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

Author

Florence Keane

Date of Award

January 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joanne B. Weidhaas

Subject Area(s)

Oncology

Abstract

Purpose: Ovarian cancer has a poor prognosis, yet pathologic and clinical data do not accurately predict which patients will ultimately succumb to their disease. We previously 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 this 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 (n=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 surgery (n=292).

Results: The KRAS-variant predicts for significantly worse survival for EOC patients 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=1.56- 441.83, 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 outcome, perhaps due to its association with platinum resistance. These data may ultimately help lead to treatment optimization and improved outcome for KRAS-variant positive EOC patients.

Comments

This is an Open Access Thesis.

Recommended Citation

Keane, Florence, "A 3'UTR KRAS-variant as a biomarker of poor outcome and platinum chemotherapy resistance in ovarian cancer" (2011). Yale Medicine Thesis Digital Library. 1570.
https://elischolar.library.yale.edu/ymtdl/1570