Molecular and immunohistochemistry-based profiling of prostatic adenocarcinoma has revealed frequent Androgen Receptor (AR) gene and protein alterations in metastatic disease. This includes an AR-null non-neuroendocrine phenotype of metastatic castrate resistant prostate cancer which may be less sensitive to androgen receptor signaling inhibitors. This AR-null non-neuroendocrine phenotype is thought to be associated with TP53 and RB1 alterations. Herein, we have correlated molecular profiling of metastatic castrate resistant prostate cancer with AR/P53/RB immunohistochemistry and relevant clinical correlates.
Twenty-seven cases of metastatic castrate resistant prostate cancer were evaluated using histopathologic examination to rule out neuroendocrine differentiation. A combination of a hybridization exon-capture next-generation sequencing-based assay (n = 26), fluorescence in situ hybridization for AR copy number status (n = 16), and immunohistochemistry for AR (n = 27), P53 (n = 24) and RB (n = 25) was used to profile these cases.
Of 27 metastatic castrate resistant prostate cancer cases, 17 had AR amplification and showed positive nuclear expression of AR by immunohistochemistry. Nine cases lacked AR copy number alterations using next-generation sequencing/fluorescence in situ hybridization. A subset of these metastatic castrate resistant prostate cancer cases demonstrated the AR-null phenotype by immunohistochemistry (five cases and one additional case where next-generation sequencing failed). Common co-alterations in these cases involved the TP53, RB1, and PTEN genes and all these patients received prior therapy with androgen receptor signaling inhibitors (abiraterone and/or enzalutamide).
Our study suggests that AR immunohistochemistry may distinguish AR-null from AR-expressing cases in the metastatic setting. AR-null status informs clinical decision-making regarding continuation of therapy with androgen receptor signaling inhibitors and consideration of other treatment options. This might be a relevant and cost-effective diagnostic strategy when there is limited access and/or limited tumor material for molecular testing.
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The authors would like to thank Irina Ostrovnaya and Marina Asher from the Precision Pathology Biobanking Center (PPBC) at Memorial Sloan Kettering Cancer Center, New York, NY for technical assistance as well as Jennifer Posada and Christine Moon for administrative assistance.
This study was supported in part through NIH/NCI Prostate Cancer SPORE Award P50CA092629 (MSKCC), NIH/NCI Cancer Center Support grant P30CA008748, CDMRP Prostate Cancer Research Program Award W81XWH-12-PCRP-TIA (to AG, VER, and HS), CDMRP W81XWH-14-2-0186 and Prostate Cancer Biorepository Network-PCRP Pathology Resource Network Award (to AG).
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Gupta, S., Vanderbilt, C., Abida, W. et al. Immunohistochemistry-based assessment of androgen receptor status and the AR-null phenotype in metastatic castrate resistant prostate cancer. Prostate Cancer Prostatic Dis (2020). https://doi.org/10.1038/s41391-020-0214-6