Management of BRCA Positive Breast Cancer Archana Ganaraj, MD February 17, 2018 UPDATE ON WOMEN S HEALTH
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
Risk Factors Age Family History Personal History of Breast Cancer Reproductive Factors Radiation Exposure
Risk Factors Age Family History Personal History of Breast Cancer Reproductive Factors Radiation Exposure
Sporadic versus Hereditary Causes of Cancer 90-93% 7-10% Sporadic Hereditary
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
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
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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
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
BRCA 1 and 2 Prevalence: 1:350 (0.3%) general population 1:40 (2.5%) Ashkenazi population 1: 5 (20%) Ashkenazi w/ family hx
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
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
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
Now What? Screening Chemoprevention Surgery
Surveillance for BRCA Carriers Breast Cancer Surveillance Procedure Age to Begin Frequency Breast Awareness Clinical Breast Exam MRI and/or Mammogram 18 25 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
Mri in BRCA + Women MMG US MRI Sensitivity 36% 33% 77% Specificity 99% 96% 95%
Now What? Screening Chemoprevention Surgery
Chemoprevention P1 Trial # of cancers found Tam Placebo General pop 124 244 p<.00001 BRCA 1 5 3 BRCA 2 3 8 Fisher et al,jnci,1998,90 (18) King, et al, JAMA,2001,286(18)
Tamoxifen In BRCA patients, Tamoxifen decreased the risk of invasive breast cancer by 62% in BRCA2 carriers No decrease in BRCA1 patients
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.31:25 2013
Now What? Screening Chemoprevention Surgery Oopherectomy
Prophylactic oophorectomy among BRCA 1/2 patients Observed # of Strategy N breast cancers Surveillance 72 8 PO 101 3 p=.01 Offit et Offit al, 2002,,ASCO; et al, 2002,,ASCO; 21 21
Prophylactic oophorectomy for Breast Cancer Risk Prospective, non-randomized, casecontrol, 122 BRCA-1 heterozygotes Strategy N # breast cancers Surveillance 79 30 (38%) PO 43 10 (23%) HR =.53; 95% CI =.33-.84 Rebbeck et al, JNCI, 1999, 91 (17) Rebbeck et al, JNCI, 1999, 91 (17)
Now What? Screening Chemoprevention Surgery Breast surgery
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: 1471-1477 The Lancet, 2002, 359,9316: 1471-1477
Effect of PM on Breast Cancer Incidence and Death Expected Observed Risk Red % Incidence Mod risk 37.4 4 90 High risk 30 3 90 Death Mod risk 10.4 0 100 High risk 19.4 2 89.7 Hartmann, NEJM, 1999, 340(2) Hartmann, NEJM, 1999, 340(2)
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)
Radical Mastectomy
Mastectomy with Reconstruction
Total Skin Sparing Mastectomy with DIEP flap
Genes Associated with Increased Risk for Breast Cancer Gene BRCA1 65-81% BRCA2 45-85% TP53 50-80% PTEN 50-85% CDH1 39-52% STK11 35-50% ATM 17-52% Lifetime Risk for Breast Cancer PALB2 20-40%* NBN Up to 30% CHEK2 15-25% NF1 15-25% P16 15-25% BRIP1 Adapted from Euhus, Surg Clin N Am 93(2013) 341-362 10-20% or higher
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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