2. Clinical Cancer Genetics in Breast and Ovarian Cancers The Role of Cancer Genetics in Precision Medicine April 17, 2018 & May 1, 2018
Kamel Abou Hussein, MD
Assistant Professor of Medicine
Division of Hematology and Oncology
Preeti Sudheendra, MD
Assistant Professor of Medicine
Division of Hematology and Oncology

3. Why Does Cancer Occur?

4. When to Suspect Hereditary Cancer
Breast cancer diagnosed ≤ 50 years
Ashkenazi Jewish ancestry and breast/ovarian (or pancreatic) cancer
Triple negative breast cancer ≤ 60
Multiple primary cancers
Breast cancer in a male
Ovarian cancer at any age
Family history and/or known familial mutation
NCCN version “Genetic/Familial High Risk Assessment: Breast and Ovarian”;

5. Cancer Risk Assessment Basics
Patient meets criteria for genetic testing
NCCN criteria
Insurance criteria
Meet with certified genetic counselor (CGC) and MD or APN
3-4 generation pedigree
Reproductive and medical history
Risk factor review
Selection of appropriate genes to be tested
Blood drawn at visit
Results disclosure
Via phone or in person
Discussion point – review both maternal and paternal family history for all types of cancers

6. Benefits of Genetic Testing
For those with cancer:
Implications for medical management
A possible answer to “Why?”
For those without cancer:
Implications for risk reduction and increased surveillance
For all:
Impact on risk of family members

7. Limitations and Risk of Testing
Negative result
Still doesn’t answer the “why?”
Doesn’t mean a person without cancer will never get cancer
Cancer risk may still be elevated
Variant of uncertain significance
Doesn’t clarify risk
Can cause anxiety
Positive result
Can cause anxiety especially in family members
Genetics is a “family affair”
Concerns about genetic discrimination

8. Next Steps Positive Result (i.e. pathogenic mutation)
Medical management based on risk by gene
Negative or VUS result
Breast cancer risk assessment (if personal or family risk factors)
Short term (5 year) risk > 1.67%
Discuss risk reduction endocrine therapy
Long term (lifetime) risk > 20%
Discuss breast MRI for surveillance
Gail and Tyrer-Cusick (IBIS) risk models

9. Managing High Breast Cancer Risk due to Personal and Family History

10. Principles of Chemoprevention
If 5 year risk > 1.67%  consider endocrine therapy for risk reduction (i.e. chemoprevention)
Duration of therapy 5 years
Choice of agents:
Tamoxifen
Raloxifene
Aromatase inhibitors – not currently approved

11. Principles of Increased Surveillance
If lifetime risk > 20%  consider use of breast MRI
MRI used in conjunction with mammogram
Optimal schedule unknown
Commonly staggered every 6 months
Particularly useful for patients with dense breasts
Discuss pros and cons of MRI

12. Managing Hereditary Breast and Ovarian Cancer (HBOC) Risk

13. Hereditary Breast Cancer Genes
High Risk
Moderate Risk
Increased Risk
BRCA1
ATM
BARD1
BRCA2
CHEK2
BRIP1
CDH1
PALB2
NBN
PTEN
RAD50
STK11
RAD51C
TP53
RAD51D
others…
Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
**possible increased risk of breast cancer for carriers**

14. BRCA 1&2 Lifetime Cancer Risks
Petrucelli N et al. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer Sep 4 [Updated 2016 Dec 15]. In: Adam MP et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle;

15. Prophylactic Mastectomy
639 FHx +
s/p B/L prophylactic mastectomy
214 “high risk”
Expected
156
Actual 3
425 “moderate risk”
37.4 4
~14 year follow up

16. Prophylactic Mastectomy for BRCA carriers
105
Bilat mastectomy
2 breast cancer cases
(1.9%)
378
No breast surgery
189 breast cancer cases
(48.7%)

17. NSABP P1 (BCPT) Other results: No difference in mortality
Most significant benefit in predicted risk >/= 5%
Adverse events:
Endometrial cancer: 36 incidences in tam vs 15 in placebo group
Sig increase in incidence of PE and cataracts
Fisher B, et al. "Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study". Journal of the National Cancer Institute (18):

18. Tamoxifen in BRCA Carriers
BRCA 1 – tend to be ER negative cancers
No risk reduction benefit of Tamoxifen (NSABP-P1)
BRCA 2 – tend to be ER positive cancers
62% risk reduction with tamoxifen (NSABP P1)
King M et al. Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2 National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251–2256

19. Risk Reducing Salpingo-Oophorectomy (RRSO) for BRCA carriers
80% risk reduction in tumor of ovary or fallopian tube
Decreased mortality esp in BRCA 1 carriers
4% incidence of finding occult malignancy
Reduction in breast cancer risk
Greatest benefit in BRCA1 carriers who had RRSO ≤ age 40
Rebbeck TR et al. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oopherectomy in BRCA 1 or 2 mutation carriers. J Natl Cancer Inst. 2009; 101:
Sherman ME et al. Pathologic findings at risk-reducing salpingo-oopherectomy. J Clin Oncol. 2014; 32:
Eisen A et al. Breast cancer risk following bilateral oophorectomy in BRCA 1 and 2 mutation carriers. J Clin Oncol 2005; 23:

20. NCCN Guidelines for BRCA Carriers
Women
Men
Breast screening
Annual MRI – start age 25-29
Annual mammo – start age 30
Discuss risk-reducing mastectomy
Recommend risk-reducing salpingo-oophorectomy
-between age done with childbearing
-uncertain benefit of screening Ca US
Breast self exam and clinical breast exam – start age 35
Prostate cancer screening – start at age 45
Both
Pancreatic screening protocol
Possible dermatology eval for melanoma

21. Cancer Genetics Program Practice Locations
2 Cooper Plaza, Camden
900 Centennial Blvd, Voorhees
100 Salem Drive, Willingboro
Locations for Inspira patients: Vineland, Mickleton, Mullica Hill

22. Cancer Genetics Program Team
Oncologists
Generosa Grana, MD (Program Director)
Christina Brus, MD
Alexandre Hageboutros, MD
A. Kamel Abou Hussein, MD
Pallav Mehta, MD
Jamin Morrison, MD
Kumar Rajagopalan, MD
Kanu Sharan, MD
Robert Somer, MD
Christian Squillante, MD
Preeti Sudheendra, MD
Advanced Practice Nurses (APNs)
Jennifer Bonafiglia, APN-C
Phyllis Duda, APN-C
Kristi Kennedy, APN-C
Helen Nichter, APN-C
Evelyn Robles-Rodriguez, APN-C
Genetic Counselors Brooke Levin, MS, LCGC Vanessa Manso, MS, LCGC Kristin Mattie, MS, LCGC Matthew Share, MS, LCGC Jennie Stone, MS, LCGC Program Staff Manager Evelyn Robles-Rodriguez, RN, MSN, APN, AOCN Administrative Coordinator Brandi Ford, CCMA, AAS (Camden) Medical Assistant Myra Salcedo, RMA (Camden)