Identification of Polymorphisms Associated with Hypertriglyceridemia and Prolonged Survival Induced by Bexarotene in Treating Non-small Cell Lung Cancer

Background: Bexarotene was evaluated in treating advanced non small cell lung cancer (NSCLC) in two phase III trials. Although a significant survival benefit was not observed for the overall bexarotene-treated population (617 patients), a third of bexarotene-treated patients who developed high-grade hypertriglyceridemia exhibited significantly longer survival. Patients and Methods: In order to identify genomic polymorphisms that could serve as potential predictive biomarkers for response and improved survival in NSCLC patients, DNA samples extracted from plasma archived from 403 patients were genotyped using Affymetrix 500K whole genome SNP arrays and/or Sequenom iPLEX™ assays. Results: Fourteen SNPs were identified on nine loci that showed significant associations with high-grade hypertriglyceridemia induced by bexarotene. Four such single nucleotide polymorphisms (SNPs) reside on the region upstream of solute carrier family 10, member 2 (SLC10A2), and one SNP is located close to lymphocyte cytosolic protein 1 (LCP1), whose expression correlated with the activity of bexarotene in tumor cells. Conclusion: We identified novel polymorphisms exhibiting significant association with bexarotene induced hypertriglyceridemia, implicating their potential in predicting bexarotene-improved survival response. Bexarotene (also called Targretin, LGD1069) is a selective modulator of retinoid X receptors (RXRs) approved for treating refractory advanced-stage cutaneous T-cell lymphoma (1, 2). A number of preclinical studies and phase I and II clinical trials have shown that bexarotene also exhibits promising antitumor or tumor prevention activity for breast cancer, renal cell carcinoma and lung cancer (3-8). Consequently, two large phase III trials (SPIRIT I and SPIRIT II) were conducted to evaluate the efficacy and safety of standard chemotherapy agents with or without bexarotene as a first-line therapy in treating advanced NSCLC. The results from both phase III trials, however, showed that the addition of bexarotene to chemotherapy did not improve overall survival in the intent-to-treat population, the primary efficacy endpoint (9, 10). A known side-effect of retinoid therapy is the elevation of serum lipids, and the majority of the bexarotene treated patients in the two SPIRIT trials developed hypertriglyceridemia, as expected. Further analysis revealed that 30-40% of the patients appeared to be more sensitive to bexarotene treatment and developed NCI grade 3 or higher hypertriglyceridemia. Survival analysis in this subgroup of patients in each of the two trials revealed significantly longer survival compared to the patients in the control arm and to patients with low-grade hypertriglyceridemia (9, 10). This intriguing correlation between survival and triglyceride level induced by bexarotene observed in both SPIRIT trials is illustrated in Figure 1A. Similar correlations were also revealed by retrospective analysis in other bexarotene cancer trials (11). These findings prompted the search for biomarkers which can predict bexarotene sensitivity and identify a subgroup of NSCLC patients whose survival could be prolonged by bexarotene treatment. The molecular mechanism underlying the rexinoid-induced hypertriglyceridemia remains largely unknown, but the varied responses exhibited by the patients within 2-4 weeks of bexarotene treatment suggests this might be due to inherent biochemical and genetic differences among the patients. Therefore, a pharmacogenomic study was performed to identify genetic variations associated with bexarotene-induced hypertriglyceridemia using patient samples from the two SPIRIT trials.