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A Qualitative Transcriptional Signature for Predicting Recurrence Risk for High-Grade Serous Ovarian Cancer Patients Treated With Platinum-Taxane Adjuvant Chemotherapy.

ABSTRACT: Resistance to platinum and taxane adjuvant chemotherapy (ACT) is the main cause of the recurrence and poor prognosis of high-grade serous ovarian cancer (HGS-OvCa) patients receiving platinum-taxane ACT after surgery. However, currently reported quantitative transcriptional signatures, which are commonly based on risk scores summarized from gene expression, are unsuitable for clinical application because of their high sensitivity to experimental batch effects and quality uncertainties of clinical samples. Using 226 samples of HGS-OvCa patients receiving platinum-taxane ACT in TCGA, we developed a qualitative transcriptional signature, consisting of four gene pairs whose within-samples relative expression orderings could robustly predict patient recurrence-free survival (RFS). In two independent test datasets, the predicted non-responders had significantly shorter RFS than the predicted responders (log-rank p < 0.05). In a test dataset containing data for patient pathological response state, the signature reclassified 12 out of 22 pathological complete response patients as non-responders and two out of 16 pathological non-complete response patients as responders. Notably, the 12 predicted non-responders in the pathological complete response group had significantly shorter RFS than the predicted responders (log-rank p = 0.0122). This qualitative transcriptional signature, which is insensitive to experimental batch effects and quality uncertainties of clinical samples, can individually identify HGS-OvCa patients who are more likely to benefit from platinum-taxane adjuvant chemotherapy.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6813654 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Qualitative Transcriptional Signature for Predicting Recurrence Risk for High-Grade Serous Ovarian Cancer Patients Treated With Platinum-Taxane Adjuvant Chemotherapy.

Liu Yixin Y Zhang Zheyang Z Li Tianhao T Li Xin X Zhang Sainan S Li Ying Y Zhao Wenyuan W Gu Yunyan Y Guo Zheng Z Qi Lishuang L

Frontiers in oncology 20191018

Resistance to platinum and taxane adjuvant chemotherapy (ACT) is the main cause of the recurrence and poor prognosis of high-grade serous ovarian cancer (HGS-OvCa) patients receiving platinum-taxane ACT after surgery. However, currently reported quantitative transcriptional signatures, which are commonly based on risk scores summarized from gene expression, are unsuitable for clinical application because of their high sensitivity to experimental batch effects and quality uncertainties of clinica ...[more]

PMID: 31681618

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Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents

Project description:BackgroundHigh-grade serous ovarian cancer (HGSOC) has poor survival rates due to a combination of diagnosis at advanced stage and disease recurrence as a result of chemotherapy resistance. In BRCA1 (Breast Cancer gene 1) - or BRCA2-wild type (BRCAwt) HGSOC patients, resistance and progressive disease occur earlier and more often than in mutated BRCA. Identification of biomarkers helpful in predicting response to first-line chemotherapy is a challenge to improve BRCAwt HGSOC management.MethodsTo identify a gene signature that can predict response to first-line chemotherapy, pre-treatment tumor biopsies from a restricted cohort of BRCAwt HGSOC patients were profiled by RNA sequencing (RNA-Seq) technology. Patients were sub-grouped according to platinum-free interval (PFI), into sensitive (PFI > 12 months) and resistant (PFI < 6 months). The gene panel identified by RNA-seq analysis was then tested by high-throughput quantitative real-time PCR (HT RT-qPCR) in a validation cohort, and statistical/bioinformatic methods were used to identify eligible markers and to explore the relevant pathway/gene network enrichments of the identified gene set. Finally, a panel of primary HGSOC cell lines was exploited to uncover cell-autonomous mechanisms of resistance.ResultsRNA-seq identified a 42-gene panel discriminating sensitive and resistant BRCAwt HGSOC patients and pathway analysis pointed to the immune system as a possible driver of chemotherapy response. From the extended cohort analysis of the 42 DEGs (differentially expressed genes), a statistical approach combined with the random forest classifier model generated a ten-gene signature predictive of response to first-line chemotherapy. The ten-gene signature included: CKB (Creatine kinase B), CTNNBL1 (Catenin, beta like 1), GNG11 (G protein subunit gamma 11), IGFBP7 (Insulin-like growth factor-binding protein 7), PLCG2 (Phospholipase C, gamma 2), RNF24 (Ring finger protein 24), SLC15A3 (Solute carrier family 15 member 3), TSPAN31 (Tetraspanin 31), TTI1 (TELO2 interacting protein 1) and UQCC1 (Ubiquinol-cytochrome c reductase complex assembly factor). Cytotoxicity assays, combined with gene-expression analysis in primary HGSOC cell lines, allowed to define CTNNBL1, RNF24, and TTI1 as cell-autonomous contributors to tumor resistance.ConclusionsUsing machine-learning techniques we have identified a gene signature that could predict response to first-line chemotherapy in BRCAwt HGSOC patients, providing a useful tool towards personalized treatment modalities.

Dataset Information

A Qualitative Transcriptional Signature for Predicting Recurrence Risk for High-Grade Serous Ovarian Cancer Patients Treated With Platinum-Taxane Adjuvant Chemotherapy.

Publications

A Qualitative Transcriptional Signature for Predicting Recurrence Risk for High-Grade Serous Ovarian Cancer Patients Treated With Platinum-Taxane Adjuvant Chemotherapy.

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