Beyond BRCA the Future is Now

Beyond BRCA the Future is Now Richard P. Frieder, MD Medical Director, Intelegene Assistant Clinical Professor Department of Obstetrics and Gynecology David Geffen School of Medicine, UCLA University of California Los Angeles, California

Who Am I? A Gynecologist. Why am I here? To help you help your patients. To save lives. Personalized Medicine and Genomics... a form of medicine that uses information about a person s genes, proteins, and environment to prevent, diagnose and treat disease National Cancer Institute (NCI), 2011

Hereditary Cancer Risk Assessment (HCRA) Obstetricians and gynecologists play an important role in the identification and management of women with hereditary breast and ovarian cancer syndrome. Evaluating a patient s risk for hereditary breast and ovarian cancer (HBOC) syndrome should be a routine part of obstetric and gynecologic practice. American College of Obstetricians and Gynecologists Practice Bulletin 103 (2009). Hereditary Cancer Risk Assessment (HCRA) Testing for inherited predisposition is well established for patients at hereditary cancer risk... to inform clinical decision making and cancer prevention. It is the role of health care providers to offer genetic testing. American Society of Clinical Oncology, 2013

Hereditary Cancer Panel Testing Then & Now A new paradigm of clinical genetic testing for inherited cancer risk Old model: Gene focused Single or small panel of highly penetrant genes Sequential analysis of specific genes/syndromes DDX based on personal and family history New model: Cancer focused Large panel of highly and moderately penetrant genes Simultaneous analysis of multiple genes/syndrome DDX based on personal and family history Before and After Panel Testing Before Panel Testing After Panel Testing Hereditary Hereditary Sporadic Sporadic

Evolution 102: What I ve seen. 1998 <10,000 tests run <500 US testers Most testing by GCs Most testing in academics Most mutations found by GCs VUS rate (BRCA) 13% Referral model accepted Point-of-care model proposed 2014 >1.2 million tests run >60,000 US testers Most testing by Docs/NPs Most testing in community Most mutations found by clinicians VUS rate (BRCA) <1.5% Referral model fails Point-of-care model superior BRCA=breast cancer gene; VUS=variant of uncertain significance. Evolution 102: I ve seen more 1998 M&M studies in progress Cost effectiveness speculated Clinician awareness low Public awareness low Insurance coverage poor Society guidelines none Physician liability low Practice revenue unknown 2014 M&M benefits confirmed Cost effectiveness confirmed Clinician awareness high Public awareness high Insurance coverage good Society guidelines ubiquitous Physician liability high Practice revenue positive

Evolution 103: Models of Care Goals Traditional GC Model* 1) To help patients to understand and adapt to medical, psychological, and familial implications of genetic contributions to disease 2) To educate patients about inheritance, testing, management, prevention, resources, and research 3) To counsel patients, and to promote informed choices and adaptation to risk or condition Point-of-Care Medical Model 1) To prevent, diagnose, and treat disease 2) To ease suffering, promote health, and lengthen life 3) To advise and guide decisionmaking with patients through informed consent *National Society of Genetic Counselors Bulletin, 2005. What Are Multigene Next Generation Sequencing Panels? Rapid simultaneous analysis of multiple genes Lower cost than sequential analysis Shorter time to diagnosis

What are Multigene Next Generation Sequencing Panels? Covers complex cancer pedigrees that cross syndromes Increases identification of causative mutations Expands spectra of cancers associated with candidate genes Up to 30% syndromic overlap between HBOC and Lynch Hereditary Cancer Panel Testing What is available TODAY! 8 to 40 gene panels of high/moderate penetrance genes Covers 8 major cancer sites and inherited cancers: Breast, Ovary, Colon, Gastric, Endometrium, Pancreas, Melanoma, Prostate (+others) Clinically actionable mutations (>2x RR or >5% AR) Captures up to 50% more mutation carriers than single-gene or syndrome-focused testing Greater clinical utility than current syndrome tests AR=absolute risk; RR=relative risk.

Who is the target population? Affected patients meeting NCCN test criteria Unaffected patients with family history, meeting NCCN test criteria Personal or family history of multiple cancers not fitting classic syndrome Previous uninformative (negative) test results www.nccn.org NCCN=National Comprehensive Cancer Network. What genes are tested? Familiar BRCA1 BRCA2 MLH1 MSH2 MSH6 PMS2 EPCAM APC MUTYH (MYH) CDKN2A (P16) HBOC LYNCH GI Polyposis Melanoma/Pancreatic

What genes are tested? Familiar New BRCA1 BRCA2 HBOC CDK4 TP53 PALB2 RAD51C MLH1 PTEN RAD51D MSH2 MSH6 PMS2 LYNCH STK11 CDH1 BMPR1A BRIP1 BARD1 NBN EPCAM SMAD4 CHEK2 APC MUTYH (MYH) CDKN2A (P16) GI Polyposis Melanoma/Pancreatic ATM CHEK1 GEN1 MRE11A RAD50 XRCC2 N Engl J Med, Foulkes WD, Inherited susceptibility to common cancers, vol. 359, 2143-2153. Copyright 2008. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

BST OVY CRC UT MEL PAN GAS PROS OTHER BRCA1,2 X X X X X X X X X X X X MLH 1, MSH6 MSH2 X X X X X X X X X X X X PMS2, EPCAM APC X X X X MUTYH X X CDKN2A X X TP53 X X X X X X X X X PTEN X X X X STK11 X X X X X X CDH1 X X X BMPR1A X X X X SMAD4 X X X X PALB2 X X X CHEK2 X X X ATM X X NBN X X BARD1 X BRIP1 X X RAD51C X X RAD 51D X Just because it comes in a box, doesn t mean it s pizza. Just because it comes in a panel, doesn t mean it s good

Not all panel tests and labs are equally accurate. Not all results are equally reliable. One wrong result affects thousands of patients. CLIA certification does not assure quality. CLIA=Clinical Laboratory Improvement Amendments. Data to Demand From Any Genetic Laboratory That We May Use 1. Published results of validation studies with numbers of patients and diagnostic accuracy 2. Published results of VUS rates for each gene in panel 3. Databases and methods used to assign variant classification 4. Periodic review schedule and notification for VUS reassignment 5. GC review confirm optimal test was ordered 6. Turn-around time 7. Genetic education and interpretive resources to physicians 8. Office assistance for process integration 9. Actual out-of-pocket cost to the patient 10. Retail total cost of test

So What Do We Need to Know? Diving Deeper Expanding Differentials, Individualizing Management Shari Goldman Snow, MD Assistant Professor Northwestern University Chicago, Illinois

Clinical Dilemma Expand Testing From Single Syndrome Many patients have personal and family history associated with multiple syndromes 6.9% of patients appropriate for HBOC testing also meet Lynch criteria 30% of patients appropriate for Lynch testing also meet HBOC criteria Saam J et al. Overlap between Lynch syndrome and hereditary breast and ovarian cancer syndrome among family histories in patients tested for hereditary cancer syndromes. The Collaborative Group of the Americas on Inherited Colorectal Cancer. Poster 2013.

Case 1: Jennifer 32-year-old healthy female Mother diagnosed with ovarian cancer at age 48 Maternal grandfather diagnosed with colon cancer at age 63 Presently plans to start mammography at age 40 and colonoscopy at age 50 Which risks does Jennifer have? Hereditary Breast & Ovarian Cancer (HBOC) Lynch Syndrome Domchek SM et al. Breast Cancer Res Treat. 2010;119(2):409-414. Vasen HF et al. Gastroenterology. 1996;110(4)1020-1027.

Case 2: Carol 56-year-old diagnosed with breast cancer at age 44 Father diagnosed with pancreatic cancer at age 62 Paternal aunt diagnosed with colon cancer at age 68 Presently has a mammogram yearly and colonoscopy every 10 years What If Carol s Test Reveals.. BRCA Breast, Ovarian, Pancreatic Add: MRI, Mastectomy, BSO, Imaging PTEN Breast, Colon, Uterine Add: MRI, Mastectomy, Colonoscopies, Hysterectomy MLH1 Negative Colon, Uterine, Ovarian, Pancreatic, Gastric Small increases over general population Add: Colonoscopies, Colectomy, Hysterectomy/BSO, Endoscopy, Imaging Continue present management BSO=bilateral salpingo-oophorectomy; MRI=magnetic resonance imaging.

Expand to Panel Screening Case 3: Julie 46-year-old healthy female, G3P3 Mother diagnosed with Stage IV colon cancer at age 58 Paternal grandmother diagnosed with colon cancer at age 60 and with ovarian cancer at age 80 Colonoscopy every 3 years from age 40 Mammogram yearly from age 40

Panel Testing Results: BRCA + BEFORE: Screening Mammogram AFTER: Add MRI, Considering Mastectomy BEFORE: Annual Pelvic Examinations AFTER: LSC BSO BEFORE: Colonoscopy every 3 years AFTER: Colonoscopy every 5 years, based on family history, negative genetic results for colon cancer LSC=laparoscopic. Expand the Differential, Individualize Management

Potential Patient Management Pitfalls MARRA S. FRANCIS, MD, FACOG WOMEN S HEALTH CONSULTANTS SAN ANTONIO, TEXAS 10:15 AM: M.J., Return OB Visit M.J. is a 37yo G3P2, uncomplicated pregnancy, currently 28 weeks gestation Expresses her desire to have a postpartum BTL Normal body habitus Chart notation that, per the patient, vasectomy was discussed and declined by her husband BTL=bilateral tubal ligation.

Labor and Delivery: 11 weeks later M.J. has a successful NSVD on Monday, epidural placed during labor Tuesday, M.J. is taken to the OR suite and a mini-lap via umbilical incision is made Postpartum BTL is successfully performed NSVD=normal spontaneous vaginal delivery. Four Years Later: M.J., 2:30 PM Gyn Problem bloating M.J. has been experiencing bloating and weight gain for the past month Examination reveals slight abdominal fluid wave and bilateral pelvic masses

Diagnosis Ultrasound confirms bilateral cystic/solid masses consistent with malignancy CT Scan reveals omental caking and a liver lesion consistent with metastatic disease CA125 = 314 U/mL (normal <35 U/mL) Stage IIIC Ovarian Carcinoma Closer Examination of Cancer Family History Paternal Grandmother: Ovarian cancer diagnosed at age 47; deceased age 49 Paternal Aunt: Colon cancer diagnosed at age 56; deceased age 60 Father: Colon cancer diagnosed at age 49; deceased age 52

Flash Back to 4 Years Prior HAD a Cancer Family History form designed to identify individuals at risk for Hereditary Cancer Syndromes been done at the first OB visit, M.J. would have been found to be at risk for both HBOC and Lynch Syndrome Single Syndrome gene testing for BRCA and Lynch would have been negative Panel Testing Results M.J. is found to be a carrier of STK11 (Peutz-Jeghers Syndrome) gene mutation

STK11 (Peutz-Jeghers Syndrome) Regulates the tumor suppressor enzyme serine/threonine kinase 11 STK11 is also involved in cellular apoptosis Clinical Significance Noncancerous hamartomatous polyps of the GI tract Cancer of: GI Tract, Pancreas, Cervix, Ovary, Breast, Skin (Melanoma) Better Medical/Surgical Management for M.J. Standard of Care for her desired sterilization would have been a recommendation for hysterectomy/ bilateral salpingo-oopherectomy sometime after 6 weeks post partum Increased colon cancer surveillance Increased skin surveillance for melanoma Increased breast cancer surveillance No guidelines on pancreatic cancer surveillance at this time

1:45 PM: T.R., Breast Problem T.R. is a 43yo G2P2, BMI 25, Breast Size 38DD Referred by plastic surgeon for preoperative breast examination and mammogram for breast reduction surgery Pap smear is up to date Prior mammogram at age 41, normal BMI=body mass index. 1:45 PM: T.R., Breast Problem (continued) Normal breast examination noted Screening mammogram done, BI-RADS 1 Three weeks later, T.R. has an uncomplicated bilateral breast reduction with lift 6-month follow-up mammogram done to have a new baseline Routine breast screening continued BI-RADS 1=Breast Imaging Reporting and Data System [category 1].

Three Years Later: 8:30 AM, T.R. Urgent Visit breast mass T.R. noticed a hard lump at the edge of her mastopexy scar Had previously contacted the plastic surgeon, who recommended massage and topical scar cream application; no change in 1 month Last mammogram 9 months ago, BI-RADS 3, increased scar tissue bilaterally noted and close interval follow-up recommended Patient had to cancel her 6-month follow-up for a family emergency and forgot to reschedule T.R. Examination Solid mass palpated at lateral edge of mastopexy scar Urgent diagnostic mammogram with ultrasound and biopsy, as needed, ordered

Diagnosis Mammogram reveals solid, spiculated mass enlarged from previous scan, and enlarged lymph nodes in axillary region Biopsy reveals high-grade invasive ductal carcinoma T.R. diagnosed with Stage IIB IDCA of the breast IDCA=infiltrating ductal carcinoma. Closer Examination of Cancer Family History Maternal Grandmother: Pancreatic cancer diagnosed at age 60; deceased age 61 Maternal Aunt: Breast cancer diagnosed at age 59; deceased age 66 Maternal First Cousin: Breast cancer diagnosed at age 46; living Mother: Pancreatic cancer recently diagnosed at age 67; undergoing treatment

Flash Back to 3 Years Prior HAD a Cancer Family History form designed to identify individuals at risk for hereditary cancer syndromes been done at the preoperative breast visit, T.R. would have been found to be at risk for HBOC Single Syndrome gene testing for BRCA would have been negative Panel Testing Results T.R. is found to be a carrier of PalB2 mutation PalB2=partner and localizer of BRCA2.

PalB2 (FANC: Fanconi Anemia, Complementation Groups) PalB2 protein works with BRCA2 gene s tumor suppressor function Clinical Significance Two abnormal copies of PalB2 result in Fanconi Anemia, increases childhood cancer rates Wilms Tumor and medulloblastoma One abnormal copy of PalB2 increases adult cancer rates Breast and pancreatic Better Medical/Surgical Management Standard of care would have been to offer bilateral risk reduction prophylactic mastectomies OR increased breast surveillance No guidelines on pancreatic cancer surveillance at this time

HOW TO INCORPORATE HEREDITARY CANCER TESTING INTO A BUSY PRACTICE Burton S. Brodsky, MD Associate Professor Wayne State University School of Medicine Detroit, Michigan ACOG Recommends the Use of Protocols and Tracking Systems To enhance quality of care and patient safety: ACOG=American College of Obstetricians and Gynecologists. 1. Committee on Patient Safety and Quality Improvement, American College of Obstetricians and Gynecologists. Committee Opinion No. 546: Tracking and reminder systems. Obstet Gynecol. 2012;120(6):1535-1537. 2. ACOG Committee on Patient Safety and Quality Improvement. ACOG Committee Opinion No. 526: Standardization of practice to improve outcomes. Obstet Gynecol. 2012;119(5):1081-1082.

Do You Need a Cancer Family History for All Patients? ACOG Committee Opinion, No. 478, March 2011 Family history plays a very important role in assessing the risk of inherited medical conditions and single gene disorders It is recommended that all women receive a family history evaluation as a screening tool for inherited risk. Family history information should be reviewed and updated regularly, especially when there are significant changes to family history SCREEN WRITTEN FHQ Use written cancer FHQ with all patients every visit Remind patients to be complete and accurate when filling out FHQ, including paternal side ACOG recommends that all women receive a family history evaluation as screening for inherited risk; this should be updated regularly. ACOG Committee Opinion 478, March 2011 FHQ=Family History Questionnaire.

Risk Assessment for Lynch Syndrome and Hereditary Breast and Ovarian Cancer Syndrome Patient Name: Physician: Date of Birth: Today s Date: This is a screening tool for cancers that run in families. Please consider these family members when completing the form: Mother/Father/Sister/Brother/Children = 1st Degree Relatives Aunt/Uncle/Grandparent/Niece/Nephew = 2nd Degree Relatives Cousin/Great Grandparent = 3rd Degree Relatives Have you or any of your relatives been tested for hereditary cancer (BRCA/Colaris) in the past? YES NO COLON AND UTERINE CANCER (Lynch Syndrome/Colaris) EXAMPLE: Two or more relatives with a Lynch syndrome Y N cancer; one under age 50 Have YOU been diagnosed with uterine (endometrial) or Y N colorectal cancer before age 50 TWO or more relatives on the same side of the family w/ any of the following, one diagnosed before 50 (please circle): Y N colon, uterine/endometrial, ovarian, stomach, small bowel, brain, kidney/urinary tract, ureter and renal pelvis THREE or more relatives on the same side of the family w/ any of the following diagnosed at any age (please circle): Y N colon, uterine/endometrial, ovarian, stomach, small bowel, brain, kidney/urinary tract, ureter and renal pelvis Y N Family member has a known Lynch syndrome mutation SELF YOUR RELATIONSHIP TO FAMILY MEMBER w/ CANCER MOTHER S SIDE FATHER S SIDE Aunt-colon Sister-uterine AGE AT DIAGNOSIS 47 yrs 60 yrs YOUR RELATIONSHIP TO FAMILY BREAST AND OVARIAN CANCER (HBOC/BRACAnalysis) SELF MEMBER w/ CANCER MOTHER S SIDE FATHER S SIDE Breast cancer at age 45 or younger Y N (in self, first or second degree family members) Ovarian cancer at any age Y N (in self, first or second degree family members) TWO relatives on the same side of the family with breast Y N cancer with one under the age of 50 THREE relatives on the same side of the family with breast Y N cancer at any age Multiple breast cancers in the same person (in the same Y N breast or in both breasts) Y N Male breast cancer at any age Ashkenazi Jewish ancestry with breast, ovarian or pancreatic Y N cancer in the same person or on the same side of the family Pancreatic cancer with breast or ovarian cancer in the same Y N person or on the same side of the family Triple Negative breast cancer under age 60 Y N (ER, PR and Her2 negative receptor status) Y N A family member with a known BRCA mutation Is there any other cancer in you or any family members not listed above (provide site, relationship and age): AGE AT DIAGNOSIS Patient s signature: Date: FOR OFFICE USE ONLY Patient is appropriate for further risk assessment and/or genetic testing Information given to patient to review Follow-up appointment scheduled on Patient offered genetic testing: Accepted OR Declined HCP Signature: a www.nccn.org EVALUATE APPLY CRITERIA Review all FHQs and document Use consistent testing criteria and evaluation methods

DIAGNOSE APPLY CRITERIA FOLLOW UP Test appropriate patients Use follow up protocol for all patients whether tested or not Document follow up appropriately MANAGE FOLLOW UP Document results and management Communication plan for patients and referring providers PLAN Manage patients according to individualized risk Document individualized medical management plan Involve other providers as appropriate

Active Use of Cancer Family History Helps to Ensure You Are Making Optimal Recommendations ACOG, 1 USPSTF, 2 and NCCN 3 guidelines exist for Hereditary Cancer Risk Assessment Optimal medical recommendations for all patient visit types: Well woman visit Problem visit OB visit May increase patient safety and quality of care USPSTF=US Preventive Services Task Force. 1. American College of Obstetricians and Gynecologists; ACOG Committee on Practice Bulletins Gynecology; ACOG Committee on Genetics; Society of Gynecologic Oncologists. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2009; 113(4):957-966. 2. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5): 355-361. 3. National Comprehensive Cancer Network. http://www.nccn.org/clinical.