In a retrospective cohort study reported in JAMA Oncology, Aggarwal et al found that metastatic castration-resistant prostate cancer could be categorized into luminal and basal subtypes, and that androgen-signaling inhibitor treatment was associated with better outcomes in patients diagnosed with luminal disease.
As stated by the investigators, “Luminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct and clinically important in predicting response to therapy. These subtypes have not been described in metastatic prostate cancer.”
Study Details
The study included data on 634 patients in four cohorts from multiple U.S. academic centers, including 266 from the Stand Up to Cancer/Prostate Cancer Foundation East Coast Dream Team (ECDT) cohort and 162 from the Stand Up to Cancer/Prostate Cancer Foundation West Coast Dream Team (WCDT) cohort. Overall survival data were available only for the ECDT and WCDT cohorts. Treatment among the 634 patients was according to physician discretion. The primary clinical outcome measure of interest was overall survival from date of tissue biopsy/molecular profiling.
Key Findings
Among the 634 patients, 288 (45%) had tumors classified as luminal and 346 (55%) had tumors classified as basal. Of 59 small cell/neuroendocrine prostate cancer tumors, 53 (90%) were basal (P < .001).
Among tumor-suppressor genes, basal tumors exhibited a higher frequency of RB1 alterations vs luminal tumors (23% vs 4%, P < .001), with no significant differences observed in PTEN loss (29% vs 32%, P = .45) or TP53 loss (33% vs 28%, P = .19). Among oncogenes, basal tumors exhibited higher rates of alterations in FOXA1 (36% vs 27%, P = .03) and MYC (73% vs 56%, P < .001), with no significant difference observed in AR alterations (74% vs 79%, P = .22).
All patients from the ECDT cohort included in survival analysis had received post-biopsy androgen-signaling inhibitor treatment. Those with luminal tumors had improved overall survival vs those with basal tumors (median = 33.1 vs 18.7 months, hazard ratio [HR] = 0.39, 95% confidence interval [CI] = 0.20–0.74, P = .004). Among WCDT cohort patients who received post-biopsy androgen-signaling inhibitor treatment, overall survival was also improved in luminal vs basal tumors (median = 32.0 vs 21.7 months, HR = 0.57, 95% CI = 0.33–0.97, P = .04).
Among all patients with luminal tumors, those who received androgen-signaling inhibitor treatment had significantly improved overall survival vs those who did not (median = 32.0 vs 8.7 months, HR = 0.27, 95% CI = 0.14–0.53, P < .001), whereas the benefit of androgen-signaling inhibitor vs no androgen-signaling inhibitor treatment did not reach significance among those with basal tumors (HR = 0.62, 95% CI = 0.36–1.04, P = .07).
The interaction between subtype and post-biopsy androgen-signaling inhibitor treatment for overall survival was statistically significant (HR = 0.42, 95% CI = 0.20–0.89, P = .02).
The investigators concluded, “These findings represent the largest integrated clinical, transcriptomic, and genomic analysis of metastatic castration-resistant prostate cancer samples to date and suggest that metastatic castration-resistant prostate cancer can be classified as luminal and basal tumors. Analogous to primary prostate cancer, these data suggest that the benefit of androgen-signaling inhibitor treatment is more pronounced in luminal tumors and support the use of androgen-signaling inhibitors in this population. In the basal tumors, a chemotherapeutic approach could be considered in some patients given the similarity to small cell/neuroendocrine prostate cancer and the diminished benefit of androgen-signaling inhibitor therapy. Further validation in prospective clinical trials is warranted.”
Shuang G. Zhao, MD, MSE, of the Department of Human Oncology, University of Wisconsin, Madison, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the Department of Defense Prostate Cancer Research Program, Stand Up to Cancer–Prostate Cancer Foundation, Movember Foundation, and others. For full disclosures of the study authors, visit jamanetwork.com.
