Genetic Testing is Clearly Indicated for Your Patient
Yes, genetic testing is absolutely indicated for your patient with two first-degree relatives with prostate cancer, and this should be pursued promptly through the urology referral. 1
Why Genetic Testing is Recommended
Men with prostate cancer who have two or more close blood relatives on the same side of the family with prostate cancer should be considered for genetic counseling and testing, with consensus support of 86% from the Philadelphia Prostate Cancer Consensus Conference. 1
The guidelines specifically lowered the threshold for the number of relatives with cancer to consider genetic testing, and importantly, eliminated the need to have Gleason score information in relatives when family history information is limited. 1
What Genes Should Be Tested
The testing panel should include multiple genes based on the hereditary prostate cancer (HPC) syndrome and related cancer predisposition syndromes: 1
Primary genes to test:
- HOXB13 (HPC syndrome) - 95% consensus 1
- BRCA1/BRCA2 (Hereditary Breast and Ovarian Cancer syndrome) - 97-98% consensus 1
- DNA mismatch repair genes (Lynch syndrome): MLH1, MSH2, MSH6, PMS2 - 73-97% consensus 1
Additional homologous recombination genes:
A comprehensive cancer predisposition next-generation sequencing panel should include at minimum: BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2. 2
What Can Be Learned from Genetic Testing
Risk Stratification and Screening Implications
BRCA2 mutations confer a 2-6 fold increased risk of prostate cancer and are associated with significantly more aggressive disease phenotype and reduced survival compared to non-carriers. 1, 2 BRCA1 mutations show a less consistent but still important association with increased risk. 1, 2
Men with identified BRCA2 mutations should begin prostate cancer screening at age 40 years, with BRCA1 carriers also strongly considered for the same. 1, 2 The positive predictive value of biopsy for detecting intermediate/high-grade cancer is significantly higher in BRCA2 carriers with PSA levels >3.0 ng/mL (2.4% vs 0.7%; P=.04). 1, 2
Treatment Implications
This is critically important: Patients with germline mutations in BRCA1/2 and ATM are candidates for PARP inhibitor therapy (olaparib, rucaparib) if they develop metastatic castration-resistant prostate cancer, through a mechanism of synthetic lethality. 5, 6, 3, 4
Patients with mismatch repair gene mutations (Lynch syndrome) may benefit from immunotherapy with PD-1 inhibitors like pembrolizumab. 5, 3, 4
Family Implications (Cascade Testing)
Identifying a germline mutation allows for cascade testing of family members, which is crucial because these mutations affect cancer risk not only for prostate cancer but also for breast, ovarian, pancreatic, and colorectal cancers depending on the specific gene. 1, 7, 4
If mutations in BRCA2, BRCA1, ATM, CHEK2, or PALB2 are found, the patient should be referred for genetic counseling to assess for hereditary breast and ovarian cancer syndrome implications for the entire family. 2, 7
Timing: How Soon Should Testing Be Done
Genetic testing should be pursued promptly as part of the initial urology evaluation. 7, 4 The testing does not need to wait for a prostate cancer diagnosis - men at high risk based on family history alone (like your patient with two first-degree relatives affected) are appropriate candidates for testing even before diagnosis. 1, 7
The National Comprehensive Cancer Network guidelines now recommend genetic testing for men with prostate cancer across the stage and risk spectrum, and for unaffected men at high risk based on family history. 2, 7
Important Clinical Pathway
- Refer to urology promptly for PSA evaluation and consideration of prostate cancer screening 7
- Simultaneously refer to genetic counseling or request the urologist coordinate genetic testing 1
- Obtain detailed three-generation family history including ages of cancer diagnoses and types of cancers (not limited to prostate cancer) 7
- Ensure testing includes comprehensive panel as outlined above, not just BRCA1/2 1, 2
Common Pitfall to Avoid
Do not wait for a prostate cancer diagnosis to pursue genetic testing in this high-risk individual. The guidelines specifically support testing in unaffected men with strong family history to identify hereditary cancer risk and inform screening strategies. 1, 2, 7 Your instinct to "nudge" the patient through family members is appropriate given the clear indication for both urologic evaluation and genetic assessment.