RB1 Mutations Linked to Worse Outcomes in Prostate Cancer Patients, Study Finds

Men whose tumors contain mutations in the retinoblastoma (RB1) gene have higher risks of prostate cancer relapse and mortality while receiving first-line conventional anti-cancer therapies, a study says.

According to researchers, genetic screenings aimed at identifying patients whose tumors may contain such genetic alterations may be crucial to pinpoint   those in need of intensive treatment.

The study with those findings, “Genomic correlates of clinical outcome in advanced prostate cancer,” was published in PNAS.

Recent studies have shown that both primary and metastatic (spreading) forms of prostate cancer are highly variable from a genomic standpoint. However, the impact of this tumor genetic variability on patients’ clinical outcomes is still poorly understood.

Researchers from The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust in collaboration with colleagues from the U.S. and other European countries, set out to investigate possible relationships between specific genetic mutations found in tumors of patients with advanced forms of prostate cancer and their long-term clinical outcomes.

To this end, they performed a full genetic characterization of 444 tumors samples collected from 429 patients who had been diagnosed with metastatic castration-resistant prostate cancer (mCRPC). Tumor genetic data was then combined with information from their cellular structure (assessed by tissue analysis) and patients’ long-term clinical outcomes.

Among the participants, 128 had been treated with abiraterone (whose brand names include Yonsa and Zytiga) or enzalutamide (marketed as Xtandi) — two standard anti-cancer hormone therapies — as first-line therapy. Analysis of these samples allowed investigators to look for possible associations between 18 recurrent genetic mutations with patients’ clinical outcomes.

Their results were similar with those reported in prior studies, with among the most commonly altered genes being the tumor protein p53 (TP53) and the androgen receptor (AR) genes, as well as important pathway signaling components as PTEN, TP53, PIK3CA, and CDK12.

From these, only mutations in RB1 — a gene involved in the control of cell growth — were strongly linked to patients’ poor survival.

Men whose tumors contained mutations in RB1 were three-times more likely to succumb to prostate cancer and nearly seven-times more likely to experience cancer relapses while on hormone therapies, compared to men whose tumors did not contain such mutations.

This finding suggests that more information is needed into the mechanisms of resistance to hormone therapies induced by loss of RB in prostate cancer patients, was well as into “potential therapeutic strategies targeting this mechanism,” researchers wrote.

“Our study really got under the bonnet of prostate cancer to understand the ‘engine’ driving tumor growth and explore how a wide range of genes affect the disease and its response to treatment,” Johann de Bono, PhD, said in a press release. De Bono is professor at the ICR, consultant medical oncologist at The Royal Marsden, and co-author of the study.

“We identified one particular genetic mutation that seems to indicate that tumors are going to be very aggressive, and that the affected men need the most intensive treatment we have available,” he said.

Researchers also found genetic mutations in TP53 and AR that also were linked to higher risks of cancer relapse. In addition, patients whose tumors contained mutations in CDK12 — a gene linked to good responses to immunotherapy — were found to be likely to have mutations in CDK4 and CCND1. Those two genes are used as therapeutic targets for Ibrance (palbociclib), a drug normally used to treat breast cancer.

“Our research could also open up various new approaches to prostate cancer treatment, and offers the intriguing suggestion that some patients could benefit from immunotherapy alongside an existing breast cancer drug,” de Bono said.

“The crucial thing now is that we make use of this information, by developing a test to identify affected men and to make sure they receive the best treatments we have available today, while also focusing our efforts on improving options for the future,” said Paul Workman, PhD, chief executive of the ICR.