for the collection and shipping of samples are included below. Please be sure to use a method of shipping that is secure and traceable. Extreme heat precautions should be taken when necessary. 6.4.1 Specimen registration and tracking USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS SYSTEM. BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance trials. Authorized individuals may access BioMS at the following URL: https://bioms.wustl.edu.bioms using most standard web browsers (Safari, Firefox, Internet Explorer). For information on using the BioMS system, please refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training videos. To report technical problems, such as login issues or application errors, please contact: 1-85555BIOMS. For assistance in using the application or questions or problems related to specific specimen logging, please contact: 1-855-55BIOMS. After logging collected specimens in BioMS, the system will create a shipping manifest. This shipping manifest must be printed and placed in the shipment container with the specimens. • All samples should be labeled with CALGB study number (40903), CALGB patient ID number, patient initials, institution, sample collection date and time and institutional surgical pathology number (tumor samples). 6.4.2 Block submission After all institutional clinical pathologic assessments have been completed on the diagnostic and surgical excision tumor blocks, the blocks must be labeled as described in the bullet point in Section 6.4.1 and shipped to the Alliance Biorepository at Ohio State University. In instances where the tissue block cannot be released due to institutional or governmental policy, please contact the CALGB Alliance Biorepository at Ohio State University at 614293-7073, to obtain a tissue-cutting schema for this protocol. Version Date: 12/15/14 18 01/15/2015 6.4.3 Whole blood submission for genomic studies Draw 20 ml of peripheral venous blood into an EDTA lavender top tube(s) prior to initiating study treatment. Invert several times to mix EDTA. Blood samples must be labeled as described in the bullet point in Section 6.4.1. Samples should be refrigerated until shipped. The sample should be shipped the same day that the blood is drawn. Samples should be sent with cold refrigerant pack by overnight express courier. All samples should be sent to the following address: Alliance Biorepository at The Ohio State University The Ohio State University Innovation Centre 2001 Polaris Parkway Columbus, OH 43240 Tel: 614-293-7073 Fax: 614-293-7967 Ship specimens by overnight courier to the Alliance Biorepository at The Ohio State University the same day they are collected. Shipment on Monday through Friday by overnight service to assure receipt is encouraged. If shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For Saturday delivery.” Do not ship specimens on Saturdays. Please be sure to use a method of shipping that is secure and traceable. Version Date: 12/15/14 19 01/15/2015 7.0 REQUIRED DATA Pre-Study Testing Interval To be completed within 28 days before registration: - All blood work - History and physical To be completed within 60 days before registration: - Diagnostic core biopsy - Breast MRI with IV contrast To be completed within 90 days before registration: - Bilateral digital mammogram Prior to Registration Tests and Observations History* and Progress Notes Physical Examination Performance Status Clinical Breast Examination Diagnostic core biopsy Drug Toxicity Assessment Laboratory Studies CBC, differential, platelets AST, ALT, bilirubin serum creatinine Estradiol assay Prior to start of letrozole Therapy Start of letrozole Therapy X X X I s Month 1 (wk 5 of tx) Month 3 (wk 13 of tx) Month 6 (wk 25 of tx) X X X X X X X X X X X X Preop Visit B Surgery Postop Visit D D D X o r X X X o n l y X X m a m m o g r a m ? I s X G Radiographic Tumor Measurements Baseline Bilateral X digital mammography** Breast MRI w/IV X I contrast** Correlative Studies Tissue blocks Blood samples Treatment Adherence Record 40903 Letrozole Medication CALGB: 40903 Medication Calendar QOL Questionnaires Questionnaires QOL u l t r a s o u Follow-up visit n 6 d months post-op▲ a c X c e p X t a b l X e E E H H A A A 2 8 C F C C C F F F C d aF y s A For consenting patients, submit diagnostic FFPE core tissue blocks within four weeks after registration and surgical FFPE tissue blocks within four weeks after surgery per sections 6.4 – 6.4.2. For consenting patients submitawhole blood for pharmacogenomic studies prior to beginning letrozole therapy only, per section 6.4.3. Version Date: 12/15/14 20 01/15/2015 l i t t l e B Note that the preoperative visit may coincide with: The 6-month visit if surgery occurs within 30 days of month 6 visit, OR the month 3 visit if patient meets progression criteria, and surgery occurs within 30 days of month 3 MRI central review. C 40903 Letrozole Medication Calendars to be given to and collected from patients (see Section 8.1). D Within 30 days post surgery. E Patients are required to have two mammograms, one at baseline and one within 4 weeks prior to surgery. This can be performed at the time of a radiographic guided localization procedure, if applicable. Mammogram must be bilateral at baseline and only the affected breast(s) at pre-surgery.” F Please see Section 6.2. for details. NOTE: Only patients who continue to receive letrozole therapy for the second 3 months will complete the month 6 QOL questionnaires. G For pts < 55 years and one year or more of amenorrhea. H The month 3 and/or 6 MRIs should be performed within 2 weeks prior to the study visit. For patients who progress per Month 3 MRI central review, the Month 6 MRI will not be required. I If the initial baseline MRI needs to be repeated in order to meet protocol requirements (ACRIN accredited scanner) the repeated MRI must be completed prior to initiating letrozole therapy. * History is required only with the “Prior to registration” progress note. ** See Section 7.1 for imaging acquisition requirements and Section 7.3 for MRI central review instructions. ▲ For patients who do not under go surgery, follow up visits is at 6 months after the end of letrozole therapy. For patients who undergo surgery, the follow-up visit will take place 6 months post completion of surgical resection. 7.1 Image acquisition requirements 7.1.1 Digital breast mammogram Patients are required to have two digital, mammograms: A baseline bilateral mammogram and mammogram(s) of the affected breast(s) prior to surgery. The two standard views (cranio-caudal and medial-lateral oblique) for each breast is to be performed per each institution’s standard of care. For some women with larger breasts, additional images may be necessary to image the entire breast as in usual clinical practice. Mammogram reports must specifically state the longest diameter of DCIS extent to document that eligibility criterion 4.8 has been met. 7.1.2 Breast MRI Participation in the CALGB 40903 study requires that all sites adhere to a standardized MR imaging protocol. The use of standardized imaging guidelines is an essential component of clinical trials in which imaging plays a central role in the research endpoints. This is of particular importance in multicenter trials where equipment, personnel, and imaging acquisition protocols can vary significantly across sites. Patients are to have three breast MRI exams: at baseline, Month 3 (week 13 of treatment) and Month 6 (week 25 of treatment, pre-surgery). Note that the Month 6 MRI will not be required for patients who progress per Month 3 MRI central review. All MRI scans must be performed per the standardized acquisition protocol as detailed in the CALGB 40903 Site Imaging Manual which is available in Appendix I and is available on the 40903 study page of the CALGB and the CTSU web sites. The breast MRI protocol includes a pre-contrast T2weighted sequence a pre-contrast diffusion-weighted imaging (DWI) sequence, and a T1weighted sequence performed once pre-contrast then a dynamic contrast-enhanced (DCE) sequence (T1-weighted sequence performed multiple times post-contrast using identical parameters as the pre-contrast T1). Version Date: 12/15/14 21 01/15/2015 General requirements • 1.5T or 3.0T whole body MRI scanner • Dedicated breast radiofrequency coil • All MRI exams for the same patient should be performed using the same scanner or the same scanner configuration (manufacturer; field strength; breast coil model). • All scanners used for study imaging should be prequalified by ACRIN. • Single dose contrast agent injection (FDA-approved gadolinium-based contrast agent); the same contrast agent brand should be used for all MRI exams for the same patient. • All MRI images submitted for an individual patient must be obtained using a consistent imaging protocol throughout the study period. • Sites are expected to review all imaging for image quality and protocol compliance. Refer to the CALGB 40903 Site Imaging Manual for detailed image acquisition and submission requirements. 7.2 Image submission requirements All study imaging (mammograms and MRI exams) should be submitted to ACRIN within 1-2 business days of acquisition and accompanied by an Image Transmittal Worksheet (ITW). Please note that all imaging must be in DICOM format. Sites have two options for submitting the digital mammogram and breast MRI exams to ACRIN: • Using ACRIN’s image transfer application (TRIADTM) • Express mailing images on a CD-ROM or DVD Due to the need for quick receipt and turnaround of the MRI exams, TRIADTM is the preferred mode of image submission. TRIAD is a software application developed by the American College of Radiology (ACR) to provide a secure web-based method of transferring and managing image data. The TRIAD software will be provided free of charge and can be installed on one or more computers of choice within the institutional network. The TRIAD software anonymizes, encrypts, and performs a lossless compression of the images before they are transferred to the ACRIN image archive in Philadelphia. Sites should initiate the TRIAD installation during the prequalification process, prior to enrolling study patients. Refer to the CALGB 40903 Site Imaging Manual for detailed image acquisition and submission requirements. 7.3 Image data quality control Sites are expected to acquire the MRI exams per the standardized MR acquisition protocol and review all imaging for image quality and protocol compliance. Upon receipt of the MRI exam at ACRIN, an initial QC review will be conducted by a qualified ACRIN Imaging Technologist. The ACRIN technologist will check for missing images/sequences, appropriate image anonymization, complete anatomical coverage of the breast parenchyma, and absence of image artifact. Missing or discrepant image data will be communicated to the site and the CALGB coordinating center. All MRI exams will undergo an additional review, including compliance with the standardized acquisition protocol, as part of the central review conducted by the UCSF Breast MRI Research Laboratory. Information regarding the central review process is provided in Section 7.4 of the clinical trial protocol. Version Date: 12/15/14 22 01/15/2015 7.4 Central review of magnetic resonance imaging Determination of radiographic response to study therapy will be determined centrally by investigators at the University of California San Francisco Breast MRI Research Laboratory (see Section 8.0). MR Image data will be archived at the ACRIN Imaging Core Laboratory (see Section 7.2) and sent from ACRIN to UCSF Breast MRI Research Laboratory for central review and quantitative analysis. DCIS diameter will be measured in the latero-medial, antero-posterior and inferiorsuperior directions, as well as the single longest diameter measured in any plane. The direction of measurement chosen on baseline MRI for longest will be maintained in 3-month and 6-month MRI exams. Following verification of image quality and protocol compliance, volumetric measurement of DCIS lesions will be performed using the signal enhancement ratio (SER) method for quantifying contrast enhancement kinetics (see Section 13.3.4). All volume assessments will be compared to the baseline study. Baseline images will be centrally evaluated and categorized according to the following: • Conforms to study MRI protocol (y/n) • MRI volume assessable (y/n) After the first 20 patients have enrolled, an analysis will be performed to assess the quality of the baseline MRI scans. DCIS volume measurements will be obtained from MRI data acquired at baseline, 3-month and 6-month treatment time points. A MRI report will be generated for each exam that includes the longest diameter and volume measurements, relevant imaging technical parameters and representative images. Following review and approval by the Imaging Co-Chair, volume measurements will be reported on the I-059 MRI Assessment form and electronic copy of the Volume SER report will be sent to the Statistical and Data Center at Duke University. 8.0 TREATMENT PLAN Questions regarding treatment should be directed to the CALGB Study Chair. Protocol Therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a bilateral MRI for disease evaluation at months 3 and 6. Treatment with letrozole is to begin within 21 days of registration, and only after notification has been received from the UCSF Breast MRI Research Laboratory that the baseline MRI is acceptable. If the baseline MRI is not acceptable, the MRI must be repeated. If the second MRI is not acceptable, the patient cannot start treatment and will be considered off study. A reimbursement form for a repeat baseline MRI is available on the 40903 study page of the CALGB and CTSU web sites. To ensure that MRI central review is performed in a timely manner: • MRI must be uploaded to the ACRIN Core Image Core Data Web site within 1-2 business days after MRI is obtained (see Section 7.2). • ACRIN will forward the MRI images to the UCSF Breast MRI Research Laboratory for central review and quantitative analysis within 1-2 business days of receipt. • Within 3 additional business days, the UCSF Breast MRI Research Laboratory will email the treating physician and institutional Lead CRA with confirmation of whether or not the baseline MRI is assessable. At the month 3 time point, patients should continue letrozole until the UCSF central review determination of disease status has been obtained. Version Date: 12/15/14 23 01/15/2015 • Patients who are found to have radiographic progressive disease (20% increase in tumor diameter) at month 3 will be scheduled for surgery within 30 days of the second (month 3) MRI central review and for a preoperative mammogram. Patients will continue letrozole until the day before surgery. • Patients with a partial response or stable disease, based on MRI longest tumor diameter, will continue to receive letrozole for the next 3 months and then have the month 6 MRI and preoperative mammogram(s). Surgery will be planned within 30 days of the final (month 6) study MRI. All patients will continue to take study drug until the day prior to surgery, whether at month 3 or at month 6. All patients will continue to take study drug until the day prior to surgery, whether at month 3 or at month 6, or may stop if they experience unacceptable toxicity. 8.1 Adherence Since patients will take oral medications at home without direct supervision, we will monitor drug compliance until the discontinuation of letrozole (the day prior to surgery) using medication calendars. On Day 1 of letrozole therapy the patient will receive three (3) CALGB: 40903 Medication Calendars (S-078), and be instructed on how to take the medication and how to use the calendars and to return the calendars at the month 1 clinic visit. The patient will bring the completed calendars with her to the Month 3 clinic visit where it will be reviewed. Patients who continue on letrozole for the second 3 months will be given three (3) more calendars and instructed to complete and return them at the 6 month visit. Since all patients will continue letrozole until the day prior to surgery, they should be given an additional calendar for recording those doses and should return the calendar to a member of the study team. It is recommended that sites should review the medication calendars with patients and inquire about missed doses. 8.2 Quality of life participants All patients who understand and are able to follow directions in English (as the assessment instruments are only available in English), and have agreed to participate, will take part in the quality of life (QOL) assessments. Please see Section 12.0 for instructions regarding assessment administration. 8.3 Adjuvant treatment considerations The study endpoint will not be affected by adjuvant treatment recommendations or treatment. It is expected that decisions regarding any adjuvant treatment will be made individually based on best practice guidelines, using informed and shared decision making between patient and provider. 8.3.1 Adjuvant radiation General treatment guidelines for postoperative radiation, as well as recommendations for adjuvant systemic therapy are not anticipated to be affected as a result of study participation. It is expected that such clinical decisions will be made with the participation of the patient and clinician according to accepted NCCN treatment guidelines for DCIS and/or current invasive cancer. Based on these guidelines, is expected that most women who undergo lumpectomy will be referred for adjuvant radiation. All adjuvant radiation therapy should be documented on the C-2058 and C-2059 forms. 8.3.2 Adjuvant hormonal therapy Published studies support consideration of tamoxifen for adjuvant treatment of DCIS following lumpectomy and radiation. There are currently no completed studies supporting Version Date: 12/15/14 24 01/15/2015 use of aromatase inhibitor therapy as adjuvant treatment for DCIS. Decisions regarding use of adjuvant systemic therapy will be made by the patient and treating physician, and will not be limited or affected by participation in this trial. There are currently no published studies that support the use of adjuvant AI for DCIS outside of a clinical trial. All adjuvant hormonal therapy should be documented on the C-2058 form. 9.0 DOSE MODIFICATIONS There will be no letrozole dose reductions. The protocol does not require monitoring of liver function tests. However, if a patient is incidentally discovered to have > grade 3 hepatic function impairment Letrozole will be held. Resume letrozole at the previous dose when hepatic toxicity resolves to < grade 2. If letrozole is held for > 3 weeks, permanently discontinue protocol therapy. If unanticipated grade 3 or 4 toxicity is encountered the patient will be discontinued from protocol therapy. 10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION 10.1 Letrozole Please refer to the FDA-approved package insert for letrozole for product information, and a comprehensive list of adverse events. Availability Letrozole tablets will be provided and distributed, free of charge, by the Division of Cancer Prevention (DCP), NCI and should be ordered using the DCP Investigational Agent Request Form. Letrozole will be shipped via priority mail. Orders placed on Monday through Thursday should be received within 2 business days. Letrozole supplies are not patient specific. Letrozole is supplied as 2.5 mg, dark yellow, film-coated tablets in bottles of 30 tablets. Storage and Stability Intact bottles of letrozole should be stored at room temperature. Administration Letrozole will be taken orally, at a dose of 2.5 mg once daily without regard to meals. Toxicities The most common adverse events reported in recent trials with letrozole in advanced breast cancer include hot flashes and nausea. Of concern, primarily with long-term use of aromatase inhibitors including letrozole, are effects on lipid metabolism with subsequent cardiovascular events and on bone resorption. Other less frequent adverse events include bone and muscle pain. 11.0 CORRELATIVE STUDIES 11.1 Evaluation of predictive and prognostic tissue biomarkers associated with letrozole response Conventional breast cancer treatment has consisted of surgery first followed by adjuvant treatment (chemotherapy, hormonal therapy, or radiation). In the last decade, this algorithm has shifted towards increased preoperative administration of systemic therapy (“neoadjuvant” therapy) in order to leverage the potential to downsize tumors prior to surgery. In prospective clinical trials, both chemotherapy and hormonal therapy significantly increased the lumpectomy rate, although neither has demonstrated a survival benefit [13, 34, 35]. However, another essential benefit of neoadjuvant therapy is that it provides real-time in vivo assessment of clinical response as well as biologic response. This has been effectively demonstrated in recent neoadjuvant endocrine trials. Version Date: 12/15/14 25 01/15/2015 Neaodjuvant treatment for breast cancer and the role of biomarker studies In the P024 trial, a study comparing neoadjuvant tamoxifen to letrozole, Ellis and colleagues showed that Ki67 is a useful biomarker of response to endocrine therapy for invasive breast cancer and further, that it helped identify subsets of ER(+) patients with greater response to AI treatment [14]. Biomarker assessment in the IMPACT study (comparison of neoadjuvant anastrazole, tamoxifen, or both) showed that degree of Ki67 reduction with endocrine treatment correlated with the observed clinical response rate [36]. In recent years, genomic characterization of tumors has also been shown to be a powerful predictive biomarker [37-40]. In the setting of DCIS, little is known about the in vivo responsiveness to systemic therapeutics, particularly with respect to predictive and prognostic biomarkers. However, there are compelling reasons to believe that DCIS poses different molecular, cellular, physiologic, and anatomic obstacles to various systemically administered therapeutics relative to invasive cancer present in the same breast due to an intact basement membrane. An important goal of ongoing DCIS preoperative trials is to document the extent of molecular and cellular effects from short term treatments on DCIS biology during the time prior to their definitive surgery. While this relatively short duration of therapy is unlikely to eliminate the DCIS lesion and may not even substantially alter DCIS morphology or grade, it is expected to alter molecular features, including protein expression and modifications, providing an early indication of the degree of responsiveness of various DCIS subsets to each therapeutic agent. These tumor cell responses may reflect therapeutic inhibition of a general tumor cell characteristic (e.g. decline in Ki67 proliferation index), loss or change in drug target expression (e.g. change in ER following either the antiestrogen tamoxifen or the aromatase inhibitor letrozole), or a combination of both types of responses. Neoadjuvant endocrine trial in ER-positive DCIS In a pilot study conducted at UCSF, patients with core biopsy-proven DCIS without invasive cancer have been treated for three months prior to surgery with endocrine therapy. Premenopausal women have been treated with tamoxifen, 20 mg PO QD, and postmenopausal patients have been treated with letrozole, 2.5 mg PO QD. Tissue blocks for correlative studies have been collected before and after endocrine therapy. H and E stains of cases have shown significant change in morphology of DCIS ducts with a 3month course of neoadjuvant treatment for DCIS; three patients have shown a complete pathological response with no further disease (DCIS or invasive cancer) in the surgical pathology specimen. Three patients were found to have invasive cancer at surgery. An interim analysis of the first half of the cohort showed significant changes in ER, PR, Ki67, and CD68 with treatment, consistent with tumor response (Table1). Increase in apoptosis was not seen by the cleaved caspase 3 assay, suggesting that increased apoptosis was not an important component of biological effect in this study. In neoadjuvant trials of hormonal therapy for invasive cancer, Ki67 has been shown to be a particularly powerful independent marker of both response to treatment and long-term prognosis [36, 41-44]. There are few published studies if KI67 as a response marker for DCIS [32, 33, 45], but these have consistently shown a significant reduction in Ki67 with either withdrawal of exogenous hormones or with administration of endocrine therapy. Thus assessment of Ki67 in neoadjuvant treatment trials for DCIS appears particularly promising. Previous large studies have shown that Ki67 as a continuous measurement (number of cells staining positive per hpf) has a non-normal distribution, such that log transformation of Ki67 data is highly recommended for analysis. Further, the proportional change in Ki67 may be a particularly informative endpoint for presurgical trials in DCIS. Version Date: 12/15/14 26 01/15/2015 Table 1. Change in biomarkers with letrozole treatment Controls n=18 Cases n=23 Biomarkers Mean Change1 Mean change P2 ER (H-score)3 -55.5 + 22.2 -113.8 + 26.2 0.07 PR (H-score)3 -38.8 + 18.3 -169.2 + 18.8 0.001 Ki-674 -3.2 + 1.7 -14.4 + 3.6 0.013 CD684 -0.06 + 1.7 29.4 + 5.8 < 0.0001 capase 35 0.8 + 0.7 0.1 + 0.7 0.13 1. Data shows mean increase (positive values) or mean decrease (negative values) over 3 months in quantitative immunohistochemical staining between diagnostic core biopsy and surgical excision. Cases were treated with neoadjuvant anti-estrogenic therapy; controls did not undergo neoadjuvant therapy. 2. Rank-sum test, controls as referent group. 3. H-score is weighted measure of intensity and percentage of positive cells. 4. Percent of cells staining positive. 5. Number of CD68-positive macrophages per high power field within DCIS ducts. 11.1.1 Study overview We propose a correlative component to this Phase II study of neoadjuvant letrozole for ER(+) postmenopausal DCIS. For patients who have consented, tissue biomarkers will be assessed at baseline. Baseline markers will be assessed on the diagnostic core biopsy specimen; treatment markers will be assessed on the surgical excision specimen. 11.2 Objectives 11.2.1 Primary objective: To determine whether Ki67 is reduced with neoadjuvant letrozole treatment for DCIS, and to compare the reduction in proliferation between radiographic responders and non-responders. 11.2.2 Secondary objectives: 11.2.2.1 To identify baseline IHC and expression biomarkers predictive of response to treatment, with response determined by the extent of Ki67 reduction. Subsets showing the greatest reduction in Ki67 would be the most likely candidates for nonoperative treatment in future studies. 11.2.2.2 To examine whether germline polymorphisms are associated with clinical endpoints, including treatment-related toxicity or efficacy outcomes, or with expression of biomarkers in tumor tissue. Version Date: 12/15/14 27 01/15/2015 11.3 Methods 11.3.1 IHC studies The 1 diagnostic and 1 surgical FFPE tissue blocks from consenting study participants will be submitted to the Alliance Biorepository at Ohio State University. Sections from the blocks will be forwarded to the UCSF Cancer Center IHC Core Research Laboratory for IHC staining. Conditions for antigen retrieval, proteolytic processing (if necessary), antibody titer, and positive and negative controls have been developed by the UCSF IHC Research Core for over 100 antigens, including all of those selected for testing in this proposal. Pretreatment by microwaving slides in 10 mM citrate buffer (pH 6) for antigen retrieval will b e used. A Ventana automated stainer is used for standard elements for all IHC assays. Positively and negatively staining cell lines will be used as controls for all assays. Table 2. IHC markers to be assessed in DCIS lesions Antigen Ab Source Mib1 (Ki67) Bcl-2 Coulter-Immunotech Dako 1 2 Cleaved caspase 3 TUNEL Dako 1 1 P16 P53 telomerase VEGF FGF HIF 1 Pharmingen Neomarkers Novocastra Santa Cruz Zymed Santa Cruz 2 2 COX-2 CD68 Biogenex Dakocytomation 1 2 DAKO 1 DAKO Zymed Boehringer Genosys Zymed (31G7) Res. Diagnostics Am Diagnostics Am Diagnostics Abcam Dako Abcam 1 1 2 2 2 2 3 3 2 2 1 ER PgR HER2/neu CK5/6 P53 EGFR CD44 UPAR PAI1 TGFCyclin D1 MMP-9 Version Date: 12/15/14 28 Priority 1 2 3 01/15/2015 11.3.2 mRNA expression studies Total RNA samples will be isolated from the diagnostic core biopsy tissue using standard methods and assayed for quality/quantity using the RT-PCR and the Aglient 2100 BioAnalyzer. Double stranded cDNA will be prepared using random-T7 RNA polymerase primers. Biotinylated cRNA will be prepared by in vitro transcription and then converted back to ssDNA. The ssDNA will be fragmented and end labeled with biotin. The minimum RNA requirement for the arrays is 100 ng total RNA. An aliquot of the fragmented cRNA is hybridized to a test chip to confirm target quality. Hybridization signal will be obtained by staining with phycoerythrin-streptavidin on the GeneChip Fluidics Station. If a strong, uniform signal is obtained, then the probe will be hybridized to the GeneChip and stained as above. Following staining, each chip will be imaged at high resolution using a fluorescent scanner that has been optimized for detection phycoerythrin-stretptavidin. Each image will be digitally analyzed and the signal intensity for each perfect match feature will be determined after subtraction of the corresponding mismatch feature. 11.3.3 Genomic studies: Exploration of the correlation between the host genetic polymorphisms of interest, specifically 4 SNPs on chromosome 14 recently identified by GWAS (rs7158782, rs7159713, rs2369049 and rs11849538) and incidence of letrozole induced musculoskeletal adverse events Little is known about host pharmacogenetic predictors of response and toxicity following anticancer therapy. Recent studies which have approached this question have primarily focused on the impact of variability in drug metabolizing enzyme genotype and response to therapy. For example, the relationship between response to tamoxifen and CYP2D6 genotype has been a subject of much study and conflicting results [84]. The impact of host genotype and response to aromatase inhibitors is much less well studied. Several investigators have explored the relationship between SNPs in CYP19A1 (the gene coding for aromatase) and outcomes following treatment with letrozole. These studies have yielded conflicting results [85-86]. Recently Ingle et al. [87] have reported a GWAS study of patients on a large cooperative group trial of adjuvant aromatase inhibitor therapy comparing anastrozole to exemestane. This analysis identified four SNPs on chromosome 14, which were correlated with increased incidence of musculoskeletal adverse events associated with aromatase inhibitor therapy. In CALGB 40903 we propose to study the SnP recently identified in the Ingle study and validate their relationship with musculoskeletal adverse events in a population of patients treated with the aromatase inhibitor therapy lerozole. The 6 month duration of treatment in CALGB 40903 exceeds the typical time of onset for these adverse events. Furthermore, since CALGB 40903 has a neoadjuvant therapy design with efficacy endpoints, we may be able to explore relationship between host genotype (such as the CYP19A1 rs4646 polymorphism) and response to therapy as well. Whole blood will be obtained from consenting study participants at baseline, prior to receipt of study treatment. The blood will be sent to the Alliance Biorepository at Ohio State University for processing. Blood samples will be processed into plasma, PBL and DNA. DNA quality will be assessed by UV spectrophotometry and by agarose gel electrophoresis. All DNA samples will be stored at the Alliance Biorepository at Ohio State University until they are distributed to the appropriate laboratory for genotyping. Samples will be genotyped using previously established methods. Phenotypic data will be extracted from the CALGB database by the CALGB Statistical Center. Statistical analyses will be conducted under the direction of the responsible CALGB faculty statistician. Version Date: 12/15/14 29 01/15/2015 These studies will include the investigation of the candidate gene variation as well as novel high density single-nucleotide polymorphisms (SNP) platforms available to survey the pattern of variation of the entire genome of an individual, allowing the identification of genes that have not previously related to the pharmacology of the drugs of interest or to a certain biological pathway. Currently, platforms with hundreds of thousands of SNPs have been extensively used in so called genome-wide associations studies (GWAS) and do not only provide information of the SNP pattern of an individual, but also on the quantitative pattern on copy number variation (including loss of heterozygosity, LOH). 12.0 ASSESSMENT OF QUALITY OF LIFE AND MUSCULOSKELETAL SYMPTOMS ASSOCIATED WITH NEOADJUVANT LETROZOLE FOR ER POSITIVE DCIS 12.1 Introduction Therapy that blocks hormones (i.e., tamoxifen, aromatase inhibitors) is a crucial component of treatment used to prevent cancer recurrence and reduce breast cancer-related mortality for women with hormone receptor positive invasive disease [46] and may also decrease recurrence in women with ductal carcinoma in situ (DCIS) [47-49]. Yet, data suggest that early discontinuation of adjuvant hormonal therapy ranges from 23% to 40% in clinical trials [50-52] and from 15% to 50% in clinical practice settings [53-57]. Side effects are a major reason for discontinuation of therapy. The proposed assessment study to CALGB 40903, a phase II study of neoadjuvant letrozole for postmenopausal estrogen receptor positive ductal carcinoma in situ (DCIS), will examine the side effects associated with taking an aromatase inhibitor, letrozole, for 3 to 6 months and explore the impact that these side effects have on quality of life (QOL) and medication taking behavior. This study will provide valuable data for future, larger studies testing strategies for side effect management, improving quality of life, and improving adherence (e.g., reducing the number of skipped pills) to hormonal therapy for breast cancer. Breast cancer is the leading cancer affecting women in the U.S., with an estimated 182,460 new cases of invasive breast cancer diagnosed in 2009 [58]. Approximately two-thirds of breast cancers are hormone-receptor positive in White women and over half are hormone-receptor positive in African American women [59, 60]. Adjuvant hormonal therapy is a crucial component of treatment used to prevent cancer recurrence and reduce breast cancer-related mortality for breast cancer patients with hormone receptor positive disease [46]. For decades, tamoxifen was the adjuvant hormonal therapy of choice. Within the past decade, however, data has emerged showing that hormonal therapy that includes an aromatase inhibitor (AI) is more effective than tamoxifen alone. AIs (e.g., letrozole, anastrozole, and exemestane) have become widely used and current guidelines endorse their inclusion at some point during adjuvant hormonal therapy for postmenopausal women with hormone receptor positive breast cancer [61]. A group of side effects common to all of these hormonal therapy agents is menopausal symptoms, such as hot flashes and vaginal symptoms. Data from clinical trials suggest that women taking AIs also experience arthralgias [62-65]. There is limited data regarding the impact of these side effects on women’s quality of life and how side effects impact adherence to adjuvant hormonal therapy. Self-efficacy theory [66] provides a theoretical model for understanding variations in abilities to cope with the side effects of aromatase inhibitor (AI) treatment and adhere to treatment. Selfefficacy refers to the belief that one can successfully perform a specific behavior to achieve a particular outcome [67]. Studies in chronic pain patients show that higher self-efficacy is associated with less pain and disability [68-70]. In a review examining the relationship between self-efficacy and outcomes for arthritis patients, Marks [71] concluded that strategies to enhance self-efficacy have a favorable impact on disability and overall health. Understanding the role of self-efficacy for coping with side effects and taking medication may enable clinicians to more Version Date: 12/15/14 30 01/15/2015 effectively intervene to improve quality of life outcomes and adherence among women taking AIs. This study will provide valuable preliminary data for a larger study testing strategies for side effect management, improving quality of life, and improving adherence (e.g., reducing the number of skipped pills) to adjuvant hormonal therapy. 12.2 Objectives and hypotheses 12.2.1 Assess side effects associated with letrozole therapy. Hypothesis: H1: Compared to baseline levels before starting letrozole, joint pain and menopausal symptoms will increase among postmenopausal women taking letrozole at month 3 and month 6. H0: There will be no change in joint pain and menopausal symptoms among postmenopausal women taking letrozole. 12.2.2 Examine the association between letrozole therapy associated side effects and quality of life. Hypothesis: H1: Greater side effects from letrozole therapy will be related to reduced quality of life and lower self-efficacy for coping with side effects at month 3 and month 6. H0: Side effects from letrozole will not affect QOL or self-efficacy for coping with side effects. 12.2.3 Examine the relationship between letrozole therapy side effects and medication taking behavior. Hypothesis: H1: Greater letrozole therapy side effects will be associated with poorer adherence to letrozole therapy and lower self-efficacy for taking hormonal therapy as prescribed. H0: Greater side effects from letrozole will have no effect on adherence to letrozole or selfefficacy for taking hormonal therapy as prescribed. 12.3 Design and procedures The accrual goal for this quality of life and musculoskeletal symptoms substudy is 106 women. All women enrolled in the 40903 treatment trial, and who understand and are able to follow directions in English will be asked to participate. Procedure: Participants in CALGB 40903 will be asked if they are interested in hearing more about the QOL assessment study. If a woman indicates that she is interested in hearing more about the study, then the study will be described in more detail and the woman will be asked if she would like to participate. Informed consent for these assessments will be part of the consent for the overall study, with an ‘opt-out’ question. After informed consent is obtained, the participant will complete these questionnaires before starting treatment with letrozole. The questionnaires to be completed include measures of treatment side effects (pain, menopausal symptoms), self-efficacy for managing side effects and adhering to hormonal therapy, beliefs about hormonal therapy, adherence to hormonal therapy, and quality of life. At the 1, 3 and 6 month study visits the same questionnaires administered at baseline (prior to the start of letrozole therapy) (MENQOL, BPI-short form, AIMS, FACT-G and Self-Efficacy for Coping with Side Effects) and the BMQ and MMAS form (total of 7 forms). Only patients who Version Date: 12/15/14 31 01/15/2015 continue to receive letrozole therapy for the second 3 months will complete the montt 6 QOL forms. At the final visit, 6 months post completion of surgical resection, or for patients who do not undergo surgery, 6 months after the end of letrozole therapy only the FACT-G Scale Form (C-650) will be completed for assessment of QOL. Measures Objective 1: Assess menopausal side effects and pain associated with hormonal therapy, letrozole. Menopause Specific Quality of Life Questionnaire (MENQOL) (CALGB: 40903 Menopause Specific Quality of Life Questionnaire[MEMOQOL] C-2033): The MENQOL [72] Intervention version is a 32-item self-report questionnaire that assesses the occurrence and severity of menopausal symptoms in the past week. It assesses four symptom domains: physical, vasomotor, psychosocial, and sexual. All items follow the same format in which the woman is asked whether she has experienced the item in the previous week. If “no”, she goes to the next item. If “yes”, she indicates how bothered she was by the item on a 7-point Likert scale ranging from 0=not at all bothered to 6=extremely bothered. Each MENQOL item is recoded as follows: If NO = IF Yes: 1 Bothered 0 = 2 Bothered 1 = 3 Bothered 2 = 4 Bothered 3 = 5 Bothered 4 = 6 Bothered 5 = 7 Bothered 6 = 8 The score for each domain is the mean of the recoded items forming that domain and ranges from 1 to 8. The scale authors suggest that 1.0 represents the Minimal Clinically Important Difference on the MENQOL Intervention version. Brief Pain Inventory (BPI-SF) (CALGB: Brief Pain Inventory Form [Short Form] C-358): The Brief Pain Inventory short form will assess levels of pain and the degree to which pain interfered with daily activities in the past week [73]. The BPI asks women to rate their pain intensity at its worst, least, and average by using a numeric scale of 0 to 10. Each rating is bounded by “no pain” at the 0 end and “pain as bad as you can imagine” at the 10 end. Using similar 0 to 10 scales, patients are also asked to rate the extent to which their pain interferes with 7 quality of life domains that include general activity, walking, mood, sleep, work, relations with other persons, and enjoyment in life. These scales are bounded by the words “does not interfere” and “interferes completely.” The score for pain intensity is the average of the 3 pain intensity items and ranges from 0 to 10. The score for interference is the average of the 7 interference items and ranges from 0 to 10. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) suggests that 1.0 represents the Minimal Clinically Important Difference on pain intensity and interference. Pain (AIMS Index) (C-2088): Pain and stiffness levels will also be assessed using items fro Arthritis Impact Measurement Scales (AIMS2)[74]. The AIMS2 is a validated measure for assessing health status, including arthritic symptoms, in subjects with rheumatic diseases and is similar to measures previously used to assess symptoms in breast cancer patients who had joint symptoms related to aromatase inhibitor therapy [75]. The AIMS2 instrument is a self- Version Date: 12/15/14 32 01/15/2015 administered questionnaire which consists of 78 items, including subscales of 4 or 5 items for each of the following: Mobility Level, Walking and Bending, Hand and Finger Function, Arm Function, Self Care Tasks, Household Tasks, Social Activity, Support from Family and Friends, Arthritis Pain, Work, Level of Tension, and Mood. In total, the questionnaire takes approximately 20 minutes to complete. This study will use the 5 items from the AIMS2 (#38-42) pertaining to arthritis pain. Items are rated from 0 (none or no days) to 5 (severe or all days). The items will be summed (possible range of 1 to 25). For stiffness, we will include 4 items modeled after the BPI pain intensity scale. Objective 2: Examine the association between letrozole therapy side effects and quality of life and psychosocial functioning. Functional Assessment of Cancer Therapy - General (FACT-G) (CALGB: FACT-G Scale Form C-650): The FACT-G [76] total score will assess quality of life in four domains: physical well-being, functional well-being, emotional well-being, and social well-being. The FACT-G includes 28 items rated 0 (not at all) to 5 (very much). Items are summed to create total score. For copyright information, go to http://www.facit.org/qview/qlist.aspx. Self-Efficacy for Coping with Side Effects (CALGB: 40903 Managing Medication Side Effects Self Efficacy C-2032): To assess women's confidence regarding their ability to cope with side effects, a modified version of a standard self-efficacy scale will be used [77]. This scale consists of 8 items each of which is presented as a question. Women will rate each belief on a 10point scale anchored on the ends by 1=not certain and 10=very certain. The 8 items are averaged to create a total self-efficacy scale. The standard self-efficacy scale on which the scale in the current study was based has a Cronbach’s alpha of .75, M=5.20 (SD=2.14), and a test-retest reliability of .87. Objective 3: Examine the relationship between letrozole therapy side effects and medication taking behavior for therapy. Medication Taking Behavior (MMAS) (CALGB: 40903 Morisky Medication Taking Scale – Modified C-2031): A modified version of the Morisky Medication Adherence Scale (MMAS) [78] will be used to assess medication-taking behavior related to hormonal therapy (e.g, forgetting to take medication, skipping doses, reducing or stopping medication when feeling better, and reducing or stopping medication when feeling worse). The Morisky Medication Adherence Scale is probably the most widely used self-report measure of medication nonadherence. The original four-item MMAS was recently expanded to the eight item version included in this study [78-79]. Each of the eight items assesses a medication-taking behavior related to adherence including forgetting to take medication, skipping doses, stopping medication when feeling better, and stopping medication when feeling worse. Items capture both intentional and unintentional non-adherence. The MMAS has demonstrated excellent validity and reliability in patients with chronic diseases [78-81]. This scale includes the 8 items from the MMAS and an additional 8 items specifically relevant to hormonal therapy. Each of the 16 items is rated on a 1 (very often) to 5 (never) scale. Item ratings are summed to create a total score. Pre and posttreatment means are unavailable for the MMAS-modified. Beliefs about Medicines Questionnaire (BMQ) (CALGB: 40903 Beliefs about Medicine Questionnaire C-2030): The Beliefs about Medicines Questionnaire Specific (BMQ) [79] can be modified to refer to specific medications. A modified BMQ Specific, including the original five items that assess the perceived necessity of hormonal therapy, the 5 original items that assess concerns about hormonal therapy, and 5 additional questions pertaining to concerns about cancer progression will be used. For the Perceived Necessity and Medication Concerns scales, patients rate their degree of agreement with each statement on a 1 (strongly agree) to 5 (strongly disagree) scale. The individual ratings of the 5 perceived necessity items are summed to create a total Perceived Necessity score (possible range 5 to 25). Similarly, the ratings of the 5 concern items Version Date: 12/15/14 33 01/15/2015 are summed to create a total Medication Concerns score (possible range 5 to 25). The Concern about Cancer Progression scale includes 4 items rated on a 6 point Likert scale (rated 1 to 6) with responses tailored to each question. These 4 items are summed to create a total Concern about Cancer Progression score. A single Perceived Risk of Progression item has been added to the Concerns about Cancer Progression Scale in order to assess patients’ perceived risk that their DCIS will progress in the next 5 years. This item is rated on a 1 (no chance) to 7 (certain to happen) scale. 12.4 Rationale and description of scoring the measures used Quality of life will be assessed 1) in general, using the FACT-G and 2) with respect to menopausal symptoms, using the MENQOL. The FACT-G was chosen for the study because it is a commonly used and valid instrument to determine quality of life in cancer patients, including those undergoing treatment. Higher scores on the FACT-G indicate worse quality of life. The MENQOL-Intervention version was chosen for this study because it is a self-administered, brief questionnaire that assesses the quality of life experience during menopause and during treatment with hormonal therapy. Higher scores on the MENQOL indicate more bothersome menopausal symptoms. Joint and muscle pain is now a well-recognized side effect of aromatase inhibitor therapy. Two measures to assess joint pain where chosen. One to assess overall pain and the extent to which the pain interferes with daily activities, the Brief Pain Inventory – short form (BPI-SF), and the other to specifically assess arthritic pain, the AIMS2 Osteoarthritis Index. Higher scores on the BPI-SF and the AIMS2 indicate greater pain. Also included is a modified version of a standard self-efficacy scale to determine a woman’s confidence in their ability to cope with side effects, with the hypothesis that women who feel less able to cope with side effects will report more severe side effects, have worse quality of life, and be more likely to discontinue therapy. In order to explore medication taking behavior, a modified version of the Morisky Medication Adherence Scale (MMAS) will be used. Higher scores on the MMAS indicate better adherence to therapy, such as skipped doses or stopped medication. A modified version of the Beliefs About Medicines Questionnaire (BMQ) Specific, will be used to determine how important the patient feels that taking their medication is to their wellbeing. Within the BMQ Specific, there two subscales: the Perceived Necessity score, which assesses patients’ beliefs about the necessity of the prescribed medication for controlling their illness and the Medication Concerns score, which assesses concerns about the potential adverse consequences of taking the medication. Lower scores indicate higher perceived necessity and more concerns abut the medication. Items to assess perceived risk of cancer progression were added, on the premise that patients who perceived greater risk of progression will be more likely to adhere to their medication. Items on this scale range from 1 to 6, with higher scores indicating a greater perceived risk of DCIS progression. 12.5 Risk/benefit of participation There are minimal risks involved in being a subject in this assessment study. There is a minimal psychological risk that participants may be made anxious by answering questions regarding side effects, perceived cancer recurrence risk, and quality of life. There are no immediate benefits to participants. However, increased knowledge about the side effects of hormonal therapy and their impact on quality of life and adherence will have long-term relevance for developing strategies to improve side-effect management and adherence to hormonal therapy. These data would also have relevance for healthcare providers discussing Version Date: 12/15/14 34 01/15/2015 hormonal therapy with breast cancer patients. The risk-benefit ratio is such that the potential benefits outweigh the risks. 13.0 CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE 13.1 Radiographic response criteria of DCIS index lesions All measurable ipsilateral DCIS index lesions identified as between > 1 and < 7 cm in longest diameter at baseline, using digital mammography followed by imaging techniques. Preliminary data suggest that mammographic findings are not altered significantly with 3 months of letrozole, thus MRI findings will be the primary criteria by which treatment response will be assessed. Evaluation of response will be based on RECIST criteria (version 1.1) according to the following response categories. 13.1.1 Complete response (CR): Disappearance of all DCIS index lesions, on MRI. Patients with radiographic CR at 3 months per MRI will continue on letrozole for an additional 3 months, and will undergo the month 6 MRI and surgical excision within 30 days of month 6 MRI review. 13.1.2 Partial response (PR): At least a 30% decrease in the longest diameter (LD) on MRI, taking as reference the baseline largest single LD. Patients with radiographic PR at 3 months will continue on letrozole for an additional 3 months, and will undergo the month 6 MRI and surgical excision within 30 days of the month 6 MRI review. 13.1.3 Progression of disease (PD): At least a 20% increase in the longest diameter (LD) taking as reference the baseline largest single LD on MRI. If PD is determined at 3 months, the patient will continue on letrozole, but will be scheduled for surgical excision. Surgical excision must be performed within 30 days of the central MRI review reporting of PD. The letrozole will be taken until the day prior to surgery. 13.1.4 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the baseline largest single LD, on MRI. If SD is determined at 3 months, the patient will continue on study drug for an additional 3 months and will undergo the final study MRI at 6 months. 13.2 Guidelines for evaluation of measureable disease 13.2.1 Clinical Examination: DCIS is generally nonpalpable at presentation, and patients with palpable DCIS or adenopathy will be excluded from the trial. Thus, evaluation on clinical examination will not be a measureable endpoint for this study. 13.2.2 Mammography: All study mammograms will be performed on a digital mammography unit. The second mammography imaging study will be performed to coincide prior to surgery, after 6 months of letrozole (or, after 3 months if MRI progression is observed at 3 months. At a minimum, two standard screening views (CC and MLO) will be obtained, with additional views obtained at the discretion of the breast imaging team. Mammographic datapoints to be collected at baseline and following completion of study drug include: 1. Largest measured diameter of DCIS extent, as visualized by extent of calcifications on mammography on CC or MLO views, and reported on the Mammogram Tracking Form C-2059 and submitted mammogram reports. 2. Extent of disease on mammography (unifocal, multifocal, multicentric, diffuse). 3. Quantification of mammographically-detected change from baseline to post-treatment mammogram. 4. BIRADS breast density score. Version Date: 12/15/14 35 01/15/2015 13.2.3 Ultrasound (US): DCIS is generally not evaluated by ultrasound and therefore, ultrasound cannot be used as evidence of measurable disease at study entry (see Section 4.8). However, if ultrasound is performed, the presence of a mass will exclude patients from participation in the trial. Ultrasound findings are not an endpoint of the study. 13.2.4 Breast MRI: Baseline, 3-month and 6-month MRI procedures are to be planned for each patient. The MRIs will be performed on ACRIN accredited scanner(s) (5.1.2) using the same imaging parameters/protocol as the study MRI parameters/protocol described in Section 7.1.2 and detailed in the CALGB 40903 Site Imaging Manual which is available in Appendix I and is available on the 40903 study page of the CALGB and the CTSU web sites. The MRIs will be performed at the following points: • MRI1: (baseline) before the patient has been registered to the study. However, if baseline MRI is not acceptable per UCSF Breast MRI Research Laboratory, the MRI must be repeated. If the second MRI is not acceptable, the patient cannot start treatment and will be considered off study. • MRI2: At 3 months after starting AI therapy • MRI3: At 6 months after starting AI therapy if no progression at 3 months Please see Section 7.1.2 for the ACRIN MRI imaging acquisition requirements and Sections 7.2 and 8.0 for image submission requirements. All MRI and mammography studies must be uploaded to the ACRIN study site within 1-2 business days of study completion. ACRIN will transmit the MRI data, within 1-2 business days, to the University of California San Francisco Breast MRI Research Laboratory. DCIS lesions will be evaluated centrally by the UCSF CALGB 40903 designated study radiologist. The 3-month MRI study will be reviewed within 3 business days. The University of California San Francisco Breast MRI Research Laboratory will email the determination of response or progression to the treating physician and the Lead CRA at each site. Patients will remain on letrozole until the day prior to surgery. MR Image Interpretation Image interpretation will be performed according to the ACR BIRADS – MRI (2003 Edition). The breast MRI lexicon provides a common language for describing architectural features, time course of contrast enhancement and disease extent. Radiologic interpretation of MR images will assess lesion size, shape, extent, distribution and kinetics as well as other characteristics including breast density and T2 appearance. Quantitative MR Image Analysis The primary criterion for continuation on study is change in maximum LD of the target lesion compared to baseline. Patients with disease progression at 3 months (see Section 13.1.3) will be referred for surgery. Patients who have not demonstrated progression will continue on letrozole therapy for an additional 3 months. The primary quantitative measurement to be made by MRI is an estimate of tumor volume. The existing malignancy criteria for defining tumor volume are based on receiver operating characteristic (ROC) optimization in a retrospective group of 180 patients with invasive cancer with histopathologic correlation who did not undergo neoadjuvant treatment. Reoptimization of malignancy criteria for DCIS post-neoadjuvant histopathology will be performed in a training set of 50 patient studies acquired at UCSF. Secondary measurements will consider enhancement characteristics of the tumor, including peak SER value, spatial distribution, and volume fractions of SER ranges. Measurements of these quantities will be compared over the course of treatment. Version Date: 12/15/14 36 01/15/2015 Tumor volume calculation is based on the signal enhancement ratio (SER) technique developed at UCSF and used in the ACRIN 6657 multi-center clinical trial. High spatial resolution contrast-enhanced MRI is performed using the three-time point method described above acquiring images before, immediately following contrast injection, and in the late phase of contrast passage, using a small molecular weight gadolinium-containing contrast agent, administered intravenously. Image analysis is performed by computing the SER value at every eligible pixel in the image, where each pixel represents an approximately 1 x 1 x 2 mm3 volume of tissue, or voxel. Eligible voxels to the SER calculation include those that meet an initial percent enhancement (PE) threshold of 70% and 35%, defined as PE = [(S1S0)/S0] x 100, where S0 and S1 represent the signal intensities (SI) of each voxel in the precontrast and first post-contrast images, respectively. SER is defined as (S1-S0)/(S2-S0), where S0 and S1 are as defined previously and S2 represents the signal intensity in the late post-contrast image. 14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 14.1 Duration of treatment Patients will undergo preoperative treatment with letrozole for a projected duration of 6 months, unless interval 3-month MRI demonstrates radiographic progression of disease (PD). 14.2 Extraordinary medical circumstances If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: • Notify the Study Chair. • Document the reason(s) for discontinuation of therapy on Forms C-2055. • Follow patients according to Section 6.1.2. 15.0 STATISTICAL CONSIDERATIONS This is a single-arm Phase II trial in which patients will receive 6 months of neoadjuvant letrozole, following which patients will undergo surgery. Patients are scheduled for interval imaging at 3 months. Patients with radiographic progression at 3 months will undergo surgery rather than continuing on drug. 15.1 Treatment study statistical plan 15.1.1 Endpoints Primary endpoints The primary study endpoints are 3-month and 6-month radiographic tumor volume. The first endpoint is denoted as V3, defined as the difference between baseline (pre-treatment) and 3month tumor volume with each measured by MRI. The second is denoted as V6, defined as the difference between baseline (pre-treatment) and 6-month tumor volume with each measured by MRI. Secondary endpoints In addition to the primary endpoint, data will be collected on additional radiographic endpoints, surgical/pathological outcomes, adverse events, and QOL measures. These will include the following: Version Date: 12/15/14 37 01/15/2015 * Radiographic response of MRI-measured tumor diameter: corresponds to the 3- month and 6-month measures of change in tumor volume, except the analysis will be on maximum tumor diameter, rather than volume. * Radiographic response as measured by mammography: corresponds to the 3- month and 6-month radiographic response of tumor diameter, except measured by mammography. * Type of primary surgery (mastectomy, lumpectomy). * Number of re-excisions required to obtain clear margins. * Extent of residual DCIS post surgery: the maximal size of DCIS tumor (cm) determined pathologically. * Presence of invasive cancer at surgery: the maximal size of invasive tumor (cm) determined pathologically. * Size of margins at surgery: size of the smallest margin (mm) at surgery. * Treatment-related adverse events. 15.1.2 Sample size with power justification Data from a pilot study conducted at UCSF on the use of neoadjuvant hormonal therapy for the treatment of DCIS in 22 women with ER-positive disease showed a mean 3-month decrease in tumor volume of 0.87 cm3 (standard deviation=1.7). This corresponds to a mean difference of 0.5 standardized units. The 3-month and 6-month response in MRI tumor volume, V3 and V6, will be estimated by calculating 95% confidence intervals around the mean change for each. Based upon the pilot data, 96 patients accrued to the current trial will allow us to estimate the true mean change to within +/- 0.34 cm. To allow for a 10% dropout rate, the study will accrue 106 patients, which would give 96 assessable patients. Patients will be considered “assessable” only if the MRIs obtained at all three timepoints (baseline, month 3 and month 6) are classified as acceptable by the 40903 study radiologist(s) at the UCSF Breast MRI Research Laboratory. With an anticipated accrual rate of 3 or 4 patients a month total accrual should be achieved in 32 months. 15.1.3 Plan of analysis Primary: We will estimate the 3-month and 6-month MRI volume response, V3 and V6, using 95% confidence intervals (CI) around the mean change for each. To determine whether tumor change during the first 3 months of treatment (V3) predicts tumor change between months 3 and 6, we will use simple linear regression to regress the 3- to 6- month changes on V3, with multiple imputation for missing data. MRI response based on tumor volume will be analyzed as a continuous variable. Secondary: Similar to the primary analysis, we will regress 6-month MRI response on 3-month response to determine whether early (3-month) tumor behavior predicts later (6-month) tumor behavior based on change in MR maximum diameter and mammographic extent of disease. To assess the secondary endpoints of radiographic response using MR tumor diameter and mammographic diameter, we will repeat the analyses above on these secondary endpoints. We assume that change in MRI assessment of tumor diameter and change of mammographic assessment of tumor diameter are normally distributed. If distributions are not, however, we will transform the data as appropriate. We will repeat the primary analysis on each of the secondary endpoints listed above. We will estimate the correlation in pre- and post-treatment Version Date: 12/15/14 38 01/15/2015 change between MRI tumor diameter and pathologic tumor size by calculating the Pearson correlation coefficient and its 95% confidence interval. To determine the proportion of patients who undergo as the definitive surgical procedure either mastectomy or lumpectomy, we will use exact binomial methods to calculate the proportion and 95% confidence interval for each surgical procedure. We will measure the secondary endpoint of re-excision as the proportion of patients who required re-excision. We will calculate using binomial methods the incidence and 95% confidence intervals of the proportion by surgical procedure. Presence of invasive cancer will also be analyzed using this approach. Other secondary endpoints that are measured on a continuous scale include: extent of residual DCIS post surgery, extent of invasive cancer and size of margins at surgery. We will describe the mean and standard deviation of each. The type and severity of treatment-related adverse events will be tabulated by treatment duration (3 versus 6 months). One interim and one final analysis are planned at 50% and 100% of information, respectively. We will tabulate types of adjuvant therapy by modality for patients registered to this study. 15.2 Correlative science statistical plan 15.2.1 Evaluation of predictive and prognostic tissue biomarker associated with letrozole response Separate analyses will be performed on two groups of biomarkers. The first group will consist of response biomarkers (Ki67, bcl2, caspase 3, CD68) which are expected to be altered from baseline as a result of therapy. The second group is comprised of candidate predictive markers which may have value in identifying those patients most likely to have the best biological response (reduction in Ki67) to AI in DCIS. 15.2.2 Response/Monitoring markers Studies have shown that Ki67 values are not normally distributed, particularly following endocrine treatment [36, 44]. Thus, a nonparametric test for repeated measures, the Wilcoxon signed rank test, will be used to determine whether Ki67 scores are lower after treatment than they were before treatment for the 96 patients in the study. Differences in Ki67 percentages in the pilot study were approximately normally distributed, so that a paired t-test was used for analysis of pilot data. In the initial study of 23 patients, treatment lowered Ki67 scores by 10% on average (sd 9%). Using 9% sd, we would be able to detect a 5% difference in Ki67 score after treatment in a sample of 50 patients with paired baseline and post-treatment samples by paired t-test. For the proposed study, we will examine the distribution of Ki67 differences in the data to see if normality of distribution is still a reasonable assumption. If the assumption of a normal distribution is not met, the signed rank test comparing Ki67 at baseline and after treatment will be used for the analysis. It is expected that power using the nonparametric test will be slightly less than that for the paired t-test. This same approach will be used for the exploratory analysis of other monitoring biomarkers (bcl2, caspase 3, CD68), but will be hypothesis generating in scope. Although some biomarkers are expected to change significantly with treatment, the analysis is not powered to specifically detect change in other biomarkers. 15.2.3 Predictive markers Secondary analyses are focused on determining whether baseline marker values can be used to predict change in Ki67. We will use recursive partitioning methods to select which of the markers and optimal cutpoints for each marker to predict (1) change in Ki67 as a continuous variable and (2) whether the amount of change is above or below the median of all Ki67 Version Date: 12/15/14 39 01/15/2015 changes. Recursive partitioning does not require any assumptions about the distribution of the Ki67 change or the predictive markers. The R implementation of recursive partitioning, rpart, includes cross-validation to help ensure that the classification tree is not over determined, i.e. the method ensures that the tree is trimmed to an optimal subset of markers and cutpoints for prediction of Ki67 differences or Ki67 difference category (above or below median). With 50 cases we should be able to define a classifier that uses up to 5 predictors reliably (using the rule-of-thumb of 10 observations per variable for prediction). 15.2.4 Identification of unique genes associated with response group Identified predictors of response will be developed using the data from expression studies. Once the micoarray data have been generated, files with the unadjusted expression data will be analyzed. Supervised clustering using the response group (“good” vs “poor”). In addition, unsupervised clustering will be performed to identify clusters based on differential gene expression by using available methods with the R statistical software package (http://cran.rproject.org). In addition to the primary clustering analysis based on all measured genes, we will perform secondary bootstrap-resampled cluster analyses using only the genes in pathways of interest (e.g. cell cycle pathway, apoptosis, inflammation, angiogenesis and differentiation). Table 1 shows the power and the required samples under significance analysis of microarray (SAM) using t-tests. For example, assuming the acceptable rate of false positive genes is 1% and the fold difference between the groups is 2.0, we will need to have a sample size of 15 patients to have 80% power to identify the genes significantly different between groups (n=15 and n=17 for 85% and 90% -power respectively). Table 1. Sample size considerations to detect genes differentially expressed between groups. % False positives Fold Differences 80% Power 85% Power 90% Power 1.00% 2 14 15 17 1.50% 2 13 14 16 2.00% 2 12 13 15 15.2.5 Expected outcomes/potential pitfalls of the study design Limitation of tissue: The most significant potential limitation of the study is that tissue may be of insufficient quality or quantity to allow testing of all biomarkers of interest. Ideally, each case will yield forty 10um sections, but a lower number of sections will mandate parsimonious use of sections for biomarker assessment. Particular effort will be made to ensure that the same markers are performed on matched baseline and treated specimens. When possible, double staining of slides with two antibodies will be preferred and attempted. Priority status assigned to each antibody is noted in Table 2 in Section 11.3.1. Controlling for treatment-independent biomarker variation: Biomarker variations may be encountered between pre-treatment and post-treatment samples that may be independent of treatment and potentially due to 1) sample heterogeneity, 2) influence of time or biopsy injury, or 3) effect of specimen size on adequacy of tissue fixation. As part of our preliminary studies, we have collected 20 paired cases of core biopsy and excision specimens in patients diagnosed with DCIS who did not undergo preoperative treatment and will plan to collect 20 more controls. Version Date: 12/15/14 40 01/15/2015 15.3 Statistical considerations for associations studies based on germline polymorphisms The analyses will be primarily limited to those patients who have self-declared their race as white and their ethnicity as non-hispanic. Based on the experience from a number of GWAS studies CALGB investigators have found, that in absence of geno-wide SNP coverage, this race and ethnicity filter is a reasonable surrogate marker for identifying a genetic European subset. It is expected that 85% of the patients will self-declare as white and non-hispanic. Furthermore it is expected that 85% of the patients will provide consent and DNA usable for genotyping. Thus, the expected sample size, assuming N=96 patients will register to the study, will be N=70. The primary question to study in this patient population is the pharmacogenomics of letrozole induced musculoskeletal adverse event (MS-AE). This will be primarily accomplished by validating SNPs implicated in letrozole induced MS-AE reported by Ingle et al [87]. Among the four (three typed and one imputed) SNPs discussed in this paper, three have a relative minor allele frequency (MAF) of about 0.09. Assuming that the probability of the event of interest is 0.3, the power of detecting a genotype relative risk (GRR) of 2.2 at the one-sided level of 0.05 under an additive model is about 0.7. The requisite analyses are more complicated than the case-control type analysis considered in the power calculation as the time of onset of pain is potentially subject to informative censoring mechanisms. Specifically, by design, the length of therapy is dependent on clinical outcome. The CALGB Statistical Center has extensive interest and investment in this research area specifically in the study of pharmacogenomics of bevacizumab induced hypertension (CALGB 80303, 90401 and 80405), docetaxel induced neutropenia (CALGB 90401), paclitaxel (CALGB 40101) and gemcitabine induced neutropenia (CALGB 80303). This expertise will be relevant in studying the pharmacogenomics of drug induced toxicity in this study. In addition, we may use the DNA collected to conduct a genome-wide association study (GWAS) to identify novel candidates or as next generation sequencing platforms become more cost effective consider exome or whole-genome sequencing. All SNPs will be evaluated for deviation from Hardy-Weinberg. In absence of a hypothesis, the association analyses will be powered for allele dosing (i.e., additive) effects. To this end, the Cochran-Armitage test (for binary endpoints), Jonkheere-Terpstra test (for quantitative traits including biomarker or gene expressions in serum or tumor RNA) and the Cox score test (for censored time-to-event outcomes) will be used to quantify marginal associations. Multivariable models, with molecular, clinical and demographic variables, will be constructed using conditional inference trees and random forests. All statistical analyses will be carried out by members of the CALGB Statistical Center under the direction of the appropriate CALGB faculty statistician. The R Statistical environment along with extension packages will be used for all analyses. 15.4 Quality of life assessment statistical plan 15.4.1 Overview of the QOL evaluation The QOL assessment study is designed to investigate the following objectives, to assess side effects associated with letrozole therapy, to examine the association between letrozole therapy associated side effects and quality of life and to examine the relationship between letrozole therapy side effects and medication taking behavior. A total of 96 patients are expected to complete the treatment study. All registered to the treatment study will have the chance to participate the study. QOL measures (including MENQOL, BPI-SF, BMQ-Modifed, FACT-G, and Self-Efficacy for Coping with Side Effects) will be taken Version Date: 12/15/14 41 patients who are QOL assessment MMAS, AIMS, at baseline (pre- 01/15/2015 treatment), Month 1, Month 3 and Month 6. The medication taking behavior measures (including MMAS and BMQ) will be taken at Month 1, Month 3 and Month 6. 15.4.2 Power analysis of QOL assessment Ninety six patients will be expected to complete the treatment study. Considering patients may not consent to QOL study and the consenting patients may have missing endpoints, we assume 90% of patients (86 patients) will complete the QOL study. In objective 1, it is hypothesized that compared to baseline levels before starting letrozole, joint pain and menopausal symptoms will increase among postmenopausal women taking letrozole at month 3 and month 6. The primary endpoints are 1 month, 3 month and 6 month changes of the MENQOL (4 domains including physical, vasomotor, psychosocial and sexual), BPI (pain intensity and pain interference) and AIMS2 (pain with 4 additional items for stiffness) and measures, defined as the difference between baseline and 3 month measurements, difference between baseline and 6 month measurements respectively. The sample size calculation and power analysis will be adjusted to account for multiple comparisons. The analysis involves changes at two time points of 8 endpoints. Using a Bonferroni correction, a type I error rate of approximately 0.003 will be used for these comparisons. With 86 patients, a medium effect size of 0.394 is detectable with 80% power at 0.003 level of significance using one-sided one sample t-test. In objective 2, it is hypothesized that greater side effects will be related to reduced quality of life and lower self-efficacy for coping with side effects at month 1, month 3 and month 6. The correlation of side effects (four domains in MENQOL including physical, vasomotor, psychosocial and sexual, 2 scales in BPI including pain intensity and pain interference) with medication taking behavior (total score of the MMAS) will be explored. For the purpose of power analysis, all these endpoints are assumed to be continuous variables and follow a normal distribution after transformation. The Fisher’s z transformation method will be used to test whether the Pearson’s correlation coefficient is greater than zero, this is equivalent to testing the regression coefficient greater than zero from a linear model with quality of life and psychosocial functioning as outcome and side effects variables as a single predictor. To control the family-wise type I error at 5% level, with 24 planned tests (the correlation of 12 paired variable in two time points), the Pearson’s correlation coefficient will be tested at a one-sided significance level of 0.002 by Bonferroni adjustment. At each measurement time point, with 24 paired measures, the study has 84% power to reject the null hypothesis H0:pho=0 under the alternative hypothesis H1: rho<-0.4 at a one-sided significance level of 0.002. In objective 3, it is hypothesized that greater side effects will be associated with poorer adherence to letrozole therapy and lower self-efficacy for taking medication at month 1, month 3 and month 6. The correlation of side effects will use (four domains in MENQOL including physical, vasomotor, psychosocial and sexual, 2 scales in BPI including pain intensity and pain interference) with medication taking behavior (medication taking behavior total score). All these endpoints are assumed to be continuous variables and follow a normal distribution after transformation. The Fisher’s z transformation method will be used to test whether the Pearson’s correlation coefficient is greater than zero, this is equivalent to testing the regression coefficient greater than zero from a linear model with medication taking behavior and self-efficacy as outcome and side effects variables as a single predictor. To control the family-wise type I error at 5% level, with 24 planned tests (the correlation of 12 paired variable in two time points), the Pearson’s correlation coefficient will be tested at a one-sided significance level of 0.002 by Bonferroni adjustment. At each measurement time point, with 24 paired measures, the study has 84% power to reject the null hypothesis Version Date: 12/15/14 42 01/15/2015 H0:pho=0 under the alternative hypothesis H1: rho<-0.4 at a one-sided significance level of 0.002. 15.4.3 Analytic methods Objective 1 Descriptive statistics (frequencies, mean, median, standard deviation) will be computed for menopausal symptoms (MENQOL) and pain (BPI and AIMS2) and for the changes of MENQOL and pain by assessment time. One-sample t-test will be used in the change of each MENQOL and pain endpoints to check if the changes are significant. Objective 2 and objective 3 Descriptive statistics (frequencies, mean, median, standard deviation) will be reported for each endpoint by assessment time. Pearson’s correlation coefficients between paired measures will be calculated as well as its 95% confidence intervals. The linear relationship between side effects and quality of life as well as psychosocial functioning in Objective 2, and the linear relationship between side effects and medication taking behavior as well as self-efficacy for taking medication in Objective 3 will be evaluated further using a linear regression model. In addition, multivariate regression will be considered to derive a composite prediction from all side effects endpoints to more accurately predict the quality of life and psychosocial functioning for Objective 2 or predict the medication taking behavior and self-efficacy for taking medication for Objective 3. A subset of side effects predictors will be selected by the strength of their univariate association with the predicting variables. These predictors will be included in the multivariate analysis with variable selection algorithms to select the final linear regression model. 16.0 EXPEDITED ADVERSE EVENT REPORTING Investigators are required by Federal Regulations to report serious adverse events as defined below. CALGB investigators are required to notify the CALGB Central Office, the Study Chair, and their Institutional Review Board if a patient has an adverse event requiring expedited reporting. All such events must be reported in an expedited manner using the NCI Adverse Event Expedited Reporting System (AdEERS). The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for reporting. All treatment areas should have access to a copy of the CTCAE version 4.0 as appropriate. A copy of the CTCAE version4.0 can be downloaded from the CTEP web site (http://ctep.cncer.gov). In the rare event when Internet connectivity is disrupted, a 24-hour notification is to be made to the NCI by telephone at 301-897-7497. An electronic report MUST be submitted immediately upon re-establishment of Internet connection. CALGB requires investigators to route all expedited adverse event reports through the Central Office for CALGB-coordinated studies. Be sure to read this entire protocol section, as requirements are described in both the table and the bullet points following the table in Section 16.1. Note that the table in Section 16.1 and the additional instructions or exclusions in Section 16.2 may conflict. The additional instructions or exclusion are protocol-specific and, in case of a conflict, the additional instructions or exclusions in Section 16.2 supersede the table in Section 16.1. Version Date: 12/15/14 43 01/15/2015 16.1 CALGB 40903 Commercial Agent Study: Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND trial within 30 Days of the Last Administration of a Commercial Agent 1 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) An adverse event is considered serious if it results in ANY of the following outcomes: 1) 2) 3) 4) 5) 6) Death A life-threatening adverse event An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via AdEERS within the timeframes detailed in the table below. Hospitalization Resulting in Hospitalization ≥ 24 hrs Not resulting in Hospitalization ≥ 24 hrs Grade 1 Timeframes Grade 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes 10 Calendar Days 24-Hour 5 Calendar Days Not required 10 Calendar Days Expedited AE reporting timelines are defined as: o “24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. 1 Serious adverse events that occur more than 30 days after the last administration of commercial agent require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for: • All Grade 4, and Grade 5 AEs that are at least possibly related to treatment Expedited 10 calendar day reports for: Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization, and that are at least possibly related to treatment. • Grade 3 adverse events that are at least possibly related to treatment NOTE: Deaths clearly due to progressive disease should NOT be reported via AdEERS but rather should be reported via routine reporting methods (e.g., CDUS and/or CTMS). Version Date: 12/15/14 44 01/15/2015 16.2 Additional instructions or exclusions to AdEERS expedited reporting requirements for Commercial Agents in a Non-IND trial: • All adverse events reported via AdEERS (i.e., serious adverse events) should also be forwarded to your local IRB. • All new malignancies should be reported through AdEERS whether or not they are thought to be related to either previous or current treatment. All new malignancies should be reported including solid tumors (including non-melanoma skin malignancies), hematologic malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and in situ tumors. In CTCAE version 4.0, the new malignancies (both second and secondary) may be reported as one of the following (1) Leukemia secondary to oncology chemotherapy, (2) Myelodysplastic syndrome, (3) Treatment-related secondary malignancy, or (4) Neoplasm other, malignant (grade 3 or 4). Whenever possible, the AdEERs reports for new malignancies should include, tumor pathology, history of prior tumors, prior treatment/current treatment including duration, any associated risk factors or evidence regarding how long the new malignancy may have been present, when and how the new malignancy was detected, molecular characterization or cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy treatment and outcome, if available. • Treatment expected adverse events include those listed in Section 11.0 and in the letrozole package insert. • The reporting of adverse events described in the table above is in addition to and does not supplant the reporting of adverse events as part of the report of the results of the clinical trial, e.g., cooperative group data reporting (see Section 6.0). Version Date: 12/15/14 45 01/15/2015 17.0 REFERENCES 1. Breast Cancer Facts and Figures 2007-2008. American Cancer Society.: Publisher; 2008. 2. 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Esserman LJ, Hylton NM, George T, Weidner N: Contrast-enhanced magnetic resonance imaging to assess tumor histopathology and angiogenesis in breast carcinoma. Breast Journal 1999, 5:13-21. 28. Orel SG, Mendonca MH, Reynolds C, Schnall MD, Solin LJ, Sullivan DC: MR imaging of ductal carcinoma in situ. Radiology 1997, 202:413-420. 29. Kuhl CK, Schrading S, Bieling HB, Wardelmann E, Leutner CC, Koenig R, Kuhn W, Schild HH: MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet 2007, 370:485492. 30. Partridte S.C., et al.: MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival. AJR AmJ Roentogenol 2005, 184:1774-81. 31. Lorenzon M., et al.: Assessment of breast cancer response to neoadjuvant chemotherapy: Is volumetric MRI a reliable tool? Eur J Radiol 2009, 71:82-8. 32. 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Colomer R, Monzo M, Tusquests I, et al.: A single nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14:811-15, 2008. 86. Garcia-Casado Z, Guerro-Zotano A, Llombart-Cussac A, et al.: A polymorphism at the 3’UTR region of the aromatase gener defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole. BMC 10:36, 2010. 87. Ingle, JN et al.: Genome-wide case-control study of musculoskeletal adverse events and functional genomics in women receiving aromatase inhibitors: Going beyond associations. Breast Cancer Res 12:4 S17 Version Date: 12/15/14 50 01/15/2015 18.0 MODEL CONSENT FORM: PHASE II STUDY OF NEOADJUVANT LETROZOLE FOR POSTMENOPAUSAL WOMEN WITH ESTROGEN RECEPTOR POSITIVE DUCTAL CARCINOMA IN SITU (DCIS) This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have ductal carcinoma in situ (DCIS), an early change in the breast that could become breast cancer in the future. Your DCIS cells are sensitive to hormones, and therefore may be treatable with anti-hormonal medications. Why is this study being done? Standard treatment for DCIS includes surgery to remove the DCIS cells from the breast, or surgery followed by radiation therapy. The purpose of this study is to test whether neoadjuvant (neoadjuvant means given before surgery) treatment with the aromatase inhibitor (anti-hormonal medication) letrozole has an effect, either good or bad, on you and on the DCIS. Mammograms are the standard method of detecting and measuring DCIS. The researchers conducting this study would also like to learn more about whether Magnetic Resonance Imaging (MRI) may be better for evaluating and measuring DCIS, compared to mammograms. The aromatase inhibitor letrozole is approved by the Food and Drug Administration (FDA) of the United States, for the treatment of breast cancer that is positive for either the estrogen receptor or the progesterone receptor in postmenopausal women. The use of letrozole in the treatment of DCIS is considered to be investigational or research. The use of MRI, as used in this study to measure the DCIS, is considered to be research. How many people will take part in the study? About 106 women will take part in this study. What will happen if I take part in this research study? Before you begin this study You will need to have the following examinations, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular DCIS care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor. • You will be asked to give your medical history and have a physical examination including a breast examination • Routine blood tests to check your blood counts, liver and kidney function, and menopausal status • A mammogram of both breasts to measure the DCIS Version Date: 12/15/14 51 01/15/2015 • A MRI with IV contrast of both breasts to measure the DCIS. If the quality of the MRI is not of acceptable quality, you will have another MRI with IV contrast of both breasts. If the repeat MRI is not of acceptable quality, you will not start treatment and will no longer be in the study. During the study If you are eligible and choose to take part, within 21 days after you have been registered to the study and your study doctor has received confirmation that your MRI scan is of acceptable quality, you will then begin treatment with the study drug letrozole one (1) tablet each day for three months. You will return to the clinic for a study visit with your study doctor after three (3) months of treatment. If your DCIS has grown you will be scheduled for surgery within 30 days. If your DCIS has gotten smaller or has remained the same you will continue the letrozole treatment for 3 more months, then return for a study clinic visit. You will be give three (3) 40903 Letrozole Medication Calendars where you will record the date, time and the number of letrozole tablets that you take each day. You will be asked to bring the calendars with you when you come for the 1, 3, 6 and month clinic study visits and, if you have had surgery, at the visit after surgery. You will continue to take the letrozole tablets until the day before your surgery. Testing and visits while receiving study treatment During the time that you are receiving study treatment you will need the following routine test: • • • Clinic visit with your study doctor for a physical examination at month 1, 3 and 6 (including a breast examination at month 3 and 6) Pre-surgery clinic visit with your surgeon within 30 days before your surgery. It is possible that this visit may be done at the same time as your month 3 or month 6 visit. A digital mammogram of the breast(s) with DCIS before surgery (either at month 3 or month 6) During the time that you are receiving study treatment you will have the following imaging test more often than the standard of care due to your participation in this study: • A MRI with IV (given through a vein) contrast of both breasts, to measure the DCIS, at month 3 and if you have continued treatment after month 3 also at month 6 MRI is a commonly used medical imaging method used to see what’s going on inside the body and measure different types of cancers. Its use in this study to measure the DCIS is considered to be research. Your MRI and mammogram images will be forwarded to the American College of Radiology Imaging Network (ACRIN) for storage and quality assurance and to the University of California San Francisco (UCSF) MRI Research Laboratory for review. These images will be de-identified to protect your privacy. Researchers at UCSF will review your images and communicate their findings with your study doctor. Testing and visits after study treatment has been completed After the study treatment has been completed, you will have a physical examination 6 months after you have stopped the letrozole therapy or 6 months after you have had surgery to remove the DCIS Version Date: 12/15/14 52 01/15/2015 from your breast. Another way to understand what will happen during the study is to read the chart below. Start reading at the left and follow the arrows across to the right. Treatment plan R E G I S T E R If your DCIS has gotten smaller or remained the same, you will continue the letrozole for 3 more months. Letrozole one tablet each day for 3 months. 3 month disease evaluation by MRI of both breasts. If your DCIS has grown you will have surgery to remove the DCIS from your breast. You will continue to take the letrozole until the day before surgery. 6 month MRI of both breasts followed by surgery. A mammogram of both breasts will be done before surgery (at month 3 or month 6) Surgery Quality of Life Survey We want to know your view of how your life has been affected by DCIS and its treatment. This “Quality of life” study looks at how you are feeling physically and emotionally during your DCIS treatment. It also looks at side effects of treatment and how you are able to carry out your day-today activities. This information will help doctors better understand how patients feel during treatments and what effects the medicine are having. In the future, this information may help patients and doctors as they decide which medicines to use to treat DCIS. You will be asked to complete the questionnaires: Before you begin the study treatment with letrozole, on your 1 month, 3 month and 6 month clinic study visit (only if you continued to receive the second 3 months of letrozole) and on the last visit, either 6 months after the surgery to remove the DCIS or if you do not have surgery 6 months after you have stopped taking the letrozole. Only one questionnaire will be completed at the final visit. It will take about 45 minutes to fill out all of the questionnaires. If any questions make you feel uncomfortable, you may skip those questions and not give an answer. You may change your mind about completing the questionnaires at any time. Just like in the treatment part of the study, we will do our best to make sure that your personal information will be kept private. I agree to take part in the quality of life study and complete the quality of life questionnaires. 1) ____Yes ____No Initials_______ Version Date: 12/15/14 53 01/15/2015 How long will I be in the study? You will be asked to take the letrozole for at least 3 months and no more than 6 months. After you have had surgery to remove the DCIS from your breast the study doctor will ask you to visit the office for a follow-up examination within 30 days after the surgery. If you are participating in the Quality of Life (QOL) Survey you will come for a final visit to complete the last survey 6 months after surgery. So it is possible that you could be in the study for 3 months, 6 months or 12 months, depending on when you have surgery to remove the DCIS from your breast and whether or not you are participating in the QOL assessments. Can I stop being in the study? Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. It is important to tell the study doctor if you are thinking about stopping so any risks from the letrozole can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; if you do not follow the study rules; or if the study is stopped. What side effects or risks can I expect from being in the study? You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the drug. In some cases, side effects can be serious, long lasting, or may never go away. You should talk to your study doctor about any side effects that you have while taking part in the study. LETROZOLE Likely (have been seen in 20% of patients) • • • Hot flashes Increased sweating Fatigue Less Likely (have been seen in 20% or less patients) • • • • • • • • • • Joint pain Muscle pain bone pain weakness arthritis backache dizziness headache sleepiness decreased appetite Version Date: 12/15/14 54 01/15/2015 • • • • • • • • nausea swelling in the legs constipation weight gain shortness of breath cough Loss of bone thickness (which can lead to broken bones) Possible increase in cholesterol level as seen on a blood test Reproductive risks: All women must be postmenopausal in order to participate in this study. Postmenopausal women by definition should not be able to conceive or bear a child. However, in the unlikely event that you are able to become pregnant while taking part in this study you should be aware that the drugs used in this study can affect an unborn baby. Therefore, you should not become pregnant or breastfeed a baby while on this study. SURGERY You will sign a separate consent form before surgery. This will be a standard surgical consent form from the institution where the surgery takes place. The possible risks and side effects of the surgery that you will have will be explained to you at that time. For more information about risks and side effects, ask your study doctor. Are there benefits to taking part in the study? Taking part in this study may or may not make your health better. While doctors hope letrozole will be more useful against DCIS compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about letrozole and MRI in the treatment of DCIS. This information could help future DCIS patients. What other choices do I have if I do not take part in this study? Your other choices may include: • • • Getting treatment or care for your DCIS without being in a study Taking part in another study Getting no treatment Talk to your doctor about your choices before you decide if you will take part in this study. Will my medical information be kept private? We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include: • • Cancer and Leukemia Group B (CALGB) Cancer Trials Support Unit (CTSU), a service sponsored by the National Cancer Institute (NCI) to provide greater access to cancer trials Version Date: 12/15/14 55 01/15/2015 • The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people Organizations that may review and store your de-identified MRI and mammogram images for research and quality assurance include: • • University of California San Francisco (UCSF) MRI Research Laboratory American College of Radiology Imaging Network (ACRIN) The CALGB has received a Certificate of Confidentiality from the federal government, which will help us to protect your privacy. The Certificate protects against the involuntary release of information about you collected during the course of the study. The researchers involved in this project may not be forced to identify you in any legal proceedings (criminal, civil, administrative, or legislative) at the federal, state, or local level. However, some information may be required by the Federal Food, Drug, and Cosmetic Act, the U.S. Department of Health and Human Services, or for purposes of program review or audit. Also, you may choose to voluntarily disclose the protected information under certain circumstances. For example, if you or your guardian requests the release of information about you in writing (through, for example, a written request to release medical records to an insurance company), the Certificate does not protect against that voluntary disclosure. What are the costs of taking part in this study? You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. The letrozole use in this study will be provided to your doctor for you, free of charge by the Division of Cancer Prevention of the National Cancer Institute (NCI). If during the study the letrozole become approved for use in treating DCIS you and /or your health plan may have to pay for the letrozole needed for you to complete this study. Even though it probably won’t happen, it is possible that the manufacturer may not continue to provide the letrozole to the Division of Cancer Prevention of the National Cancer Institute (NCI) for some reason. If this would occur, other possible options are: • • You might be able to get the letrozole from the manufacturer or your pharmacy but you or your insurance company may have to pay for it. If there is no letrozole available at all, no one will be able to get more and the study would close. If a problem with getting letrozole occurs, your study doctor will talk to you about these options. There will be no charge to you for the cost of the month 3 or month 6 MRI scans. You will not be paid for taking part in this study. For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. Version Date: 12/15/14 56 01/15/2015 Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy. What happens if I am injured because I took part in this study? It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment. What are my rights if I take part in this study? Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form. Who can answer my questions about the study? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] *You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) at 888-657-3711 (from the continental US only). [*Only applies to sites using the CIRB.] Related Studies Please note: This section of the informed consent form is about additional research studies that are being done with people who are taking part in the main study. You may take part in these additional studies if you want to. You can still be a part of the main study even if you say ‘no’ to taking part in any of these additional studies. You can say “yes” or “no” to each of the following studies. Please mark your choice for each study. Version Date: 12/15/14 57 01/15/2015 Please read this section of the informed consent on related research studies and ask about anything that is not clear to you. This is to inform you of the possible risks, benefits and limits of giving your samples for research. You are being asked to give some of your samples (called specimens) and related information to be used for research. This may help researchers learn more about how to prevent, find and treat cancer and other diseases. The choice to have your samples used for the research described in this consent and stored for future research is up to you. No matter what you decide, it will not affect your medical care and it will not affect whether you take part in other studies. You will not be paid for taking part in these studies. What are samples and where are they stored? A sample is any material taken from your body such as tissue, blood, urine and other fluids. If you agree, your samples will be stored for research in a Cooperative Group bank supported by the National Cancer Institute. A Cooperative Group bank contains samples and information. Your samples are kept along with those from other people in this bank. Researchers then ask for samples from the bank to study them. What information will be collected? Your samples will be sent to the CALGB Bank. Any personal information sent with the samples to the bank is not given to researchers. The personal information is used only by the bank. Your privacy will be protected to the fullest extent possible. This will be discussed later in the section “How will information related to my samples be protected?” Other information that might be stored for future research by the Cancer and Leukemia Group B includes: • • • • • • Dates of medical procedures Any diagnosis and stage of your disease (if you have cancer) Your age and race Medical and family history Treatments you had How you responded to treatments What will happen to my samples if I agree to give them for research? Your samples will be stored in the CALGB Bank. The samples will be kept until they are used up or destroyed. The samples are given a code to protect your privacy before they are used. Any related information given to researchers will also be coded. Researchers will receive the code instead of any information that might directly identify you. You or your doctor will not be given reports or other information about the research that uses your samples. This information will not be put into your health record. Results may be used for future research. You will not be named or identified by other personal information if any results are published. Most publications contain results from many patients. Your samples and related information will be used only for research and will not be sold. It is Version Date: 12/15/14 58 01/15/2015 possible that research may help to create new products or treatments. If this should happen, you will not be paid. Because the information gained from the research studies performed on your samples can be very useful to the research community, several groups including the National Institute of Health (NIH) have requested that some of these data be placed in a central database. Therefore, some of the coded research information may be sent to a central database. The goal is to speed up the process of discovery of new treatments, prevention and diagnosis of disease. The information will continue to be made available for approved research. Your name or contact information will not be put in the database. What kind of research will be done with my samples? Many types of research use normal or diseased (cancerous) samples. Researchers can study proteins, RNA and DNA (genes). The study of genes (DNA) is often called genetic research. Your samples may be looked at: • To see if a trait is passed down in families from one generation to the next (inherited). This type of research may help to explain why some cancers run in families or why some people have side effects of treatment while others do not. This is often studied through blood cells and DNA (genes). • To learn about changes in the body that happen after you were born (non-inherited). For example, being in the sun too much can cause changes in cells that lead to skin cancer. As part of this study researchers want to learn more about the possibility of predicting whether the study treatment will work by studying your DCIS tissue samples, and would also like to investigate whether substances in your blood, called tumor markers, are related to the way that your body responds (or doesn’t respond) to the study treatment. Qualified researchers can submit a request to use the samples stored in the Cooperative Group bank. A science committee at the Cooperative Group, and/or the National Cancer Institute, will review each request. There will also be an ethics review to ensure that the study is necessary and proper. Researchers will not be given your name or any other information that could identify you. Neither you nor your doctor will be notified when research will be conducted or given reports or other information about any research that is done using your samples. Will it help me if I give my sample for research? Using your samples for research will probably not help you. We do hope the research results will help people in the future. The best way to prevent, find or treat cancer and other diseases is by studying human samples and data. What are the risks of giving my samples for research? • There can be mild pain, or some bleeding or bruising when blood is drawn. Rarely, an infection can happen where the needle was placed. Feeling dizzy or fainting can also happen, but may only last a few minutes after blood is drawn. • There is a risk that your information could be misused. The chance of this happening is very small. We have many protections in place to lower this risk. See the next section, “How will the information related to your samples be protected?” Your privacy will be protected to the fullest extent possible. Version Date: 12/15/14 59 01/15/2015 • There can be a risk in knowing genetic information. New health information about inherited traits that might affect you or your blood relatives could be found during a research study. Even though your genes are unique, you share some of the same genes with your blood relatives. Very rarely health or genetic information could be misused by employers, insurance companies, and others. For example, life insurance companies may charge a higher rate based on this information. Some states have laws to protect against genetic discrimination [list appropriate state information if your state has such laws]. A new federal law called the Genetic Information Non-Discrimination Act, or GINA is in effect. This law helps to lower the risk of health insurance or employment discrimination. The law does not include other types of misuse by life insurance or long term care insurance. To learn more about the GINA Law, please check the Internet or ask the study staff. Although we are not able to know all of the risks from taking part in research on inherited traits, we believe that the risks to you and your family are very low, because research results will not be returned to you or your doctor. How will information related to my samples be protected? We have many ways to protect the information related to your samples: • Your samples and information receive a unique code. Researchers only receive coded samples and information, and will not be able to link the code to you. Only approved people in the Cancer and Leukemia Group B can match you to the code on your samples and related information. • Strict security safeguards are in place to reduce the chance of misuse or unplanned release of information. Steps we take include, but are not limited to, restricted access to buildings, rooms and freezers housing patient samples, numeric coding of both patient data and samples, and password protected access to databases housing patient data. • Before samples are given to researchers, studies are reviewed for the quality of the science and for patient protection. Records from research studies can be reviewed by the Cooperative Group, by the sponsor, and by government agencies. This is to make sure the research follows the rules of the Cooperative Group and state or federal laws. • In most cases, research results will not be returned to you or your doctor. If research results are required to make a decision regarding your treatment on this study then research results may be shared with you or your doctor. If research results are published, your name and other personal information will not be given. • The Cancer & Leukemia Group B (CALGB) also has a Certificate of Confidentiality from the U.S. Department of Health and Human Services. The Certificate protects against the forced release of personal information from the Cooperative Group bank or database. What this means is that CALGB cannot be forced to disclose your identity to any third party. It is possible that for some legal proceedings, the Certificate of Confidentiality could be over-ridden by a court of law. Making your choice The choice to take part is up to you. You may choose not to let us use and store your samples. If you decide not to let us store and use your samples, you will still receive the same medical care. Version Date: 12/15/14 60 01/15/2015 You may also take part in other research studies. To learn more, ask the study staff for the booklet called “Giving Samples for Research" or visit http://www.cancer.gov. You may want to read the section “What types of research use samples?” [If approved by IRB also include “Patient Information Brochure” in this statement.] If you decide that your samples can be kept, you may change your mind at any time. Contact the study staff at your hospital and let them know that you do not want your samples used for research [Insert contact number]. Then, any sample that remains in the bank will no longer be used. Samples or related information that have already been given to or used by researchers cannot be returned or destroyed. Thank you for considering whether to allow your samples to be used for the research described above and/or banked for future research. The researchers want to learn more about the possibility of predicting whether the study treatment will work by studying your DCIS tissue samples. If you agree a sample of your DCIS tissue, which was taken at the time of diagnosis for routine testing, and a sample of DCIS tissue that will be taken at the time of surgery will be sent to a CALGB research laboratory for these studies. 2) My tissue specimens may be used for the research described above. ____Yes ____No Initials_______ Genetic Studies on Blood The researchers would like to investigate whether substances in your blood, called tumor markers, are related to the way that your body responds (or doesn’t respond) to the study treatment. These tumor markers may be inherited through your family, and could be passed to your children. These are also called genetic studies. Blood taken before study treatment will be used to learn how certain genes influence the effectiveness and side effects of your treatment. In order to study the genes the DNA must be removed from your blood sample. DNA is the substance that makes up your genes. Genes are the units of inheritance that are passed down from generation to generation. They are responsible for eye color, hair color, blood type and hundreds of other traits. New scientific tools will now allow researchers to look at your whole DNA, not just one part or one gene. This kind of research can provide information to researchers about the development of cancer and response to treatment. It can also provide information about a variety of other conditions and diseases, including heart disease, diabetes and Alzheimer’s disease. Because the information gained in these genetic studies can be very useful to the research community, the National Institutes of Health (NIH) has requested that these data be placed in a central database housed at the NIH. The goal is to speed up the process for discovery of new treatment, prevention and diagnosis of disease. Researchers must get approval from the NIH before they can access the research results and healthrelated information from your specimen. All information will be coded with a unique number. Researchers will not have access to your identity; they will only see coded information. Version Date: 12/15/14 61 01/15/2015 Blood for these studies will be taken only once before the first dose of study treatment. About 4 teaspoons of blood will be taken. 3) My specimen may be used for the genetic research described above. ____Yes ____No Initials_______ Storage of tissue and blood The researchers would also like to store any portion of the tissue and blood that is not used up by the related study described above. These samples may be stored indefinitely. You can still take part in the treatment study, and the research study described above without giving your consent for your samples to be stored. It is not possible for you or the CALGB to know what studies of breast disease may be appropriate in the future. We ask that you give permission in advance for other studies to be performed using the tissue without being re-contacted to give permission for each test. Please read each sentence below and think about your choice. After reading each sentence, check "Yes" or "No". If you have any questions, please talk to your study doctor or nurse, or call our research review board at IRB's phone number. No matter what you decide to do, it will not affect your care. 4) My specimens may be kept for future use in research to learn about, prevent, or treat breast disease. ____Yes ____No Initials_______ 5) My specimens may be kept for use in research to learn about, prevent or treat other health problems (for example: diabetes, Alzheimer's disease, or heart disease). ____Yes ____No Initials_______ 6) Someone may contact me in the future to ask me to take part in more research. ____Yes ____No Initials_______ Where can I get more information? You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237) You may also visit the NCI Web site at http://cancer.gov/ • For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ • For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will not include information that can identify you. At most, the Web site will include a summary of study results. You can search this Web site at any time. Version Date: 12/15/14 62 01/15/2015 You will get a copy of this form. If you want more information about this study, ask your study doctor. Signature I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study. Participant ________________________________ Date _____________________________________ Version Date: 12/15/14 63 01/15/2015 SITE IMAGING MANUAL APPENDIX I CALGB 40903 SITE IMAGING MANUAL CALGB 40903 Phase II Study of Neoadjuvant Letrozole for Postmenopausal Estrogen Receptor Positive Ductal Carcinoma in SITU (DCIS) Version: 3.0 Date: August 27, 2013 Version Date: 12/15/14 64 01/15/2015 TABLE OF CONTENTS 1.0 Overview of Imaging Requirements …………………………………………………………… 2 2.0 Imaging Qualification …………………………………………………………………………… 2 2.1 Protocol-Specific Application 2.2 MR Qualification Form – Imaging Equipment 2.3 MRI Test Scans 2.4 MRI Qualification Review and Notification 2.5 Changes to Qualified Scanner 3.0 Bilateral Digital Breast Mammogram …………………………………………………………… 3 3.1 Imagine Schedule 3.2 Imaging Procedure 4.0 Breast MRI ……………………………………………………………………………………… 4 4.1 Imaging Schedule 4.2 Standardized Imaging Procedure 4.1.1 Exam Preparations 4.1.2 Contrast Agent Administration 4.1.3 Image Acquisition Protocol 5.0 Image Submission ……………………………………………………………………………… 5.1 TRIADTM 5.1.1 Current TRIAD Users 5.1.2 TRIAD Installation 5.1.3 Submission of Study Imaging 5.1.4 Submission of Test Scans 5.2 CD/DVD 5.3 Image Transmittal Worksheet 6 6.0 Quality Control ………………………………………………………………………………… 6 Appendices: I. Protocol-Specific Application II. MR Qualification Form III. TRIAD Pre-Study Worksheet IV. Image Transmittal Worksheet (ITW) CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 1 65 01/15/2015 1.0 OVERVIEW OF IMAGING REQUIREMENTS MRI Qualification TRIADTM Installation Image Acquisition Image Submission 2.0 Submit prior to study enrollment: • Protocol-Specific Application • MR Qualification Form and 2 test scans for each scanner Should be installed prior to study enrollment for secure, electronic submission of imaging to ACRIN. Mammogram, per routine acquisition protocol • Mammo-1: Baseline/Pre-treatment • Mammo-2: Pre-surgical MRI, per study-standardized acquisition protocol • MRI-1: Baseline/Pre-treatment • MRI-2: 3 Month Follow-up • MRI-3: 6 Month Follow-up Submit all mammograms and MRI imaging to ACRIN via TRIADTM. IMAGING QUALIFICATION The use of standardized imaging guidelines is an essential component of clinical trials in which imaging plays a central role in the research endpoints. This is of particular importance in multicenter trials where equipment, personnel, and imaging acquisition protocols can vary significantly across sites. Thus, the use of standardized imaging guidelines helps control the inter- and intra-variability inherent in multicenter imaging trials. Participation in CALGB 40903 requires sites to adhere to a standardized MR imaging protocol. Mammograms will be performed per your institutions standard of care and will not require trial-‐specific qualification. Qualification of the MR imaging is required prior to enrollment of study participants. The qualification process will be managed by the ACRIN Imaging Core Laboratory on behalf of CALGB. The purpose of the qualification process is to help ensure that study imaging is of high quality and performed per the standardized MRI acquisition protocol. Suboptimal image quality and/or imaging not performed per the trial-standardized protocol can result in exclusion of the imaging exam(s) and/or the entire case from analysis. Therefore, routine QC and adherence to the image acquisition protocol are of great importance. 2.1 Protocol-Specific Application (PSA) The first step in the qualification process is to complete a Protocol-Specific Application (PSA), provided with this Manual. The application captures information regarding site personnel and general imaging capabilities. 2.2 MR Qualification Form (MRQF) – Imaging Equipment Sites are required to identify at least one 1.5T or 3T scanner for imaging of CALGB 40903 study patients. A MR Qualification Form (provided with this manual) is required for each scanner to be used during the study. In choosing which scanners to qualify, please note that it is preferred (best practice) that all study imaging for a given patient be performed on the same scanner. CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 2 66 01/15/2015 When this is not possible, all imaging for a given patient must be performed using the same magnet configuration (same scanner manufacturer, model, field strength and breast coil). Required imaging equipment: • at least one 1.5T or 3.0T whole body MRI scanner • dedicated breast radiofrequency coil 2.3 MRI Test Scans Two clinical test scans, acquired per the standardized protocol described in Section 4.0, are to be submitted for each scanner. All imaging must be submitted in DICOM format. Qualification imaging can be submitted electronically via TRIADTM or saved to CD/DVD and shipped to ACRIN, along with a copy of the submitted MR Qualification Form. See Section 5.0 for image submission instructions. 2.4 MRI Qualification Review and Notification The test scans will be evaluated for general image quality and compliance with the standardized MR acquisition protocol. ACRIN will notify the site via e-mail regarding the results of the qualification review. If the test MRI scans are approved, ACRIN will provide notification of qualification via email to the site, the CALGB coordinating center and CTSU. If the scans are not approved, ACRIN will notify the site by email and provide recommended corrections. Approval of the test scans is mandatory prior to a site registering a participant onto the trial. 2.5 Changes to Qualified Scanner(s) Changes in the scanner used to image CALGB 40903 study patients should be reported to the ACRIN Imaging Core Lab immediately via email. The addition of a new scanner for study imaging will require full qualification. Software and/or hardware upgrades to already qualified scanners will be reviewed by the ACRIN Imaging Core Lab to determine whether additional QC testing or test scans will be required. In either case, use of a new scanner or software/hardware upgrades, sites should consult ACRIN prior to scanning study patients. 3.0 BILATERAL DIGITAL BREAST MAMMOGRAM 3.1 Imaging Schedule Mammo-1 Baseline (within 60 days prior to study) Mammo-2 Prior to Surgery Submit to ACRIN within 1-2 business days of image acquisition. 3.2 Imaging Procedure The two standard views (cranio-caudal and medial-lateral oblique) for each breast are to be performed per your institutions standard of care. For some women with larger breasts, additional images may be necessary to image the entire breast, same as in standard clinical practice. CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 3 67 01/15/2015 4.0 BREAST MRI 4.1 Imaging Schedule MRI 1 Baseline (pre-treatment) MRI 2 3-Month (week 13 of treatment) MRI 3 6-Month (week 25 of treatment, pre-surgery) Submit to ACRIN within 1-2 business days of image acquisition. 4.2 Standardized Imaging Procedure All breast MRI scans performed should be performed per the standardized acquisition protocol provided below. The protocol includes a T2-weighted sequence, a diffusion-weighted imaging (DWI) sequence, and a dynamic contrast-enhanced (DCE) sequence. Please review the patient preparations and acquisition parameters carefully as this imaging protocol may or may not align with your institution’s routine/standard of care Breast MRI protocol. When setting up this acquisition protocol for the first time, the protocol should be saved to the scanner’s protocol menu under an easily recognizable name, such as CALGB 40903; this will help avoid future confusion about which imaging protocol to select. Please note that some facilities limit access to the protocol menu so this may require special user permissions. 4.1.1 ! Exam Preparations Place an intravenous catheter in the arm or hand prior to the start of imaging for contrast injection. Sites should adhere to routine clinical guidelines for the safe administration and monitoring of contrast media. ! Patients should be scanned prone and centered to the table. ! Please use universal MRI safety precautions. NOTE: Patients should be scanned in a consistent manner throughout the duration of their enrollment – same imaging protocol, same contrast agent brand, on the same scanner or the same scanner configuration (manufacturer, model, field strength and breast coil model). 4.1.2 Contrast Agent Administration For the DCE sequence, gadolinium contrast agent should be administered intravenously at a dose of 0.1 mmol/kg body weight and rate of 2 ml/second, followed by a 20 ml saline flush. Contrast injection should begin simultaneously with the start of data acquisition. 4.1.3 Image Acquisition Protocol Acquisition parameters for each of the pulse sequences are provided in Table 1. Care should be taken to select the smallest FOV and slice coverage that completely encompasses both breasts and axilla – this should be the same on all exams of the same patient. * ! Bilateral pre-contrast T2-weighted fast spin echo (FSE) or STIR ! Pre-contrast diffusion-weighted spin echo, echo planar imaging (DW SE-EPI) ! Pre-contrast 3D T1-weighted gradient echo (GE) * ! DCE: Post-contrast dynamic multi-phase 3D T1-weighted GE ( > 8 minutes) * Pre-contrast T1 images should be checked prior to contrast injection to confirm acceptable fatsuppression. Pre- and post-contrast T1 sequences MUST have identical image parameters to allow subtraction/maps; transmit and receive gain settings should remain constant. CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 4 68 01/15/2015 Table 1: CALGB 40903 Pulse Sequence-specific Acquisition Parameters Parameter T2-weighted DWI Sequence type FSE or STIR DW SE-EPI 2D or 3D sequence 2D 2D Slice orientation Axial or sagittal Axial Laterality Bilateral Bilateral Frequency direction A/P R/L Phase direction R/L (axial) A/P S/I (sagittal) FOV - frequency 260-360 mm (axial) 180260-360 mm 220 mm (sagittal) FOV - phase 260-360 mm (axial) 180260-360 mm 220 mm (sagittal) Matrix – frequency 256-512 192 (acquired) Matrix – phase (acquired) 192 ≥ 256 In-plane resolution ≤ 1.4 mm ≤ 1.9 mm Fat-suppression Active fat-sat Active fat-sat recommended TR 2000-10000 ms 6,000 ms TE 70-140 ms Minimum TE Echo Train Length TI (STIR sequence) Flip Angle B values Slice thickness (acquired) Number of slices Slice Gap Parallel imaging factor No. of excitations or averages k-space ordering Sequence acquisition time Contrast (2 ml/sec injection rate) Total post-contrast imaging duration 260-360 mm 260-360 mm 384-512 ≤ 16 150 ms (1.5T) 300 ms (3.0T) 90 degrees N/A ≤ 4 mm Variable; complete bilateral coverage ≤ 1.0 mm ≤2 ≤2 N/A N/A ≥ 256 ≤ 1.4 mm Active fat-sat recommended 4-10 ms 1.3 or 4.2 ms fat/water inphase N/A N/A 90 degrees 0, 800 s/mm2 5 mm Variable; complete bilateral coverage No gap 2 5 10-20 degrees N/A ≤ 2.5 mm ≥ 60; complete bilateral coverage No gap ≤2 ≤2 N/A N/A ≤ 7 minutes ≤ 4 minutes N/A N/A N/A N/A -k to +k standard, non-centric 80 sec ≤ scan time ≤ 100 sec Pre- and Post-contrast, identical parameters ≥ 8 minutes following injection CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 T1-weighted GE 3D Axial Bilateral A/P R/L Page 5 69 01/15/2015 5.0 IMAGE SUBMISSION Participating sites are to submit all mammography and MR imaging to the ACRIN Imaging Core Laboratory. Images should be submitted as soon as possible (within 1-‐2 business days) after acquisition. It is important to note that all imaging must be provided in DICOM format. Please contact ACRIN with any questions regarding the image submission process. 5.1 Submission of Study Imaging - TRIADTM Due to the need for quick receipt and turnaround of the MRI exams, TRIADTM is the preferred mode of image submission. Though setting up TRIAD requires some upfront effort, sites typically find the benefits of TRIAD outweigh the initial set-up effort. Benefits of TRIAD include: • • • • • Elimination of costs associated with burning and express shipping CD/DVDs Reduced effort associated with burning and express shipping CD/DVDs Reduced risk of protocol deviations associated with delayed image submission Reduced risk of accidental release of protected health information (PHI) Reduced risk of protocol deviations associated with ‘over-anonymization’ of image set TRIAD is a standards-based system developed by the American College of Radiology (ACR) to provide a secure web-based method of transferring and managing image data. The TRIAD software will be provided free of charge and can be installed on one or more computers of choice within the institutional network. The TRIAD application can then be configured as a DICOM destination on the scanner(s) and/or PACS for direct network transfer of the study imaging. The TRIAD software anonymizes, encrypts, and performs a lossless compression of the images before they are transferred to the ACRIN image archive in Philadelphia. 5.1.1 Current TRIAD Users TRIAD user permissions are trial-specific. To submit images to the CALGB 40903 image archive, current users of TRIAD need to contact TRIAD support to have the CALGB 40903 study (TRIAD study #4510) added to their permissions profile. 5.1.2 TRIAD Installation Sites without TRIAD will need to communicate with their IT department for assistance with the initial steps outlined in the TRIAD Pre-Study Worksheet (provided with this manual) prior to scheduling TRIAD installation. The TRIAD Installation Guide and TRIAD Users Guide can be found at https://triad.acr.org/Learning.htm. To contact TRIAD Support call 215-940-8820 or email [email protected]. 5.1.3 De-identification As part of the image submission process, sites will identify the patient by entering the patient’s CALGB research ID (subject ID or case number). TRIAD will then remove or replace specific protected health information (PHI), such as patient name and medical record number, and re-identify the image set with the research ID provided by the site. Sites are asked not to de-identify imaging exams prior to uploading the image sets to TRIAD as many anonymization applications are not designed specifically for research purposes and, in addition to removing PHI, also remove key scanner and technical data required by researchers. CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 6 70 01/15/2015 Additional information regarding TRIAD, including default and customized anonymization profiles, can be found in the TRIAD Users Guide (https://triad.acr.org/Learning.htm). Please note that image sets with missing data will require resolution and resubmission of the image set. 5.2 Submission of Study Imaging – CD/DVD TRIAD submission of study imaging is strongly recommended, however, in some cases study imaging may be sent via CD/DVD but should first be approved by the ACRIN Imaging Core Laboratory; this will be determined on a site-‐by-‐site basis. Each CD/DVD should contain only one exam and the jacket should be labeled with the study ID (CALGB 40903), NCI site ID, CALGB patient ID, and exam time point (e.g. MRI-‐1 or Mammogram-‐2). Do not affix adhesive labels directly to the CD/DVD. Include a printed copy of the submitted ITW and ship to: American College of Radiology 1818 Market St, Suite 1600 Philadelphia, PA 10903 Attn: ACRIN Core Lab, CALGB 40903 5.3 Submission of Test Scans Since test scans will be acquired using volunteers or clinical patients, all PHI must be removed from the image set (being careful not to remove site identifiers or technical data) prior to saving the images to CD/DVD and shipping to ACRIN. Each CD/DVD should contain only one exam; the jacket should be labeled as Test Scans and include the study ID (CALGB 40903) and NCI site ID. Do not affix adhesive labels directly to the CD/DVD. Ship to ACRIN at the address provided above in Section 5.2. 5.3 Image Transmittal Worksheet (ITW) A CALGB 40903 ITW (provided with this manual) must be submitted for each exam at the time of image submission. The ITW should be completed in full and submitted via email to [email protected] or uploaded to TRIAD with the imaging exam. 6.0 QUALITY CONTROL (QC) Sites are expected to acquire the MRI exams per the standardized MR acquisition protocol and review all imaging for image quality and protocol compliance. Upon receipt of the images at ACRIN, an initial QC review will be conducted by a qualified ACRIN Imaging Technologist. The ACRIN technologist will check for missing images/sequences, appropriate image anonymization, complete anatomical coverage of the breast parenchyma, and absence of image artifact. Missing or discrepant image data will be communicated to the site and the CALGB coordinating center. All MRI exams will undergo an additional review, including compliance with the standardized acquisition protocol, as part of the central review conducted by the UCSF Breast MRI Research Laboratory. Information regarding the central review process is provided in Section 7.3 of the clinical trial protocol. CALGB 40903 Site Imaging Manual, Version 3.0 Version Date: 12/15/14 Page 7 71 01/15/2015
