Study shines light on precision medicine pathway in mCRPC

A recent study showed the capacity to classify metastatic castration-resistant prostate tumors as luminal and basal, and examined the personalized medicine potential unlocked by identifying these subtypes.¹

Findings from the study indicated that androgen signaling inhibitors (ASI) were found to be more effective in luminal tumors, and a chemotherapy approach should be considered for basal tumors. The median overall survival (OS) in those with basal tumors was 33.3 months vs 18.7 months for luminal tumors in those treated in the East Coast Dream Team (ECDT) cohort with 266 patients using poly-A enriched data with ASI post biopsy (ECDT HR, 0.39; 95% CI, 0.20-0.74; P = .004). Treatment with an ASI resulted in significantly better median survival for those with luminal tumors at 32.0 months vs 8.7 months for basal tumors (HR, 0.27; 95% CI, 0.14-0.53; P <.001). Moreover, patients who had basal tumors experienced a lower effect size that was no longer significant (HR, 0.62; 95% CI, 0.36-1.04; P = .07).

OS was examined in 80 patients in the ECDT cohort and 123 in the West Coast Dream Team (WCDT) cohort. Overall, only 19 patients in the WCDT cohort received chemotherapy for their disease prior to treatment enrollment. In the ECDT cohort, those with luminal tumors treated with ASI post-biopsy had better OS than those with basal tumors at 32.0 months vs 21.7 months (HR, 0.57; 95% CI, 0.33-0.97; P = .04), with no significant difference being found in those who were not treated with ASI post-biopsy.

The median OS in the ECDT cohort was 28.1 months vs the WCDT cohort of 25.7 months following treatment with post-biopsy ASI. When both cohorts were pooled for an interaction analysis, it was found that there was an interaction between subtype and post-biopsy ASI therapy (HR, 0.42; 95% CI, 0.20-0.89; P = .02). Of those who had never received ASI treatment, those with luminal tumors had a better OS than those with basal tumors (HR, 0.39; 95% CI, 0.20-0.74; P = .005), with similar interaction in the ASI-naïve subset (HR, 0.07; 95% CI, 0.01-0.48; P = .007).

A total of 634 metastatic CRPC samples were collected across 4 cohorts. A basal group was detected in 346 samples, and a luminal group in 288. Among the small cell/neuroendocrine prostate cancer (SCNC) samples, 53 were classified as basal.

The most luminal-enriched pathway was the androgen response pathway identified by the gene set enrichment analysis, as well as SCNC in basal tumors. Basal-enriched pathways were associated with cell cycle and cell division which is consistent with increased expression of proliferative genes including MKI67.

A higher rates of basal tumors were reported to have RB1 alterations (23%), compared with luminal tumors (4%; Fisher exact test; P <.001). There was no significant difference between PTEN mutation loss between patients with basal tumors (29%) and luminal tumors (32%; Fisher exact test; P = .45), or TP53 loss (33% vs 28%, respectively; Fisher exact test; P = .19). Higher alteration rates in FOXA1 were observed in the basal tumors cohort (36%) vs luminal tumors (27%; Fisher exact test; P = .03) and MYC (73% vs 56%, respectively; Fisher exact test; P <.001). However, there was no significant difference in androgen receptor pathways between the 2 groups (74% vs 79%; Fisher exact test; P = .22).

Reference

1. Aggarwal R, Rydzewski NR, Zhang L, et al. Prognosis associated with luminal and basal subtypes of metastatic prostate cancer. JAMA Oncol. 2021;7(11):1644-1652. doi:10.1001/jamaoncol.2021.3987