BACKGROUND: The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention. METHODS: Individuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3–12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing. RESULTS: Twenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses ( P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological ( P = 0.04) and clinical ( P = 0.01) responses. CONCLUSION: To our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent. TRIAL REGISTRATION: NCT02581137 FUNDING: NIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870

Cancer screening is an important way to reduce the burden of cancer. The COVID-19 pandemic created delays in screening with the potential to increase cancer disparities in the United States (U.S.). Data from the 2014–2020 Behavioral Risk Factor Surveillance System (BRFSS) survey were analyzed to estimate the percentages of adults who reported cancer screening in the last 12 months consistent with the U.S. Preventive Services Task Force (USPSTF) recommendation for cervical (ages 21–65), breast (ages 50–74), and colorectal cancer (ages 50–75) prior to the pandemic. Cancer screening percentages for 2020 (April–December excluding January–March) were compared to screening percentages for 2014–2019 to begin to look at the impact of the COVID-19 pandemic. Screening percentages for 2020 were decreased from those for 2014–2019 including several underserved racial groups. Decreases in mammography and colonoscopy or sigmoidoscopy were higher among American Indian/Alaskan Natives, Hispanics, and multiracial participants, but decreases in pap test were also highest among Hispanics, Whites, Asians, and African-Americans/Blacks. Decreases in mammograms among women ages 40–49 were also seen. As the 2020 comparison is conservative, the 2021 decreases in cancer screening are expected to be much greater and are likely to increase cancer disparities substantially.

Renal cell carcinoma (RCC) is one of the top 10 cancers in the United States. This study assessed RCC health disparities in American Indians/Alaska Natives (AIs/ANs) and Hispanic Americans (HAs) focusing on advanced-stage and mortality. RCC patients’ data were obtained from the National Cancer Database (NCDB) and Arizona Cancer Registry (ACR). Logistic and Cox regression analyses were performed to ascertain the effect of race/ethnicity on stage and mortality, adjusting for neighborhood socioeconomic factors, rural/urban residence pattern, and other factors. In both data sets, AIs/ANs had significantly increased odds of advanced-stage RCC in the unadjusted model, but not in adjusted models. Mexican Americans had higher odds of advanced-stage compared to non-Hispanic Whites in NCDB (OR 1.22, 95% CI: 1.11–1.35) and ACR (OR 2.02, 95% CI: 1.58–2.58), even after adjusting for neighborhood characteristics. AIs/ANs did not show increased mortality risk in NCDB after adjusting for neighborhood characteristics, while the association remained significant in ACR (HR 1.33, 95% CI: 1.03–1.72). The great risk of all-cause and RCC-specific mortality was observed in U.S.-born Mexican Americans in Arizona (HR 3.21, 95% CI: 2.61–3.98 and sub-distribution HR 2.79, 95% CI: 2.05–3.81). RCC disparities in AIs/ANs is partially explained by neighborhood factors, but not in HAs.

Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol^® in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by GST genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.