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Medical therapy: what is new, what is useful. toward a personalized treatment Prof. Francesco Cognetti Regina Elena National Cancer Institute Rome, Italy Breast Cancer: From Epidemiology to Treatment Tunis, November 14th, 2008 Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths, by Sex, United States, 2008 From Jemal, A. et al. CA Cancer J Clin 2008;58:71-96. Copyright ©2008 American Cancer Society Cancer Mortality Rates over the Past 50 Years EBCTCG, Lancet 2005 Five Year Relative Survival Rates for Breast Cancer: 1973 - 2005 Localized Regional Distant 1973 85 53 <10 2002 98 83 26 Cancer survivors increased from 3 M to 9 M in the same period CA, Jan 1973 and Jan 2007 Relative and absolute risk reduction Intervention produces a 35% relative risk reduction Initial risk Initial risk Final risk Final risk 65% 42% 20% 13% Node-negative Difference: 7% Node-positive 23% Factors Influencing Selection of Systemic Therapy for Primary Breast Cancer Risk of recurrence Or death Benefit from treatment Optimal Treatment selection Comorbidities Toxicities Tumor characteristics: ER, PR, HER-2 Adjuvant! • Validated computer-based model – Estimates 10-year DFS and OS[1-3] • Used to estimate individual risk for breast cancer recurrence – Began development 15 years ago – Can be used for other malignancies • Prognostic estimates based on – Nodal involvement, Tumor size – Histological grade – ER, PgR, and HER2 receptor status – Options Include additional information • Efficacy estimates based on – Type of adjuvant therapy – Age, ER status, Her2 status (only for trastuzumab) 1. Ravdin PM, et al. J Clin Oncol. 2001;19:980-991. 2. Olivotto IA, et al. J Clin Oncol. 2005;23:2716-2725. 3. http://www.adjuvantonline.com. Adjuvant! Background • San Antonio tumor bank originally designed to help physicians assess patient prognosis • Evidence-based estimates of benefit for diverse adjuvant treatment options • 2 major changes since 1998 – Use of more complete data from SEER database – Addition of more current adjuvant therapies • Provides baseline prognostic estimate of recurrence with adjuvant therapy – Applies data from meta-analyses and individual trials to estimate net benefit • More than 50,000 users; applied to > 100,000 cases/year http://www.adjuvantonline.com. Adjuvant! Validation 90 Adjuvant! Online Breast Cancer Outcomes Unit database 80 Percentage • Validated using the BCCA’s Breast Cancer Outcomes Unit database – Outcome estimates made in a blinded fashion – Estimates to the BCCA actual patient outcomes • Results statistically similar 70 60 50 40 30 20 10-Yr OS Olivotto IA, et al. J Clin Oncol. 2005;23:2716-2725. 10-Yr BCSS 10-Yr EFS HER2 and Adjuvant! • Benefit estimates for use of trastuzumab available in Adjuvant! Version 9.0 (not yet available) – HER2 included as a variable • HER2 expression prognostic for breast cancer – Modest independent relative risk of 1.5 • Trastuzumab now included as adjuvant therapy option – Projections of benefit for trastuzumab only for 3 years because of short follow-up on current trials Slamon DJ, et al. N Engl J Med. 2001;344:783-792. Gene expression array-identified subtypes of Breast Cancer Unsupervised Hierarchical Clustering of Primary Breast Cancers Perou et al. Nature 2000;406:747-52. PERSONALIZED MOLECULAR MEDICINE BREAST CANCER LUMINAL Hormonal Manipulation HER2 Trastuzumab Lapatinib BASAL Chemotherapy Rich Neve Breast Cancer Subtypes according to race and menopausal status Carey LA et al, JAMA 2006 Breast Cancer Specific Survival by Subtype in the Carolina Breast Cancer Study (n=496) Carey LA, et al. JAMA 295:2492-502, 2006 Management of ER+/HER2Breast Cancer Choice of Modalities Highly Incompletely Endocrine Endocrine Responsive Responsive Her2 neg ET ET (consider adding CT according to risk) (consider adding CT according to risk) Endocrine NonResponsive CT Inhibition of Estrogen-Dependent Growth Antiestrogens Estrogen biosynthesis Nucleus Estrogen biosynthesis Aromatase inhibitors Tumor cell Inhibition of cell proliferation Endocrine Treatment Schema Adjuvant or First-line Therapy Premenopausal Postmenopausal SERM Aromatase Inhibitor or SERM Recurrent Disease Ovarian Ablation Aromatase Inhibitor or Antiestrogen Third-line Therapy Aromatase Inhibitor (only following ablation of ovarian function) Progestins or SERD Fourth-line Therapy Progestin / Androgens Androgens Second-line Therapy Comparative Efficacy of Adjuvant Hormonal Therapies Therapies % Reduction in Annual Odds of Recurrence Death 50 P<0.00001 33 P<0.00001 Anastrozole vs. Tamoxifen (ATAC) 22 P=0.007 12 P=0.2 Letrozole + Tamoxifen vs. Tamoxifen (BIG98, MA-17) 19-43 P=0.003-0.00008 14-24 P=0.25->0.05 Anastrozole + Tamoxifen vs. Tamoxifen (ITA) 64 P=0.006 82 P=0.07 Exemestane + Tamoxifen vs. Tamoxifen (IES) 26 P<0.0001 17 P=0.04 Tamoxifen vs. no Tamoxifen (5 years) Adjuvant Hormonal Therapy for Premenopausal Women with ER-Positive Breast Cancer • LHRHa appears equivalent to adjuvant CMF for ER+ breast cancer. • Is LHRHa + tamoxifen better than each component? • Should LHRHa be added to best chemotherapy + tamoxifen? • Or only to those who remain premenopausal after chemotherapy? Effect of Combined Adjuvant Hormone and Chemotherapy for Primary Breast Cancer Patient Group <50 Years of Age CT vs CT + T(5) Annual Reduction in Odds of (% + SD) Recurrence Death 40 + 19 39 + 22 T vs T + CT 21 + 13 25 + 14 CT vs CT + Ov 10 + 9 8 + 10 54 + 8 49 + 10 19 + 3 11 + 4 > 50 Years of Age CT vs CT + T(5) T vs T + CT EBCTCG 1996 & 1998 Management of HER2+ Breast Cancer Choice of Modalities Highly Incompletely Endocrine Endocrine Endocrine NonResponsive Responsive Responsive Her2 pos ET + ET + CT + Tratuzumab Trastuzumab Trastuzumab + CT + CT HER2+ tumors treatment selection • Chemotherapy – Anthra vs non-Anthra regimens – Low risk/endocrine-responsive tumors • Endocrine therapy – Tam vs aromatase inhibitors • Trastuzumab – Concomitant vs sequential – Duration HER2 and Responsiveness of Breast Cancer to Adjuvant Chemotherapy Overall Survival According to the Type of Adjuvant Chemotherapy in Women with HER2 Amplification on FISH Overall Survival According to the Type of Adjuvant Chemotherapy in Women without HER2 Amplification on FISH Pritchard KI, et al. N Engl J Med 2006;354:2103-11 HER-2 as a Surrogate Marker of Anthracycline Efficacy HER-2 amplified Di Leo et al. Clin Cancer Res 2003; 8:1107-16 Benefit from Anthracyclines by HER2 Status - Disease-Free Survival Study HR 95% CI NSABP B11 0.60 0.96 0.44-0.82 0.75-1.23 NSABP B15 0.84 1.02 0.65-1.08 0.86-1.20 Belgian 0.65 1.35 0.34-1.27 0.93-1.97 Milan 0.83 1.22 0.46-1.49 0.91-1.64 Danish 0.75 0.79 0.53-1.06 0.60-1.05 NCIC MA.5 0.52 0.91 0.34-0.80 0.71-1.18 Overall 0.90 0.82-0.98 HER2 specific 0.71 1.00 0.61-0.83 0.90-1.11 Heterogeneity 25=5.3, p=.38 Heterogeneity 25=7.6, p=.18 Anthracycline Better Nonanthracycline Better p=.01 0.4 0.6 0.9 1 HER2+ HER22 Test for interaction 2=13.2, p<.001 Gennari A, et al. Presented at: 29th Annual SABCS; Dec 14-17, 2006; San Antonio, Tex. 5 Benefit from Anthracyclines by HER2 Status - Overall Survival Study HR 95% CI NSABP B11 0.66 0.90 0.47-0.92 0.69-1.19 NSABP B15 0.82 1.07 0.63-1.06 0.89-1.28 GUN 3 0.85 1.64 0.27-2.71 0.85-3.14 Milan 0.61 1.26 0.32-1.16 0.89-1.79 Danish 0.73 0.82 0.50-1.05 0.59-1.13 NCIC MA.5 0.65 1.06 0.42-1.02 0.83-1.44 Overall 0.91 0.83-1.00 HER2 specific 0.73 1.03 0.62-0.85 0.92-1.16 Heterogeneity 25=5.2, p=.39 Heterogeneity 25=5.5, p=.36 Anthracycline Better Nonanthracycline Better p=.056 0.4 0.6 0.9 1 Test for interaction 2=12.2, p<.001 HER2+ HER22 Gennari A, et al. Presented at: 29th Annual SABCS; Dec 14-17, 2006; San Antonio, Tex. 5 Trastuzumab in early breast cancer: studies designs of the adjuvant trials Baselga at al., The Oncologist, 2006 Similarities in patient characteristics from adjuvant trials • The median age of patients in all trials was virtually identical (49 years) • 40% of patients in all of the trials had T1 tumors • The percentage of patients with hormone receptor-positive tumors was approximately 50% Differences in patient characteristics from adjuvant trials • Node negative disease (29% in BCIRC, 32 % in HERA, 6%in the joint analysis of B31 and N9831) • Only in HERA trial random assignment occurred after completion of adjuvant chemotherapy and radiation • The central confirmation of tumor HER2 positivity was required only in HERA and BCIRG trials Trastuzumab Adjuvant Trials: Efficacy Results Trial and arm N° pts N° events 3-year DFS (%) HR 95% CI AC-TH 1.672 133 87 0.48 0.39-0.59 AC-T 1.679 261 75 AC-DH 1.074 128 87 0.61 0.48-0.76 DCarboH 1.075 142 86 0.67 0.54-0.83 AC-D 1.073 192 81 H 1.703 218 81 0.64 0.54-0.76 Control 1.698 321 74 CT+H 115 12 89 0.42 0.21-0.83 CT alone 116 27 78 B31/N9831 BCIRG 006 HERA FinHer Summary of Trastuzumab efficacy in early breast cancer: Disease free-survival a. Recurrence-free survival Baselga at al., The Oncologist, 2006 Open Questions • Cardiotoxicity • Treatment duration • Concomitant or sequential • Timing of Hormonotherapy • Role of lapatinib in the adjuvant setting Management of TripleNegative Breast Cancer Basal-like Breast Cancer • 10-20% of tumors HER2 Basal • Low HER2 expression • Low ER (and related genes) • Common in BRCA1 carriers Luminal • 50% are p53 mutant Proliferation • Very proliferative Basal-like Breast Cancer Frequent, early relapses N= 311 p < 0.0000001 Triple-negative breast cancers • Respond well to “standard chemotherapy” but relapse early and with greater frequency • Most BRCA1-mutated breast cancers belong to this group; they represent 20%-25% of triple negatives. • Many triple-negative BC have mutated p53 • Many triple-negative breast cancers (especially the pure squamous tumors) have EGFR overexpression EGFR-directed Therapy for TripleNegative Breast Cancer • Cetuximab alone has negligible activity • Gefitinib and Erlotinib alone have marginal activity • The activity of platinum salts is currently under evaluation, usually in combination of chemotherapy or EGFR-directed therapy • The state-of-the-art remains anthracyclines + taxanes, although taxane + platinum combinations are used by some Treatment by Molecular Class Class Treatment Additional Therapies ± chemotherapy ER and/or PRexpressors Aromatase inhibitors SERMs HER2-amplified Trastuzumab, lapatinib ± chemotherapy, hormone therapy Triple-negative (ER, PR, HER2) Chemotherapy (Platinum salts [?]) ± bevacizumab Basaloid EGFR-inhibitors (?) Platinum salts (?) Courtesy of Hortobagyi GN OUR STUDIES IN EARLY BREAST CANCER SEQUENTIAL EPIRUBICIN-DOCETAXEL-CMF AS ADJUVANT THERAPY FOR NODE-POSITIVE EARLY STAGE BREAST CANCER: UPDATED RESULTS OF THE TAXit216 RANDOMIZED TRIAL F. Cognetti, M. De Laurentiis, A. De Matteis, L. Manzione, C. Boni, S. Palazzo, M. Di Palma, P. Papaldo, S. De Placido, A.R. Bianco On Behalf of the Taxit 216 Investigators PRESENTED AT ESMO MEETING, SEPTEMBER 2008 TAXit 216 Original Study Design Epi N+ Pre/Post 65 yrs Epi CMF TXT CMF n=997 ddEpi ddEpi: Epirubicin 120 mg/m2 d1 q14 ddTXT: Docetaxel 100 mg/m2 d1 q14 hd-CTX: Cyclophosphamide 3000 mg/m2 q21 ddTXT hd-CTX Feasibility Arm: closed after 25 pts Objectives • Primary objective: – Disease-Free Survival (DFS), defined as time to BC recurrence, contralateral BC, second non-BC malignancy, or death • Secondary objectives – Overall Survival (OS) – Safety – Recurrence-free survival (RFS), defined as DFS but excluding contralateral cancer and non-breast second malignancy – Subgroup analysis according to: – – – – age (≤50 vs >50) menopausal status ER status (positive vs negative) nodal status (N1-3 vs N4+) Disease Free Survival E→T→CMF E→CMF HR= 0.82 (95%CI: 0.64–1.03; P=0.1337) P=0.1337) Relapse Free Survival E→T→CMF E→CMF ||| |||||| | |||||||||| | | | | || ||| |||| | | | ||| | || | E→T→CMF | || ||| | || ||| ||| ||| | || | |||||| || ||| ||| | | | ||| |||||||||| ||||||||||||| || | ||||| | |||||||| || | |||||||||||||| ||||||||| | |||| || ||||||||||| |||| |||| ||||||||||||| || ||||||| |||||| |||||||||||| | |||||| | ||||||||| |||||||||||| ||||| |||||||| ||| |||| || | ||||| || ||||||| ||| | || | | | | | 0.8 E→CMF 0.7 Probability of survival 0.9 1.0 Overall Survival | |||| | || 0.6 |||| || || 0.5 HR=0.67( 95%CI: 0.48–0.94; P=0.0168). months 0 12 24 36 48 60 72 84 96 E-CMF E-T-CMF 486 0 458 438 406 370 247 81 21 3 486 458 436 403 377 256 87 20 2 Subgroups analysis DFS Arm B better Arm A better RFS OS Arm B better Arm A better Arm ArmBBbetter better Arm ArmAAbetter better Age,y ≤<5050 >> 5050 Menopausal status Pre Post ER Negative Positive Unknown Nodes 1-3 >4 All 0.30 0.50 0.83 1.00 1.40 2.00 0.30 0.50 0.77 1.00 1.40 2.00 0.30 0.50 0.67 1.00 1.40 2.00 Conclusions • Incorporating docetaxel into a block-sequential E-CMF regimen was associated with – Improved DFS (HR 0.82; 95%CI 0.64–1.03; P=0.1337) – Significantly improved RFS (HR 0.75; 95%CI 0.59–0.96; P= 0.0394) – Significant improved OS (HR 0.67; 95%CI 0.48–0.94; P=0.0168) • The observed treatment benefit is independent of age, ER status, menopausal status, and nodal status • This advantage comes at the cost of an increased, but manageable toxicity Clinical trials in breast cancer in Italy: the Gruppo Italiano Mammella (GIM) •Intergroup: GONO-GOCSI-GOIRC-GOL •Participating centers: 100 italian centers •Main focus: phase III study in early breast cancer –Chemotherapy –Endocrine therapy –Supportive care A phase III randomized study of sequential Epidoxorubicin plus Cyclophospamide followed by Docetaxel (ECD) versus the combination of 5-Fluorouracil, Epidoxorubicin and Cyclophospamide (FEC) as adjuvant treatment of node-negative early breast cancer patients GIM 1: phase III randomized study EC 90/600 q21 x 4 DOCETAXEL 100 q21 x 4 FEC 600/75/600 q21 x 6 Study objectives and details • Primary objective: to compare Disease Free Survival (DFS) between treatment groups • Secondary objective: to compare Overall Survival (OS) to compare Safety • Start date: 13/11/2003 • Protocol status ongoing • Participating centers: 98 • Total randomized patients: 1289 Protocol GIM 2 A phase III randomized study of EC followed by Paclitaxel versus FEC followed by Paclitaxel, all given either every 3 weeks or 2 weeks supported by Pegfilgrastim, for node positive breast cancer patients • Primary objective: to compare Disease Free Survival (DFS) from adding of 5-Fluorouracil to EC followed by Paclitaxel to compare Disease Free Survival (DFS) of schedule every 2 weeks versus 3 weeks • Secondary objective: to compare Safety GIM-2: study design and objectives ARM A ARM C EC x 4 T x 4 q. 3 w EC x 4 T x 4 q. 2 w + Pegfilgrastim ARM B ARM D FEC x 4 T x 4 q. 3 w FEC x 4 T x 4 q. 2 w + Pegfilgrastim Factorial study aimed at assessing two separate hypothesis: • Factor 1: A+C vs B+D = the efficacy and safety of 5-FU in addition to ECT • Factor 2: A+B vs C+D = the efficacy and safety of a 50% increase in dose-density Study details • • • • Start date: 20/03/2003 Protocol status: closed 03/07/2006 Participating centers: 91 Total randomized patients: 2091 PROTOCOL GIM4 LETROZOLE ADJUVANT THERAPY DURATION STUDY (LEAD): STANDARD VERSUS LONG TREATMENT with AROMATASE INHIBITORS A PHASE III STUDY IN POSTMENOPAUSAL WOMEN WITH EARLY BREAST CANCER Study design Phase III randomized study • Postmenopausal • TAM 2-3 yrs R LETROZOLE 5 YRS LETROZOLE 3-2 YRS Study objectives and details • Primary objective: • Start date: to compare Disease 27/07/05 Free Survival (DFS) between treatment • Protocol status: groups ongoing • Secondary objectives: to compare Overall Survival (OS) to compare Safety • Participating centers: 100 • Total randomized patients: 1508 PROTOCOL GIM-5 CYPLEC STUDY: CYP19 LETROZOLE CORRELATION STUDY Letrozole Extended-Adjuvant Therapy After Tamoxifen Study of Gene CYP19 Correlation with Letrozole Efficacy in Postmenopausal Early Breast Cancer Patients CYPLEC – GIM 5 Multicenter, not comparative, prospective, phase IIIb study of GIM group Postmenopausal Tamoxifen pts 4,5-6 yrs. ER and/or PgR + Registration Letrozole 5 years Total Patients: 2400 during a 3-year period Primary objective: correlation between a Single Nucleotide Polymorphism (SNP) of CYP19 and Disease Free Survival (DFS) Hypothesis: 86% of power to detect a relative reduction of relapse of 46%: 4-yrs DFS for TC genotype = 91% 4-yrs DFS for CC or TT genotype = 95% Study objectives and details • PRIMARY OBJECTIVE • Start date: Correlation DFS - SNP of 27/07/05 CYP19 gene • Protocol status: ongoing • SECONDARY OBJECTIVES • Participating centers: Correlation SNP of CYP19 gene 100 and: 1) letrozole plasma • Total enrolled patients: concentration 478 2) aromatase inhibition by plasma estrone-S 3) OS 4) Safety PROMISE (GIM-6) Prevention of chemotherapy – induced menopause by temporary ovarian suppression with Triptorelin vs control in young breast cancer patients. A randomized phase III multicenter study Randomized phase III study Age <45 yrs Stage I-II-III Candidate for chemotherapy Only CT CT + Triptorelin Study Objectives and details • Primary objective: • – to evaluate efficacy of Triptorelin to prevent • chemotherapy-induced amennorreha • Start date: 29/05/2003 Protocol status: closed Participating Centers: 30 • Total randomized patients: • Secondary objective: 282 – to compare safety of chemotherapy associated to Triptorelin vs only chemotherapy 21-Gene RS Assay 16 cancer and 5 reference genes from 3 studies Proliferation Ki-67 STK15 Survivin Cyclin B1 MYBL2 Estrogen ER PgR Bcl2 SCUBE2 GSTM1 Invasion Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 BAG1 - 0.07 x BAG1 CD68 Reference Beta-actin GAPDH RPLPO GUS TFRC Category RS (0-100) Low risk RS < 18 Int risk High risk RS ≥ 18 and < 31 RS ≥ 31 Paik S, NEJM 351(27):2817, 2004 Recurrence Score as a Continuous Predictor 40% Intermediate Risk Group Distant Recurrence at 10 Years Low Risk Group 35% High Risk Group My RS is 30, What is the chance of recurrence within 10 yrs? 30% 25% 20% 15% 10% 5% 95% CI 0% 0 5 10 15 20 25 30 Recurrence Score 35 40 45 50 Tamoxifen Benefit and 21-Gene RS Assay NSABP B-14 Tamoxifen Benefit Study in N-, ER+ Patients Design Placebo—Eligible N-, ER+ Tamoxifen—Eligible Objective Determine whether the 21-gene RS assay captures • Prognosis • Response to tamoxifen • Both Paik et al SABCS 2005. Abstract 510. NSABP B-14 Results: DRFS—Low, Intermediate, & High RS Groups Risk Group, % Patients 10-Yr Rate Recurrenc e 95% CI 51 22 27 6.8 14.3 30.5 4.0-9.6 8.3-20.3 23.637.4 Low (RS < 18) Intermediate (RS 18-30) High (RS ≥ 31) Test for the 10-year DRFS comparison between the low and high risk groups: P < .00001 Paik S, et al. N Engl J Med. 2004;351:2817-2826. NSABP B-14 Results: DRFS—Low, Intermediate, & High RS Groups (cont’d) DRFS, % 100 90 338 patients 80 149 patients 70 181 patients 60 50 40 30 Low risk (RS < 18) Intermediate risk (RS 18- 30) High risk (RS ≥ 31) 20 10 0 0 2 4 6 8 10 Years 12 14 Paik S, et al. N Engl J Med. 2004;351:2817-2826. Copyright © 2004. Massachusetts Medical Society. All rights reserved. 16 1.0 1.0 0.8 0.8 DRFS DRFS NSABP B-14 Benefit of Tamoxifen By RS Risk Category 0.6 Low Risk (RS < 18) 0.4 N Placebo 171 Tamoxifen 142 0.2 0 0 2 4 6 0.6 Intermediate Risk (RS 18-30) 0.4 N Placebo 85 Tamoxifen 69 0.2 0 8 10 12 14 16 Years 1.0 0 2 4 6 8 10 12 14 16 Years DRFS 0.8 0.6 0.4 0.2 0 Paik S, et al. ASCO 2005. Abstract 510. 0 Permission granted to print. High Risk (RS ≥ 31) N Placebo 99 Tamoxifen 79 2 4 6 8 10 12 14 16 Years Interaction P = .06 Chemotherapy Benefit and 21-Gene RS Assay NSABP B-20 Chemo Benefit Study in N-, ER+ Patients Design Tamoxifen + MF N-, ER+ Tamoxifen + CMF Tamoxifen Objective Determine the magnitude of the chemotherapy benefit as a function of 21-gene RS assay Paik S, et al. ASCO 2005. Abstract 510. Benefit of Chemotherapy Based on RS 10 yr 96% 95% 1.0 Low Risk (RS < 18) 0.6 0.4 Tam + Chemo Tam 0.2 N 218 135 0 2 4 6 Years 8 Events 11 5 P = .76 10 0.8 10 yr 89% 90% 0.6 Intermediate Risk (RS 18-30) 0.4 Tam + Chemo Tam 0.2 0 2 4 0.8 10yr 88% 0.6 60% High Risk (RS≥31) 0.4 0.2 Tam + Chemo Tam N 117 47 0 0 Paik S, et al. ASCO 2005. Abstract 510. Permission granted to print. N 89 45 0 12 1.0 DRFS 0 DRFS DRFS 0.8 1.0 2 4 6 Years 8 Events 13 18 P = .001 10 12 6 Years 8 Events 9 8 P = .71 10 12 ASCO Guidelines “The Oncotype DX tumor marker test is recommended for patients with node-negative breast cancer that is ER positive and/or PgR positive, which is the case for 50 percent of breast cancer patients. The test measures multiple genes at once to estimate the risk of breast cancer recurrence. Patients with a low recurrence score may be able to receive only hormone therapy and avoid chemotherapy. Sparing patients from unnecessary treatment may not only improve their quality of life, but it also will reduce overall health care costs” Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007;25:5287-5312. Oncotype DX™ - TAILORx - Study Design Oncotype DX™ Assay No Minimal Chemotherapy Benefit Group Recurrence Score <11 (~29% of Population) Uncertain Chemotherapy Benefit Group Recurrence Score 11-25 (~44% of Population) Established Chemotherapy Benefit Group Recurrence Score >25 (~27% of Population) Stratify Tumor Size ≤2.0 cm vs. ≥ 2.1 cm Post menopausal vs. Pre-or Peri-menopausal Planned chemotherapy: Taxane-containing (i.e. paclitaxel, docetaxel) vs. Non-taxane-containing Randomize Arm A Hormonal Therapy Arm B Hormonal Therapy Arm C Chemotherapy Plus Hormonal Therapy Arm D Chemotherapy Plus Hormonal Therapy MINDACT Design (Microarray in Node-Negative Disease May Avoid Chemotherapy Trial) Evaluate clinico-pathological risk (Adjuvant!) AND 70-gene signature risk 32% N=3300 55% N=780 Discordant cases Clinical pathological AND 70-gene signature HIGH risk 13% Clinical pathological AND 70-gene signature Clin-Path HIGH risk LOW risk 70-gene LOW risk Clin-Path LOW risk 70-gene HIGH risk n=1920 Use Clin-Path risk to decide on adjuvant chemotherapy or not chemotherapy R Use 70-gene risk to decide on adjuvant chemotherapy or not No chemotherapy All hormone responsive patients receive endocrine therapy Buyse M et al, JNCI 2006 WHAT’S NEW IN METASTATIC BREAST CANCER • HER-2 POSITIVE DISEASELAPATINIB • HER-2 NEGATIVE DISEASEBEVACIZUMAB Geyer C et al. N Engl J Med 2006;355:2733-2743 Geyer C et al. N Engl J Med 2006;355:2733-2743 Geyer C et al. N Engl J Med 2006;355:2733-2743 ECOG 2100 Bevacizumab added to weekly paclitaxel in first line Metastatic Breast Cancer R A N D O M I Z E Paclitaxel + Bevacizumab Paclitaxel 28-day cycle: Paclitaxel 90 mg/m2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15 Miller et al. SABCS 2005 Improved Progression-Free Survival with Bevacizumab Added to Paclitaxel Pac. + Bev. 11.4 months 1.0 Paclitaxel 6.11 months PFS Probability 0.8 0.6 HR = 0.51 (0.43-0.62) 0.4 Log Rank Test p<0.0001 0.2 0.0 0 Miller K, SABCS 05 6 12 18 Months 24 30 484 events reported Bevacizumab in Clinical Subsets Group ER+, PR+ ER+, PRER-, PRNo adj chemo Non-taxane Taxane Age 27 - 49 Age 50 - 64 Age 65 - 85 DFI 0 - 24 mos. DFI > 24 mos. < 3 sites 3 or more sites Overall Miller K, SABCS 05 Ratio 95% Conf Int N 0.39 (0.29, 0.53) 200 80 0.86 (0.52, 1.43) 0.47 (0.35, 0.63) 184 0.60 (0.44, 0.82) 178 0.51 (0.39, 0.67) 234 0.38 (0.25, 0.59) 86 0.45 (0.32, 0.63) 155 0.44 (0.33, 0.58) 232 0.79 (0.53, 1.17) 111 0.57 (0.43, 0.75) 204 0.47 (0.37, 0.60) 294 0.48 (0.37, 0.61) 252 0.54 (0.41, 0.71) 245 0.51 (0.43, 0.62) 680 0.0 0.5 1.0 1.5 HAZARD RATIOS FOR DISEASE PROGRESSION Conclusions • Chemotherapy, endocrine therapy, and targeted therapy improve prognosis in breast cancer • There is a rationale for combination targeted therapies • Evolving technology will lead to better selection of patients and treatments, resulting in enhanced therapeutic ratio and reduced mortality from breast cancer • Cooperation between centers in planning and conducting clinical trials is fundamental in the fight against cancer