Abstract 5554: Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small cell lung cancer
Authors: Lamba Jatinder Kaur , Fridley Brooke L. , Ghosh Taraswi M. , Yu Qing , Mehta Gaurav , Gupta Pankaj 
Published: May 2015

Background: Lung carcinoma is the most common malignancy worldwide, and the leading cause of cancer deaths. Histologically, majority of lung cancers are non-small cell carcinomas (NSCLC). The 5-year relative survival of patients with metastatic NSCLC remains dismal at &lt;5%, with a median survival of &lt;6 months in unselected patients. Platinating agent+taxane based combination chemotherapy is a standard treatment for advanced NSCLC patients with adequate organ function and performance status, and whose tumor lack driver mutations amenable to treatment with a specific inhibitor. Combination chemotherapy achieves objective response in only about 25% patients, improves survival modestly, and is associated with diverse side effects. Although clinical factors such as age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of inter-individual variation in response and toxicity. Purpose: The present study was carried out with the aim of identifying pharmacogenomic markers predictive of response and toxicity in patients with advanced NSCLC treated with carboplatin and paclitaxel. Methods: Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC and treated with carboplatin and paclitaxel was isolated from FFPE specimens. SNPs in the key candidate genes of relevance to carboplatin and paclitaxel were selected using multiple databases. Overall 63 SNPs in 29 genes were genotyped using Sequenome platform at University of Minnesota Genomics Center. After filtering for SNPs with minimum allele frequency of less than 5%, 57 SNPs were evaluated for association with survival and toxicity was evaluated using appropriate statistical tests. Results: The overall response rate was 19% (all partial responses). Stage and performance status were significantly associated with progression free survival (PFS). After adjusting for these covariates, we identified significant associations of SNPs in the drug transporters ABCB1, ABCC1 as well as of SNPs in GSTM3 and NQO1 with PFS (p&lt;0.05). With respect to both hematological and non-hematological toxicity, we found that SNPs in ABCB1, ABCG2 and ABCC2 were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes, ERCC1, ERCC4 and XPC were significantly associated with diarrhea, neutropenia and sensory neuropathy, respectively. Conclusion: Our study provides a comprehensive evaluation of the associations of platinating agent and taxane pathway genes with outcome as well as toxicity associated with these medications in advanced NSCLC. Identification of these predictive markers, in conjunction with other known prognostic factors, may help optimize therapeutic decisions to maximize benefit and minimize toxicity.

Citation Format: Jatinder Kaur Lamba, Brooke L. Fridley, Taraswi M. Ghosh, Qing Yu, Gaurav Mehta, Pankaj Gupta. Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5554. doi:10.1158/1538-7445.AM2014-5554