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Kara J. Milliron, MS, CGC Certified Genetic Counselor Breast and Ovarian Cancer Risk Evaluation Program University of Michigan Comprehensive Cancer Center These slides are the property of the presenter. Do not duplicate without express written consent. I am a contract genetic counselor with Informed Medical Decisions, Inc. These slides are the property of the presenter. Do not duplicate without express written consent. Introduction to breast cancer pathology Triple negative breast cancer (TNBC) TNBC and BRCA1/2 BRCA1/2 genetic testing and the NCCN guidelines Cases Other genetic causes of TNBC These slides are the property of the presenter. Do not duplicate without express written consent. Breast profile: A Ducts B Lobules C Dilated section of duct to hold milk Invasive lobular 10% D Nipple Invasive ductal 80% E Fat F Pectoralis major muscle G Chest wall/rib cage Enlargement A Normal duct cells B Basement membrane C Lumen (center of duct) These slides are the property of the presenter. Do not duplicate without express written consent. Modified Bloom Richardson Grade Scored Based Grade on three characteristics o Degree of tubule formation o Nuclear pleomorphism o Mitotic activity on a scale 1-3 I Grade II Grade III These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. 1985: Her2neu discovered by 2 independent labs 1987: Her2neu amplification shown to be a poor prognostic factor in breast cancer 1998: Addition of trastuzumab proven beneficial in Her2neu + metastatic patients These slides are the property of the presenter. Do not duplicate without express written consent. ER negative 15% of all invasive breast cancers Risk Factors o dx <50 years PR negative o A. American ancestry o High BMI o Young age menarche o High parity Her2Neu negative o Young age of FLB o Lack of breast feeding These slides are the property of the presenter. Do not duplicate without express written consent. Ductal NOS o Poorly differentiated o High nuclear grade o Highly proliferative Rare histological subtypes Medullary Good Prognosis Adenoid cystic Metaplastic Poor Prognosis These slides are the property of the presenter. Do not duplicate without express written consent. Estimated New Female Breast Cancer Cases by Age, US, 2011* Age In Situ Cases Invasive Cases Est. TNBC (total) cases (~15%) < 40 1,780 11,330 1700 < 50 14,240 50,430 7564 50-64 23,360 81,970 12,296 65+ 20,050 98,080 14,712 All ages 57,650 230,480 36,272 *Rounded to the nearest 10. Source: Total estimated cases are based on 1995-2007 incidence rates from 46 states as reported by the North American Association for Central Cancer Registries. Total estimated deaths are based on data from US Mortality Data, 1969-2007, National Center for Health Statistics, Centers for Disease Control and Prevention. American Cancer Society, Surveillance Research, 2011 These slides are the property of the presenter. Do not duplicate without express written consent. ACT dose dense fashion most common TC every 3 weeks can be utilized in some patients Platinum agents have recently emerged as drugs of interest o One trial that treated 28 women with stage II or stage III TNBC with four o o o o cycles of neoadjuvant cisplatin resulted in a 22% pCR rate CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and adriamycin plus cyclophosphamide chemotherapy in the neoadjuvant setting. Triple Negative Trial (NCT00532727), is evaluating carboplatin against docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC. Currently, there is no established role for adding platinum agents to the treatment of early-stage TNBC outside of a clinical trial. These slides are the property of the presenter. Do not duplicate without express written consent. African American Non-African American Pre-menopausal 39% 16% Post-menopausal 14% 16% Carolina Breast Cancer Study JAMA 2006 These slides are the property of the presenter. Do not duplicate without express written consent. Bassett Coates Gordon Ansell Neale Eley Perkins Simon (>49 yo) Simon (<50 yo) Franzini Howard Wojcik Yood El Tamer Roetzheim Albain Premen Albain Postmen Polednak Bradley Jatoi 1995-99 Crowe Combined .1 .5 1 mortality hazard 5 AA Mortality Risk: 1.28 (95% CI 1.18-1.38) (22% excess risk of death) Newman et al, JCO 2006 These slides are the property of the presenter. Do not duplicate without express written consent. 10 Higher Mortality Advanced Stage Distribution Lower lifetime incidence Younger age distribution Increased risk of adverse tumor factors Higher incidence of male breast cancer Socioeconomic disparities Delivery of Care Tumor biology Genetics Lifestyle & Reproductive Experiences Environmental exposures Diet/Nutrition These slides are the property of the presenter. Do not duplicate without express written consent. 60% of breast cancers in Ghanian women are TNBC Location of many of the slave colonies several hundred years ago These slides are the property of the presenter. Do not duplicate without express written consent. Parallels between hereditary breast cancer (BRCA1/2) and breast cancer in individuals with African ancestry o younger age distribution o increased prevalence of ER-neg, aneuploid tumors o higher risk of male breast cancer Is African ancestry associated with a heritable marker for high-risk breast cancer subtypes? These slides are the property of the presenter. Do not duplicate without express written consent. How Much Breast and Ovarian Cancer is Hereditary? These slides are the property of the presenter. Do not duplicate without express written consent. Causes of Hereditary Breast and Ovarian Cancer Syndrome These slides are the property of the presenter. Do not duplicate without express written consent. BRCA1 BRCA2 Year cloned 1994 1995 Chromosome location 17q21 13q12 5.6 kb/22 exons 10.2 kb/26 exons # of amino acids 1, 863 3, 418 # of mutations reported >1, 230 >1,380 Genomic DNA/coding exons Inheritance pattern Autosomal Dominant Autosomal Dominant These slides are the property of the presenter. Do not duplicate without express written consent. Breast cancer to age 80 Ovarian Male BRCA2 50-85% 50-85% cancer to age 80 20-60% breast cancer Prostate BRCA1 cancer Pancreatic Melanoma cancer up to 27% ~1% ~6% Slight ↑ Slight ↑ Slight ↑ 1.5-5% Slight ↑ Slight ↑ These slides are the property of the presenter. Do not duplicate without express written consent. Breast cancers in BRCA1 carriers80% Triple negative Breast cancer in BRCA2 carriers20% Triple negative o Mutation Carrier frequency in general population 1/300-1/800 o Mutation Carrier frequency in A. Jewish population 1/40 These slides are the property of the presenter. Do not duplicate without express written consent. Gonzalez-Angula CCR 2011 o 77 unselected TNBC o 15% incidence of BRCA1 mutation (one somatic) (12) o 3.9% incidence of BRCA2 mutation (3) o 9/14 had no first degree family history of cancer o However, 22/77 or (30%), DID have a family history of breast and ovarian cancer o In addition 12/77 (16%) HAD a first degree relative with breast cancer o 6/14 found to be BRCA carriers had not been referred to genetic counseling These slides are the property of the presenter. Do not duplicate without express written consent. Diagnosed age < 60 y with a TNBC These slides are the property of the presenter. Do not duplicate without express written consent. Estimated New Female Breast Cancer Cases by Age, US, 2011* Age In Situ Cases Invasive Cases Est. TNBC (total) cases (~15%) < 40 1,780 11,330 1700 < 50 14,240 50,430 7564 50-64 23,360 81,970 12,296 65+ 20,050 98,080 All ages 57,650 230,480 *Rounded to the nearest 10. 21,560 potential patients tested for BRCA1/2 from these cases alone Healthcare cost 14,712 for testing $4000 X 21,560 36,272 = $86,240, 000.00 ~$107,800 to find 1 BRCA1/2 positive individual Source: Total estimated cases are based on 1995-2007 incidence rates from 46 states as reported by the North American Association for Central Cancer Registries. Total estimated deaths are based on data from US Mortality Data, 1969-2007, National Center for Health Statistics, Centers for Disease Control and Prevention. American Cancer Society, Surveillance Research, 2011 These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. 46 year old G1P1 Filipino female s/p L lumpectomy o 1.8 cm invasive ductal carcinoma o Triple negative o 0/3 SLN Menarche: 11 FLB: 23 These slides are the property of the presenter. Do not duplicate without express written consent. s/p 4 cycles AC s/p 2 cycles T Carries BRCA2 mutation R3052W Recorded 8 times in the BIC located in exon 24 of BRCA2 Bilateral mastectomy with reconstruction is scheduled for the near future Plans on BSO, scheduled with Dr. Pearlman to further discuss options Scheduled with Dr. El Munzer to discuss risks, benefits, and limitations of pancreatic cancer screening These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. 51 year old G4P3SAB1 Caucasian female s/p R lumpectomy o 2 foci 0.3 cm and 0.7 cm invasive ductal carcinoma o Triple negative o 0/1 SLN s/p 3 cycles AC s/p 1 cycle of Taxol, developed toxicity s/p 15 weeks of weekly Taxotere s/p radiotherapy These slides are the property of the presenter. Do not duplicate without express written consent. Patient is adopted with some knowledge about family history BRCA1/2 genetic testing-no mutation detected Based on negative test results, not felt to be at increased risk for ovarian cancer These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. 59 year old G0 Chinese female s/p Left breast biopsy Discrepancy in size of tumor via imaging—u/s 1.5 cm vs MRI 3 cm No definitive cancer surgery Lymph nodes not sampled Triple negative Due to NCCN guidelines, requested BRCA1/2 genetic testing These slides are the property of the presenter. Do not duplicate without express written consent. BRCA1/2 genetic testing revealed a variant of uncertain significance (VUS) BRCA1 G1157R 1st reported observation of this VUS These slides are the property of the presenter. Do not duplicate without express written consent. dx 60's Colon c a nc e r d. Alzheimer' s ~ 75 dx 50's d. Colon c ance r 60 d. 65 CO PD ? Lung c a nc e r Use d toba cc o 69 s/p TAH/ BSO d. 50's MI 73 d. 53 MI d. 75 ? Ane ury sm/ CVA/MI d. 70 Lung c a nc e r Use d toba cc o 3 41 dx 41 4 49 44 50's 50's 50's dx 41 DC IS d. 40's Choke d MR 6 20 These slides are the property of the presenter. Do not duplicate without express written consent. 30 41 year old G2P2 Caucasian female s/p 4 cycles AC, and 3 cycles T (neo-adjuvant) R breast cancer 2.1 X 2.4 X 2.6 cm via U/S Triple negative 0/8 SLN These slides are the property of the presenter. Do not duplicate without express written consent. Patient was found to have BRCA2 VUS N1910S 1st observation These slides are the property of the presenter. Do not duplicate without express written consent. Genetic counseling-what do they mean to the patient? Does everyone agree on the interpretation? Inconsistency between DNA diagnostic laboratories and between countries on interpretation and reporting of variants In US-Myriad Genetic Laboratories alone reports and interprets These slides are the property of the presenter. Do not duplicate without express written consent. BRCA1/2 o ~ 7% of overall test results o ~ 15% of test results if of African American descent o Most seen < 3 times Few are likely to be associated with a high risk of disease BUT knowing which ones is difficult to ascertain These slides are the property of the presenter. Do not duplicate without express written consent. Unfortunately, since these were the first observation of these VUS, and there is no family history of cancer, additional investigation at this time is not helpful. Due to rarity of VUS, follow HBOC guidelines BSO to be considered by both patients in the near future once they have completed breast cancer treatment These slides are the property of the presenter. Do not duplicate without express written consent. Another Cause of TNBC These slides are the property of the presenter. Do not duplicate without express written consent. Autosomal recessive (i.e. 2 PALB2 mutations) Characterized by: o Thumb deformity o Kidney malformation o Small stature o Developmental delay o Microcephaly o Bone marrow failure These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. PALB2 is a low penetrence breast cancer susceptibility gene Encodes a BRCA2 interacting protein Rahman et al. 2007 o Found monoallelic truncating mutations in 10/923 (1%) familial breast cancer families and 0/1084 (0%)controls These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. These slides are the property of the presenter. Do not duplicate without express written consent. Carriers are at a 2-3 fold increased risk of developing breast cancer May confer a higher RR for male breast cancer vs. female breast cancer Ovarian cancer risk not studied Clinical management for unaffected individuals is based on family history These slides are the property of the presenter. Do not duplicate without express written consent. Heikkinen et al CCR 2009 2% (19/947) of familial breast cancer patients in S. Finland had mutations Tumors of the PALB2 mutation carriers were more often o triple negative o basal-like subtype o higher expression of Ki67 o lower expression of cyclin D1 Increased risk for pancreatic cancer These slides are the property of the presenter. Do not duplicate without express written consent. Is becoming more complex o age is only a number We are testing based on cancer pathology (i.e. TNBC) We may need to test for multiple genes This will impact o Integration of genetic testing into diagnostic and treatment flow o Multiple genes tested (will insurers pay?) o ? increase the uptake of bilateral mastectomy (patients not wanting to wait for all information before making a surgical decision) These slides are the property of the presenter. Do not duplicate without express written consent. Cancer risk management for those with inherited susceptibility is a challenging and dynamic process Consistent protocols for counseling/help manage/recontact these high risk patients How to Contact us Clinic coordinator: Kara J. Milliron, MS, CGC 734.764.0107 or 734.936.6266 pager number 8881 These slides are the property of the presenter. Do not duplicate without express written consent. Sofia D.Merajver, MD, PhD Celina Kleer, MD Mark D. Pearlman, MD Kathleen Diehl, MD Breast Care Center Hematology/Oncology Surgical Oncology Radiation Oncology Gynecology Oncology Clinic Radiology Obstetrics and Gynecology Primary Care Clinics These slides are the property of the presenter. Do not duplicate without express written consent. Genes: The Link to Our Past—The Bridge to Our Future: These slides are the property of the presenter. Do not duplicate without express written consent.
