ASCO 2022: Genomic Alterations and Evolution in Patients With Prostate Cancer With Histologic Evidence of Neuroendocrine Differentiation

( Increasingly neuroendocrine prostate cancer (NEPC) is both looked for and diagnosed, matching the rise of awareness of the potential treatment-emergent transdifferentiation and the earlier clinical use of highly potent AR targeted therapies. Histological, clinical, and genomic markers are associated with the presence of NEPC, yet the specific program that results in the development of treatment-emergent NEPC (tNEPC) is yet to be codified.


The authors sought to better characterize the sequence of genomic events that lead to tNEPC development. To this goal, they collected in-house targeted sequencing data from 1447 patients with prostate cancer. These data were matched to histological data, including pathologically confirmed NEPC with notation of the first sample with “unequivocal” evidence of NEPC. This study used descriptions in pathology reports of “neuroendocrine carcinoma,” “neuroendocrine features,” or “neuroendocrine differentiation.” Those patients with changes not fulfilling these criteria but suggestive of early NE differentiation, such as double negative, amphicrine, or rare/focal staining for NE markers, were analyzed separately.


ASCO 2022_Ethan Barnett, MA_0 


Overall, 150 samples from 95 (6.6%) patients with pathologically confirmed NEPC were included in the analysis. Among these, 18 had samples collected and available for prior to NEPC and following NEPC. Patients with CRPC who developed NEPC (n = 70) were more likely to harbor RB1 alterations than those patients who maintained adenocarcinoma histology (50% vs 12%, q < 4.14e-10). In contrast, AR alterations, including amplification and/or putative driver missense mutations, were enriched in those patients without subsequent development of NEPC (n = 380)(63% vs 21%, q < 10-10). Enrichment of other genes was also reported, including TP53, AMER1, ARID5B, YAP1, SOX2, and NKX2.1, although without correction for multiple comparison testing. NKX2.1 amplifications were exclusive to NEPC samples.

ASCO 2022_Ethan Barnett, MA_1 

Perhaps as the most powerful deployment of this data set was the comparison of pre- to post-differentiation samples. Barnett et al. report that the presence of a TP53 alteration in an NEPC sample reflected a pre-differentiation TP53 alteration (8 of 11 patient pairs). In contrast, RB1 alterations in NEPC samples were detected infrequently in the paired pre-NEPC sample (1 of 8).

ASCO 2022_Ethan Barnett, MA_2 

Those patients with pathological findings consider to be suggestive of early or impending transformation represented a minority of the cohort (n = 54, 3.7%). In the CRPC samples from these patients, mutations were enriched in RB1, MAP2K2, MUTYH, and CTNNB1. FOXA1 mutations were more commonly seen in those patients without transformation.


The authors conclude that their findings are consistent with prior data indicating that importance of RB1 alterations in NEPC development, although acknowledge that the limitations of targeted sequencing mean they cannot exclude the subclonal presence of RB1 mutant minority clones prior to development of histologically bona fide NEPC. Also highlighted were possible enrichment in emergent NEPC markers such as YAP1. These data indicate that additional paired pre- and post-transformation data are needed, and may benefit from not only larger numbers but more sophisticated genomic evaluation (e.g. WGS) to expand on these intriguing data.


Presented by: Ethan Barnett, Memorial Sloan Kettering Cancer Center, New York, NY


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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