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Alterations in the RB1 Gene and Outcomes in Metastatic Castration-Resistant Prostate Cancer

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Key Points

  • Patients with RB1 mutations were 3.3 times more likely to die and 6.6 times more likely to relapse during the course of the study than other men who also had standard treatment but did not have the mutation.
  • RB1 was the only gene found to have such an impact on survival, but mutations in two further genes—p53 and the androgen receptor gene—were associated with an increased risk of relapse on abiraterone or enzalutamide.
  • Men whose tumors had mutations in a gene linked to a good response to immunotherapy, CDK12, often also had mutations in the genes CDK4 and CCND1, which are the targets of a breast cancer drug called palbociclib.

Scientists have identified a genetic mutation in the tumors of some men with prostate cancer that is linked to very poor survival, and which could be used to help select certain patients for more intensive treatment. These findings were published by Abida et al in the Proceedings of the National Academy of Sciences.

The retinoblastoma gene, known as RB1, is so called because mutations in it cause a rare children’s eye cancer of the same name, and the gene is known to play a central role in stopping healthy cells from dividing uncontrollably.

The study researchers believe testing men for the mutation could identify those with especially aggressive disease who need the most intensive available treatments. They are also studying new ways to treat patients with the high-risk gene.

Analysis Methods and Findings

The team looked in detail at the DNA sequence, the activity of genes, and the histopathology of 444 tumor samples from 429 men with advanced prostate cancer. The team wanted to identify which of the many genes linked to prostate cancer were the most important indicators of patient survival and response to the standard treatments for prostate cancer abiraterone and enzalutamide. 

Patients with mutations in the RB1 gene in their tumors were 3.3 times more likely to die and 6.6 times more likely to relapse during the course of the study than other men who also had standard treatment but did not have the mutation.

RB1 was the only gene found to have such an impact on survival, but mutations in two further genes—p53 and the androgen receptor gene—were associated with an increased risk of relapse on abiraterone or enzalutamide.

Mutations in DNA repair genes BRCA1, BRCA2, and ATM and in PI3K genes were relatively common, but had no impact on treatment with abiraterone or enzalutamide or on overall survival.

However, the research did identify clues for how some patients with prostate cancer could be treated more effectively. Men whose tumors had mutations in a gene linked to a good response to immunotherapy, CDK12, often also had mutations in the genes CDK4 and CCND1, which are the targets of a breast cancer drug called palbociclib. That suggests that combining immunotherapy with palbociclib could be an effective treatment for this group of men.

The researchers concluded, “This large analysis integrating metastatic castration-resistant prostate cancer genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.”

Disclosure: This study was funded by the Prostate Cancer Foundation and Stand Up to Cancer. For full disclosures of the study authors, visit pnas.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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