Based on previously mentioned exclusion criteria, a cohort of 1,376 patients with index SCCHN was followed prospectively for development of SPM. Median follow-up time was 26 months (range 0 to 142.4 months). 110 (8.0%) patients developed SPM. Of patients with SPM, 43 (39%) had second SCCHN, 38 (35%) developed other tobacco-associated cancers, and 29 (26%) developed other non tobacco-associated malignancies. Of the 43 patients with SPM of the head and neck, 24 (56%) were synchronous SCCHN primaries. Of these 24 patients with synchronous SCCHN, 2 had bilateral oral cavity cancers, 3 had bilateral oropharyngeal cancers, 1 had bilateral hypopharyngeal cancers, and the remainder had simultaneous cancers of more than one head and neck subsite.
Demographics, exposure, and clinical variables for the total cohort of patients, the patients who did not develop SPM, and the patients who developed SPM are summarized in . The mean age at diagnosis for the total patients was 57.3 years (range, 18-94 years, median, 57 years), and the mean age of patients who developed SPM was significantly older compared with the mean age of patients who did not develop a SPT (60.8 years vs. 57 years, respectively; P < 0.01). Although the participants in this study were predominantly male (76.0%) and non-Hispanic whites (84.0%), gender and ethnicity were not associated with SPM development (p = 0.734 for gender and P = 0.100 for ethnicity; respectively). Compared with the SPM-free group, patients who developed SPM were older (P < 0.001) and were more likely smokers (p = 0.022) and drinkers (P = 0.05). However, compared with the SPM-free group, patients who developed SPM had similar characteristics with respect to index cancer site (P = 0.118), index cancer stage (P = 0.830), and treatment (P = 0.982).
Distribution of Selected Participant Characteristics (n = 1376)
Genetic data was available for 1,211 (88.0%) patients in the cohort. Consistent with previously published studies (6
), 50.4% of patients were GSTM1
null, 20.7% were GSTT1
null, and 9.9% were both GSTM1
null. Valine allele frequencies were 36.3% and 8.7% for the GSTP1
105 and 114 codons, respectively.
The association between these GST polymorphisms and risk of SPM development is shown in . Patients with the GSTM1 and GSTT1 null genotypes had no significantly higher risk of SPM development than those with the wild-type genotype. Similarly, when the GSTM1 and GSTT1 genotypes were combined, the risk of SPM development among patients with both either M1 or T1 null genotype and both M1 and T1 null genotypes were not significantly different from that among patients with GSTM1 and GSTT1 wild-type genotypes. However, when data were adjusted for age, sex, ethnicity, smoking, and alcohol (), patients with the GSTP1 105 variant genotype had a 1.7-fold elevated risk for developing SPM compared to patients with the wild-type genotype (HR, 1.7; 95% CI, 1.1-2.5). We did not observe the similar association between the patients with GSTP1 114 variant genotypes and those with GSTP1 114 wild-type genotype. After we combined the risk genotypes of GSTP1 105 and GSTP1 114 polymorphisms, the patients with 1-2 or 3-4 risk genotypes had a 1.6- or 2-fold increased risk for SPM development compared with the patients with 0 risk genotypes (HR, 1.6; 95% CI, 1.1-2.5 and HR, 2.0; 95% CI, 0.9-4.3, respectively). Moreover, the risk was significantly increased in a dose-response manner, suggesting that the two polymorphisms may have a joint effect on the risk of SPM development (Ptrend = 0.018).
Association of GST Polymorphisms and SPM Risk
Results were similar when SPM risk was stratified according to SPM type (). Patients with the GSTP1 105 variant genotype had a 2.2-fold increased risk for SCCHN SPM (HR, 2.2; 95% CI, 1.1-4.6) and a 1.7-fold elevated risk for SCCHN or other-tobacco associated SPM (HR, 1.7; 95% CI, 1.0-2.7). Patients with 3-4 GSTP1 risk genotypes had a 3.3-fold increased risk for SCCHN SPM (HR, 3.3; 95% CI, 1.0-10.5) and a 2.3-fold elevated risk for SCCHN or other-tobacco associated SPM (HR, 2.3; 95% CI, 1.0-5.3) as compared to patients with no risk genotypes. When SPM risk was stratified according to smoking status at the time of diagnosis of index SCCHN (never versus ever smokers), there was no significant difference in the hazards ratios among these two subgroups (data not shown).
Association of GST Polymorphisms and SPM Risk Stratified by SPM Type
To evaluate combined effects of a panel of GST polymorphisms that act in the same carcinogen metabolizing pathway, which may amplify the effects of associations of these polymorphisms with the risk of SPM development among SCCHN patients, we combined the risk genotypes of these four polymorphisms for further combined analysis for the entire cohort patients (). We found that the distribution of the combined risk genotypes was borderline significantly or significantly different between patients who developed SPM and those who did not (P = 0.096 for quartile categories and P = 0.035 for dichotomized categories). Patients with 2, 3, or 4 risk genotypes experienced a shorter SPM-free survival compared with patients with 0 or 1 risk genotypes (log-rank, P = 0.039, ). Similarly, patients with 3 or 4 risk genotypes had a short SPM-free survival compared with patients with 0 or 1 or 2 risk genotypes (Log-rank, P = 0.015, ). After adjusting for age, sex, ethnicity, smoking, and alcohol, there was a step-wise increase in SPM risk with increasing number of risk genotypes (Ptrend = 0.004). Patients with 4 risk genotypes had a 2.6-fold significantly elevated risk of SPM as compared to patients with 0 or 1 risk genotypes (HR, 2.6; 95% CI, 1.1-6.1). We also found that patients with 3 or 4 risk genotypes had a 1.7-fold significantly elevated risk for SPM as compared to patients with 0 or 1 or 2 risk genotypes ((HR, 1.7; 95% CI, 1.2-2.5).
Association of GST Risk Genotypes and SPM Risk
SPM-free survival of patients with SCCHN by the combined risk genotypes of GST genes (in quartile categories)
SPM-free survival of patients with SCCHN by the combined risk genotypes of GST genes (in dichotomized categories)