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1.
Anticancer Res ; 31(6): 2303-11, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21737656

ABSTRACT

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.


Subject(s)
Carcinoma, Non-Small-Cell Lung/blood , Hypertriglyceridemia/chemically induced , Hypertriglyceridemia/genetics , Lung Neoplasms/blood , Tetrahydronaphthalenes/adverse effects , Bexarotene , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Case-Control Studies , Clinical Trials, Phase III as Topic , DNA/blood , DNA/genetics , Female , Genetic Predisposition to Disease , Humans , Hypertriglyceridemia/blood , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide , Tetrahydronaphthalenes/therapeutic use
2.
J Clin Oncol ; 26(11): 1879-85, 2008 Apr 10.
Article in English | MEDLINE | ID: mdl-18398153

ABSTRACT

PURPOSE: The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m(2)/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. RESULTS: A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss >or= 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. CONCLUSION: Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/secondary , Lung Neoplasms/drug therapy , Bexarotene , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Humans , Hypertriglyceridemia/chemically induced , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Transplantation , Paclitaxel/administration & dosage , Survival Analysis , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects
3.
J Clin Oncol ; 26(11): 1886-92, 2008 Apr 10.
Article in English | MEDLINE | ID: mdl-18398154

ABSTRACT

PURPOSE: This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted. RESULTS: A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm). CONCLUSION: The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Triglycerides/blood , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bexarotene , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Cisplatin/administration & dosage , Disease Progression , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/chemically induced , Hypertriglyceridemia/mortality , Lung Neoplasms/blood , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Survival Rate , Tetrahydronaphthalenes/adverse effects , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine
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