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1 Kara J. Milliron, MS, CGC Certified Genetic Counselor Breast and Ovarian Cancer Risk Evaluation Program University of Michigan Comprehensive Cancer Center

2 I am a contract genetic counselor with Informed Medical Decisions, Inc.

3 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

4 Breast profile: A Ducts B Lobules C Dilated section of duct Invasive lobular 10% to hold milk 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)

5 Modified Bloom Richardson Grade Scored on a scale 1-3 Based on three characteristics o Degree of tubule formation o Nuclear pleomorphism o Mitotic activity Grade I Grade II Grade III

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7 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

8 ER negative PR negative Her2Neu negative 15% of all invasive breast cancers Risk Factors o dx <50 years o A. American ancestry o High BMI o Young age menarche o High parity o Young age of FLB o Lack of breast feeding

9 Ductal NOS o Poorly differentiated o High nuclear grade o Highly proliferative Rare histological subtypes Medullary Adenoid cystic Metaplastic Good Prognosis Poor Prognosis

10 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, < 50 14,240 50, ,360 81,970 12, ,050 98,080 14,712 All ages 57, ,480 36,272 *Rounded to the nearest 10. Source: Total estimated cases are based on 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, , National Center for Health Statistics, Centers for Disease Control and Prevention. American Cancer Society, Surveillance Research, 2011

11 AC T 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 o o o o One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pcr rate CALGB (NCT ), evaluated the benefit of carboplatin added to paclitaxel and adriamycin plus cyclophosphamide chemotherapy in the neoadjuvant setting. Triple Negative Trial (NCT ), 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.

12 African American Non-African American Pre-menopausal 39% 16% Post-menopausal 14% 16% Carolina Breast Cancer Study JAMA 2006

13 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 Crowe Combined mortality hazard AA Mortality Risk: 1.28 (95% CI ) (22% excess risk of death) Newman et al, JCO 2006

14 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

15 60% of breast cancers in Ghanian women are TNBC Location of many of the slave colonies several hundred years ago

16 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?

17 How Much Breast and Ovarian Cancer is Hereditary?

18 Causes of Hereditary Breast and Ovarian Cancer Syndrome

19 BRCA1 BRCA2 Year cloned Chromosome location Genomic DNA/coding exons 17q21 13q kb/22 exons 10.2 kb/26 exons # of amino acids 1, 863 3, 418 # of mutations reported >1, 230 >1,380 Inheritance pattern Autosomal Dominant Autosomal Dominant

20 BRCA1 BRCA2 Breast cancer to age % 50-85% Ovarian cancer to age % up to 27% Male breast cancer ~1% ~6% Prostate cancer Slight Slight Pancreatic cancer Slight 1.5-5% Melanoma Slight Slight

21 Breast cancers in BRCA1 carriers 80% Triple negative Breast cancer in BRCA2 carriers 20% Triple negative o Mutation Carrier frequency in general population 1/300-1/800 o Mutation Carrier frequency in A. Jewish population 1/40

22 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

23 Diagnosed age < 60 y with a TNBC

24 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, < 50 14,240 50, ,360 81,970 12, ,050 98,080 14,712 All ages 57, ,480 36,272 *Rounded to the nearest ,560 potential patients tested for BRCA1/2 from these cases alone Healthcare cost for testing $4000 X 21,560 = $86,240, ~$107,800 to find 1 BRCA1/2 positive individual Source: Total estimated cases are based on 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, , National Center for Health Statistics, Centers for Disease Control and Prevention. American Cancer Society, Surveillance Research, 2011

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27 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

28 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

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30 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

31 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

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33 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

34 BRCA1/2 genetic testing revealed a variant of uncertain significance (VUS) BRCA1 G1157R 1 st reported observation of this VUS

35 dx 60's Colon cancer d. Alzheimer' s dx 50's d. Colon cancer d. 50's MI ~ d. 65 CO PD? Lung s/p TAH/ BSO cancer Used tobacco 73 d. 53 MI d. 75? Ane ury sm/ CVA/MI d. 70 Lung cancer Used tobacco 3 41 dx 's dx 41 DCIS d. 40's Choked MR 50's 50's

36 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

37 Patient was found to have BRCA2 VUS N1910S 1 st observation

38 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

39 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

40 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

41 Another Cause of TNBC

42 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

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44 PALB2 is a low penetrence breast cancer susceptibility gene Encodes a BRCA2 interacting protein Rahman et al o Found monoallelic truncating mutations in 10/923 (1%) familial breast cancer families and 0/1084 (0%)controls

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47 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

48 Heikkinen et al CCR % (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

49 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)

50 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 or pager number 8881

51 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

52 Genes: The Link to Our Past The Bridge to Our Future: