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Molecular subtyping may predict which prostate cancers benefit from androgen deprivation therapy
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The identification of prostate cancer subtypes based on luminal and basal lineage may provide a clinical tool to personalize androgen deprivation therapy use after surgery, according to a study published in JAMA Oncology.
For instance, men with luminal B prostate cancer tumors responded better to postoperative ADT than men with nonluminal B tumors.
“We believe this work not only represents a significant step forward in our understanding of prostate cancer heterogeneity but also is a potential classifier that may identify patients who benefit from postoperative ADT on a clinical-grade platform and provide guidance in personalizing patient care,” Felix Y. Feng, MD, associate professor of radiation oncology at Helen Diller Comprehensive Cancer Center at University of California, San Francisco, and colleagues wrote.
There is mounting evidence that basal cells may play a role in the development of prostate cancer, in addition to the already established role of glandular luminal cells.
Because prostate cancer and breast cancer are hormonally driven tumors that share many oncogenic pathways, researchers sought to determine if the PAM50 gene expression classifier used to identify major molecular subtypes of breast cancer could also identify luminal- and basal-like subtypes in prostate cancer.
Researchers used the PAM50 classifier to divide 1,567 retrospectively collected (median follow-up, 10 years) and 2,215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes.
Distant metastasis-free survival (DMFS) served as the primary endpoint. Secondary endpoints included biochemical recurrence-free survival (bRFS), prostate cancer–specific survival (PCSS) and OS.
Retrospective samples included 538 (34.3%) luminal A cases, 447 (28.5%) luminal B cases and 582 (37.1%) basal cases. Researchers classified the prospective samples as luminal A (n = 737; 33.3%), luminal b (n = 723; 32.6%) and basal (n = 755; 34.1%) basal.
Researchers found enrichment of luminal lineage markers NKX3.1 and KRT18 in luminal-like cancers, and basal lineage CD49f in basal-like cancers, which demonstrated a connection between these subtypes and established prostate cancer biology.
Among men in the retrospective cohort, luminal B prostate cancers had the poorest clinical prognoses (10-year bRFS, 29%; DMFS, 53%; PCSS, 78%; OS, 69%). Basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%) showed better outcomes.
Multivariable analyses adjusted for clinicopathologic variables showed patients with basal and luminal A tumors had better independent prognosis than patients with luminal B tumors for bRFS (basal, HR = 0.81; 95% CI, 0.69-0.96; luminal A, HR = 0.79; 95% CI, 0.66-0.93) and DMFS (basal, HR = 0.66; 95% CI, 0.53-0.82; luminal A, HR = 0.55; 95% CI, 0.43-0.69). Patients with luminal A tumors had better outcomes than patients with luminal B tumors for PCSS (HR = 0.5; 95% CI, 0.35-0.71) and OS (HR = 0.69; 95% CI, 0.55-0.87).
Researchers conducted an exploratory subgroup analysis of 315 men treated with ADT (n = 105) or not treated with ADT (n = 210) to investigate whether these subtypes could predict response to hormonal therapy.
Although both luminal A and B subtypes appeared associated with increased androgen receptor expression and signaling, only luminal B prostate cancers appeared significantly associated with postoperative response to ADT (10-year metastases rate with vs. without ADT, 33% vs. 55%).
However, in patients with nonluminal B subtypes, patients treated with ADT had worse DMFS than untreated patients (10-year metastases rate, 37% vs. 21%; P for interaction = .006).
“We demonstrated that patients with luminal B tumors benefit more from ADT than do those with nonluminal B tumors,” Feng and colleagues wrote. “We did not find the same benefit from ADT for patients with luminal A tumors, perhaps because these patients already have a better prognosis; thus, aggressive treatment may make little difference in the eventual outcome.”
Researchers grouped patients with adjuvant and salvage ADT because stratification would have reduced the number of patients and statistical power of the study. Therefore, Feng and colleagues noted that the results should be considered hypotheses generating and should be independently validated in a randomized clinical trial.
The study raises intriguing questions about the biology of localized prostate cancer, Wassim Abida, MD, PhD, genitourinary oncologist at Memorial Sloan Kettering Cancer Center, and Howard I. Scher, MD, chief of genitourinary oncology at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medicine, wrote in an accompanying editorial.
“The authors skillfully applied an analytically validated expression-based classifier to clinically annotated localized prostate cancer datasets, paving the way to prospective studies that will support the use of the biomarker for identifying patients who will benefit from postoperative ADT,” Abida and Scher wrote. “Beyond this, the study raises rich questions regarding the potential drivers of aggressive early prostate cancer, where androgen receptor pathway status alone does not clearly explain aggressive behavior.”– by Chuck Gormley
Disclosure: A. Alfred Taubman Medical Research Institute, Evans Foundation, Prostate Cancer Foundation and V Foundation for Cancer Research funded this study. Feng reports ownership in PFS Genomics; consultant roles with Celgene, Dendreon, GenomeDx, Medivation/Astellas, Merck and Sanofi; and research funding from Varian Medical Systems. Please see the full study for a list of all other researchers’ relevant financial disclosures. Scher reports personal fees from Astellas and Sanofi Aventis, and research funding from Janssen Diagnostics, Janssen Pharmaceuticals and Medivation. Abida reports no relevant financial disclosures.
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