ASCO 2022: Association of RB1 Mutational Status with Overall Genomic Landscape in Neuroendocrine Prostate Cancer (NEPC)

(UroToday.com) Neuroendocrine prostate cancer (NEPC) is an increasingly common and particularly aggressive subtype of prostate cancer. The molecular program that gives rise to development of NEPC remains incompletely understood. Among the genomic alterations associated with NEPC is alterations in RB1, although this is known to not be necessary nor sufficient for transformation. Here Dr. Grivas and colleagues sought to evaluate the impact of RB1 in NEPC cases.


This series began with 13,496 cases of clinically advanced prostate cancer from which 415 cases (3.1%) of NEPC (or small cell prostate cancer) were identified. Sequencing was performed via a hybrid capture-based clinical genomic profiling assay with FDA approval (FoundationOne CDx) Tumor mutational burden (TMB) was measured on 0.8 Mb of sequenced DNA. Other clinically actionable markers measured included microsatellite instability (at 95 loci) and PD-L1 expression via IHC (Dako 22C3).

61% (253) of NEPC cases harbored an alteration in RB1, which was seen comparatively less frequently (5.8%) in the non-NEPC group (p<0.0001). This is consistent with prior reports. Harboring an RB1 alteration was associate did not appear to impact the frequency of other overall pathologic genomic alteration per tumor (RB1+ 5.1 vs RB1- 4.2, NS). However, the absence of an RB1 alteration was associated with higher frequency of amplifications (7.4% v 2.8%, p = 0.03), and total number of AR alterations all together and isolated to amplifications.

RB1 mutations were associated with alterations in PTEN and TP53, and an absence of CCND1 alteration. Other targetable kinases or druggable alterations (i.e. homologous recombination, PARPi) were not differently assorted by RB1 mutational status.

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Evaluation of potential markers of sensitivity to immune checkpoint inhibitors, including MSI, PD-L1 status, and TMB was performed. Alterations of MDM2 and CDK12 was more common in the RB1-unaltered group. Low PD-L1 was associated with RB1 mutation. Other markers showed no association with RB1 status.

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The authors also included two case examples, as one reproduced below, of an RB1 unmutated NEPC case demonstrating an absence of membranous PD-L1 expression via IHC. Despite this, copy number profiling revealed a modest amplification of CD274 (PD-L1).

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In conclusion, the authors suggest that these data demonstrating genomic association with RB1 alterations can result in potential clinical actionability. This could be of significant value in NEPC, a disease with few effective therapies. Additional landscape data and mechanistic investigation is warranted based on these data.

Presented by: Petros Grivas, MD, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA
 

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

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