Genomic Data Affects Prognosis of Advanced Prostate Cancer

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome.

Various genomic and histologic features of prostate cancer have been described as conferring a worse prognosis. Among these is the presence of neuroendocrine or small-cell characteristics in tumors, sometimes referred to as aggressive variant prostate cancer or neuroendocrine prostate cancer.

A large international team of scientists led by the Memorial Sloan Kettering Cancer Center (New York, NY, USA) 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. They 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.

Reviews were conducted on H&E-stained frozen sections, allowing for review of the exact material that was used for nucleic acid extraction. Flash-frozen needle biopsies and matched normal samples underwent nucleic acid extraction and extracted DNA underwent whole-exome library construction and somatic mutation analysis. Amplifications and homozygous deletions for a set of 20 genes previously implicated in prostate cancer underwent further confirmatory review of segmentation files. Transcriptome libraries were prepared using polyA+ RNA isolation, or captured using Agilent SureSelect Human All Exon V4 reagents or in some cases using both polyA and capture methods.

The team used these genomic and transcriptomic data, and 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. When they focused on 18 recurrently mutated genes in 128 patients who received androgen receptor signaling inhibitor drugs, they saw ties between relapse, or shorter time on treatment, and shifts in genes such as AR, TP53, or RB1. The RB1 gene alterations alone showed significant interactions with patient survival following androgen receptor signaling inhibitor treatment, the scientists reported, though chromosomal aneuploidy in general also tended to correspond with shorter survival times and relapse.

The authors concluded that that RB1 loss is the molecular factor 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 RB, and potential therapeutic strategies targeting this mechanism. The study was published on May 6, 2019, in the journal Proceedings of the National Academy of Sciences.

Related Links:
Memorial Sloan Kettering Cancer Center