Updated National Comprehensive Cancer Network (NCCN) Guidelines® on prostate cancer reflect the growing importance of integrating tumor genetic testing and genomically-informed disease management into clinical practice, said speakers from the NCCN Prostate Cancer Panel at the 2019 National Comprehensive Cancer Network (NCCN) Annual Meeting, held March 21–23 in Orlando, Florida.
“Homologous recombination [HR] mutations occur in about 15% to 25% of patients with metastatic castrate-resistant prostate cancer [mCRPC],” said Emmanuel S. Antonarakis, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. HR results from double-strand DNA damage such as that induced by ionizing radiation, and affects several genes, including BRCA1 and BRCA2, FANC, ATM, PALB2, RAD50, RAD51, NBN, MRE11, BLM, and ATR.
“There may be enrichment for DNA repair gene mutations in high-grade prostate cancers and in certain histological subtypes,” Antonarakis said.
DNA mismatch repair (MMR) gene mutations, such as those affecting MSH2, MSH6, MLH1, and PMS2 are found in an estimated 5% of mCRPC cases overall.
Overall, one study found bi-allelic DNA repair defects (MMR and HRD mutations) in 21% of 150 patients, Antonarakis noted. In addition, 49% of patients with prostatic ductal cancer have been found to harbor DNA repair gene mutations (14% MMR mutations and 31% HRD mutations), he reported.
The roles of germline vs somatic—and mono-allelic versus bi-allelic mutations—are not yet clear, Antonarakis cautioned.
The updated 2019 NCCN Guidelines® recommend consideration of tumor testing for HR mutations and microsatellite instability or deficient MMR (dMMR) among patients with either regional spread or distantly-metastasized prostate cancer. Germline mutations should be tested in all newly-diagnosed men with NCCN high-risk, very high-risk, regional, or metastatic prostate cancer.
Such testing can inform treatment decision-making. In 2017, the US Food and Drug Administration (FDA) issued accelerated approval for pembrolizumab programmed cell death 1 (PD-1) immune checkpoint inhibition for patients with unresectable or metastatic microsatellite instability–high or dMMR cancers. It was the first approval for a cancer treatment based not on cancer type but mutations.
The updated NCCN Guidelines® recommend consideration of metastatic tumor testing for microsatellite instability–high or dMMR status. For adenocarcinoma CRPC without visceral metastases, patients with prior abiraterone or enzalutamide therapy should be considered for treatment with docetaxel or radium-223, or pembrolizumab for patients whose tumors test positive for high microsatellite instability or dMMR.
“In the second-line mCRPC setting, pembrolizumab is appropriate in men with MMR deficiency/microsatellite instability–high status,” Dr. Antonarakis said. “In patients with germline or somatic HRD mutations, investigational PARP [poly (ADP-ribose) polymerase] inhibitor therapy may be considered.”
However, the FDA approval of pembrolizumab for dMMR or microsatellite instability–high tumors was based on tumor response data that included only two patients with prostate cancer, Antonarakis noted.
DNA repair deficiencies can also be the result of inherited germline mutations, and this possibility should be explored as part of patients’ initial risk stratification. Upon diagnosis with prostate cancer, patients should be asked about any known high-risk germline mutations and careful genomic family histories should be undertaken, according to the updated NCCN recommendations.
Family histories indicative of germline mutations include a brother, father, or multiple family members having been diagnosed with prostate cancer before age 60 years, or more than one relative with breast, ovarian, or pancreatic cancer, which can suggest heritable BRCA2 mutations—or more than one relative with colorectal, endometrial, gastric, ovarian, pancreatic, small bowel, urothelial, kidney, or bile duct cancer, which might result from Lynch syndrome, said James L. Mohler, MD, of the Roswell Park Comprehensive Cancer Center in Buffalo, New York. Ashkenazi Jewish ancestry is also a familial risk factor.
The updated NCCN recommendations include consideration of genetic counseling and germline testing for HR mutations among men with imaging-confirmed mCRPC. The FDA granted olaparib breakthrough therapy designation for treating mCRPC positive for BRCA1, BRCA2, or ATM mutations. In 2018, rucaparib was similarly granted breakthrough therapy designation for BRCA1/2-mutated mCRPC among patients who had received at least one prior androgen receptor–directed therapy and taxane-based chemotherapy.
Germline testing can be undertaken using next-generation whole-genome sequencing or targeted exomic gene testing, noted Mohler. Costs for whole-genome testing continue to decline, making that option more attractive.
“By reducing cost with targeted sequencing, you could miss mutations that affect patients and their treatment later on,” cautioned Mohler.
