Divine Journal CA Precision Therapy Era: Prostate Cancer Germline Testing Is Indispensable, When Does "Hereditary" Cancer Need Genetic Testing

Inherited gene mutations that significantly increase prostate cancer risk are also associated with aggressive disease and poorer survival outcomes
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Based on the latest review published by the journal CA, this article sorts out the significance of germline mutations in prostate cancer screening and precise treatment, as well as the relevant recommendations of the NCCN guidelines, hoping to provide practical information for doctors and patients! Germline mutation testing has become an integral part of precision therapy Currently, multiple genes have been incorporated into prostate cancer genetic testing guidelines to assess prostate cancer risk and guide targeted therapy
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In May 2020, the FDA approved 2 PARP inhibitors for metastatic castration-resistant prostate cancer (mCRPC)
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Lucaparib is approved for the treatment of BRCA-mutated mCRPC after progression on prior AR inhibitors and platinum-based chemotherapy
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Olaparib is approved for the treatment of mCRPC with homologous recombination repair mutations that have progressed following treatment with enzalutamide or abiraterone + prednisone
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BRCA1 and BRCA2 mutations qualify patients with mCRPC to receive either lucaparib or olaparib, and multiple other genetic mutations are also considered for olaparib, including ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PP2R2A, RAD51B/RAD51C/RAD51D and RAD54L
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Therefore, multiple genetic testing is critical to identify mCRPC patients most likely to benefit from precision therapy, as well as to identify inherited cancer syndromes
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Germline mutations and prostate cancer risk Germline mutations (inheritable) in DNA repair genes are found in 5% to 10% of localized prostate cancers and 12% to 17% of metastatic prostate cancers
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Germline mutations in multiple genes are associated with increased risk of prostate cancer (high risk: >4-fold; intermediate risk, 2-3-fold), higher incidence of metastatic disease, and response to various therapies (Table 1)
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BRCA1 and BRCA2 are key prostate cancer susceptibility genes and are associated with hereditary breast and ovarian cancer syndromes
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Germline mutations in BRCA2 are associated with increased prostate cancer risk, higher mortality, and younger age at diagnosis
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BRCA1 mutations are also associated with an increased risk of prostate cancer, but to a lesser extent
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Mutations in DNA mismatch repair genes (MLH1, MSH2, PMS2, MSH6, EPCAM) associated with Lynch syndrome, especially MSH2, are also associated with a somewhat increased risk of prostate cancer
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HOXB13, the first inherited prostate cancer gene identified, increases prostate cancer risk 10-fold in European men and increases the risk of early-onset disease
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Table 1.
Germline mutations associated with susceptibility to prostate and other cancers and their response to related treatments The significance of genetic testing in prostate cancer management Screening Germline mutation testing has greatly influenced prostate cancer screening
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An interim analysis of the IMPACT study showed that BRCA2 mutation carriers had a higher incidence of prostate cancer, were younger at diagnosis, and were more likely to be diagnosed with clinically significant disease compared with wild-type (77% vs 40%)
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The NCCN Early Detection of Prostate Cancer (version 2.
2021) guidelines recommend that personal and family history of high-risk germline mutations should be considered in prostate cancer screening
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For patients with germline BRCA1 or BRCA2 mutations, prostate-specific antigen (PSA) screening should be initiated at age 40 and annual screening should be considered
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The 2019 Philadelphia Prostate Cancer Consensus also supports that men with BRCA2 carriers should be screened for early prostate cancer, while considering early prostate cancer screening for BRCA1, HOXB13, DNA mismatch repair, and ATM carriers
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Thus, prostate cancer screening strategies may gradually incorporate more genes
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Progression-free survival (PFS) and overall survival (OS) data from multiple precision therapy studies suggest germline and/or somatic mutations in DNA repair genes (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, and CHEK2) Patients with metastatic or advanced prostate cancer are more likely to benefit from PARP inhibitors and platinum-based chemotherapy
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Currently, PARP inhibitors approved or under investigation for prostate cancer include olaparib, lucaparib, niraparib, tarazopanib and veliparib
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Based on the PROfound study, olaparib has been approved, and olaparib can improve previous AR inhibitors and homologous recombination repair gene mutations BRCA1, BRCA2 or ATM (cohort A) or BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL , PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L (cohort B) patients
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Lucaparib has been approved for patients with BRCA-mutated mCRPC based on the TRITON2 study
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Subsequent approval will be contingent on the ongoing Phase III TRITON3 study
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Niraparib received Breakthrough Therapy Designation for the treatment of BRCA-mutated mCRPC based on interim results from the Phase II GALAHAD trial
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Niraparib has shown antitumor activity in refractory mCRPC patients, especially in biallelic BRCA mutation carriers
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Given the importance of germline mutations in guiding treatment selection for mCRPC, the NCCN Prostate Cancer (version V1.
2022) guidelines recommend germline testing for all patients with metastatic or high-risk/very high-risk localized disease, and recommend testing for BRCA1, BRCA2, ATM , PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2; testing for other genes such as HOXB13 is also recommended
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Which prostate cancers require germline mutation testing? In view of the rapid improvement in awareness of prostate cancer susceptibility genes and the increase in indications for germline mutation testing, the NCCN guidelines incorporate germline mutation testing recommendations from multiple expert groups, including the 2019 Philadelphia Prostate Cancer Consensus, European Advanced Prostate Cancer Consensus, American Society of Urology/American Society of Radiation Oncology/American Society of Urologic Oncology guidelines, American Society of Clinical Oncology policy statement update, and American Society of Medical Genetics and Genomics practice guidelines, among others
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NCCN guidelines recommend germline testing for men with prostate cancer with any of the following characteristics: metastatic disease, high/very high risk disease (based on Gleason score ≥7, disease stage and PSA level at diagnosis), intraductal or screening Histology or Jewish ancestry
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In general, family history collection should include 3-generation information on both the maternal and paternal sides of the family, diagnosis of all cancers in male and female blood relatives, age at diagnosis, cancer treatment options, cancer deaths, death by age, and Jewish ancestry
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In NCCN guidelines, family history of cancer focuses on identifying risk for hereditary breast cancer, ovarian cancer syndrome, Lynch syndrome, or hereditary prostate cancer
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Germline mutation testing in men diagnosed with high prostate and with any of the following conditions (NCCN Prostate Cancer, Version V1.
2022): - High risk, very high risk, localized or metastatic prostate cancer with or without prostate cancer with Men with any of the following criteria (NCCN Prostate Cancer, Version V1.
2022; NCCN Genetic/Familial High Risk Assessment - Breast, Ovarian, and Candidal Cancer, Version V1.
2022): - Jewish ancestry - Family history of high-risk germline mutations (eg, BRCA1/BRCA2, Lynch syndrome) - family history of cancer "strong" family history of prostate cancer including a brother or father or multiple family members diagnosed with prostate cancer at <60 years (but not clinically defined grade 1, i.
e.
Gleason score ≤6; individual, scattered, well glands only) or death from prostate cancer
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Three or more types of cancer in the paternal or maternal family, especially if the age at diagnosis is ≤50 years old: bile duct cancer, breast cancer, colorectal cancer, endometrial cancer, stomach cancer, kidney cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer Carcinoma (but not clinically defined grade 1, i.
e.
, Gleason score ≤6; individual, scattered, well-glandular only), small bowel, or urothelial carcinoma
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- Known family history of germline mutation, germline mutation gene testing should include MLH1, MSH2, MSH6 and PMS2 (Lynch syndrome) and homologous recombination genes: BRCA1, BRCA2, ATM, PALB2 and CHEK2
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Cancer susceptibility: Next-generation sequencing technologies, including at least BRCA1, BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2, should be considered
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Mutation testing of other suitable genes (eg, HOXB13) should be based on the clinical situation
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BRCA mutation testing (NCCN Genetic/Familial High Risk Assessment: Breast, Ovarian, Pancreatic Cancer, V1.
2022): - Metastatic prostate cancer - Gleason score ≥ 7 and more than 1 close relative < 50 years old with ovarian Cancer, thyroid cancer, or metastatic prostate or breast cancer, or - ≥ 2 close relatives diagnosed with breast or prostate cancer at any age, or - Jewish ancestry - Prostate cancer screening recommendations include: BRCA1/BRCA2 starting at age 40 Carrier Screening NCCN Early Detection of Prostate Cancer, Version V2.
2021: - Prostate cancer screening recommendations include: BRCA1/BRCA2 carrier screening starting at age 40 Conclusions and future directions Guidance believes that germline mutation testing is currently suitable for advanced or patients with metastatic prostate cancer
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Germline mutation testing is expected to become more integrated into the management of patients with localized or early/low-risk disease
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Prostate cancer screening is increasingly "individualized"
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Overall, germline mutation testing provides men and their relatives with information on hereditary cancer risk and screening
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Primary care providers (PCPs) are central to the evaluation of genetic mutation testing in men at or at risk for prostate cancer
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Close collaboration between oncologists, urologists, primary care physicians, cancer genetics specialists and counselors – and more importantly, patients and their families – is required to ensure optimal genetics for men and their families assessment to improve clinical outcomes
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Reference: Genetic testing in prostate cancer management: Considerations informing primary care.
First published: 24 February 2022.
https://doi.
org/10.
3322/caac.
21720.
Edited by A Cancer Journal for Clinicians: XY Reviewer: XY Typesetting: XY execution: Uni master class, scan the code to enter ▼▼▼