Do Statins Improve Survival in Head and Neck Cancer Patients? An Investigation of Cancer Outcomes and Biologic Mechanisms.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an especially debilitating cancer with unacceptably low survival among patients, which differs depending on the site and stage of disease. Statins possess anti-cancer properties that may inhibit disease development and progression through various mechanisms including, anti-inflammation, immunomodulation, and cholesterol-lowering. Although studies have investigated the association between statins and health outcomes among cancer patients with disease in various sites, research among HNSCC patients is limited and the mechanisms explaining the relationship are not clearly established. Aim 1 of this dissertation investigates whether statin use influences HNSCC outcomes including, all-cause mortality, disease-specific mortality, and disease recurrence. Due to the differences in etiology and prognosis among patients with human papillomavirus (HPV) positive tumors and patients with HPV-negative tumors, HPV was assessed as an effect modifier. Statin use was found to be protective among all patients for all-cause mortality but only appeared to be protective for disease-specific mortality and disease recurrence among patients whose disease was HPV-positive. After the utilization of various analytic methods to address missing data, the protective associations did not change. Aim 2 examined the association between statin use and both tumor-infiltrating lymphocytes (TILs) and circulating cytokines among HNSCC patients at diagnosis. There was a statistically significant positive association between statin use and TILs, particularly FoxP3, but similar to our findings in Aim 1, only among HPV-positive patients. We observed no association between statin use and circulating cytokines even after conducting a principal component analysis to reduce dimensionality among the highly correlated cytokine measures. Aim 3 explored whether cholesterol may be the mechanism by which statins exert any observed influence on HNSCC risk or outcomes. Genetic data from the Michigan Genomics Initiative was utilized to conduct a case-control study of HNSCC risk and a survival analysis among HNSCC cases. Mendelian randomization analysis was conducted examining the association between instruments predicting hypercholesterolemia (total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG)) and HNSCC risk as well as outcomes among HNSCC patients. Cholesterol-related instruments were not associated with HNSCC risk, but there was a positive association between the TC instrument and both all-cause mortality and disease recurrence among HNSCC patients. The findings from this dissertation demonstrate that statins are protective against all-cause mortality among all HNSCC patients. Statins were protective for disease-specific mortality and disease recurrence, particularly among patients with HPV-positive tumors. Potential mechanisms that explain this association may be related to a synergistic relationship between statin use and the presence of HPV, leading to a more favorable immune response. Improving TC among HNSCC patients may improve all-cause mortality and disease recurrence, but future research is necessary to elucidate the impact of cholesterol-lowering on HNSCC outcomes. Larger and more diverse studies further investigating these observations are necessary to validate this research. Overall, this dissertation provides evidence to support the future development of an adjuvant clinical trial of statin therapy in HNSCC patients. If these findings are supported in larger, more diverse patient populations, statin use may be a relatively safe adjuvant tertiary treatment option for patients with HNSCC.