A 3 ' UTR KRAS-variant as a biomarker of poor outcome and platinum chemotherapy resistance in ovarian cancer

A 3’UTR KRAS-variant as a Biomarker of Poor Outcome and Platinum Chemotherapy Resistance in Ovarian Cancer Florence K. Keane , Elena S. Ratner , Michelle Glasgow, Lingeng Lu, Yanhong Deng , Sunitha Nallur , Trupti Paranjape , Linda Steele , Mihaela C. Cristea , Dionyssios Katsaros , Daniel Zelterman , Thomas J. Rutherford , Sharon Sand , Jeffrey N. Weitzel , Susan L. Neuhausen , Herbert Yu, Alessandro D. Santin , Frank Slack , Peter E. Schwartz , and Joanne B. Weidhaas 4 Yale University School of Medicine, New Haven, CT; Department of Gynecological Oncology, Yale University, New Haven, CT; Department of Epidemiology and Public Health, Yale University, New Haven, CT; Department of Therapeutic Radiology, Yale University, New Haven, CT; Department of Population Sciences, Beckman Research Institute of the Cit y of Hope, Duarte, CA; Department of Medical Oncology, City of Hope, Duarte, CA; Department of Gynecological Oncology, University of Turin, Italy; Division of Clinical Cancer Genetics, City of Hope, Duarte, CA; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT Purpose: Ovarian cancer has a poor prognosis, yet pathologic and clinical data do not ac cura ely predict which patients will ultimately succumb to their disease. We prev iously reported an association between rs61764370, a germline functional variant in the 3’UTR of the KRAS oncogene, and epithelial ovarian cancer (EOC) risk. Here we evaluate t his variant as a biomarker of clinical outcome and chemotherapy resistance in EOC. Patients and Methods: Four groups of EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed: Sporadic EOC patients ( =451); BRCA mutant EOC patients (n=79); EOC patients treated with neoadjuvant chemotherapy ( n=122), and; EOC patients treated adjuvantly with platinum-based chemotherapy after cytoreductive sur gery (n=292). Results: The KRAS-variant predicts for significantly worse survival for EOC patie nts over 55 years-old by multivariate Cox regression analysis (HR=1.71, 95% CI= 1.09 – 2.69, p = 0.02). However, for the subgroup of EOC patients with known BRCA mutations, the KRAS-variant did not predict altered outcome (HR=0.994, CI=0.28-3.56, p=0.99). KRAS-variant positive EOC patients respond poorly to neoadjuvant carboplatin and paclitaxel chemotherapy , having significantly more residual disease remaining after surgery ( OR=26.27, CI=1.56441.83, p=0.0232). In addition, EOC patients that harbor the KRAS-variant are more likely to be resistant to adjuvant platinum chemotherapy (OR=2.86, CI=1.13-7.23, p=0.026). Conclusions: These findings expand the potential importance of the KRAS-variant in EOC, from acting as a marker of risk to being a biomarker that predicts worse outc ome, perhaps due to its association with platinum resistance. These data may ultimately hel p lead to treatment optimization and improved outcome for KRAS-variant positive EOC patients. Acknowledgements This project would not have been possible without the guidance and encouragement of my thesis advisor, Joanne B. Weidhaas, M.D., Ph.D. Her support since the summer of 2007 has been instrumental to my success during medical school. I would like to thank Lena Chin, Ph.D. for her identification of the KRAS-variant. Elena Ratner, M.D.’s previous work on the prevalence of the KRAS-variant in hereditary cases of ovarian cancer led to this project. Elena’s assistance with c ollection and analysis of patient data also increased my understanding of the clinical course and tre atment of ovarian cancer. I would also like to acknowledge the members of the Weidhaas laboratory, particularly Sunitha Nallur, Trupti Paranjape, and Phong Trang. Their support and encouragement made the lab a wonderful place to learn and work. Lingeng Lu provided guidance on the statistical analyses. This project was supported by funding from the Yale Office of Student Research and a grant from the Ruth L. Kirschstein National Research Service Award (5 T35 HL07649-24). Finally, I would like to thank my family for their love and encouragement. Table of