Hereditary Breast Cancer. Nicole Kounalakis, MD Assistant Professor of Surgery University of Colorado Medical Center

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1 Hereditary Breast Cancer Nicole Kounalakis, MD Assistant Professor of Surgery University of Colorado Medical Center

2 Outline Background Assessing risk of patient Syndromes BRCA 1,2 Li Fraumeni Cowden Hereditary Diffuse Gastric Cancer Conclusions

3 Background Breast cancer 1 in 8 women 12% of women living up to age % have a family hx breast cancer Genetic syndromes in breast cancer All breast cancers: 5-6% 5 Ashkenazi women: 12-13% 13% Most common genetic syndrome is BRCA1/2 American Cancer Society 2010 Malone KE et al. JAMA 1998

4 Hereditary breast and ovarian cancer Most common reason for visit to genetics counselor BRCA syndromes Mutation and syndromes defined in 1993, 1994

5 Cancer and genetic mutations All cancers develop from genetic mutations Sporadic cancers: Mutations are NOT passed on or inherited

6 Hereditary cancers High penetrance If the genetic mutation is present high likelihood of cancer Vertical transmission Autosomal dominant Features of Clustering of other cancers Early onset of cancer

7 Familial cancers Familial cancers Lower penetrance genes Autosomal recessive Associated with clustering of sporadic cancers Shared environment

8 Genetics in hereditary breast cancer syndromes Gene Syndrome Chromosome site Gene frequency Gene penetrance BRCA1 HBOC 17q21 rare Very high BRCA2 HBOC 13q12-13 rare High p53 Li- Fraumeni 17p13.1 Very rare High CDH1 HDGC 16 Very rare Very High PTEN Cowden 10q Very rare High

9 Assessing risk of genetic syndrome Patient: do I have a genetic syndrome?

10 Questions pertaining to the patient Personal hx of breast cancer with one of the following Age: <45 Bilateral breast cancers Combination of breast + Thyroid, sarcoma, adrenocortical,, pancreatic, gastric cancer, endometrial, brain tumors ovarian, fallopian, peritoneal cancer Ashkenazi jewish descent or male with breast cancer At any age NCCN guidelines 10/21/10

11 Questions about the family Family member with known genetic mutation Male breast cancer Bilateral breast cancers Breast cancer + ovarian/fallopian tube/primary peritoneal Thyroid, sarcoma, adrenocortical,, endometrial, gastric cancers, pancreatic, brain tumors all from same side of the family NCCN guidelines 10/21/10

12 BRCA1 Cancer risks breast 55-85% ovarian 40-50% Elevated risk Prostate (unclear %) Pancreatic cancer <10 % Chen, S, et al. J Clin Oncol 07; 25:1329 Ford et al Am J Hum 1998

13 BRCA2 Cancer risks Breast 50-85% Ovarian 15-25% Male breast cancer % Prostate 35-40% Pancreatic cancer <10% Levy-Lahad et al Br J Cancer 2007

14 BRCA1 vs 2 Similarities and differences Similarities Rarely present with in situ disease High risk of contralateral cancer or new primary Differences Tumor biology Triple negative tumors = BRCA1 ER/PR+ tumors = BRCA2 Age of onset BRCA1: younger age of onset in both breast and ovarian Male breast cancer only seen in BRCA2

15 BRCA carriers vs noncarriers For BRCA1 Worse short term, long term overall survival with breast cancer Triple negative breast cancers For BRCA2 Similar survival to noncarriers ER/PR+ tumors Lee et al Breast Cancer Res Treat (2010)

16 Summary of breast cancer risk in BRCA patients

17 How to test for BRCA 1/2 For patients without cancer Ask if any living relatives have had breast/ovarian cancer Test them for genetic mutation first

18 How to test a high risk patient Myriad Genetics Laboratories Known family mutation yes no Test mutation in patient $385 Perform full sequencing $ BRCA pt If both sides of family are affected, perform full sequencing $3120

19 Ashkenazi Jewish pts Test 3 known genetic mutations $ BRCA pt If both sides of family are affected, perform full sequencing $3120

20 Myriad and genetic testing

21 BRCA pt, no cancer: surveillance Exams 18 yo: : monthly breast self-examination examination 25 yo: : clinical breast examination 2-4x/yr 2 Mammography & MRI 25 yo: : annually, both or individualized based on the earliest age of onset in the family Ovarian cancer screening 35yo 2x/yr with ultrasound, pelvic exam and serum CA-125 NCCN guidelines 2010 American Cancer Society guidelines 2010

22 Surveillance with MRI in BRCA pts BRCA 1 sens BRCA 1 spec BRCA 2 sens BRCA 2 spec MRI 92% 79% 58% 82% Mam. 23% 92% 50% 94% Both 92% 74% 92% 78% Leach et al, Lancet 2005

23 Men with BRCA2 mutation Scant literature Breast self exam, education Consider baseline mammogram Annual mammograms for gynecomastia,, glandular breast tissue Adhere to prostate screening guidelines

24 Prevention with tamoxifen No data on cancer prevention in BRCA mutation carriers taking tamoxifen

25 BRCA pts: Surgical options Bilateral prophylactic mastectomies Pros risk for breast cancer by >90% Will potentially eliminate need for chemotherapy, radiation Cons No overall survival benefit lower breast cancer risk in BRCA2 than previously reported High ppv of mammogram/mri screening in diagnosing an early stage breast cancer Rebbeck TR J Clin Oncol 2004; 22:

26 BRCA pts: surgical options Prophylactic bilateral oopherectomy risk of gynecological cancers risk of breast cancer If done in premenopausal women Improves survival Overall survival Breast cancer specific survival Ovarian cancer specific survival Domchek et al JAMA 2010

27 Pt refuses mastectomies + + Lumpectomy, xrt, chemo BSO Tamoxifen Metcalfe K et al J Clin Oncol 2004

28 By adding tamoxifen,, BSO to breast conservation treatment risk of contralateral breast 18.8% for BRCA1 carriers vs 43.4% 13.1% for BRCA2 carriers vs 34.6% Metcalfe K et al J Clin Oncol 2004

29 BRCA mutations targeted BRCA1 pts therapy Triple negative tumors Currently no targeted systemic treatment BRCA mutation Research in these pts has led to greater understanding of triple negative cancers

30 Parp inhibition in BRCA mutations Cell growth= cancer BRCA deficient cell Cell death= no cancer

31 Triple negative breast cancers Worse outcomes recurrence survival Younger age of diagnosis Ethnic groups Increased in African American women No targeted treatments

32 Summary for BRCA pts Genetic testing/ counseling for pts with >10% risk or greater Aggressive surveillance starting at 25 Annual MRI, mammograms Ovarian cancer screening Surgical options Bilateral mastectomies, BSO Breast conservation, BSO, tam

33 Li-Fraumeni syndrome Inherited genetic syndrome Autosomal dominant P53 mutation 1% of all inherited breast cancer syndromes Wide spectrum of tumors Soft tissue, bone sarcomas Brain, adenocortical tumors Leukemia Premenopausal breast cancer

34 Cancer risk 50% of carriers develop cancer by age 30 90% by age 70 Breast cancer 20-30% of pts will develop breast cancer Increased risk of multiple breast cancers ¼ of pts with breast cancer also have another type of cancer Hisada M, J Natl Cancer Inst. 1998

35 Pedigree of Li Fraumeni family

36 Screening/treatment Breast cancer Annual mammograms, MRI Bl mastectomies Poor screening for most cancers associated with syndrome Targeted survellience based on family hx Annual comprehensive physical exam Focus on skin, neurologic exams

37 Cowden syndrome Very rare hereditary syndrome 1 in 200,000 Named after the Cowden family First documented to have the disease in 1963 PTEN mutation Multiple harmatomas and/or cancerous lesions Skin, mucous membranes, breast, thyroid, endometrium,, brain, colon Macrocephaly Developmental delay

38 Breast cancer lifetime risk 25-50% 50% Avg age Thyroid disease 70% of pts with Cowden disease All have characteristic mucocutaneous lesions Kerotoses, trichilemmomas,, papules

39 Skin features of Cowden syndrome

40 Cowden syndrome management Women Clinical breast exam annual 25yo Mammogram, MRI annual at 30-35yo 35yo Endometrial cancer screening Surgical options Mastectomies, hysterectomy Men and women Annual comprehensive physical exam starting at 18 yo Thyroid US at 18, consider annual Frequent dermatologic exams

41 Hereditary diffuse gastric cancer Autosomal dominant cancer syndrome CDH1 gene mutation risk: Results in E cadherin protein Diffuse type gastric cancer 70% risk Lobular breast cancer 20-40% lifetime risk Guilford et al Gastric Cancer (2010) 13: 1 10

42 Occurs in 1% of pts with DGC Seen in various ethnic groups rarely found in countries w/ high rates of sporadic gastric cancer Korea, Japan Seen in Europe Higher incidence: New Zealand Maori Indigenous Polynesian population

43 Gastric cancer Highly penetrant Mean age dx: : 40 Median age dx: : 33 Youngest diagnosed: 14 By age of 80yrs old 67% men, 83% women have gastric cancer Present with advanced disease Linitis plastica,, rare nodal involvement Multiple submucosal foci Difficult to screen

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45 Who should be tested Diffuse gastric cancer Two 1 st or 2 nd degree relatives One must be <50 yo 3 cases at any age Using these criteria ½ of pts will have this syndrome offered at yrs old

46 Endoscopic surveillance Controversial Cancer infiltrates beneath intact epithelium Rarely seen during endoscopy Annual endoscopy recommended only when Refusing surgery <20 yo Prior to surgery in known carriers

47 Surgery Prophylactic total gastrectomy At age of 20 yrs old rare for advanced disease to develop <20yrs Need to resect all gastric mucosa 3-44 cm above GE jxn: document squamous esophageal mucosa to duodenum Prophylactic bilateral mastectomies Or survellience: : MRI, mammograms

48 Summary Review of the main hereditary breast cancer syndromes Very rare, high penetrance Assess, screen, treat these patients Syndromes increased our understanding of the cancers involved