Vast Majority of Advanced Prostate Tumors Have Actionable Mutations

About 89% of prostate cancer tumors sequenced as part of a comprehensive precision medicine study have mutations that can be targeted with available therapies. The results of this study, which included tissue samples from 150 men with metastatic prostate cancer, were published in Cell.

While prior studies have sequenced localized, primary prostate tumors, this current study is the first major analysis of advanced prostate disease that is refractory to most available prostate cancer therapies.

Led by Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and professor of pathology at the University of Michigan Health System, and Charles L. Sawyers, MD, chair of the human oncology and pathogenesis program at Memorial Sloan Kettering Cancer Center, this study from an international team pooled patient biopsies from eight institutions in the United States and Europe. Two central sites processed the samples, conducting in-depth whole-exome DNA and RNA sequencing analyses of bone and soft-tissue biopsies. The researchers were able to obtain fresh biopsy samples from living patients with metastatic castration-resistant prostate cancer (CRPC).

The results suggested that most men with hormone-refractory, advanced prostate cancer have potential treatments available to them based on their unique prostate tumor mutational profile. According to Chinnaiyan, the study provides evidence that clinical sequencing, still rarely done outside of the academic research setting, could benefit patients with prostate cancer.

In 40% to 60% of the cases, there was at least one driver mutation in the androgen receptor (AR), ETS genes, TP53, or PTEN. Mutations in the AR were found in 62.7% of the tumors. AR mutations were expected, as it has previously been shown that metastatic CRPC resistant to advanced prostate cancer therapies such as enzalutamide and abiraterone may be associated with the AR gene.

This new study now provides a broader spectrum of these therapy-resistant mutations. Nineteen percent of the metastatic samples had aberrations in BRCA1, BRCA2, and ATM-all part of DNA repair pathways. Certain BRCA1 and BRCA2 mutations are known to confer a higher risk of breast and ovarian cancers. More of these mutations were observed in the advanced tumors compared with prior studies using primary prostate tumors. Eight percent of mutations were in the germline.

PARP inhibitors have already been approved in BRCA-positive ovarian cancer, suggesting potential for their role in prostate cancers with this type of aberration.

“Up to now, precision cancer medicine activities in advanced prostate cancer have been limited by lack of ability to acquire clinical samples from patients at the time of failure of hormone treatment and a lack of comprehensive genomic data for potentially actionable alterations,” said Sawyers, in a statement.

“This…study demonstrates the feasibility of comprehensive and integrative genomics on prospective biopsies from individual patients to enable precision cancer medicine activities in this large patient population,” he added.

This study, as part of a Stand Up To Cancer/Prostate Cancer Foundation grant, is continuing with the goal of sequencing a total of 500 metastatic CRPC tumors to begin to connect specific advanced prostate cancer driver mutations with treatments that can target these mutations.