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Cancer Genetics

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

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Cancer Genetics

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

  2. I have no disclosures.

  3. 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

  4. May 14th, 2013

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

  6. 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

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

  8. Imaging Left Breast

  9. 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

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

  11. Additional History

  12. Additional History • Genetic Testing Sent • BRCA 2 gene mutation identified

  13. 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

  14. 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

  15. Sporadic Cancer Two acquired mutations Hereditary Cancer One inherited and one acquired mutation Sporadic Versus Hereditary Cancer

  16. HBOC Cancer Risks *Melanoma risk also increased

  17. 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 alternatingwith 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 40or once child-bearing is complete

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

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

  20. Inheritance: Autosomal Dominant

  21. 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

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

  23. Imaging

  24. 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

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

  26. 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

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

  28. 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].

  29. 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

  30. 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

  31. 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)

  32. Inheritance: Autosomal Dominant

  33. 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

  34. 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 Single Gene to Panel Testing

  35. 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 Multi-Gene (NGS) Panels

  36. Why Bother with Genetic Counseling?

  37. More labs to choose from

  38. More tests to choose from

  39. Potential Results

  40. More potential for “complicated” results

  41. 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

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