Genetic Testing For Ovarian Cancer: When, How And Who? Judith Balmaña, MD, PhD University Hospital Vall d Hebron Barcelona, Spain

Why Would We Consider Genetic Testing in Patients With Ovarian Cancer? Estimation of the lifetime risk of cancer in an individual and/or her family Identification of individuals at sufficient risk to consider enhanced screening or prevention strategies Identification of tumors that might respond to specific therapies

Inherited Mutations in Women With Ovarian Cancer NBN 1% PALB2 2% MRE11 1% MSH6 3% RAD50 1% RAD51C 2% TP53 4% Mutation rate: 24% - 18% BRCA1/2-6% Other genes BARD1 1% CHEK2 6% BRIP1 5% BRCA1 47% BRCA2 27% Walsh T, et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037.

Domchek SM, et al. JAMA. 2010;304(9):967-975. Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861. Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250. Detection of BRCA1/2 Mutations Has Clear Clinical Utility in Ovarian Cancer High risk of developing ovarian cancer Risk-reducing oophorectomy is associated with lower ovarian cancer risk, breast cancer risk, and all-cause mortality A targeted therapy (olaparib, PARPi) is approved by the EMA and the FDA for two different indications in BRCA1/2-associated ovarian cancer

Olaparib activity in patients with platinum-sensitive recurrent highgrade serous ovarian cancer and BRCA mutation Olaparib activity in patients with advanced ovarian cancer and three or more lines of prior therapy and germline BRCA mutation Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861. Domchek SM, et al. Gynecol Oncol. 2015 Dec 23. [Epub ahead of print].

Treatment-Free Interval in BRCA Mutation Carriers vs Patients With Sporadic EOC Platinum-based chemotherapy Non platinum-based chemotherapy Tan DS, et al. J Clin Oncol. 2008;26(34):5530-5536.

BRCA1/BRCA2 Mutations and OC Survival 5-year survival: BRCA1 44% BRCA2 61% No mutation 25% Bolton KL, et al. JAMA. 2012;307(4):382-390. Zhong Q et al. Clin Cancer Res. 2014;21(1):211-220.

When to Order BRCA Testing? At diagnosis or during first-line treatment At the time of recurrence Potential Barriers to BRCA Testing Unrecognition of who should be tested Difficult interpretation: Variants of uncertain clinical significance If negative: Consider family history and other non-brca genes Familial implications: duty to warn Communication, time consuming referral to cancer genetics? Cost

Histology and Ovarian Cancer Gene Mucinous, n = 16: NO mutations Norquist BM, et al. JAMA Oncol. 2015 Dec 30. [Epub ahead of print].

Somatic Mutations in BRCA1 and BRCA2 235 unselected ovarian cancers 44 mutations: 30% were somatic Somatic mutations were more frequently novel No somatic mutations detected in tumors from patients with germline mutations PFS was not significantly different based upon the origen of the mutation (P =.69) Hennessy BT, et al. J Clin Oncol. 2010;28(22):3570-3576.

Is Platinum Response a Predictor of BRCA Mutation? Response to treatment at first progression Treatment response was based on a 50% decrease in CA-125, maintained for 28 days 25% (4/16) of tumors responding to platinum on a third occasion had a pathogenic somatic BRCA mutation (Alsop et al. J Clin Oncol. 2012) Alsop K, et al. J Clin Oncol. 2012;30(21):2654-2663.

136/254 (51%) BRCA1 or BRCA2 mutated: 96 germline 18 somatic (7% overall) Small group, but no differences according to mutation origin (ie, germline or somatic) Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.

BRCA Testing Is Moving From Cancer Risk Assessment to Therapeutic Predictive Biomaker Moreno L, et al. Clin Transl Oncol. 2016 Jan 7. [Epub ahead of print].

Models to Incorporate BRCA Testing in Mainstream Oncology Practice Traditional genetic counseling Established method Too cautious? Delays testing Treating clinician Established relationship with patient: no delay Training of clinicians required/lack of time Will it hamper pre/post-test counselling? Nurses/genetic counselors Does not delay testing Cheaper than in-person or clinicians Training of specialist nurses/genetic counselors required

Oncologist Provides Initial BRCA Testing: UK and Scotland Model Patient with breast/ovarian cancer Family member without cancer BRCA testing Cancer Team Patient referred to Genetics Team if detailed discussions required Genetics Team Negative BRCA test Positive BRCA test Clear protocols to delineate patient pathway Clear approval process for testing for non-geneticists including online training modules and resources George A, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 881PD.

Local Hospital (England) and Scottish Health Board Guidelines for BRCA Testing Procedures in Patients With Ovarian Cancer (as of October 2014) George A. Br J Cancer. 2015;113(Suppl 1):S17-S21.

BRCA Testing BRCA germline testing in all epithelial invasive, non-mucinous, ovarian cancer cases Individualize the most appropriate time based on the clinical utility of the findings and the available resources Consider BRCA somatic testing for targeted/platinum-based therapeutic decision making

Warn family members BRCA Testing Operationalize according to local resources: Primary oncology service versus cancer genetics If a deleterious variant or a VUS are identified: Always refer to cancer genetics team What to do if no BRCA mutation is identified...? Age at diagnosis? Histology? Family history? Panel testing?

Frequency of Inherited Mutations Beyond BRCA1/2 in Women With Ovarian Cancer 1915 women with ovarian cancer from University of Washington, GOG218 and GOG 262 Enrolled at diagnosis, not selected for age or family history Targeted capture and multiplex sequencing assay 18% carried a germline mutation: 15% in BRCA1 or BRCA2 3% in BRIP1, RAD51C, RAD51D, PALB2, BARD1 0.4% in a MMR gene Norquist BM, et al. JAMA Oncol. 2015 Dec 30. [Epub ahead of print].

Relevance of Inherited Mutations Beyond BRCA1/2 in Women With Ovarian Cancer Genes Cases Controls Mean Age Relative Risk BRIP1 0.92% 0.09% /0.6% BARD1 0.12% 0.06% (P =.39) PALB2 0.28% 0.09% (P =.08) 63.8y (93%>50y) 55.5 y (53-60) 56 y (49-65) 3.4 (2-5) 5.8% at 80y NBN 0.28% 0.23% (P =.61) NA - - - RAD51C 0.41% 0.07% 70% >50y RAD51D 0.35% 0.04% 92% >50y 5.2 (1.1-24) 5% at 70y 12 (1.5-90) 12% at 70y Ramus S, et al. J Natl Cancer Inst. 2015;107(11). pii: djv214. Song H, et al. J Clin Oncol. 2015;33(26):2901-2907. Norquist BM, et al. JAMA Oncol. 2015 Dec 30. [Epub ahead of print].

BRIP1: Ready for the Clinics? Aproximately 1% of ovarian cancer cases Mean age at diagnosis 63 years; 93% above age 50 years Estimated lifetime risk 5.8% (similar to having one first degree relative with ovarian cancer) Modest increase of breast cancer risk (RR 2.0) Sensitivity to platinums, but not to PARPi HR-Pathway Gene Genetic Alteration Type Germline/Somati c Inference HRD Molecular Subgroup RECIST Response CA-125 Response BRIP1 Splice Germline Biomarker negative SD No BRIP1 Truncation Germline Biomarker negative SD No Ramus S, et al. J Natl Cancer Inst. 2015;107(11). pii: djv214. Seal S, et al. Nat Genet. 2006;38(11):1239-1241. Bridge WL, et al. Nat Genet. 2005;37(9):953-957. McNeish IA, et al. J Clin Oncol. 2015;33(suppl): Abstract 5508.

Song H, et al. J Clin Oncol. 2015;33(26):2901-2907. Loveday C, et al. Nat Genet. 2011;43(9):879-882. Loveday C, et al. Nat Genet. 2012;44(5):475-476. McNeish IA, et al. J Clin Oncol. 2015;33(Suppl): Abstract 5508. RAD51C and RAD51D: Ready for the Clinics? Approximately 1% of ovarian cancer cases Most diagnosed above age 50 years Estimated lifetime risk of ovarian cancer between 5% to 12% (yet very wide confidence intervals) No conclusive increased risk of breast cancer Sensitivity to platinum and PARPi Tumor With RAD51C Alterations Are BRCA-Like (High Genomic LOH) and Responded to Rucaparib HR-Pathway Gene Genetic Alteration Type Germline/Somatic Inference HRD Molecular Subgroup RECIST Response CA-125 Response NBN Truncation Germline Biomarker negative PR Yes RAD51C Truncation Germline BRCA-like PR Yes RAD51C Homozygous del Somatic BRCA-like PR Yes RAD51C Splice Germline BRCA-like PR Yes RAD51C Splice Germline BRCA-like SD Yes

Courtesy of Mark Robson

More Considerations Sequential testing versus panel testing If panel testing: Which genes? What is the clinical utility of non-brca genes? Who should order and interpret the findings of panel testing?

My Conclusions There is robust evidence to support BRCA testing in ovarian cancer patients Individualize who, when, and how to order BRCA testing according to clinical utility, local resources, and preserving the full implications of a germline genetic test Panel testing and tumor sequencing are progressively being incorporated in clinical practice Genetic testing in ovarian cancer requires a multidisciplinary approach to cope with its multiple implications