Germline Mutations Hereditary Breast and Ovarian Cancer Risk and Management Issues

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1 Germline Mutations Hereditary Breast and Ovarian Cancer Risk and Management Issues Jeffrey N. Weitzel, M.D. Cancer Screening & Prevention Program

2 Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom) June U.S. Supreme Court rules that as nature, genes cannot be patented Kesselheim A and Mello M. N Engl J Med 2010; /NEJMp

3 BRCA1- and BRCA2-Associated Cancers: Lifetime Risk Breast cancer 50%-85% (often early age at onset) Second primary breast cancer 40%-60% Ovarian cancer 15%-45% Absolute risk likely to be higher than 10% - Prostate cancer Absolute risk 10% or lower - Male breast cancer - Fallopian tube cancer - Pancreatic cancer

4 BRCA1 and BRCA2 On chromosomes 17 and 13, respectively Autosomal dominant transmission Proteins have a role in genomic stability >2,000 different mutations, polymorphisms, and variants distributed over both genes BRCA1 Nonsense Missense Splice-site Breast Cancer Information Core

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6 BRCA: Selected Examples of Founder Mutations Population BRCA1 Mutations BRCA2 Mutations Ashkenazi Jewish Icelandic 185delAG 5382insC 6174delT 999del5 British 6-kb duplication of exon del4 6503delTT Dutch (Netherlands) Chinese 2804delAA Large deletions of exons 13 & delG Russian 5382insC 4153delA African A. 1832del5 5296del4 Hispanic 185delAG deletion exons insT

7 Inherited Genomic Rearrangements of BRCA1 and BRCA2 35/300 (12%) sequence negative high risk families Other: CHEK2 n=14 (5%) TP53 n=3 (1%) Walsh et al, JAMA 295: , 2006

8 k Comprehensive genetic testing includes full sequencing of BRCA1/BRCA2 and detection of large genomic rearrangements.

9 Influence of BRCA1 Genotype on Histopathology in Breast Cancer (BC) Less likely to express estrogen receptor or Her2/neu Have a high nuclear grade Show less tubule formation Have a higher mitotic count Medullary histology more common (~ 6%) More BRCA1 mutations in triple negative DCIS is less associated with BRCA1 than BRCA2 BRCA testing may be appropriate for triple negative BC or early onset DCIS, especially if family history of BC and/or OC Eisinger et al. Cancer Res 56:471, 1996; Claus et al, JAMA 293: , 2005; Breast Cancer Linkage Consortium. Lancet 349:1505, 1997; Kandel (ASCO), 2006

10 Contribution of known genes to explaining familial aggregation of breast cancer BRCA1 BRCA2 TP53 PTEN ATM CHEK2,BRIP1,PALB2 CASP8 Other familial risk factors (genes, environment) 8 WGA SNPs

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12 Li-Fraumeni Syndrome Bilateral Breast, Breast, 40 Osteosarcoma, 42 Leukemia, 33 TP53-mutation carrier Affected with cancer Breast, 35 Soft tissue sarcoma, 7 Brain tumor, 32 Leukemia, 6 ASCO

13 Cowden Syndrome Pedigree Multinodular goiter, dx 25 Follicular thyroid cancer, dx 35 Trichilemmomas, dx 21 Breast cancer, dx 35 Noncarrier Affected Risk for uterine, but not ovarian ca in CS Macrocephaly Papillomatous papules Multinodular goiter, dx 22 Eng C. J Med Genet. 2000;37:

14 Emerging Breast Cancer Phenotype in Women with TP53 Germline mutations Cohort of TP53 Carriers N ER+ Her2/neu+ LiFE Consortium 32 84% 63% Masciari et al. BCRT 2012 UK 9 83% Wilson et al. J Med Genet 2010 MDACC/Chi 30 70% 67% Melhem-Bertrandt et al. Cancer 2012 Women < 40 BC, unselected for FHx % 22-33% Collins et al. BCRT 2011; Gonalez- Angulo et al. Cancer 2012

15 Cancer Screening & Prevention Program Genetic Predisposition Testing Is a Multi-Step Process Identify at-risk patients Provide pretest counseling Obtain informed consent Select and offer test Disclose results Provide post-test counseling and follow-up

16 Estimating Cancer Risk Family History Empiric Data Genetic Testing

17 Adequate Family Structure for both Maternal and Paternal Lineage 88 y d. 73 y 85 y 87 y 62 y 55 y 58 y 60 y 57 y 65 y 55 y Br 47 Breast Cancer Limited Paternal Family Structure 88 y d. 73 y 85 y 87 y Weitzel et al. JAMA 297(2007) y 55 y d. 36 y MVA 60 y 57 y 65 y d. 55 y Br 47 Breast Cancer

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19 HEREDITARY BREAST AND OVARIAN CANCER Br- Pm Br- 45 ex9-12del + 81 Br Br- Pm Pr- 50 Br Ov

20 Clinical Management of BRCA Mutation-Negative Patients Negative BRCA1 and/or BRCA2 test result NO Member of family w/ known BRCA1 or BRCA2 mutation? YES Emphasize empirically increased risk of breast and/or ovarian cancer Provide individualized risk-management plan Emphasize risk of sporadic cancer Encourage adherence to population screening guidelines

21 Clinical Management of BRCA Mutation-Positive Patient Cancer Screening & Prevention Program Possible testing for other adult relatives Positive BRCA1 or BRCA2 test result Prophylactic surgery Lifestyle changes Increased surveillance Chemoprevention

22 Dense Breast Tissue Size? Time Mammo

23 MRI and Breast Cancer Detection in BRCA Carriers - Sensitivity N with mutations Invasive cancers % by MRI % by mammogram Warner (2004) Kriege (2004) % 31% % 33% MARIBS (2005) % 23% TOTAL % 30% Breast MRI may be considered the standard of care for high risk patients

24 Cumulative incidence of early-stage (stages 0 to I) breast cancer in magnetic resonance imaging (MRI) Warner E et al. JCO 2011;29:

25 Is risk reduction mastectomy (RRM) effective? Skin-Sparing Mastectomy With Immediate Reconstruction Comparison of 214 high risk women who underwent RRM ( ) to sister controls: 3 cases BC observed vs expected = 92% Risk Reduction Hartmann L. et al, NEJM, 340:77, 1999; JNCI 93:1633, 2001 Study of 483 BRCA carriers: >90% risk reduction Rebbeck, T.R., et al. JCO 22:1055, 2004

26 New Primary Cancer Risk and Modifiers Among 491 BRCA Carriers 10-year contralateral breast cancer risk 43.4% for BRCA1; 34.6% for BRCA2 Age 50 at diagnosis: HR 0.63; 95% CI Tamoxifen use: HR 0.59; 95% CI Oophorectomy: HR 0.44; 95% CI year ovarian cancer risk after breast cancer: 12.7% for BRCA1, 6.8% for BRCA2 (p=0.03) Ovarian cancer was the cause of death in 25% of the Stage I breast cancer patients Metcalfe et al. J Clin Oncol 2004, 22: Gyn Onc 2005; 96:

27 Options for breast cancer patients with BRCA mutations Surgical options for the breast therapeutic mastectomy versus breast conservation therapy on affected breast risk reduction mastectomy on contralateral breast Hormonal risk reduction options BSO tamoxifen Screening mammography MRI

28 Decisions, decisions Oncologic Consultation Treatment Genetic Cancer Risk Assessment Prevention

29 Options for BRCA1, BRCA2 Carrier Prophylactic Oophorectomy CA125 Screening Chemoprevention CASH study. N Engl J Med 316:650, Rosenberg L et al. Am J Epidemiol 139:654, Ursin G et al. Cancer Res 57:3678, Narod et al, NEJM 339:424, 1998Narod SA, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 carriers. J Natl Cancer Inst 2002;94:

30 Oophorectomy Reduces Ovarian Cancer, Breast Cancer, and all cause mortality Greatest breast cancer risk reduction among BRCA1 mutation carriers without a prior dx of breast cancer who had their oophorectomy < age 50 HR: 0.15 (95% CI )

31 Genetic status is on the cusp of helping to determine composition of breast and ovarian cancer treatment regimens

32 PARP inhibition and tumor-selective synthetic lethality DNA damage (SSBs) DNA replication (accumulation of DNA DSBs) PARP PARP inhibition Normal cell with functional HR pathway HR-deficient tumor cell (e.g. BRCA 1/2 -/- ) HR-mediated DNA repair Cell survival Tumor-selective cytotoxicity Cell death Impaired HRmediated DNA repair DSB, double-strand break; HR, homologous recombination SSB, single-strand break Farmer H et al. Nature 2005;434: Bryant HE et al. Nature 2005;434: McCabe N et al. Cancer Res 2006;66:

33 PARP inhibitors in cancer therapy Agent Company Single / Combination therapy AG Pfizer (New York, NY) Route of administr ation Disease Single IV Advanced BC and OC Clinical status Phase 1 in solid tumors, phase 2 in BC and OC AZD2281 (Olaparib) ABT-888 (Veliparib) BSI-201 (Iniparib) GPI AstraZeneca/Ku DOS (London, UK) Abbott Laboratories (North Chicago, IL) Sanofi-Aventis (Bridgewater, NJ) MGI Pharma (Bloomington, MN) Single, combinations with carbo/paclitaxel or paclitaxel alone Combination with carbo, temozolomide, or cisplatin/vinorelbine Oral Advanced BC and OC Phase 2, 3 ongoing Oral Advanced BC Phase 1, 2, 3 ongoing Gemcitabine/carboplatin IV Triple-negative BC Combination with temozolomide Phase 2, 3 ongoing Oral Solid tumors Phase 1 planned

34 Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer: Best % change from baseline in target BC lesions by prior chemotherapy Olaparib 400 mg bid cohort ORR, n (%) 11 (42) CR, n (%) 1 (4) PR, n (%) 10 (39) Previous anthracycline, taxane and capecitabine Best % change from baseline * * * * * Increasing tumor shrinkage * *Prior platinum Tx Tutt et al. Lancet 2010

35 Protocol NCI #8264: ABT-888 +/- Carbo Adv/Mets BRCA- Breast Cancer Safety Lead-In 21 patients ABT mg BID >2 cycles ABT mg BID + Carbo AUC=5 Post-progression Endpoints: BRCA1 vs. BRCA2 RECIST Criteria PFS ABT-888 single agent; post-progression for combination Safety & Tolerability, Pharmacokinetics Correlative studies will include biomarkers of PARP and carboplatin effect, as well as prospective analyses of mechanism(s) of resistance in vivo selection for BRCA reversion mutants that restore the reading frame and functional domains such as HRR may be one mechanism of drug resistance

36 How Much Breast and Ovarian Cancer Is Hereditary? It depends on what tests you use to answer the question 15% -20% Breast Cancer 5% 7% 10-23% Sporadic Family clusters Hereditary Ovarian Cancer

37 Proportions ovarian, fallopian tube, or peritoneal cancer patients with respective germ-line loss-of-function mutations Walsh T et al. PNAS 2011;108:

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39 Domchek SM, et al. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J. Clin. Oncol. 2013;31(10):

40 Weitzel et al. Genetics, Genomics, and Cancer Risk Assessment: State of the Art and Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 2011;61:

41 Clinical Utility and professional mediation of genetic testing directed by HCP directed by individual clinical utility accepted high penetrance DTC testing clinical utility unclear intermediate penetrance low penetrance variants American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 2010.

42 Cancer Screening & Prevention Program Breast and Ovarian Cancer Screening and Prevention Key advances and evidence for advice: There are advances in protocols for screening (MRI), risk reduction (RRSO, RRM), and targeted treatment Warner et al, 2004; Kriege et al, 2004; Rebbeck et al, 2002, Kauff et al, 2002; Weitzel et al, 2007 GCRA influences surgical decisions in a risk-appropriate way and should be considered for women with newly diagnosed early stage breast cancer and suspicion of BRCA gene mutation Timing of GCRA in the sequence of events in cancer diagnosis and treatment is dependent on both patient and provider variables and limitations Weitzel et al, 2003; Schwartz et al, 2004, 2005.

43 Cancer Screening & Prevention Program Breast and Ovarian Cancer Screening and Prevention Key advances and evidence for advice: BRCA testing for early onset DCIS, and for single cases of BC <50 years if limited family structure; <60 if triple negative Claus et al, 2005; Kandel et al, 2006; Weitzel et al, 2007 Large rearrangements account for a significant proportion of high risk families without sequence detected BRCA mutations Walsh et al, 2006; Weitzel et al, 2007; MGL 2012 Documented efficacy of interventions for BRCA mutation carriers drives medical necessity and liability issues, making GCRA a standard of care GCRA along with risk reduction interventions are cost-effective tools for increasing quality-adjusted life