Jason P. Wilson, MD, MBA, FACS Deena Wahba, MSc, CGC Cancer Genetics Jason P. Wilson, MD, MBA, FACS Deena Wahba, MSc, CGC

I have no disclosures.

Objectives Provide Examples of Genetic Testing in Clinical Practice Describe Current State of Genetic Testing Provide Guidance on When to Refer patients for Genetic Testing Provide Guidance on Direct to Consumer Products

May 14th, 2013

https://www. nytimes. com/2019/04/16/health/23andme-brca-gene-testing https://www.nytimes.com/2019/04/16/health/23andme-brca-gene-testing.html

23andMD Testing for BRCA1/2 Genotyping for 3 particular mutations within the BRCA1 and BRCA2 genes Tests ONLY for 3 mutations common in the Eastern European (Ashkenazi) Jewish population >1800 known pathogenic mutations in BRCA1 and BRCA2 Provides pre-results online education (autoplay) FDA recommends confirmatory testing through clinical lab if positive Concerns re: false reassurance with “negative” results

Case 1 37 year old female Palpable mass left breast Mammogram showed a 1.3 cm mass 12:00

Imaging Left Breast

Pathology Left: Invasive Ductal Carcinoma Grade 3, poorly differentiated ER-, PR-, Her-2 – (FISH: Not amplified) Clinical T1cN0M0 (Stage IA AJCC 7th) MRI no additional disease

Additional History Family History: Pat. grandmother: Breast Cancer (37) Pat. Aunt: Breast cancer (49) Pat. Cousin: Breast Cancer (37)

Additional History

Additional History Genetic Testing Sent BRCA 2 gene mutation identified

Surgery Bilateral mastectomy with reconstruction Pathology: 2.5 cm cancer, negative margins, negative nodes Stage IIA (T2N0M0) Went on to chemotherapy and thus far doing well

Hereditary Breast and Ovarian Cancer Syndrome (HBOC) BRCA1 or BRCA2 Mutation  HBOC Normal function: Tumor Suppressors Incidence of Germline Mutations: BRCA1: 1/974 BRCA: 1/734 Ashkenazi Jewish: 1/40 Genes: BRCA1 and BRCA2- Tumor Suppressors Incidence of mutation: BRCA1: 1/974 BRCA2: 1/734 Ashkenazi Jewish: 1/40 BRCA: Breast Cancer BRCA1 found prior to BRCA2

Sporadic Versus Hereditary Cancer Sporadic Cancer Hereditary Cancer Two acquired mutations One inherited and one acquired mutation Why we see younger ages… hereditary cancer = 2 more hit because already have one non-working copy of BRCA

HBOC Cancer Risks Cancer Type General Population BRCA1 Carrier Breast Cancer (BC) 12% 47-66% Triple negative 40-57% ER+/PR+ 2nd BC within 5 yrs of first 2% 20% Ovarian 1-2% 35-46% 13-23% Male Breast 0.1% 5-10% Prostate 15-18% 30% 39% Pancreatic 0.50% 1-3% 2-7% Always stress: does not mean you will get cancer!!! Increased lifetime risk *Melanoma risk also increased

BRCA Guidelines Female Breast Cancer Management: Monthly breast self-examinations, beginning at age 18 Yearly breast MRI beginning at age 25 Bi-yearly breast screening including breast MRI alternating with mammograms every 6 months beginning at age 30 Consider use of chemopreventative medication (~50% risk reduction) Consider prophylactic mastectomy (>90% risk reduction) Ovarian Cancer Management Pelvic examination, trans-vaginal ultrasound with color doppler, and CA-125 blood test every 6 months, beginning at age 30 Recommend bilateral salpingo-oophorectomy (BSO) by age 40 or once child-bearing is complete *Mutation carriers have a 50% chance of developing BC by age 50, compared to gen. population 2% * What makes us suspicious: young ages, multiple females generation to generation, combination of certain cancers (ovarian, breast), triple negative (er/pr/her2 = 18%), bilateral,rare (male breast) * Limitations of family hx: male heavy, paternal contribution, small family size, limited info/adoption/no contact/etc *Homozygous mutations in BRCA2 → Fanconi anemia type D

Clinic breast exam beginning at age 35 BRCA2 Mutation Carriers Males Clinic breast exam beginning at age 35 Prostate screening beginning at age 45

Male and Female Males and Females BRCA2 Mutation Carriers Males and Females Consider research based pancreatic cancer screening (CAPs protocol) Consider annual dermatologic and ocular exams (melanoma)

Inheritance: Autosomal Dominant

Case 2 68 yo female Asymptomatic History significant for a strong family history of gastric cancer (father, paternal uncle, and a nephew) Genetic testing revealed a CDH1 gene mutation

Case 2 Patient previously underwent a prophylactic total gastrectomy Presented for annual mammography Left: Architectural distortion

Imaging

Biopsy Path: Invasive Lobular Carcinoma Grade: 2 ER 100%, PR 100%, Her-2 – Staging: T2N0M0 Anatomic: IIA Prognostic: IB MRI for staging shows right masses

Biopsy Path: Invasive Lobular Carcinoma Grade: 2 ER: 100%, PR 100%, Her-2- Staging: T2N0M0 Anatomic: IIA Prognostic: IB

Surgery Bilateral mastectomies Final pathology: Left: multifocal carcinoma (ductal and lobular) 23 mm, negative margins and nodes Right multifocal lobular carcinoma, 25 mm, negative margins and nodes Prognostic IA Right; IIA Left

Further Therapies Likely Chemotherapy, but consultations pending for further adjuvant therapy

Hereditary Diffuse Gastric Cancer Syndrome (HDGC) CDH1 Mutation  HDGC Normal Gene Function: Tumor Suppressor Cancer Risks (to age 80): Gastric Cancer Male: 70% (CI 59%-80%) Female: 56% (CI 44%-69%) Breast Cancer Female Lobular Breast Cancer: 42% (CI 23%-68%) [Hansford et al 2015].

Gastric Cancer Management Average age at diagnosis is 38yrs EGD with biopsies of stomach Every 6-12 months: multiple random biopsies & biopsies of subtle lesions Begin 5-10yrs prior to youngest diagnosis of gastric cancer in family No proven effectiveness/benefit Negative biopsies ≠ no cancer

Gastric Cancer Management Recommendation: Prophylactic Total Gastrectomy (PTG) Performed between 18-40yrs Once growth period complete unless early onset gastric cancer in family PTG specimen showed early gastric cancer in ALL “prophylactic” cases  [Norton et al 2007] In young healthy individuals with an experienced healthcare team: Mortality <1% Morbidity is 100% (rapid intestinal transit, diarrhea, eating habit alterations, and weight loss, malabsorption  osteoporosis, malnutrition) F/U with a dietician extremely important

Breast Cancer Management Lobular Breast Cancer: 42% (CI 23%-68%) Average age at diagnosis is 53yrs Monthly self breast beginning at 20 Biannual clinical breast beginning at 30 Breast MRI beginning at age 30 Breast MRIs preferred as mammography has a lower sensitivity for lobular breast cancer Consideration of prophylactic mastectomy (>90% risk reduction) Chemoprevention options (~50% risk reduction)

Inheritance: Autosomal Dominant

Case 2 CDH1 mutation explains her diagnosis with bilateral invasive lobular carcinoma Underwent bilateral mastectomy  risk for third primary is reduced by >90% Patient underwent prophylactic gastrectomy in 2011 States her daughter was negative for the familial CDH1 mutation

Individual Risk Factors Bilateral, multifocal tumors, multiple primaries Atypical age/gender/site Breast cancer ≤50 Male breast cancer any age Ovarian cancer any age Triple negative breast cancer ≤60 Ashkenazi Jewish ancestry Family Risk Factors 1st degree relative with any of the individual risk factors above >1 relatives with breast/pancreatic/prostate cancer

Single Gene to Panel Testing Pre-2012: single gene (or targeted genes) testing ~2012 labs introduce breast, colon, ovarian and pan-cancer panels (absent BRCA1/2) June 2013 SCOTUS strikes down gene patents

Multi-Gene (NGS) Panels Single gene/syndrome testing is hard to justify now Seldom order BRCA1/2 or CDH1 Genetic tests to look at dozens of genes related to cancer Similar cost and turn around time as gene specific testing

Why Bother with Genetic Counseling?

More labs to choose from Not all labs are created equal Insurance may use a specific laboratory Insurance may require additional documentation Insurance may even require genetic counseling

More tests to choose from Other high and moderate risk breast cancer and other cancer risk genes We have moved beyond BRCA1/2 only Pandora’s Box? How many genes is too much? Is there such a thing as TMI? How much depends on patient preference?

Positive Negative Unclear Potential Results A gene variant known to increase cancer risk was detected May affect cancer screening, prevention, and treatment Positive No cancer causing variant was detected Cancer risks may still be increased based on personal and family history Screening and prevention based on personal and family history Negative A genetic variant was found, but impact on cancer risk is unclear Result is not positive or negative Unclear

More potential for “complicated” results 14-25% in Caucasians and up 50% in African Americans Increased rate of Variants of Uncertain Significance (VUS) More common in elderly patients or those who have had chemotherapy Can rarely indicate an underlying heme malignancy Potential for mosaicism e.g. Lynch in a breast cancer family or vice versa Potential for “surprise” results

Conclusion Identifying individuals with hereditary cancer syndromes significantly impacts patients AND their families and improves health outcomes Genetic testing landscape has expanded drastically over the past 10 yrs Be wary with DTC testing sensitivity and specificity Genetic counseling referrals are available to ensure patients receive detailed information about genetic testing and understand genetic test results