Classification of metastatic castration-resistant prostate cancer (mCRPC) tumors as luminal or basal may lead to better treatment decisions in these patients, according to results from a recent study published in JAMA Oncology.
In this largest clinical, transcriptomic, and genomic analysis of mCRPC tumor samples to date, researchers concluded that mCRPC patients with luminal tumors will benefit more from treatment with androgen-signaling inhibitors (ASIs), whereas those with basal tumors should be considered for chemotherapy.
In primary prostate cancer—but not mCRPC—the luminal and basal subtypes have been shown to be molecularly distinct and clinically important in predicting response to therapy, according to Shuang G. Zhang, MD, of the University of Wisconsin, Madison, and fellow researchers.
“To our knowledge, all studies evaluating luminal/basal subtypes within prostate cancer have been limited to primary prostate cancer tissue, in part due to the difficulties in obtaining biopsies from metastases, which are often confined to bone. Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. It is now well established that AR signaling persists in a substantial proportion of patients with mCRPC, and is the basis of the efficacy and US Food and Drug Administration approval of a number of androgen-signaling inhibitors (ASIs) in this patient population. We therefore hypothesized that, as in primary prostate cancer, luminal and basal subtypes exist in mCRPC and provide important molecular and clinical information that may be relevant to AR-targeted therapies,” they wrote.
In this retrospective analysis of four recent clinical trial mCRPC cohorts—including the Fred Hutchinson Cancer Research Center, Weill Cornell Medicine, Stand Up 2 Cancer/Prostate Cancer Foundation East Coast Dream Team (ECDT), and Stand Up 2 Cancer/Prostate Cancer Foundation West Coast Dream Team (WCDT)—Zhang and colleagues sought to identify the luminal and basal subtypes both clinically and molecularly and assess survival differences in mCRPC patients, especially after androgen-signaling inhibitor (ASI) therapy.
In all, 634 patients were included, of whom 45% had luminal tumors and 55% had basal. About 90% of the small cell/neuroendocrine prostate cancer (SCNC) tumors were basal (P<0.001).
Overall survival data were available only for the ECDT (80 patients) and WCDT cohorts (123 patients), and demonstrated worse overall survival in patients with basal tumors compared with luminal tumors only in those who underwent ASI post-biopsy (ECDT: HR: 0.39; 95% CI: 0.20-0.74; P=0.004; WCDT: HR: 0.57; 95% CI: 0.33-0.97; P=0.04). In the ECDT cohort, patients with luminal tumors had better overall survival compared with those who had basal tumors, (median overall survival: 33.1 versus 18.7 months, respectively; HR: 0.39; 95% CI, 0.20-0.74; P=0.004).
Patients with luminal tumors who received ASI treatment had significantly better survival (HR: 0.27; 95% CI: 0.14-0.53; P<0.001), while patients with basal tumors did not (HR: 0.62; 95% CI: 0.36-1.04; P=0.07), leading Zhang et al to conclude that the interaction term between tumor subtype and ASI treatment was statistically significant (HR: 0.42; 95% CI: 0.20-0.89; P=0.02).
Analysis of RNA sequencing revealed that—as in primary prostate cancer—mCRPC luminal tumors overexpressed AR pathway genes, while more basal tumors had a significantly higher rate of RB1 loss (4% versus 23%, respectively; P<0.001), FOXA1 alterations (27% versus 36%; P=0.03), and MYC alterations (56% versus 73%; P<0.001).
Rodwell Mabaera, MD, PhD, of Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, commented on the significance of these findings in choosing effective treatments for patients with mCRPC.
“The identification of RB1, FOXA1, and MYC alterations in basal tumors is of particular interest because each of these pathways has been implicated in androgen-independent mCRPC progression and resistance to ASIs. In particular, RB1 and TP53 loss was associated with resistance to androgen receptor antagonists and increased dependence on DNA damage repair pathways, opening the prospect that PARP inhibitors may be effective in this subgroup of patients. Thus, there are likely subgroups within the basal tumors that may benefit from chemotherapy or molecularly targeted treatments while a subset remains dependent on androgen pathway signaling,” he wrote in an accompanying editorial.
Mabaera also stressed the significant need for better prognostic markers.
“Despite the considerable treatment advances over the past 15 years, metastatic castration-resistant prostate cancer (mCRPC) continues to contribute to significant mortality and morbidity, with an estimated 34,130 deaths projected in the US in 2021,” he wrote.
“Because the molecular background of castration-resistant progression is incompletely understood, the selection of treatment for mCRPC is based on clinicopathologic risk stratification. However, individuals within clinically defined risk categories of mCRPC display widely different outcomes, with a subset of patients developing refractory disease associated with poor survival despite the many therapeutic options available. As such, the development and validation of prognostic and predictive biomarkers to improve the selection of therapy for mCRPC represent an important need,” he added.
“Collectively, the findings suggest the applicability of the luminal-basal subtypes to mCRPC and provide a framework for unraveling the molecular complexity of mCRPC… This study’s findings also provide a rationale to expect that these subtypes represent a potentially powerful tool for personalized therapeutic decision-making that may improve outcomes in mCRPC,” Mabaera concluded.
Study limitations include the limited availability of treatment information and possible treatment selection bias.
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Classification of tumors in patients with metastatic castration-resistant prostate cancer (mCRPC) as luminal or basal can inform treatment decisions and better predict prognosis.
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Patients with luminal tumors may benefit more from androgen-signaling inhibitor therapies, while those with basal tumors may do best with chemotherapeutic approaches.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This research was supported by a Department of Defense Prostate Cancer Research Program Physician Research Award, a Stand Up To Cancer–Prostate Cancer Foundation Prostate Cancer Dream Team Award, and by the Movember Foundation (administered by the American Association for Cancer Research, the scientific partner of SU2C). Additional funding was received from the Prostate Cancer Foundation, a UCSF Benioff Initiative for Prostate Cancer Research award, the Swedish Research Council and the Swedish Society of Medicine, the National Cancer Institute, and the University of Wisconsin Carbone Cancer Center Support Grant.
Zhang has a pending patent application for a molecular signature in breast cancer unrelated to this work licensed to Exact Sciences, and pending patent applications with Decipher Biosciences on luminal and basal subtypes in prostate cancer, as well as other molecular signatures in prostate cancer unrelated to this work. He also received the Department of Defense Prostate Cancer Research Program Physician Research Award.
Mabaera reported grants from the National Institutes of Health supporting protected research time and funds research expenses outside the submitted work
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Topic ID: 78,25,580,730,25,192,73,925,482,96
