Hereditary Genetics focusing on Prostate Cancer

1. Click here for title
Click here for subtitle
Morgan Pressel Center for Cancer Genetics

2. Completing the Human Genome Map

5. Prostate cancer and Genetic testing
• How can Genetic testing change screening recommendations
• How can Genetic testing impact treatment of advanced disease
• How can Genetic testing be life saving for family members

6. Prostate Cancer
• Most frequently diagnosed cancer in US men - 36% of
all cancers
• Lifetime risk for men in US: 15-20%
• 241,000 new cases diagnosed in 2012 (estimated)
• 5-10% is heritable
• ~40% under 55y
• Higher in families with
breast/ovarian cancer 5-10%

8. Significant Family History
• First degree relatives with prostate cancer or multiple family members
diagnosed less than 60, maternal or paternal
• Known germline mutation, especially in Lynch syndrome genes or BRCA or
PALB2
• Family history of Breast cancer, ovarian cancer, pancreatic cancer,
colorectal, uterine cancer, small bowel or urothelial cancers especially if
multiple cancers in one individual or young age, triple negative breast
cancer
• Three generations of prostate cancer, or three first degree relatives with
prostate cancer
• Metastatic castrate resistant prostate cancer

9. Major categories genetic syndromes prostate
cancer
• HOX B13
• DNA Damage Repair genes
• MMR genes

11. Factors suggestive of genetic contribution to
prostate cancer
• multiple affected first-degree relatives (FDRs) with
prostate cancer, including three successive
generations with prostate cancer in the maternal or
paternal lineage;
• early-onset prostate cancer (age ≤55 years);
• prostate cancer with a family history of other cancers
(e.g., breast, ovarian, pancreatic
• HoxB13 has been shown to account for Hereditary
prostate cancers, but only 3% of young prostate
cancers, favorable prognosis.

15. DNA Damage Repair pathways BRCA

16. Hereditary Breast and Ovarian
Prostate Cancer

17. Timeline BRCA Testing
• Genetic family syndromes recognized long before the
causative genes were discovered
• BRCA became clinically available in 1995
• Patients tested who were at risk, where information could
change outcome
• Test has been updated with most recent update in 2014
• Survival changes with prevention of Ovarian cancer
• Many are wary due to reluctance to pursue bilateral
mastectomy which is an option not a mandate
• Long recognized that inheritance is just as likely to be
paternal as maternal
• Evolving benefits to men’s health: changing landscape in
inherited testing for prostate cancer

20. Families with Prostate cancer
and other cancers
• Pritchard et al. NEJM 2016
• 11.8% of men with metastatic Prostate Cancer had
association germline DNA repair gene mutations
• BRCA2 > ATM >CHEK2 >BRCA1 >RAD51D >PALB2
• No associated with + FH of PCa
• Associated with +FH of other cancers: breast
cancer (24), ovarian cancer (10),
leukemia/lymphoma (6), pancreas cancer (7), other
GI cancers (18).

22. Lynch Syndrome

25. Lynch Syndrome Associated Cancers
Cancer risk estimates compared to general population up to age
70*varies by mutation type
Cancer type General Risks Lynch Risk Mean Age onset
Colon 5.5% 80%
Uterine 2.7% 40%
Stomach 1% 11-19%
Ovary 1.6% 9-12%
Hepatobiliary 1% 2-7%
Urinary Tract 1% 4-5%
Small Bowel 1% 1-4%
Brain 1% 1-3%

26. Utility of genetic testing results
• Genetic information for treatment
• Genetic information predict positive biopsy for elevated PSA
• Gene carriers have higher risk of relapse prostate cancer
• Genetic predisposition to additional cancers

27. Strength of Association for Prostate Cancer
Presented By Veda Giri at 2018 ASCO Annual Meeting

29. Impact Study Baseline Paper: BRCA cohort
• Chances of positive biopsy (Positive predictive value PSA)is higher for
BRCA 1(41%) and BRCA2 (44%) compared to controls (General
population rate for elevated PSA is 24%)
• 46-60% of BRCA 2 biopsy prostate cancers are intermediate or high
grade compared to 27% general population
• In the impact study, the only cancers in men under 50 were BRCA 1
and BRCA 2 carriers
Bankroft et al, Euro Urology
2014

31. Now…
Presented By Heather Cheng at 2018 ASCO Annual Meeting

32. Precision Treatment in Advanced Prostate Cancer
Presented By Heather Cheng at 2018 ASCO Annual Meeting

33. Strength of Association for Prostate Cancer
Presented By Veda Giri at 2018 ASCO Annual Meeting

35. Prostate cancer Consensus:
Candidates for genetic testing
• Hereditary syndrome features: HBOC, Hereditary
Prostate cancer, Lynch Syndrome
• Men with Metstatic castrate resistant prostate
cancer
• Men with somatic (tumor sequencing) that
identified likely germline risk genes.
• Testing should be performed in the setting of
education and shared decision making

36. Consensus conference prostate
cancer: what genes to test
• HOXB13
• BRCA1/2
• Lynch Syndrome genes
• ATM if part of treatment decision making

37. Consensus proposed
actionability: prostate genetic
testing
BRCA2 factored into early screening, age 40 or
ten years prior to earliest prostate cancer, yearly
and factor into management for early stage
Prostate cancer
HOXB13 age 40 or ten years prior to earliest
prostate cancer, yearly
BRCA1 and ATM factor into management for late
stage Prostate cancer

38. NCCN Guidelines 2018
Risk Group Clinical Germline testing
High risk or regional Localized, high riskT3-T4or Gleason
score high or PSA >20
DNA repair genes(BRCA1, 2 ATM
PALB2), DNA MMR and FANCA
Metastatic DNA repair genes(BRCA1, 2 ATM
PALB2), DNA MMR and FANCA
Low risk -intermediate T1c-T2<60, family history of other
syndrome cancers
DNA repair genes(BRCA1, 2 ATM
PALB2), DNA MMR and FANCA
Family History only <60, family history breast, ovary,
pancreas, prostate cancer, colon
cancer suggestive of Lynch
DNA repair genes(BRCA1, 2 ATM
PALB2), DNA MMR and FANCA
(HOXB13)

39. Medicare Criteria

40. Conclusions
• Germline testing is indicated in prostate cancer indicated for individuals
meeting risk criteria
• Testing is indicated due to the actionability including:
• DNA repair gene mutations such as BRCA 1 and 2 and PALB2 and ATM have
therapeutic implications for metastatic disease
• MMR mutations may have implications for PD-1 and immunotherapies for
metastatic disease
• Identification increased risk supports earlier screening with PSA and
indications for diagnostic work up of PSA, studies underway for use of MRI
• Life saving implications for family members if Lynch or BRCA mutations
identified