Clinical and genomic hallmarks of low PSA secretors in metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5051 Background: Metastatic disease burden out of proportion to low serum PSA level is frequently used as a clinical surrogate for the diagnosis of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC), although many t-SCNC patients (pts) have normal or elevated PSA levels. The clinical and genomic characteristics of mCRPC pts who are Low PSA Secretors have not been previously described. Methods: Eligible mCRPC patients (pts) underwent image-guided needle biopsy. Formalin-fixed paraffin embedded tissue was evaluated with targeted next-generation DNA sequencing. Fresh frozen tissue from the same metastatic tumor underwent RNA-seq. A validated AR transcriptional signature was applied. Low PSA Secretors were defined as pts with PSA < 5 ng/mL plus ≥ 6 metastases on conventional imaging at the time of tumor biopsy. Clinical and genomic characteristics were compared between low PSA Secretors and all other pts. Results: Of 89 evaluable pts, 9 (10%) were identified as Low PSA Secretors. There was no difference between Low PSA Secretors and all other pts in: serum PSA at diagnosis, frequency of Gleason ≥ 8 adenocarcinoma at diagnosis, and serum level of LDH, alkaline phosphatase, or hemoglobin at the time of biopsy. Lung and/or liver metastases were more common in low PSA secretors (67% vs. 33%, p = 0.04). There was no difference in serum level of LDH, alkaline phosphatase, or hemoglobin. Tumor biopsies from Low PSA Secretors were more likely to fall within a previously defined t-SCNC transcriptional cluster (80% vs. 6%, p < 0.001). RB1 loss or inactivating mutations appeared to be enriched in Low PSA Secretors (40% vs. 12%, p = 0.09); there was no difference in frequency of TP53 alterations between subgroups. AR transcriptional signature scores were lower in the Low PSA Secretor group (median score -3.63 vs. 0.66, p < 0.001). Conclusions: Low serum PSA levels in relation to metastatic tumor burden may be a reliable surrogate for the detection of mCRPC that harbors the transcriptional and genomic hallmarks of t-SCNC. Validation studies are warranted.