Which Genomic Alterations Are Linked to Poor Outcomes in Advanced Prostate Cancer?
Posted: Friday, May 31, 2019
Of all molecular factors, the retinoblastoma gene, or RB1, seems to be most strongly associated with poor clinical outcomes in patients with metastatic castration-resistant prostate cancer, according to research findings published in PNAS (Proceedings of the National Academy of Sciences of the United States of America). The report—the integrative analysis of genomic alterations, gene expression, histopathology, and clinical outcomes—is reportedly the largest single metastatic castration-resistant prostate cancer data set to date, according to Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues and may serve as a community resource for future interrogation of clinical and molecular associations.
“We [found] that RB1 loss is the molecular factor most strongly associated with poor clinical outcomes in a contemporary cohort, highlighting the need for further investigation into mechanisms of resistance to [androgen receptor] therapies induced by loss of RB and potential therapeutic strategies targeting this mechanism,” the authors concluded.
The analysis included 444 tumors from 429 men diagnosed with advanced prostate cancer. The investigators focused on whole-exome sequencing, gene expression, and histopathology with clinical outcomes, including survival time and treatment with next-generation androgen-signaling inhibitors enzalutamide and abiraterone acetate.
Of the molecular factors, RB1 alteration alone was significantly associated with poor survival. Alterations in RB1, androgen receptors, and TP53 were associated with a shorter time on treatment with androgen receptor–signaling inhibitors. The authors found no link between alterations in PI3K pathway genes or alterations in the DNA damage repair genes BRCA2, BRCA1, and ATM in regard to overall survival and time on treatment with an androgen-signaling inhibitor.
“It is worth noting that the association [with RB1 was] strong despite likely underestimation of RB1 loss by examining genomic homozygous loss alone, as RB1 loss has also been shown to occur epigenetically, through structural genomic events like tandem duplication of partial exons, and focally, by immunohistochemistry,” the authors observed.
Disclosure: The study authors’ disclosure information may be found at pnas.org.
