Functional promoter rs2868371 variant of HSPB1 associates with radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with radio(chemo)therapy.
ABSTRACT We investigated the association between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and the risk of radiation-induced esophageal toxicity (RIET) in patients with non-small-cell lung cancer (NSCLC).
The experimental dataset comprised 120 NSCLC patients who were treated with radio(chemo)therapy between 2005 and 2009, when novel radiation techniques were implemented at MD Anderson. The validation dataset comprised 181 NSCLC patients treated between 1998 and 2004. We genotyped two SNPs of the HSPB1 gene (rs2868370 and rs2868371) by TaqMan assay.
Univariate and multivariate analyses of the experimental dataset showed that the CG/GG genotypes of HSPB1 rs2868371 were associated with significantly lower risk of grade ⩾3 RIET than the CC genotype (univariate hazard ratio [HR] 0.30; 95% confidence interval [CI], 0.10-0.91; P=0.033; multivariate HR 0.29; 95% CI, 0.09-0.97; P=0.045). This difference in risk was replicated in the validation cohort despite the different radiation techniques used during that period.
The CG/GG genotypes of HSPB1 rs2868371 were associated with lower risk of RIET, compared with the CC genotype in patients with NSCLC treated with radio(chemo)therapy. This finding should be validated in large multi-institutional prospective trials.
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ABSTRACT: We investigated potential associations between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and overall survival in US patients with non-small cell lung cancer (NSCLC). Using available genomic DNA samples from 224 patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped 2 SNPs of HSPB1 (NCBI SNP nos. rs2868370 and rs2868371). We used both Kaplan-Meier cumulative probability and Cox proportional hazards analyses to evaluate the effect of HSPB1 genotypes on survival. Our cohort consisted of 117 men and 107 women, mostly white (79.5%), with a median age of 70 years. The median radiation dose was 66 Gy (range, 63-87.5 Gy), and 183 patients (82%) received concurrent platinum-based chemotherapy. The most common genotype of the rs2868371 SNP was CC (61%). Univariate and multivariate analyses showed that this genotype was associated with poorer survival than CG and GG genotypes (univariate hazard ratio [HR] = 1.39, 95% confidence interval [CI], 1.02-1.90; P=.037; multivariate HR = 1.39; 95% CI, 1.01-1.92; P=.045). Our results showed that the CC genotype of HSPB1 rs2868371 was associated with poorer overall survival in patients with NSCLC after radio(chemo)therapy, findings that contradict those of a previous study of Chinese patients. Validation of our findings with larger numbers of similar patients is needed, as are mechanical and clinical studies to determine the mechanism underlying these associations.International journal of radiation oncology, biology, physics 05/2012; 84(2):e229-35. · 4.59 Impact Factor
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ABSTRACT: PURPOSE: To date, no biomarkers have been found to predict, before treatment, which patients will develop radiation pneumonitis (RP), a potentially fatal toxicity, after chemoradiation for lung cancer. We investigated potential associations between single nucleotide polymorphisms (SNPs) in HSPB1 and risk of RP after chemoradiation for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Subjects were patients with NSCLC treated with chemoradiation at 1 institution. The training data set comprised 146 patients treated from 1999 to July 2004; the validation data set was 125 patients treated from August 2004 to March 2010. We genotyped 2 functional SNPs of HSPB1 (rs2868370 and rs2868371) from all patients. We used Kaplan-Meier analysis to assess the risk of grade ≥2 or ≥3 RP in both data sets and a parametric log-logistic survival model to evaluate the association of HSPB1 genotypes with that risk. RESULTS: Grade ≥3 RP was experienced by 13% of those with CG/GG and 29% of those with CC genotype of HSPB1 rs2868371 in the training data set (P=.028); corresponding rates in the validation data set were 2% CG/GG and 14% CC (P=.02). Univariate and multivariate analysis confirmed the association of CC of HSPB1 rs2868371 with higher risk of grade ≥3 RP than CG/GG after adjustment for sex, age, performance status, and lung mean dose. This association was validated both in the validation data set and with Harrell's C statistic. CONCLUSIONS: The CC genotype of HSPB1 rs2868371 was associated with severe RP after chemoradiation for NSCLC.International journal of radiation oncology, biology, physics 01/2013; · 4.59 Impact Factor
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ABSTRACT: Patients with unresectable stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy often develop esophagitis that may lead to unplanned treatment interruptions, which may severely reduce rates of locoregional tumor control and survival. No effectivetreatment that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of normal tissue protection using epigallocatechin-3-gallate (EGCG) has been reported, its actual clinical practicability remains obscure. This is a phase I study of EGCG in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (cisplatin and etoposide) was given concurrently with radiation. EGCG solution was swallowed three times a day after the occurrence of grade 2 esophagitis at six concentration levels and dose escalation followed a standard phase I design. Esophageal toxicity and patient-reported pain was recorded weekly. Twenty-four patients with AJCC stage IIIA (six) and IIIB (eighteen) completed the course of therapy. Twelve had squamous histology, ten adenocarcinoma, and two not specified. Patients were treated in six cohorts at six dose levels of EGCG. RT was not interrupted with a median dose of 64Gy. There were no dose-limiting toxicities reported in all EGCG dosing tiers. Dramatic regression of esophagitis to grade 0/1 was observed in 22 of 24 patients, whereas grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy. The pain score was also reduced from a mean of 4.58 (N=24), 1.29 (N=24), 1.42 (N=24), 0.96 (N=23) to 1.13 (N=16) every week in turn. We conclude that the oral administration of EGCG is feasible, safe and effective. The phase II recommended concentration is 440μmol/L.Radiotherapy and Oncology 01/2014; · 4.52 Impact Factor