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Pharmacogenomic Strategies Provide a Rational Approach to the Treatment of Cisplatin-Resistant Patients With Advanced Cancer

David S. Hsu, Bala S. Balakumaran, Chaitanya R. Acharya, Vanja Vlahovic, Kelli S. Walters, Katherine Garman, Carey Anders, Richard F. Riedel, Johnathan Lancaster, David Harpole, Holly K. Dressman, Joseph R. Nevins, Phillip G. Febbo, Anil Potti

From the Division of Medical Oncology, Department of Medicine; Institute for Genome Sciences and Policy; Department of Surgery, Duke University, Durham, NC; and the Division of Gynecologic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL

Address reprint requests to Anil Potti, MD, Duke University, Department of Medicine, Box 3841 Medical Center, Durham, NC 27710; e-mail: anil.potti{at}duke.edu

Purpose: Standard treatment for advanced non–small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. However, response rates are highly variable. Newer agents, such as pemetrexed, have shown significant activity as second-line therapy and are currently being evaluated in the front-line setting. We utilized a genomic strategy to develop signatures predictive of chemotherapeutic response to both cisplatin and pemetrexed to provide a rational approach to effective individualized medicine.

Methods: Using in vitro drug sensitivity data, coupled with microarray data, we developed gene expression signatures predicting sensitivity to cisplatin and pemetrexed. Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 samples from patients previously treated with cisplatin.

Results: Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict sensitivity in vitro and, in the case of cisplatin, to predict treatment response in patients treated with cisplatin. The accuracy of the cisplatin predictor, based on available clinical data, was 83.1% (sensitivity, 100%; specificity 57%; positive predictive value, 78%; negative predictive value, 100%). Interestingly, an inverse correlation was seen between in vitro cisplatin and pemetrexed sensitivity, and importantly, between the likelihood of cisplatin and pemetrexed response in patients.

Conclusion: The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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