ASCO 2022: Association of RB1 Mutational Status With Overall Genomic Landscape in Neuroendocrine Prostate Cancer

( At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Petros Grivas discussing the association between RB1 mutational status and the genomic landscape of neuroendocrine prostate cancer (NEPC).

NEPC represents a relatively rare, high-grade aggressive form of prostate cancer. Better understanding the biology of this disease is important to identify treatment approaches for patients with this poor prognosis subset of disease. To this end, Dr. Grivas and colleagues assessed whether RB1 mutation status would impact the genomic features of NEPC.

To do so, the authors identified 415 cases (3.1%) with a diagnosis of small cell prostate cancer or NEPC as determined by the submitting physician among a series of 13,496 cases of clinically advanced prostate cancer. These patients underwent sequencing using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). The tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. 

Among the 415 patients with a diagnosis of small cell prostate cancer or NEPC, 253 (61%) showed evidence of genomic alterations in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 genomic alterations among patients with the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of pathogenic GA per tumor than the RB1 mut- NEPC (5.1 vs 4.2).

Age and TMPRSS2-ERG fusion frequency were similar between the groups.

RB1 Mut- NEPC was associated with significantly higher amplification and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured a significantly greater frequency of PTEN GA. Genomic alterations in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were found in similar proportions in both groups.

ASCO 2022_Petros Grivas_Abstract 5063_1 

For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 (PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were uncommon in both groups. gLOH was higher in RB1 mut+ than RB1 mut- (P =.005). There were more cases of non-European ancestry in the RB1 mut- group. APC I1307K mut were found in 3/162 (1.9%) RB1 mut- NEPC only.

Thus, the authors conclude that, in patients with NEPC, the presence of RB1 mutation is associated with various genomic alterations that may have clinical relevance. This may be important in informing future trial design.

Presented by: Petros Grivas, MD, Ph.D. is an Associate Professor and the Clinical Director of the Genitourinary Cancers Program at the University of Washington, and an Associate Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.



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