Genetics update: Hereditary gynecologic cancer, Multi‐ Testing, Risk‐reducing surgery Kathryn Maurer, MD Gynecologic Oncologist University of Utah and Huntsman Cancer Institute Disclosures

• No financial disclosures

• Not a genetic counselor Outline Objectives • Hereditary Ovary Cancer • Identify patients for • Moderate risk genetic counseling/testing • Hereditary Endometrial • Know the risks and Cancer managements for newer • Lynch intermediate risk genes • Genetic testing updates • Know multigene panel • Multigene panels results and how to interpret • Risk‐reducing surgery “controversies” • Understand indications and principles of RRS The Big Picture Hereditary ovarian cancer Hereditary Ovarian Cancer

• Hereditary Breast and Ovarian Cancer Syndrome (BRCA1 and BRCA2) • New Susceptibility Genes • RAD51C • RAD51D • BRIP1 • Lynch Syndrome (MLH1, MSH2, EPCAM, MSH6, PMS2) Who Should Have Genetic Counseling for Hereditary Breast and Ovarian Cancer?

Personal history of, or close family member with: • Epithelial ovarian, fallopian tube, or primary peritoneal cancer • Breast cancer diagnosed before age 45 • Triple negative breast cancer (less than 60) • Two breast cancer primaries • Breast cancer at any age with – >1 close relative with breast cancer <50y – >1 close relative with ovarian cancer – >2 close relatives with breast or pancreatic cancer – Ashkenazi Jewish descent • Male breast cancer • Family member with a known gene mutation

http://www.nccn.org SGO Statement

Why Have Genetic Counseling?

• Thorough genetic risk assessment • Education about the condition(s) in question • Explanation of testing process, insurance coverage, and protection against genetic discrimination • Clarification of risks to patient and family • Facilitation of referrals to appropriate providers for medical management • Required for insurance to cover genetic testing • Experience in result interpretation • Psychosocial support How Much Ovarian Cancer is Hereditary?

Sporadic Hereditary 23%

Others BRCA2 BRCA1

Walsh et al. PNAS 2011; 108(44): 18032–18037. Hereditary Breast & Ovarian Cancer Syndrome (HBOC) • Caused by mutations in BRCA1 and BRCA2

• Accounts for 13‐18% of all cases of ovarian cancer

• Prevalence: 1:500 (1:40 Ashkenazi Jews)

• Autosomal Dominant inheritance, rarely de novo

Zhang et al. Gynecologic oncology. 2011;121(2):353-357. Walsh et al. PNAS 2011; 108(44): 18032–18037. Frequency of mutations by age of diagnosis

First-degree relative w/ ovarian or early-onset breast cancer = 46% mutation positive No significant family history = 8% mutation positive

Zhang et al Gyn Oncology 2011;121(2):353-357 Frequency of mutations by tumor histology

Zhang et al Gyn Oncology 2011;121(2):353-357 HBOC: NCCN Management Options (Women) Intervention Recommendation Breast self‐exam/ Monthly, beginning at age 18 awareness Clinical breast exam Every 6‐12 months, beginning at 25 Mammogram & MRI MRI Annually, beginning at 25*; Mammogram annually age 30‐75y Mastectomy Discuss option on case‐by‐case basis BSO Recommended at 35‐40* or upon completion of childbearing Transvaginal US + CA‐125 Data do not support routine screening, but may be considered at clinician discretion Chemoprevention Consider OCPs, tamoxifen/raloxifene Full body skin exam Consider d/t risk of melanoma Investigational protocols Consider for pancreatic cancer surveillance

NCCN Guidelines 1.2020 Risk Reduction Options

50%

Narod et al. NEJM, 1998;339:424-8 Robson et al. Cancer, 2005;103:44-51 Rebbeck et al. JCO, 2004;22:1055-62 Kauff et al. NEJM, 2002;346:1609-15 Rebbeck et al. NEJM 2002;346:1616-22 RRSO BRCA and RRSO

• 1‐4% risk of occult cancer at the time of surgery • 5‐8% Tubal intraepithelial carcinoma (TIC) • Callahan et al. J Clin Oncol 2007; Finch et al. Gynecol Oncol 2006, Powell et al. Int J Gyneol Cancer 2011 • 1‐4% risk of primary peritoneal cancer after • Finch et al Gynecol Oncol 2006, Kauff et al J Clin Oncol 2008, Kauff et al NEJM 2002, Rebbeck et al NEJM 2002. • No additional screening after risk‐reducing surgery Moderate risk ovarian cancer genes

Prevalence of RAD51B, RAD51C, RAD51D

Cases Family Hx Controls Lifetime Ov (N=3,429) (N=2,000) (N=2,772) Ca Risk RAD51B 0.06% 0.05% 0 ‐ RAD51C 0.41% 0.35% 0.07% 5.2% RAD51D 0.35% 0.25% 0.04% 12% Any mutation 0.82% 0.65% 0.11% ‐

Song H et al. 2015 JCO RAD51C, RAD51D Ovarian Cancer Risks

RAD51C Odds Ratio: 5.2 (95% CI 1.1 to 24; p=0.019) • Cumulative risk to age 50: 1.3% • Cumulative risk to age 70: 5.2%

RAD51D Odds Ratio: 12 (95% CI 1.5 to 90; p=0.035) • Cumulative risk to age 50: 3.0% • Cumulative risk to age 70: 12.0%

Song H et al. 2015 JCO Ovarian Cancer in RAD51C, RAD51D

• High‐grade serous (71%) • All diagnosed > 40 y, most > 50 y • Family history of ovarian cancer • No significant increase in risk of breast cancer

Song H et al. 2015 JCO Prevalence of BARD1, BRIP1, NBN, PALB2

Cases Family Hx Controls Case vs. (N=3,236) (N=2,000) (N=3,447) control BARD1 0.12% 0.15% 0.06% P=0.39 BRIP1 0.92% 0.60% 0.09% P=1x10‐4 NBN 0.28% 0.15% 0.23% P=0.61 PALB2 0.28% 0.35% 0.09% P=0.08 Any 1.6% 1.25% 0.5% mutation

Ramus SJ et al. 2015 JNCI Ovarian cancer in BRIP1

• Older age at diagnosis (Average 63.8 y) • High grade serous • Family history of ovarian cancer in 50% • Lifetime risk of ovarian cancer = 5.8% • Relative risk = 11.22 (95% CI 2.33 to 34.1) • No significant increase in breast cancer risk

Ramus SJ et al. 2015 JNCI RAD51C, RAD51D, BRIP1 • <2% of all ovarian cancers • NCCN guidelines 1.2020: Ovarian Cancer in Lynch syndrome

• Lynch syndrome accounts for <1% of ovarian cancers overall • Higher representation in endometrioid and clear cell histology • Chui et al found 10/48 (21%) non‐serous epithelial ovarian cancers were MMR ‐deficient but germline testing was not performed to confirm Lynch syndrome • Results of MSI/IHC screening are often discordant in ovarian cancer • Average age of diagnosis: 40’s

Pal et al BMJ. 2012 107, 1783–1790 Chui et al Am J Surg Pathol 2014 38 1173-1181 Lee et al Genet test molec biomark 2014 18 229-235 Lynch Syndrome—caused by mismatch repair genes

*Additional cancer risks that range from 1‐4% include renal pelvic, small bowel, ureter, and brain cancer Ovarian Cancer Risk in Lynch Syndrome

Bonadona V et al. JAMA 2011; Moller P et al. Gut 2015 *Low sample size Age Specific Risks for Ovary Cancer Hereditary endometrial cancer Hereditary Endometrial Cancer

• Lynch Syndrome (MLH1, MSH2, EPCAM, MSH6, PMS2) • Cowden Syndrome (PTEN) • Polymerase Proofreading Associated Polyposis (POLD1, POLE) Lynch Syndrome

• Also known as Hereditary Non‐Polyposis Colon Cancer (HNPCC) • Accounts for approximately 1/35 (2.9%) colon cancer cases and 1/43 (2.3%) endometrial cancer cases • Caused by mutations in Mismatch Repair (MMR) Genes • MLH1 • MSH2 • EPCAM • MSH6 • PMS2 • Autosomal Dominant Inheritance

Hampel Cancer Res 2006;66:7810-7 Who Should Have Genetic Counseling for Lynch Syndrome? • Colon or uterine cancer diagnosed before age 50 • Personal history of > 1 Lynch Syndrome cancer* • Personal history of colon or uterine cancer at any age • With > 1 relative with LS cancer < 50; or • > 2 relatives with LS cancer at any age • Abnormal MSI or IHC results • Relative with known Lynch Syndrome mutation *LS cancers: colorectal, uterine, gastric, ovary, pancreas, small bowel, ureter, or renal pelvis, biliary tract, sebaceous gland neoplasms, brain Who should be tested? Endometrial Cancer Risk in Lynch Syndrome

Bonadona V et al. JAMA 2011; Moller P et al. Gut 2015; Senter L et al Gastroenterology 2008 *Low sample size Colon Cancer Risk in Lynch Syndrome

Bonadona V et al. JAMA 2011; Moller P et al. Gut 2015; Senter L et al Gastroenterology 2008 *Low sample size Lynch Syndrome: Other Cancer Risks to Age 70

Cancer Site General Population Lynch Syndrome Stomach <1% 11-19% Hepatobiliary tract <1% 2-7% Urinary tract <1% 4-5% Small bowel <1% 1-4% CNS <1% 1-3% Lynch Syndrome: Management

Intervention Recommendation Colonoscopy Every 1-2 yrs beginning at age 20-25

Upper GI endoscopy Consider every 3-5 years starting at age 40

Capsule endoscopy If +FHx can consider TV US, CA 125, Not sufficiently sensitive or specific to support Endometrial Biopsy routine recommendation, can consider Hyst +/-BSO Consider at age 35 or after completion of childbearing, timing individualized No BSO for MSH6 or PMS2 Urinalysis & Consider UA every 1 year beginning at age Ultrasound 35; MSH2/fam hx Dermatology exam Annual Physical exam Annual – include neurological exam Other Hereditary Cancer Testing Signs of a hereditary cancer syndrome

• ‘Red flags’ for hereditary cancer: o Early‐onset cancer diagnosis (<50y) o Multiple primaries in one person o Patterns of multiple cancers in a family • Certain cancers warrant hereditary cancer evaluation at any age: o Ovarian Cancer o Paraganglioma/pheochromocytoma o Adrenocortical carcinoma (ACC) o Male breast cancer o Pancreatic cancer o Prostate Cancer Gleason score ≥ 7* Genetic Counseling and Testing How do we identify hereditary cancer syndromes?

• Genetic testing evaluates genes for sequencing and deletion/duplications • Can be performed via a blood or buccal/saliva sample • Single genes (i.e. BRCA1/2) can be studied or panels can be tested • Panels encompass multiple genes all associated with an increased risk for a particular cancer • Typically only includes genes with national guidelines for management recommendations • If a mutation is identified in a family member, site‐specific testing occurs • Genetic testing results include: • Positive, Negative • Variant of Uncertain Significance (VUS) Genetic Testing – Changing Times

• Shift from single gene testing to multi‐gene testing at similar costs • Quality multi‐gene panel testing lower than BRCA1/2 costs in 2013 • More genes have NCCN guidelines for cancer risk management • Ability to identify new causative genes in strong family histories that allow for cost savings in family members • Panel testing also increases identified patients with an increased risk for cancer When do we consider panel testing?

Lynch Syndrome?! Hereditary Breast and Ovarian Cancer?! (BRCA1/2) Multi‐gene panel testing

• 10 panels (5‐49 genes)

• 10 panels (6‐29 genes) • Build your own • 9 panels (7‐34 genes) • Build your own • 1 panel (25 genes)

• 2 panels (23‐60 genes) Some examples of commonly ordered panels Ambry Genetics

Myriad Genetics

Invitae Genetics 25 genes 24 genes 40 genes BRCA1 xxx BRCA2 xxx CDH1 xxx PTEN xxx STK11 xxx TP53 xxx Gene panels – Examples ATM xxx BARD1 xxx BRIP1 xxx CHEK2 xxx • Examples of genes covered on three different MRE11A xx MUTYH xxx clinically available gene panels NBN xxx PALB2 xxx • All considered “broad” panels and not tied to RAD50 xx RAD51C xxx risk for one or two specific cancers only EPCAM xxx MLH1 xxx MSH2 xxx MSH6 xxx PMS2 xxx APC xxx BMPR1A xxx SMAD4 xxx CDK4 xx CDKN2A xx• For which genes are there consensus guidelines on RAD51D xx ATR x what cancer screening/risk reduction options are BAP1 x CHEK1 x best for mutation carriers?

FAM175A/Abraxas x GALNT12 x GEN1 x GREM1 x HOXB13 x PRSS1 x RAD51 x RET x TP53BP1 x VHL x XRCC2 x PROs and CONs of Panel Testing If possible, confirm patient report!

• Wise provider: Has there been any genetic testing in your family?

• Patient: Yes! My sister had a genetic test done and she told me it was fine. And I did a genetic test a few months ago and the results were good!

• Really wise provider: Can I see a copy of these test results? Tumor Testing vs. Germline Testing

Somatic Tumor Testing Germline Testing (i.e. Foundation One) • Identifies genetic changes in • Mutations in the blood are the tumor itself expected to be all over the • Determines pathways that body may be amenable to • Indicates a mutation that is treatment passed among generations • Mutations in the tumor are • Increases risk for certain often not hereditary, but may types of cancer be Direct to Consumer Testing

• 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) • the 185delAG and 5382insC variants in the BRCA1 gene and the 6174delT variant in the BRCA2 gene • Three founder mutations in the Ashkenazi Jewish population • Does not cover the majority of BRCA mutations

• Per NCCN: • Confirmatory testing from a certified lab is recommended • Changes of patient’s medical management based solely on DTC not recommended Risk‐reducing surgery What about hormone replacement therapy?

‐ Improved endocrine symptoms and sexual function with HRT ‐ Breast cancer risk not altered by estrogen replacement after RRSO ‐ Progestin contained hormone regimens may have less favorable cancer risk profile Progestin Are they a candidate containing may be less safe: for hormone Chlebowski et replacement? al JAMA Oncol 2015

Mixed data What about Do they have Potential increased risk of serous BRCA1? uterine cancer the uterus? Possibly related to Tamoxifen use?

Do they have other indications or contra‐indications? What about tubes first, ovaries later? Conclusions from Pilot:

1) Salpingectomy was found to be safe 2) It identified a cohort of highly motivated women seeking an alternative to RRSO, 3) It did not establish whether bilateral salpingectomy prevents ovarian cancer, for that outcome will require a much larger number of patients followed beyond the age of risk for OC. Recommend BS in a clinical trial setting.

An ideal candidate is a healthy mutation carrier who has completed childbearing, desires permanent sterility, and is 2–3 years younger than the NCCN recommended age for oophorectomy, with minimal prior intra‐abdominal surgeries. Stay tuned…. Be familiar with who warrants genetic referral/testing

Ask patient with family history of cancer if testing done on those individuals (or have them find out!)

For patient who reports testing, get the results. Put in your EMR.

Know the gene and the specific risks

Take Home If doing risk‐reducing surgery, know the protocol and Points confirm pathology Think about the uterus

Give hormones

When in doubt: NCCN guidelines, genetics counselors, and your friendly gynecologic oncologist! QUESTIONS?