Scoring System Based on DNA Repair Pathways Predicts Outcomes and Response to Platinum Therapy

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A potentially important tool to identify patients with advanced-stage ovarian cancer likely to benefit from platinum-based chemotherapy and redirect those with poor predicted outcomes to alternative treatments was developed using gene-expression data and validated in two independent datasets. While the scoring system still needs to be tested prospectively in a clinical trial, the developers believe “the score is ready for such testing, which must be performed before more widespread adoption in ovarian cancer patients as a prognostic tool,” they wrote in an article published in the Journal of the National Cancer Institute.

“Gene expression data was extracted from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovarian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways.” Patients were divided into low-score (0–10) and high-score (11–20) groups, and overall survival was analyzed by Kaplan–Meier method, the authors explained. “Results were validated in two gene expression microarray datasets.”

Patients in the high-scoring group had 5-year overall survival of 40% vs 17% in the low-scoring group (P < .001) and results were reproduced in the validation datasets (P < .05). “The score positively correlated with complete response rate, recurrence-free survival, and progression-free survival,” the investigators stated.

Development of the ability to predict overall survival and outcomes to chemotherapy using prognostic markers is critical, particularly in patients with ovarian cancer, because there are currently no good clinical measures to predict response to standard platinum-based chemotherapy. “Although 30% of patients receive no benefit from standard platinum-based chemotherapy, many patients undergo multiple cycles of futile, potentially toxic treatment,” the authors noted.

“With further validation, the score can become an important tool that can be used in such advanced-stage ovarian cancer patients before initiation of first-line therapy to help direct them toward treatments with the greatest benefit/risk ratio. Patients in the lowest scoring category of 7 or less, with a median [overall survival] of 2.1 years, stand to benefit the most from alternate therapies, such as enrollment in phase I clinical trials or treatments that target alternate DNA repair pathways, such as radiation,” they continued.

“Conversely, patients in the highest scoring category of 14 and above derive the greatest most durable benefit from platinum and taxane chemotherapy.” The authors also hypothesized that patients in the highest-scoring category would benefit most from poly-ADP ribose polymerase (PARP) inhibitors. ■

Kang J, et al: J Natl Cancer Inst 104:670-681, 2012.




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