A novel marker integrating multiple genetic alterations better predicts platinum sensitivity in ovarian cancer than HRD score.

Platinum-based chemotherapy is the first-line treatment strategy for ovarian cancer patients. The dismal prognosis of ovarian cancer was shown to be stringently associated with the heterogeneity of tumor cells in response to this therapy, therefore understanding platinum sensitivity in ovarian cancer would be helpful for improving patients' quality of life and clinical outcomes. HRDetect, utilized to characterize patients' homologous recombination repair deficiency, was used to predict patients' response to platinum-based chemotherapy. However, whether each of the single features contributing to HRD score is associated with platinum sensitivity remains elusive. We analyzed the whole-exome sequencing data of 196 patients who received platinum-based chemotherapy from the TCGA database. Genetic features were determined individually to see if they could indicate patients' response to platinum-based chemotherapy and prognosis, then integrated into a Pt-score employing LASSO regression model to assess its predictive performance. Multiple genetic features, including bi-allelic inactivation of BRCA1/2 genes and genes involved in HR pathway, multiple somatic mutations in genes involved in DNA damage repair (DDR), and previously reported HRD-related features, were found to be stringently associated with platinum sensitivity and improved prognosis. Higher contributions of mutational signature SBS39 or ID6 predicted improved overall survival. Besides, arm-level loss of heterozygosity (LOH) of either chr4p or chr5q predicted significantly better disease-free survival. Notably, some of these features were found independent of HRD. And SBS3, an HRD-related feature, was found irrelevant to platinum sensitivity. Integrated all candidate markers using the LASSO model to yield a Pt-score, which showed better predictive ability compared to HRDetect in determining platinum sensitivity and predicting patients' prognosis, and this performance was validated in an independent cohort. The outcomes of our study will be instrumental in devising effective strategies for treating ovarian cancer with platinum-based chemotherapy.