2. Breast Cancer Risk Assessment & Prevention Strategies Generosa Grana, MD Professor, Cooper Medical School of Rowan University Director, MD Anderson Cancer Center at Cooper

3. Overview 1.Factors that affect breast cancer risk 2.Tools to assess risk 3.Role of genetics in this process 4.Prevention and Screening

4. Assessing Risk of Cancer Factors to Assess: Family history Type of cancers, age, bilaterality… Reproductive factors Age menarche, menopause, first live birth Personal health history biopsy, obesity, etc.

5. Utility of Risk Assessment Benefits of Risk Assessment: To individualize risk To make decisions about: – Genetic testing – Screening (age to initiate, screening interval, screening modalities, diseases to screen for) – Chemoprevention – Prophylactic surgery To plan lifestyle / dietary / or other interventions - HRT How to assess Models available Role of genetic testing

6. Risk Models - Considerations – What information can the risk model give you? Breast cancer – risk (lifetime, 10 year, 5 year) Gene mutation – prior probability – Is the model validated and in what populations? – What are the benefits of a particular model? – What are the limitations of a particular model?

7. Risk Models Breast Cancer Risk Gail Claus – Not validated, outdated (data collected before BRCA testing) Breast Cancer Risk & BRCA Mutation IBIS/Tyrer-Cuzick BRCAPRO – No personal risk factors (except oophorectomy), no 3 rd degree relatives BOADICEA – No personal risk factors, cumbersome data entry

8. Gail Model Used to determine lifetime and 5 year risk of breast cancer – Lifetime: MRI if >20% – 5 year risk: chemoprevention if > 1.67% Cannot be used; – if patient has had breast cancer or LCIS – Patient is mutation positive – <35 years old Fails to capture: paternal history, age of cancers, ovarian or other cancers

9. IBIS (Tyrer-Cuzick) International Breast Cancer Intervention Study

10. Validated in European population Used to determine lifetime and 10 year risk of breast cancer – Lifetime: MRI – 10 year: not intended for determination of chemoprevention suitability Can be used if: – patient has had LCIS – patient is mutation positive Tends to overestimate risk if there is a history of benign breast disease such as hyperplasia or if a woman has a history of LCIS

11. Usefulness of Risk Information Vs. Usefulness of Genetic Information Both Imaging recommendations Lifestyle change Drug therapy Prophylactic surgery Risk InformationGenetic Information Individual onlyIndividual & Family Numerical valueMore precise assessment

12. BRCA1-2 Mutations Increase the Risk of Cancer More Than Other Factors Relative risk of breast cancer Family history BRCA1-2 mutation Early menarch Late age at birth of 1st child Benign breast disease Hormone replacement therapy Alcohol use

13. Evolving face of Gene Testing HEREDITARY BREAST CANCER GENES HIGH RISKMODERATE RISKINCREASED RISK BRCA1ATMBARD1 BRCA2CHEK2BRIP1 CDH1PALB2NBN PTEN RAD50 STK11 RAD51C TP53 RAD51D many others… Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) **possible increased risk of breast cancer for carriers**

14. Risk Associated with BRCA1/2 Breast Cancer Population riskCarrier risk By age 40.5%10-20% By age 502%33-50% By age 707%56-87% Ovarian Cancer 1%44% BRCA1 27% BRCA2 Ford. Lancet 1994;343:692-695 Struewing. NEJM 1997;336:1401-1408 Easton. AJHG 1995;56:265-271

15. Risks of Other Cancers Male breast cancer (primarily BRCA2) < 6% by age 70 Prostate (BRCA2, possibly BRCA1) 20% by age 80; 3- to 7-fold increase RR Pancreatic cancer (BRCA2) (Rare BRCA1) 2-3% by age 80; 3- to 4-fold increase RR Colon Little or no increased risk Melanoma (BRCA2) Am J Hum Genet 1997;61: 120-8 JNCI 1999;15:1310-6 Dis Colon Rectum 1999;42:1041-5

16. Risk associated with other genes Hereditary Diffuse Gastric Cancer Syndrome CDH1 gene Diffuse gastric cancer – 67-83% risk Lobular cancer of the breast -39-52% risk Peutz-Jeghers Syndrome STK11/LKB1 gene Breast cancer- 44-50% Ovarian cancer – 18-21% risk (ovarian sex cord tumors the most common) Lynch Syndrome Mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2 Ovarian cancer –4-24% risk (4-24% with MLH1 and MSH2, 1-11% for MSH6) Breast cancer risk – conflicting data Uterine cancer risk -25-60% MLH1 and MSH2; 15-26% MSH6 and PMS2) NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

17. Beyond Brca1/2 Understanding of role played by these genes in cancer development – Brca1 /2 alterations also play a role in non-hereditary forms of Breast cancer Understanding of interaction of these genes with other pathways in the cancer cell – RAD etc. Identification of Drugs that may target these cancers – PARP inhibitors, platinum compounds

18. Patient vs. Family Issues Patient – Impact on Risk, Prevention & Treatment Family – Impact on risk & prevention Societal – Societal Screening ??

19. Features of Hereditary B/O Cancer Breast BRCA1: more likely to be ER/PR (-) BRCA2: more likely to be ER/PR (+) Prognosis appears to be the same as for sporadic breast cancer of same histology Ovary Predominantly papillary serous Prognosis may be better than for sporadic ovarian cancer Lancet 1998;351:316-21 J Clin Oncol 1999;17:3396-402 New Engl J Med 1996;335:1413-6 JAMA 2000;283:2260-5

20. Clinical Management of BRCA Mutation-Positive Patient Positive BRCA1 or BRCA2 test result Possible testing for other adult relatives (FDR at 50% risk) Increased surveillance Prophylactic surgery Lifestyle changes Prevention ASCO

21. Increased Surveillance - Breast Recommendations for women: Breast awareness starting at age 18 Clinical breast exam every 6-12 months starting at age 25 (no clinical trials done) Breast screening: – Age 25-29 – annual breast MRI preferred or mammogram if MRI not available (individualize if breast cancer diagnosed in family < 25) – Age 30-75-annual mammogram + MRI – Age >75- management on individual basis Ongoing research looking at various imaging modalities and schedule (Lowry et al. Cancer 2012) Recommendations for Men Breast self exam training and education starting age 35 Clinical breast exam yearly starting age 35 NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

22. Increased surveillance - Ovary For those not selecting salpingo- oophorectomy: Can do transvaginal US and Ca-125 – but data do not support routine ovarian screening and these two tests have not been shown to be sufficiently sensitive or specific to support a recommendation. NCCN version 2.2016 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

23. Surveillance- other Education regarding signs and symptoms of cancers associated with mutations. No specific guidelines for screening for pancreas or melanoma – but may be individualized Ongoing research looking at screening for pancreas cancer – endoscopic US…

24. Chemoprevention Tamoxifen & Evista – ~ 50 % reduction in high risk women – data in mutation carriers very limited Aromatase Inhibitors - ~50% reduction in high risk women OCP – reduce risk of ovarian cancer by ~50% in Brca1 and ~60% in Brca2 – OCP conflicting data on breast cancer risk – Increased risk in Brca1 but not in Brca2 Narod et al NEJM 1998 Moorman et al JCO 2013 Haile et al Cancer Epid Bio & Preven 2006

25. Selection of Drug Therapy Factors to consider Menopausal status – tamoxifen in pre & post; AI and Evista in post only Other health issues: – Bone health, prior ho TE events – Severity of vasomotor symptoms, Toxicity – Tamoxifen -increased risk endometrial cancer, cataracts, TE events; + effect bone – Evista- increased TE events; + effect bone – AI – arthralgias, negative effect on bone

26. Prophylactic Surgery Mastectomies Prophylactic mastectomies Decrease risk of breast cancer by ~ 90% Psychosocial effects of surgery Type and timing of reconstruction Hartman et al. NEJM 1999 Hartman et al NEJM 2001 Meijers-Heijboer et al. NEJM 2001 Rebbeck et al JCO 2004

27. Prophylactic surgery - ovaries Bilateral salpingo-oophorectomy Recommended for women between 35-40 and upon completion of child bearing. Reduced risk of ovary, fallopian or primary peritoneal cancer - 80-85% Reduced all cause mortality by 77% - among all ages in Brca1 but only in ages 41-60 in Brca2 ( Detection of clinically occult neoplasm at time of RRSO – 4.6% in Brca1 and 3.6% in Brca2 RRSO reduces risk of breast cancer by ~50% Greater protective effect for women undergoing surgery 51 Impact on & management of menopausal symptoms Rebbeck et al NEJM 2004 Rebbeck et al JCO 2005 Chlebowski et al

28. Salpingectomy vs. Oophorectomy SGO Clinical Practice Statement: Salpingectomy for Ovarian Cancer Prevention November 2013 “Salpingectomy may be appropriate and feasible as a strategy for ovarian cancer risk reduction” women who have BRCA1 or BRCA2 germline mutations should be counseled regarding bilateral salpingo-oophorectomy, after completion of childbearing, as the best strategy for reducing their risk of developing ovarian cancer. In the event that these women opt to delay or forego risk-reducing bilateral salpingo- oophorectomy, they should be counseled regarding risk-reducing salpingectomy when childbearing is complete followed by oophorectomy in the future, although the safety of this approach has not been studied

29. Lifestyle modification Much research ongoing looking at each of these areas. Data exists in general population and in breast cancer survivors but no data on mutation carriers Exercise Alcohol consumption Dietary strategies

30. Thank you! questions / comments?