Management of BRCA Positive Breast Cancer. Archana Ganaraj, MD February 17, 2018 UPDATE ON WOMEN S HEALTH

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1 Management of BRCA Positive Breast Cancer Archana Ganaraj, MD February 17, 2018 UPDATE ON WOMEN S HEALTH

2 The number of American women who have lost their lives to breast cancer outstrips the total number of American lives lost in the Civil War, World War I and II, the Korean War and the Vietnam War combined. Over the past 30 years, in the United States alone, over one million women have died of breast cancer. Over 230,000 women a year are diagnosed with new breast cancers

3 Risk Factors Age Family History Personal History of Breast Cancer Reproductive Factors Radiation Exposure

4 Risk Factors Age Family History Personal History of Breast Cancer Reproductive Factors Radiation Exposure

5 Sporadic versus Hereditary Causes of Cancer 90-93% 7-10% Sporadic Hereditary

6 Family History 90% of all breast cancer is sporadic 5-10% of breast cancers are hereditary Of the hereditary cancers 52% are related to the BRCA-1 gene 32% are related to the BRCA-2 gene 16% are related to other genes

7 BRCA genes are tumor suppressors The majority of hereditary breast cancers are caused by mutations in the BRCA 1 and BRCA 2 genes BRCA genes are tumor suppressor genes- these genes help to repair breaks in double stranded DNA As long as the gene is functioning normally, it helps to prevent cancer from forming

8 Mike s new wife is very comely. Mike s new wife it very comely. Mike s new wife is very homely.

9 How tumor suppressor function is lost 2 normal genes 1 normal and 1 damaged gene 2 damaged genes Tumor develops 11 damaged normal and gene 1 normal damaged gene gene 2 damaged genes Tumor develops

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11 Hereditary Breast and Ovarian Cancer BRCA - 1 gene increases risk for breast, prostate cancer ovarian, and prostate cancer BRCA - 1 gene increases risk for breast, ovarian, and BRCA - 2 gene increases risk for male breast cancer, stomach, pancreas, gallbladder and bile ducts, melanoma, prostate, BRCA and - 2 ovarian gene increases carcinoma risk for male breast cancer, stomach, pancreas, gallbladder and bile ducts, melanoma, prostate, and ovarian carcinoma

12 BRCA 1 and 2 Prevalence: 1:350 (0.3%) general population 1:40 (2.5%) Ashkenazi population 1: 5 (20%) Ashkenazi w/ family hx

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14 BRCA-1 and BRCA-2 Lifetime Risk of Developing Cancer (age 90) BRCA-1 and -2 Ave pop Breast 50-85% 12% Ovarian 16-60% 1% Struewing JP et al. NEJM 1997;336:1401-8, Ford D et al. Am J

15 NCCN guidelines for genetics work-up: affected Breast Cancer Diagnosis At or Under age 45 At or Under age 60 with triple negative subset One breast cancer at any age and any of the following: >1 relative with breast cancer < 50 >1 relative with ovarian cancer at any age >2 relatives with breast or pancreatic at any age Personal history of pancreatic cancer at any age From a population at risk Any individual with personal/family history of >3 various cancers/features: Cancers: breast, pancreatic, prostate (Gleason >7), melanoma, sarcoma, ACC, brain tumors, leukemia, diffuse gastric, colon, endometrial, thyroid, kidney, Features: dermatologic manifestations, macrocephaly, hamartomatous polyps of GI tract

16 NCCN guidelines for genetics work-up: unaffected Any of the following Known mutation >2 breast primaries in a single individual >2 individuals with breast primaries on same side of the family, one < 50yo Ovarian Cancer Male Breast Cancer First or Second degree relative with breast cancer < 45yo Any individual with personal/family history of >3 various cancers/features: Cancers: breast, pancreatic, prostate (Gleason >7), melanoma, sarcoma, ACC, brain tumors, leukemia, diffuse gastric, colon, endometrial, thyroid, kidney, Features: dermatologic manifestations, macrocephaly, hamartomatous polyps of GI tract

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20 Now What? Screening Chemoprevention Surgery

21 Surveillance for BRCA Carriers Breast Cancer Surveillance Procedure Age to Begin Frequency Breast Awareness Clinical Breast Exam MRI and/or Mammogram Every 6 12 months Age 25 for MRI (preferred) or mammography Age 30 for both MRI and mammography Individualized to younger ages based on the earliest diagnosis in the family

22 Mri in BRCA + Women MMG US MRI Sensitivity 36% 33% 77% Specificity 99% 96% 95%

23 Now What? Screening Chemoprevention Surgery

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25 Chemoprevention P1 Trial # of cancers found Tam Placebo General pop p< BRCA BRCA Fisher et al,jnci,1998,90 (18) King, et al, JAMA,2001,286(18)

26 Tamoxifen In BRCA patients, Tamoxifen decreased the risk of invasive breast cancer by 62% in BRCA2 carriers No decrease in BRCA1 patients

27 Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers This study looked at 1,538 BRCA 1 and 881 BRCA 2 mutation carriers who had a prior diagnosis of breast cancer. Of those, 383 BRCA 1 and 454 BRCA 2 patients took Tamoxifen post diagnosis There was a 42% decrease in breast cancer incidence among BRCA 1 carriers There was a 52% decrease in breast cancer incidence among BRCA 2 carriers Phillips et al, JCO;vol.31:

28 Now What? Screening Chemoprevention Surgery Oopherectomy

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30 Prophylactic oophorectomy among BRCA 1/2 patients Observed # of Strategy N breast cancers Surveillance 72 8 PO p=.01 Offit et Offit al, 2002,,ASCO; et al, 2002,,ASCO; 21 21

31 Prophylactic oophorectomy for Breast Cancer Risk Prospective, non-randomized, casecontrol, 122 BRCA-1 heterozygotes Strategy N # breast cancers Surveillance (38%) PO (23%) HR =.53; 95% CI = Rebbeck et al, JNCI, 1999, 91 (17) Rebbeck et al, JNCI, 1999, 91 (17)

32 Now What? Screening Chemoprevention Surgery Breast surgery

33 Conservative Management of breast cancer in BRCA1/2 patients Ipsilateral Contralateral 5y 10y 5y 10y Sporadic 15% 20% 4% 7% N=105 Genetic 22% 41% 22% 31% N= 22 The Lancet, 2002, 359,9316: The Lancet, 2002, 359,9316:

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35 Effect of PM on Breast Cancer Incidence and Death Expected Observed Risk Red % Incidence Mod risk High risk Death Mod risk High risk Hartmann, NEJM, 1999, 340(2) Hartmann, NEJM, 1999, 340(2)

36 Prospective study of PM in patients with BRCA 1 & 2 mutations Strategy N #cancers Surveillance 63 8 Prophylactic Mastectomy 76 0 p=.003 Meijers-Heijboer et al, NEJM,2001, 345(3)

37 Radical Mastectomy

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39 Mastectomy with Reconstruction

40 Total Skin Sparing Mastectomy with DIEP flap

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43 Genes Associated with Increased Risk for Breast Cancer Gene BRCA % BRCA % TP % PTEN 50-85% CDH % STK % ATM 17-52% Lifetime Risk for Breast Cancer PALB %* NBN Up to 30% CHEK % NF % P % BRIP1 Adapted from Euhus, Surg Clin N Am 93(2013) % or higher

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45 Who Should Be Tested? NCCN Guidelines for panel testing Consider when More than one gene could explain potential inherited condition Individuals tested negative with past genetic testing for single syndrome Exercise Caution Ideally offered by cancer genetics professionals including pre- and post test counseling Risks, management of moderated genes may not be clear Certain mutations in the same gene may pose different risks Commercial tests differ, important to select quality lab

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48 Knowledge is Power and Hope! 12 year survivor 55 year survivor