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RB1 Alterations in Advanced Prostate Cancer Associated With Poor Outcome

NEW YORK (GenomeWeb) – New research suggests that recurrent mutations in the RB1 gene, which encodes the retinoblastoma protein, are associated with aggressive disease and decreased survival following anti-androgen hormone treatment in men with advanced prostate cancer.

"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," co-author Johann de Bono, a cancer researcher and medical oncologist affiliated with the UK's Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust, said in a statement.

For a study published this week in the Proceedings of the National Academy of Sciences, de Bono and colleagues from the UK, the US, Switzerland, and Italy used exome sequencing and RNA sequencing to assess coding mutations and transcriptomic features in samples from more than 400 individuals with metastatic, castration-resistant prostate cancer (mCRPC) who also had clinical data available.

"Our study identifies molecularly defined groups of patients who may benefit from a more aggressive treatment approach," the authors wrote, "with the genomic and outcome data made available to the research community for further interrogation."

For their study, the researchers focused on a matched tumor-normal dataset for 429 mCRPC patients treated at seven centers around the world, using exome sequencing to profile coding alterations in 444 prostate, lymph node, bone, liver, lung, or other biopsy samples from these cases. They also performed RNA sequencing on 332 tumor samples from a subset of 323 mCRPC patients.

Using these genomic and transcriptomic data, the team looked at the frequency and interactions between new and known genomic alterations in the advanced prostate cases, identifying frequent mutations in genes such as the androgen receptor gene AR, ETS, TP53, or PTEN, as well as co-occurring alterations affecting genes such as CDK12, CDK4, and CCND1 that fall in cell cycle pathways previously linked to potential immune activity against tumors.

Those findings hint at the possibility of clinical trials with a CDK4/6 inhibitor, such as Pfizer's breast cancer drug Ibrance (palbociclib), in combination with checkpoint blockade immunotherapy, the authors noted, though "[f]urther laboratory studies will be needed to explore this and other potential biological interactions identified through genomic analysis."

The data also made it possible for the team to explore relationships between specific tumor alterations and patient outcomes following existing prostate cancer treatments, such as taxane chemotherapy or hormone-targeted therapy.

When they focused on 18 recurrently-mutated genes in 128 patients who received androgen receptor signaling inhibitor drugs such as Janssen Pharmaceutical's Zytiga (abiraterone) or Astellas Pharma and Pfizer's Xtandi (enzalutamide) , for example, the researchers saw ties between relapse, or shorter time on treatment, and shifts in genes such as AR, TP53, or RB1.

But the RB1 gene alterations alone showed significant interactions with patient survival following androgen receptor signaling inhibitor treatment, the researchers reported, though

chromosomal aneuploidy in general also tended to correspond with shorter survival times and relapse.

"We find that RB1 loss is the molecular factors most strongly associated with poor clinical outcomes in a contemporary cohort, highlighting the need for further investigation into mechanisms of resistance to AR therapies induced by loss of [the retinoblastoma protein], and potential therapeutic strategies targeting this mechanism," the authors concluded.