Integration of tumor genetic testing and genomically-informed therapies into clinical practice for patients with advanced prostate cancer are featured in updated National Comprehensive Cancer Network guidelines on the management of prostate cancer (version 2.2019).
Integration of tumor genetic testing and genomically-informed therapies into clinical practice for patients with advanced prostate cancer are featured in updated National Comprehensive Cancer Network (NCCN) guidelines on the management of prostate cancer (version 2.2019).
In addition, populations for whom germline testing is recommended as part of an initial prostate cancer diagnosis or initial risk stratification for clinically localized disease have been updated.
In 2018, a positive family history of prostate cancer was updated to include careful interrogation of the presence of germline mutations. In version 2.2019, “We’ve given a lot more detail to this, where we now are helping practitioners and patients to know what they’re supposed to be inquiring about as part of the careful history,” said James L. Mohler, MD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, speaking at the NCCN annual conference in Orlando, FL. “So we want to take a more careful genomic family history. We’re really asking the question, do our patients have evidence of, in their families, Lynch syndrome or homologous recombination [HR] gene abnormalities?”
In the update, which was published in the Journal of the National Comprehensive Cancer Network (2019; 17:479-505), a positive family history for prostate cancer constitutes having a brother, father, or multiple family members who were diagnosed with prostate cancer at <60 years of age or who dies from prostate cancer; being of Ashkenazi Jewish ancestry; or having ≥3 cancers on the same side of the family, especially when diagnosed at ≤50 years of age.
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“The next thing that we recognized since the last guideline that represented a change is the importance of paying attention as to whether patients have evidence of intraductal carcinoma,” said Dr. Mohler. Intraductal cancer is commonly confused with ductal cancer, he said, but intraductal cancer demonstrates a higher incidence of gene mutations.
In the updated guidelines, for initial risk stratification and staging work-up for clinically localized disease, germline testing is recommended in very low-, low-, and intermediate- risk groups if they have a positive family history or intraductal histology, and in all patients in the high- and very high- risk groups.
Germline testing can be performed using next-generation whole-genome sequencing or targeted exomic gene testing. Although targeted sequencing is the less expensive option, the cost of next-generation sequencing continues to decline.
“Obviously, by reducing cost by doing targeted sequencing, you could miss mutations that might affect the patients’ course of disease later, and their treatment,” said Dr. Mohler, who is chair of the NCCN’s Prostate Cancer Guidelines Panel.
Next: MMR mutations in 3%-5% of mCRPCMMR mutations in 3%-5% of mCRPC
The MMR pathway is the most important single-stranded DNA repair mechanism. The genes that control the MMR pathway are MSH2, MSH6, MLH1, and PMS2. The prevalence of all MMR mutations in metastatic castration-resistant prostate cancer (mCRPC) is 3% to 5%.
HR genes are responsible for fixing double-stranded DNA damage, such as that induced by ionizing radiation. Within this category, the most famous genes are BRCA1 and BRCA2, but also include ATM,PALB2,RAD50,RAD51,NBN,MRE11,BLM, and ATR. HR mutations occur in 15% to 25% of patients with mCRPC, noted Emmanuel S. Antonarakis, MD, associate professor of oncology and urology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
In one study, bi-allelic DNA repair defects are found in 21.3% of patients with mCRPC.
“Interestingly, the unusual histologic types, including ductal carcinoma and separately intraductal, are greatly enriched for all of the DNA repair mutations,” he said. In a recently published study by his group, 49% of patients with prostatic ductal cancer had actionable DNA repair mutations (14% in MMR genes and 31% in HR deficiency genes).
Enrichment for MMR defects is also apparent in high-grade primary tumors. His group also found that 8% of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) were enriched for MSH2 loss compared with 0.4% of tumors with any other scores. The overall prevalence of MMR mutations was 1.2%.
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In patients with regional spread or metastatic prostate cancer, the updated guidelines recommend consideration of tumor testing for HR gene mutations and for microsatellite instability (MSI) or mismatch repair deficiency (dMMR).
MMR deficiency informs therapy; PD-1 inhibition with pembrolizumab (KEYTRUDA) has been found to improve outcomes in any type of cancer with dMMR compared with MMR-proficient tumors. On this basis, pembrolizumab was approved by the FDA for the treatment of metastatic MSI-high or dMMR cancer.
In the updated prostate cancer guidelines, pembrolizumab is recommended as second-line or beyond for the treatment of M1 mCRPC with MSI-H or dMMR. The level of evidence for the use of pembrolizumab in this setting is category 2B “simply because there’s no prospective data yet,” said Dr. Antonarakis. The indication for pembrolizumab treatment of MSI-H/dMMR prostate cancer is based on clinical studies that included only two patients with prostate cancer, he observed.
Inhibitors of poly (ADP-ribose) polymerase [PARP] are capable of inducing synthetic lethality in tumors with deficiencies in HR-mediated DNA repair, such as those harboring BRCA1 mutations. PARP inhibitors are not included in the most recent guidelines for the management of patients with prostate cancer and germline or somatic HR gene mutations, but they can be considered for such patients, he said. The FDA granted olaparib Breakthrough Therapy designation for the treatment of BRCA1/2- or ATM-mutated mCRPC, and rucaparib for the treatment of BRCA1/2-mutated mCRPC with at least one prior androgen receptor-directed therapy and taxane-based chemotherapy.