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

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

7. 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

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

9. Imaging Left Breast

10. 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

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

12. Additional History

13. Additional History Genetic Testing Sent
BRCA 2 gene mutation identified

14. 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

15. 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

16. 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

17. 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

19. 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

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

21. 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)

22. Inheritance: Autosomal Dominant

23. 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

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

25. Imaging

26. 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

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

28. 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

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

30. 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].

31. 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

32. 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

33. 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)

34. Inheritance: Autosomal Dominant

35. 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

37. 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

38. 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

39. 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

42. Why Bother with Genetic Counseling?

43. 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

44. 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?

45. 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

46. 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

47. 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