Loss of STK11 Suppresses Lipid Metabolism and Attenuates KRAS-Induced Immunogenicity in Patients with Non-Small Cell Lung Cancer.

As many as 30% of non-small cell lung cancer (NSCLC) patients harbor oncogenic KRAS mutations, which lead to extensive remodeling of the tumor immune microenvironment. Though co-mutations in several genes have prognostic relevance in KRAS-mutated patients, their effect on tumor immunogenicity are poorly understood. In the present study, a total of 189 NSCLC patients underwent a standardized analysis including immunohistochemistry, whole exome DNA sequencing, and whole transcriptome RNA sequencing. Patients with activating KRAS mutations demonstrated a significant increase in PD-L1 expression and CD8+ T-cell infiltration. Both were increased in the presence of a co-occurring TP53 mutation and lost with STK11 co-mutation. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes, and increase in several genes involved in lipid metabolism, notably Lipoprotein Lipase (LPL), Low Density Lipoprotein Receptor (LDLR), and LDLRAD4. Conversely, in the immune-excluded KRAS/STK11 co-mutated group, we observed diminished lipid metabolism and no change in anaerobic glycolysis. Interestingly, in patients with low expression of LPL, LDLR, or LDLRAD4, KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were associated with increased immunogenicity and associated with improved overall survival. Our data further suggest that the loss of STK11 may function as a metabolic switch, suppressing lipid metabolism in favor of glycolysis, thereby negating KRAS-induced immunogenicity. Hence, this concept warrants continued exploration, both as a predictive biomarker and potential target for therapy in patients receiving ICI-based immunotherapy.

Neighborhood-level deprivation and survival in lung cancer.

BACKGROUND: Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation. RESULTS: A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03-3.19). CONCLUSIONS: Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival.

Association Between Uveal Melanoma and Allostatic Load.

BACKGROUND/AIM: Allostatic load (AL) is a measure of chronic stress that is associated with worse cancer outcomes. The purpose of this retrospective cohort study was to investigate the relationship between AL and uveal melanoma (UM) clinical features. PATIENTS AND METHODS: AL score was calculated as a composite of ten biomarkers in 111 patients with UM from the University of Illinois Hospital. One point was assigned to an AL score for each biomarker based on predetermined cutoff values. Linear and logistic regression analyses evaluated the relationship between AL score and several tumor clinical characteristics. RESULTS: High AL score had a significant relationship with extraocular extension (p=0.015). There was also a significant difference in mean blood glucose levels between the different tumor size groups (p=0.029). Higher AL scores also had a trend of being associated with a smaller tumor size (p=0.069). CONCLUSION: AL score was significantly associated with the presence of extraocular extension for uveal melanoma, while the smallest tumor size group was associated with the highest blood glucose level. No other significant correlations were found between AL and other clinical features of UM. The relationship between AL score and extraocular extension warrants further investigation. Additional research is needed to evaluate socioeconomic factors and their effect on the relationship between chronic stress and the clinical features of UM.

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

PURPOSE: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. EXPERIMENTAL DESIGN: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. RESULTS: We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. CONCLUSIONS: In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

Analysis of demographics and the impact of adjuvant radiotherapy on a nationwide cohort of patients with high-grade spinal meningiomas.

Background: Although typically benign, 5% of spinal meningiomas (SMs) present with higher-grade features (World Health Organization grades 2 and 3). High-grade SMs are poorly studied and the role of adjuvant radiotherapy in their management remains controversial. We hence aimed to study the demographic characteristics of this rare tumor and investigate the outcomes associated with the use of surgery with adjuvant therapy in contrast to surgery alone. Methods: The National Cancer Database was queried for patients with SMs from 2004 to 2017. Basic statistics were used to identify differences between low- and high-grade tumors in terms of baseline characteristics. Surgery with and without adjuvant radiotherapy were compared after (1:1) propensity-score matching. Kaplan-Meier survival analysis was conducted to study overall survival. All analyses were performed on R. Results: A total of 13 184 patients diagnosed with SMs were included, of whom only 5% (n = 669) had high-grade SMs. Patients with high-grade SMs presented at a younger median age (57 years [IQR: 44-68] versus 65 years [54-75]; P < .001) and were more commonly males (33% vs 20%; P < .001). After propensity-score matching, survival analysis revealed similar overall survival outcomes in patients with high-grade SM undergoing both surgery and radiotherapy as compared to those only receiving surgery (P = .19). Conclusions: This study reveals major demographic differences between high- and low-grade SMs. There were no benefits associated with the use of adjuvant radiotherapy. However, due to confounding, overall survival outcomes between patients receiving surgery alone and those receiving surgery with adjuvant radiotherapy are not causally interpretable.

Race and Ethnicity Reporting and Enrollment Disparities in Clinical Trials Leading to FDA Approvals for Breast Cancer Between 2010 and 2020.

BACKGROUND: We determined the race and ethnicity demographics and reporting trends of clinical trials leading to Food and Drug Administration (FDA) approvals for breast cancer. METHODS: We collected enrollment and reporting data from clinical trials leading to FDA novel and new use approvals for breast cancer from 2010 to 2020 from Drugs@FDA, ClinicalTrials.gov, and associated journal manuscripts. Enrollment demographics were compared to the US cancer population estimates obtained using National Cancer Institute-Surveillance, Epidemiology, and End Results and 2010 US Census databases. RESULTS: Seventeen drugs received approval based on 18 clinical trials with a total enrollment of 12,334. For approvals from 2010 to 2015 and from 2016 to 2020, there was no significant difference in race (80% vs. 91.6%, P = .34) or ethnicity reporting (20% vs. 33.3%, P = .5) on ClinicalTrials.Gov, manuscripts, and FDA labels. For trials that reported race and ethnicity, White, Asian, Black, and Hispanic patients represented 73.8%, 16.4%, 3.7%, and 10.4% of trial participants. Relative to their US cancer incidence, Black (31% of expected) patients were underrepresented compared with White (90% of expected), Hispanic (115%), and Asian (327% of expected) patients. CONCLUSION: We observed no significant difference in race and ethnicity reporting in pivotal clinical trials leading to FDA approval for breast cancer from 2010 to 2020. Black patients were underrepresented in these pivotal trials relative to White, Hispanic, and Asian patients. Ethnicity reporting remained low throughout the study period. Innovative approaches are needed to ensure equitable benefit of novel therapeutics.

Assessment of Regional Variability in COVID-19 Outcomes Among Patients With Cancer in the United States.

Importance: The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography. Objective: To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States. Exposures: Patient residence was categorized into 9 US census divisions. Cancer center characteristics included academic or community classification, rural-urban continuum code (RUCC), and social vulnerability index. Main Outcomes and Measures: The primary outcome was 30-day all-cause mortality. The secondary composite outcome consisted of receipt of mechanical ventilation, intensive care unit admission, and all-cause death. Multilevel mixed-effects models estimated associations of center-level and census division-level exposures with outcomes after adjustment for patient-level risk factors and quantified variation in adjusted outcomes across centers, census divisions, and calendar time. Results: Data for 4749 patients (median [IQR] age, 66 [56-76] years; 2439 [51.4%] female individuals, 1079 [22.7%] non-Hispanic Black individuals, and 690 [14.5%] Hispanic individuals) were reported from 83 centers in the Northeast (1564 patients [32.9%]), Midwest (1638 [34.5%]), South (894 [18.8%]), and West (653 [13.8%]). After adjustment for patient characteristics, including month of COVID-19 diagnosis, estimated 30-day mortality rates ranged from 5.2% to 26.6% across centers. Patients from centers located in metropolitan areas with population less than 250 000 (RUCC 3) had lower odds of 30-day mortality compared with patients from centers in metropolitan areas with population at least 1 million (RUCC 1) (adjusted odds ratio [aOR], 0.31; 95% CI, 0.11-0.84). The type of center was not significantly associated with primary or secondary outcomes. There were no statistically significant differences in outcome rates across the 9 census divisions, but adjusted mortality rates significantly improved over time (eg, September to November vs March to May: aOR, 0.32; 95% CI, 0.17-0.58). Conclusions and Relevance: In this registry-based cohort study, significant differences in COVID-19 outcomes across US census divisions were not observed. However, substantial heterogeneity in COVID-19 outcomes across cancer care delivery centers was found. Attention to implementing standardized guidelines for the care of patients with cancer and COVID-19 could improve outcomes for these vulnerable patients.

Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence.

BACKGROUND: Smoke-free ordinances (SFO) have been shown to be effective public health interventions, but there is limited data on the impact SFO on lung cancer outcomes. We explored the effect of county-level SFO strength with smoking prevalence and lung cancer incidence in Indiana. METHODS: We obtained county-level lung cancer incidence from the Indiana State Cancer Registry and county-level characteristics from the Indiana Tobacco Prevention and Cessation Commission's policy database between 1995 and 2016. Using generalized estimating equations, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. RESULTS: Of Indiana's 92 counties, 24 had a SFO by 2011. In 2012, Indiana enacted a state-wide SFO enforcing at least moderate level SFO protection. Mean age-adjusted lung cancer incidence per year was 76.8 per 100,000 population and mean smoking prevalence per year was 25% during the study period. Counties with comprehensive or moderate SFO had a smoking prevalence 1.2% (95% CI [-1.88, -0.52]) lower compared with counties with weak or no SFO. Counties that had comprehensive or moderate SFO also had an 8.4 (95% CI [-11.5, -5.3]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. CONCLUSION: Counties with stronger smoke-free air ordinances were associated with decreased smoking prevalence and fewer new lung cancer cases per year. Strengthening SFO is paramount to decreasing lung cancer incidence.