Purpose: From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer.Experimental Design: We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors.Results: Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4:A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P ¼ 0.01] and XRCC1:Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P ¼ 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2:Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P ¼ 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P ¼ 0.03], comparing number of variant alleles with reference of zero variants.Conclusions: None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.

BACKGROUND:The purpose of the study was to identify predictors of weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. METHODS: This study was conducted as part of a phase 3 chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Their baseline characteristics, including lifestyle habits, diet, and quality of life, were assessed as potential predictors. Predictors were identified using multiple linear regressions. The reliability of the model was assessed by bootstrap resampling. A receiver operating characteristics curve was generated to estimate the model's accuracy in predicting critical weight loss (!5%). RESULTS: The mean weight loss was 2.2 kg (standard deviation, 3.4). Five factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P<.001), higher pre-RT body weight (P<.001), stage II disease (P ¼ .002), dysphagia and/or odynophagia before RT (P ¼ .001), and a lower Karnofsky performance score (P ¼ .028). There was no association with pre-RT lifestyle habits, diet, or quality of life. The bootstrapping method confirmed the reliability of this predictive model. The area under the curve was 71.3% (95% confidence interval, 65.8-76.9), which represents an acceptable ability of the model to predict critical weight loss. CONCLUSIONS: These results could be useful to clinicians for screening patients with early stage HN cancer treated by RT who require special nutritional attention. Cancer 2010;116:2275-83.

Purpose: Recognized prognostic factors do not adequately predict outcomes of head and neck cancer (HNC) patients after their initial treatment. We identified from the literature nine potential serum prognostic markers and assessed whether they improve outcome prediction.Experimental Design: A pretreatment serum sample was obtained from 527 of the 540 HNC patients who participated in a randomized controlled trial. During follow-up, 115 had a HNC recurrence, 110 had a second primary cancer (SPC), and 216 died. We measured nine potential serum prognostic markers: prolactin, soluble interleukin-2 (IL-2) receptor-α, vascular endothelial growth factor, IL-6, squamous cell carcinoma antigen, free β-human choriogonadotropin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and soluble epidermal growth factor receptor. Cox regression was used to identify a reference predictive model for (a) HNC recurrence, (b) SPC incidence, and (c) overall mortality. Each serum marker was added in turn to these reference models to determine by the likelihood ratio test whether it significantly improved outcome prediction. We controlled for the false discovery rate that results from multiple testing.Results: IL-6 was the only serum marker that significantly improved outcome prediction. Higher levels of IL-6 were associated with a higher SPC incidence. The hazard ratio comparing the uppermost quartile to the lowest quartile of IL-6 was 2.68 (95% confidence interval,

Low pretreatment vitamin D status has been associated with worsened disease outcomes in patients with cancer at various sites. Its prognostic significance in head and neck cancer (HNC) patients has not been studied. Patients with HNC who participated in a randomized trial were evaluated for: (i) total intake of vitamin D from diet and supplements using a validated food frequency questionnaire (all trial participants, n 5 540) and (ii) pretreatment serum 25-hydroxyvitamin D through a radioimmunoassay (n 5 522). The association of dietary/serum measures of vitamin D status with HNC recurrence, second primary cancer (SPC) incidence, and overall mortality was evaluated using multivariate Cox proportional hazard models. There was no significant association between dietary or serum vitamin D measures and the three HNC outcomes. The hazard ratios (HRs) comparing the highest with the lowest quartile of dietary/supplemental vitamin D intake were 1.10 (95% confidence interval (CI): 0.66-1.84) for recurrence, 1.05 (95% CI: 0.63-1.74) for SPC, and 1.27 (95% CI: 0.87-1.84) for overall mortality. HRs comparing the uppermost to the lowest quartile of serum 25-hydroxyvitamin D levels were 1.12 (95% CI: 0.65-1.93) for recurrence, 0.72 (95% CI: 0.40-1.30) for SPC, and 0.85 (95% CI: 0.57-1.28) for overall mortality. There was no effect modification by cancer stage, season of initial treatment, or trial arm. Among patients with HNC, vitamin D status before treatment does not influence disease outcomes. Our results contrast with those from most published studies, which suggest prognostic significance of vitamin D status in cancer patients at least in subgroups.Geographical variations in cancer mortality have been associated with latitude and solar ultraviolet-B radiation.1 Photosynthesis of vitamin D 3 (cholecalciferol) occurs in the skin by the action of solar ultraviolet-B radiation. The overall vitamin D status in a person depends on both cholecalciferol and on ergocalciferol (vitamin D 2 ) levels. The 25-hydroxyvitamin D, the major circulating form of vitamin D, reflects well the cumulative effects of exposure to sunlight and dietary intake of vitamin D.2 It has been reported that cancer specific mortality 3 or all cause mortality 4 was lower for patients with cancer diagnosed during the summer or the fall, the seasons with the highest blood levels of 25-hydroxyvitamin D, than for those diagnosed in the winter.The prognostic significance of circulating 25-hydroxyvitamin D levels among cancer patients has been examined in a limited number of studies. [5][6][7][8][9][10][11] Higher 25-hydroxyvitamin D levels were associated with better overall survival in patients with non-small-cell lung cancer with stage IB-IIB but not in those with stage IA, III, or IV. 5,6 In the Nurses' Health Study and the Health Professionals Follow-up Study, 304 participants were diagnosed with colorectal cancer.7 Higher prediagnosis 25-hydroxyvitamin D levels were associated with a significant reduction in overall mortality but not with cancer specific mo...

BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I-II radiationtreated HNC patients (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median followup time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P ¼ .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P ¼ .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs. Cancer 2012;118:1554-