Table 1.
Panel consensus on prostate cancer (PC) genetic testing.
| Consensus Statements | Ref. | |
|---|---|---|
| 1. Indications for Genetic Testing in PC | ||
| 1.1 FH of PC and Related Cancers | ||
| 1.1.1 | FH of PC and/or related cancers is defined as having any of: - PC (except localized Grade Group 1) in brother, father or multiple family members diagnosed at age < 60 years; - Death from PC in a first-degree relative aged < 60 years; - Known germline mutations of BRCA1/2 or DNA MMR genes in the family; - BRCA1/2m-associated cancer or Lynch syndrome (namely: bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate [except localized Grade Group 1], small bowel or urothelial cancer) in ≥ 3 members on the same side of the family. |
(17–20) |
| 1.2 Familial Risks of PC | ||
| 1.2.1 | FH of prostate and related cancers should be obtained for patients with newly diagnosed PC. | (19, 21) |
| 1.2.2 | Cancer surveillance and prophylactic measures should be discussed with germline mutation carriers. | (19, 22) |
| 1.2.3 | For BRCA2m carriers, PC screening may start at age 40 years. | (18, 23) |
| 1.2.4 | For BRCA2m carriers, PC screening may be performed 10 years before the youngest PC diagnosis in the family. | (18) |
| 1.3 Germline Testing Upon PC Diagnosis | ||
| 1.3.1 | Germline testing should be considered in PC patients with any of the following: - Metastatic disease - Ductal or intraductal histology - Positive FH. |
(24–26) |
| 1.4 Consent and Genetic Counseling | ||
| 1.4.1 | Germline genetic testing should be coupled with informed consent and the provision of genetic counseling for adequate management. | (27) |
| 1.4.2 | In Hong Kong, genetic counseling resources are scarce. There is a large unmet need of patients with suspected cancer-associated mutations who would benefit from genetic counseling services from accredited providers. | (28, 29) |
| 1.5 Hereditary Driver Mutations | ||
| 1.5.1 | HRR genes (BRCA1/2, ATM, PALB2) and MMR genes (MLH1, MSH2, MSH6 and PMS2) should be considered in germline testing for PC patients. | (18, 19, 30–32) |
| 1.6. Ethnic Considerations | ||
| 1.6.1 | In Hong Kong, the knowledge base on genetic testing in PC (indications, choices and implications, etc.) may be quite limited. Genomic research in Hong Kong PC patients (e.g. BRCAm prevalence and variants) would help to clarify the local situation. | (33–37) |
| 2. Testing Methods and Technical Considerations | ||
| 2.1 Germline vs. Somatic Testing | ||
| 2.1.1 | Genetic variants detected by somatic (or tumor) testing that are potentially inherited, especially those involving the HRR or MMR genes, should be subject to germline confirmation by testing a peripheral blood sample. | (28, 38) |
| 2.1.2 | Large genomic rearrangements (LGR), for example exon level deletions of the BRCA1/2 genes, may escape detection on somatic (tumor) testing by NGS. If FH is positive or the patient is otherwise suspected of inherited cancer, germline genetic testing by a peripheral blood sample should be considered. | (39) |
| 2.2 Tissue Sample Availability | ||
| 2.2.1 | Formalin-fixed paraffin-embedded (FFPE) tumor tissue submitted for genomic profiling should be examined by a histopathologist to confirm the diagnosis and to identify the region of interest for tumor cell enrichment as indicated for somatic testing. | (40) |
| 2.2.2 | The availability and quality of biopsy samples should be considered when somatic testing is planned, since longer tissue storage duration is associated with lower testing success rates. | (41, 42) |
| 2.3 Testing Levels and Coverage | ||
| 2.3.1 | Genomic profiling should be performed by NGS panel that covers the potentially actionable targets in PC such as DNA damage repair (HRR, MMR and Fanconi anemia genes, and CDK12), phosphatidylinositol-3-kinase (PI3K), and RAS/RAF/MEK pathways. | (43, 44) |
| 2.3.2 | Mutational study of the HRR genes is used to indicate homologous recombination defect (HRD). However, HRD is not completely covered by gene mutational study but may need other tests such as genomic signatures or functional assays to detect. | (45, 46) |
| 2.3.3 | Apart from direct sequencing of the MMR genes or promoter methylation study, MMR defect is also indicated by MSI phenotype as detectable by PCR on paired tumor normal sample, NGS genomic profiling, or immunohistochemistry (IHC) study of MMR gene expression on tumor cells. | (47, 48) |
| 2.3.4 | There are biomarkers for predicting anti-PD-1 effects, e.g. tumor mutational burden, MSI and PD-L1 expression by IHC, but the results of these tests may not correlate with one another. | (49, 50) |
| 2.3.5 | Apart from tissue biopsy, liquid biopsy for circulating tumor DNA (ctDNA) is an emerging, practical, minimally invasive solution to identify predictive or prognostic genomic alterations and to monitor therapy response, especially in patients with inaccessible tumor or who are poor surgical candidates. | (8, 9) |
| 3. Therapeutic Implications | ||
| 3.1. Risk Assessment for Localized PC Patients | ||
| 3.1.1 | BRCA2m carriers who are PC patients should not be offered active surveillance. | (7, 51) |
| 3.1.2 | Some tissue-based genetic assays (which are mostly related to cell cycle mutations; e.g. Prolaris, Decipher and Oncotype Dx) can provide useful information for detailed risk assessment in localized PC, and consequently, counseling patients on active surveillance or treatment. | (52–57) |
| 3.2 Genetic Testing in mHSPC | ||
| 3.2.1 | Based on current evidence, genetic testing (including genes involved in DNA HRR, such as BRCA1/2) might not have an impact on initial treatment selection in patients with mHSPC, but may be helpful for prognostic counseling and longer-term treatment planning. | (58, 59) |
| 3.3 Systemic Therapies for mCRPC | ||
| Genetic testing can help to guide the use of systemic therapies in mCRPC patients who failed standard treatments, because: (3.3.1 - 3.3.4) | ||
| 3.3.1 | Anti-tumor activity with PARPi, e.g. olaparib, rucaparib, niraparib, talazoparib etc., was seen in mCRPC patients with HRR mutations. | (5, 60–63) |
| 3.3.2 | Among various HRR mutations, tumors harboring BRCA1/2m appeared to derive the greatest clinical benefit from PARPi. | (5, 60, 61) |
| 3.3.3 | mCRPC patients with HRR mutations, in particular BRCA2m, who had prior androgen receptor-targeted agents ± chemotherapy should consider for olaparib (based on PROfound study) or other PARPi. | (5) |
| 3.3.4 | Patients with MSI-high or MMR-deficient tumors may have potential clinical benefit with immune-checkpoint inhibitors, e.g. pembrolizumab. | (64–66) |
| 3.3.5 | To derive optimal treatment benefits, all mCRPC patients should be tested for actionable genetic mutations. | (19) |
| 3.3.6 | Somatic testing is the preferred method for testing actionable genetic mutations. | – |
| 3.3.7 | Platinum-based chemotherapy may have anti-tumor activity in mCRPC patients with HRR mutations (e.g. BRCA1/2m). | (67, 68) |
BRCAm, BRCA gene mutation; FH, family history; HRR, homologous recombination repair; mCRPC/mHSPC, metastatic castration-resistant/hormone-sensitive prostate cancer; MMR, mismatch repair; MSI, microsatellite instability; NGS, next-generation sequencing; PARPi, poly adenosine diphosphate-ribose polymerase inhibitors.