Angela L. Mazul

Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents

OBJECTIVES To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers. METHODS Data from 1362 head and neck SCC (HNSCC) diagnosed 2002-2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n=388), U.S. (CHANCE study, n=472), and Europe (ARCAGE study, n=502). Tumors were centrally tested for p16INK4a and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models. RESULTS There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58yearsandmedian follow-up of 3.1years (IQR=1.4-5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16+/HPV16+) compared to 333 HPV-unrelated (p16- and/or HPV16-) cases (HR=0.25, 95%CI=0.18-0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p⩽0.01) and after adjustment, remained significantly reduced (aHR=0.34, 95%CI=0.24-0.49). Among non-OP HNSCC, neither p16 (aHR=0.83, 95%CI=0.60-1.14), HPV16 DNA (aHR=1.20, 95%CI=0.89-1.63), or p16+/HPV16+ (aHR=0.59, 95%CI=0.32-1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction=0.02). CONCLUSION HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC.

Oral health and human papillomavirus-associated head and neck squamous cell carcinoma.

Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal squamous cell carcinoma (OPSCC), yet few studies have examined whether this association is modified by human papillomavirus (HPV) status.

Previous tonsillectomy modifies odds of tonsil and base of tongue cancer.

Background:Tonsillectomy is a commonly performed surgical procedure that involves removal of the palatine tonsils. The purpose of this study is to examine the association between previous tonsillectomy and odds of oropharyngeal squamous cell carcinoma (OPSCC) in a large population-based case–control study. We hypothesise that previous tonsillectomy is associated with a decreased odds of tonsil cancer with no impact on the odds of developing base of tongue (BOT) cancer.Methods:This was a population-based, frequency-matched case–control study with multinomial logistic regression, including 1378 controls, 108 BOT cancer cases, and 198 tonsil cancer cases. Demographic and risk factor data were collected using a structured questionnaire during an in-home visit conducted by trained nurse-interviewers. The human papillomavirus (HPV) tumour status was determined through Luminex-based multiplex PCR and p16 status by immunohistochemistry.Results:Previous tonsillectomy was associated with a nearly two-fold increased odds of BOT cancer (OR=1.95, 95% CI 1.25–3.06, P=0.003) and a large decrease in the odds of tonsil cancer (OR=0.22, 95% CI 0.13–0.36, P<0.001). When HPV status was considered, tonsillectomy was associated with a decreased odds of HPV-positive tonsil cancer (OR=0.17, 95% CI 0.08–0.34, P<0.001) and an increased risk of HPV-positive BOT cancer (OR=2.46, 95% CI 1.22–4.95, P=0.012). When p16 status was considered, tonsillectomy was associated with an increased odds of p16-positive BOT cancer (OR=2.24, 95% CI 1.16–4.35, P=0.017) and a decreased odds of p16-positive tonsil cancer (OR=0.14, 95% CI 0.07–0.31, P<0.001).Conclusions:Previous tonsillectomy modifies the odds of both tonsil and BOT cancer, with decreased odds of tonsil cancer and increased odds of BOT cancer. A history of previous tonsillectomy may play a role in OPSCC risk stratification when considered along with other covariates such as sexual history, smoking status, and age.

Prognostic significance of non-HPV16 genotypes in oropharyngeal squamous cell carcinoma

OBJECTIVES Recent studies have found that cases with oropharyngeal squamous cell carcinoma (OPSCC) positive for HPV16 genotype have better overall survival compared with cases positive for other HPV genotypes. We sought to further replicate these studies and determine if this relationship is modified by expression of p16 tumor suppressor protein. MATERIAL AND METHODS We identified 238 OPSCC cases from the Carolina Head and Neck Cancer Study (CHANCE) study, a population based case-control study. Tumors that tested positive solely for HPV16 genotype and no other genotypes with PCR were classified as HPV16-positive. Tumors positive for any other high-risk HPV genotype were classified as non-HPV16-positive. Expression of p16 in the tumor was determined with immunohistochemistry. Follow-up time was calculated from the date of diagnosis to date of death or December 31, 2013. Overall survival was compared with the Kaplan-Meier curves and log-rank test. Hazard ratios (HR) adjusted for smoking, alcohol use, sex, race, and age was calculated with the Cox proportional hazard regression. RESULTS Cases with HPV16-positive OPSCC had better overall survival than cases with non-HPV16-positive OPSCC (log-rank p-value: 0.010). When restricted to OPSCC cases positive for p16 expression, the same trend continued (log-rank p-value: 0.002). In the adjusted model, cases with non-HPV16-positive OPSCC had greater risk of death compared to cases with HPV16-positive tumors (HR: 1.92; 95% CI: 1.03, 3.60). CONCLUSIONS This finding indicates that HPV genotyping carries valuable prognostic significance in addition to p16 status and future survival studies of OPSCC should take into account differing HPV genotypes.

BMI Loci and Longitudinal BMI from Adolescence to Young Adulthood in an Ethnically Diverse Cohort

Objective:The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood.Subjects:In ancestry-stratified models of 5962 European American (EA), 2080 African American (AA) and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity single-nucleotide polymorphisms (SNPs) with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood. For SNPs nominally associated with BMI change (P<0.05), we interrogated age differences within data collection Wave and time differences between age categories that overlapped between Waves.Results:We found SNPs in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 were significantly associated (P<0.0015≈0.05/34) with BMI change in EA and the ancestry-combined meta-analysis. rs9939609 in FTO met genome-wide significance at P<5e−08 in the EA and ancestry-combined analysis, respectively [Beta(se)=0.025(0.004);Beta(se)=0.021(0.003)]. No SNPs were significant after Bonferroni correction in AA or HA, although five SNPs in AA and four SNPs in HA were nominally significant (P<0.05). In EA and the ancestry-combined meta-analysis, rs3817334 near MTCH2 showed larger effects in younger respondents, whereas rs987237 near TFAP2B, showed larger effects in older respondents across all Waves. Differences in effect estimates across time for MTCH2 and TFAP2B are suggestive of either era or cohort effects.Conclusion:The observed association between variants in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 with change in BMI from adolescence to young adulthood suggest that the genetic effect of BMI loci varies over time in a complex manner, highlighting the importance of investigating loci influencing obesity risk across the life course.

The interaction between physical activity and obesity gene variants in association with BMI: Does the obesogenic environment matter?

Little is known about how obesity susceptibility single nucleotide polymorphisms (SNPs) interact with moderate to vigorous physical activity (MVPA) in relation to BMI during adolescence, once obesogenic neighborhood factors are accounted for. In race stratified models, including European (EA; N=4977), African (AA; N=1726), and Hispanic Americans (HA; N=1270) from the National Longitudinal Study of Adolescent to Adult Health (1996; ages 12-21), we assessed the evidence for a SNPxMVPA interaction with BMI-for-age Z score, once accounting for obesogenic neighborhood factors including physical activity amenities, transportation and recreation infrastructure, poverty and crime. Eight SNPxMVPA interactions with suggestive significance (p<0.10; three in each EA, and AA, two in HA) were observed showing attenuation on BMI-for-age Z score in adolescents with ≥5 versus <5 bouts/week MVPA, except for rs10146997 (near NRXN3). Findings were robust to the inclusion of neighborhood-level variables as covariates. These findings suggest that any attenuation from MVPA on a genetic susceptibility to obesity during adolescence is likely not operating through obesogenic neighborhood factors.

RNA Oncoimmune Phenotyping of HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas by Nodal Status

Importance Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16–positive/p16-positive OPSCCs. Design, Setting, and Participants This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16–positive tumors were used in this study. Main Outcomes and Measures Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative–like from node-positive–like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population’s prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Conclusions and Relevance Many HPV-16 and p16-positive tumors are treated as “lower-risk,” but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.

Poor oral health affects survival in head and neck cancer

INTRODUCTION Poor oral health has emerged as a risk factor for squamous cell carcinoma of the head and neck (HNSCC) but its impact on survival has not been examined. We sought to estimate the impact of oral health indicators on survival in a population-based HNSCC cohort. MATERIALS AND METHODS Cases (n=1381) and age-, sex- and race-matched controls (n=1396) were participants in the Carolina Head and Neck Cancer Epidemiologic Study (CHANCE). Vital status was determined via linkage with the National Death Index. Survival was considered at 5years post-diagnosis or study-enrollment for controls. Oral health was assessed using self-reported indicators including frequency of routine dental exams and tooth brushing. We used Kaplan-Meyer analyses and Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS Routine dental visits during the preceding 10years were associated with decreased mortality risk (>10 visits: HR=0.6, 95% CI=0.4-0.8) after adjusting for confounders. This effect was most pronounced for oral cavity cancer-(e.g., >10 visits: HR=0.4, 95% CI=0.2-0.9). Dental visits were also positively associated with survival among controls. No other routine health screening (e.g., eye exams) was associated with survival. CONCLUSION We found significant associations between markers of oral health and survival among both HNSCC cases and controls. This association was most pronounced for sites closer to the dentition. Oral health may have a direct effect on tumor biology due to the associated immune or inflammatory response. It may also represent a proxy for wellness or unmeasured social determinants of health.

HPV-Positive Oropharyngeal Squamous Cell Carcinoma among Patients Taking Adalimumab for Autoimmune Disorders:

T he incidence of human papillomavirus (HPV)–associated oropharyngeal cancer (OPSCC) is rising and now accounts for the majority of oropharyngeal carcinomas. Recent evidence has linked immune dysregulation to both the reactivation of viral infections such as HPV and the risk of viral-associated cancers. However, this association has not been investigated in oropharyngeal cancer. In addition, many patients with autoimmune disease are now treated with biopharmaceuticals (biologics), potent immunosuppressants that may compound this risk. Tumor necrosis factor a (TNFa)–blocking agents in particular have been associated with reactivation of latent viruses, including HPV. However, a link between biologics and oropharyngeal carcinoma also remains unexplored. The purpose of this study is to characterize the presentation, treatment course, and outcomes in patients with HPVpositive OPSCC on biologics treated at a single tertiary care cancer center.

The complex relation between race, sex, and human papillomavirus status in head and neck cancer

Fakhry et al present the results of an important study examining prognostic indicators in oropharyngeal and nonoropharyngeal squamous cell carcinoma. In a large head and neck cancer cohort drawn from 2 tertiary-care cancer centers, they examine the impact of sex, race, and human papillomavirus (HPV) on outcomes in oropharyngeal and nonoropharyngeal cancer. They demonstrate that sex affects the prognosis differentially in oropharyngeal cancer and nonoropharyngeal cancer. Importantly, they also demonstrate that race does not affect survival for patients with oropharyngeal cancer after adjustments for the HPV status. Much of the literature on HPV-positive oropharyngeal cancer is focused on outcomes for non-Hispanic white males; the importance of this study is that it challenges us to think about this disease outside this specific demographic. This study is an important contribution to the extensive body of literature on racial disparities in head and neck cancer, particularly with respect to the impact of race on outcomes for patients with HPV-positive oropharyngeal cancer. African Americans account for less than 10% of head and neck squamous cell carcinoma patients, but they contribute disproportionately to the morbidity and mortality associated with this disease process. African American patients tend to present at higher disease stages, and previous studies have suggested that differential access to care and treatment protocols have contributed to this disparity. Reports have also demonstrated that African American patients have worse overall head and neck cancer survival when age, disease stage, and treatment received are controlled. Previous studies suggested that racial disparities in head and neck cancer were driven largely by racial differences in HPV-positive oropharyngeal cancer, with a disproportionately high number of cases among non-Hispanic whites versus African Americans. In the current study, relatively large percentages of the cases in both the oropharyngeal cancer cohort and the nonoropharyngeal cancer cohort are African American. The finding that no difference exists in overall survival by race challenges much of the existing literature on racial disparities in head and neck cancer, and it suggests that these findings may not be generalizable outside tertiary-care cancer centers. Race represents many different exposures such as socioeconomic status, cultural background, and access to care as well as a physical phenotype. The impact of race on head and neck cancer survival may differ with the socioeconomic status of the population being examined. Although data on socioeconomic status are not presented in this study, it is possible that the current study disproportionally includes high-income and highly educated cases, and race may simply be a measure of a physical phenotype instead of representing a cultural background, access to care, or socioeconomic status. Fakhry et al’s work serves as a landmark study on the impact of sex on oropharyngeal and nonoropharyngeal cancer survival. The authors demonstrate that females have a survival advantage in oropharyngeal cancer after adjustments for the HPV status that is not present in nonoropharyngeal cancers. The findings on sex and survival with respect to nonoropharyngeal cancer are largely in line with previous research. In a matched pairs analysis of male and female head and neck cancer patients treated at MD Anderson, Roberts et al demonstrated no difference in survival by sex across all tumor sites. The finding that sex differentially affects survival in oropharyngeal and nonoropharyngeal cancers is important and may have implications for treatment decision making and for understanding the natural history of HPV-positive and HPVnegative head and neck cancer. However, although this represents the largest cohort of females with oropharyngeal cancer, the issue of generalizability is again raised. Similarly to race, sex is a nonmodifiable risk factor that can represent multiple exposures within a population and thus lead to differing results according to the population sampled. There is the potential