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Approximately 5% of localized and up to 12% of metastatic prostate cancer (PCa) patients carry pathogenic germline variants, with BRCA2 being the most prevalent alteration.
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Different guidelines recommend germline sequencing in patients with metastatic disease, a family history of PCa or specific high-risk features in order to optimize treatment, assess personal cancer risk and prognosis and further guide family counselling for cancer predisposition syndromes.
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In localized disease, underlying pathogenic germline variants should trigger shared decision-making when deciding on active surveillance and (intensified) curative treatment options.
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In metastatic PCa patients with BRCA1/2 or ATM alterations, targeted treatment with poly-ADP-ribose polymerase inhibitors (PARP) inhibitors offers promising options. Additionally, a subset of metastatic PCa patients with mismatch repair (MMR) alterations could benefit from immune checkpoint inhibition.
Germline alterations in PCa
Indications for genetic testing
Philadelphia prostate cancer consensus conference 2019 [15] |
Recommended: Metastatic PCa Men with first-degree relatives or two or more male relatives with either: PCa diagnosis at age < 60 years PCa-related death Metastatic PCa Consider: Advanced stage of disease (≥ T3a) Intraductal/ductal pathology PCa with Gleason pattern ≥ 8 ≥ 2 cancers in HBOC or Lynch syndrome in any relatives within one family trait Ashkenazi Jewish ancestry |
NCCN prostate cancer guidelines [12] |
Recommended: Metastatic PCa Regional, node-positive PCa High-risk or very high-risk localized PCa Personal history of breast cancer ≥ 1 first-, second-, or third-degree relative with breast, endometrial or colorectal at age ≤ 50 years or male breast, ovarian, exocrine pancreatic cancer or advanced PCa at any age ≥ 1 first-degree relative with PCA diagnosis at age ≤ 60 years ≥ 2 first-, second- or third-degree relatives with breast or PCa at any age ≥ 3 first- or second-degree relatives with Lynch syndrome-related cancer Known FH or familial PGVs Ashkenazi Jewish ancestry Consider: Intermediate-risk PCa with intraductal/cribriform pathology Personal history of exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract or small intestinal cancer |
EAU guidelines on prostate cancer [14] |
Weak strength rating: Metastatic PCa High-risk PCa with FH of PCa at age < 60 Any PCa with multiple family members < 60 years or FH with PCa-related death FH of high-risk PGVs FH of multiple cancers within one family trait |
AUA guidelines on localized and advanced prostate cancer [16] |
Recommended: Metastatic PCa Consider: Adverse tumor characteristics Strong personal history of associated cancers Strong FH of PCa Strong FH of associated cancers Known PGVs Ashkenazi Jewish ancestry |
Clinical management of PCa patients with germline mutations
PCa screening
Active surveillance
Localized prostate cancer
Metastatic prostate cancer
Conclusion
Study | Patients included | Genes tested | Type of testing | Study design | Impact on clinical management |
---|---|---|---|---|---|
Screening | |||||
3027 | BRCA1/2 + additional 3 MMR genes | Germline | Prospective | PSA screening is indicated for BRCA2, MSH2 and MSH6 PGV carriers | |
Active surveillance | |||||
Carter et al. [23] | 1211 | BRCA 1/2, ATM + additional 51 DNA repair genes (n = 54) | Germline | Prospective | PGVs in BRCA1/2 and ATM are associated with aggressive PCa |
Localized prostate cancer | |||||
Castro et al. [26] | 1302 | BRCA1/2 (n = 2) | Germline | Retrospective | Outcomes for conventional treatment of localized PCa was worse in BRCA 1/2 carriers compared to noncarriers |
Metastatic castration-resistant prostate cancer | |||||
De Bono et al. PROfound: olaparib [28] | 4425 | BRCA 1/2, ATM + additional 12 other genes | Somatic | Randomized phase III | PFS was superior in patients with HRR alterations treated with olaparib compared to enzalutamide or abiraterone |
Fizazi et al. TRITON3: rucaparib [30] | 4855 | BRCA 1/2, ATM | Germline + somatic | Randomized phase III | PFS was longer in PCa patients with underlying BRCA alterations treated with rucaparib compared to control medication |
Clarke et al. PROPel: olaparib + abiraterone [29] | 796 | BRCA 1/2, ATM + additional 11 genes | Somatic | Randomized phase III | Combination of abiraterone and olaparib prolonged PFS irrespective of HRR alteration status |
Chi et al. MAGNITUDE: niraparib + abiraterone [32] | 742 | BRCA 1/2, ATM + additional 6 genes | Somatic | Randomized phase III | Niraparib + abiraterone prolonged PFS in patients with underlying HRR alterations |
Agarwal et al. TALAPRO-2: talazoparib + enzalutamide (ongoing) [31] | 805 | BRCA 1/2, ATM + additional 9 genes | Somatic | Randomized phase III | PFS improved in patients treated with talazoparib + enzalutamide irrespective of HRR gene alterations |
Le et al. [36] | 86 | MLH1, MSH2, MSH6, PMS2 | Germline + somatic | Nonrandomized phase II | MMR-deficient cancers responded to PD‑1 blockage irrespective of tumor type |