Background: Racial segregation is linked to poorer neighborhood quality and adverse health conditions among minorities, including worse cancer outcomes. We evaluated relationships between race, neighborhood social disadvantage, and cancer survival. Methods: We calculated overall and cancer-specific survival for 11,367 non-Hispanic Black (NHB) and 29,481 non-Hispanic White (NHW) individuals with breast, colorectal, lung, or prostate cancer using data from the Metropolitan Detroit Cancer Surveillance System. The area deprivation index (ADI) was used to measure social disadvantage at the census block group level, where higher ADI is associated with poorer neighborhood factors. Associations between ADI and survival were estimated using Cox proportional hazards mixed-effects models accounting for geographic grouping and adjusting for demographic and clinical factors. Results: Increasing ADI quintile was associated with increased overall mortality for all four cancer sites in multivariable-adjusted models. Stratified by race, these associations remained among breast (NHW: HR = 1.16, P < 0.0001; NHB: HR = 1.20, P < 0.0001), colorectal (NHW: HR = 1.11, P < 0.0001; NHB: HR = 1.09, P = 0.00378), prostate (NHW: HR = 1.18, P < 0.0001; NHB: HR = 1.18, P < 0.0001), and lung cancers (NHW: HR = 1.06, P < 0.0001; NHB: HR = 1.07, P = 0.00177). Cancer-specific mortality estimates were similar to overall mortality. Adjustment for ADI substantially attenuated the effects of race on mortality for breast [overall proportion attenuated (OPA) = 47%, P < 0.0001; cancer-specific proportion attenuated (CSPA) = 37%, P < 0.0001] prostate cancer (OPA = 51%, P < 0.0001; CSPA = 56%, P < 0.0001), and colorectal cancer (OPA = 69%, P = 0.032; CSPA = 36%, P = 0.018). Conclusions: Area-level socioeconomic disadvantage is related to cancer mortality in a racially diverse population, impacting racial differences in cancer mortality. Impact: Understanding the role of neighborhood quality in cancer survivorship could improve community-based intervention practices.
ERCC1/XPF is a heterodimeric DNA endonuclease critical for repair of certain chemotherapeutic agents. We recently identified that ERCC1- and p53-deficient lung cancer cells are tolerant to platinum-based chemotherapy. ATR inhibition synergistically re-stored platinum sensitivity to platinum tolerant ERCC1-deficient cells. Mechanistically we show this effect is reliant upon several functions of ATR including replication fork protection and altered cell cycle checkpoints. Utilizing an inhibitor of replication protein A (RPA), we further demonstrate that replication fork protection and RPA availability are critical for platinum-based drug tolerance. Dual treatment led to increased formation of DNA double strand breaks and was associated with chromosome pulverization. Combination treatment was also associated with increased micronuclei formation which were capable of being bound by the innate immunomodulatory factor, cGAS, suggesting that combination platinum and ATR inhibition may also enhance response to immunotherapy in ERCC1-deficient tumors. In vivo studies demonstrate a significant effect on tumor growth delay with combination therapy compared with single agent treatment. Results of this study have led to the identification of a feasible therapeutic strategy combining ATR inhibition with platinum and potentially immune checkpoint blockade inhibitors to overcome platinum tolerance in ERCC1-deficient, p53-mutant lung cancers.
The role of socioeconomic status and race on cancer survivorship has been identified, however, the role of neighborhood disadvantage and race in cancer survivorship has not been well studied. This analysis aimed to evaluate the relationship between a comprehensive measure of neighborhood-level social disadvantage and cancer survivorship in the racially diverse population of metropolitan Detroit. We calculated overall and cancer-specific survival for 11,367 Non-Hispanic Black (NHB) and 29,481 Non-Hispanic White (NHW) individuals with breast, colorectal, lung, and prostate cancer using data from the Metropolitan Detroit Cancer Surveillance System. Neighborhood socioeconomic disadvantage was measured by the Area Deprivation Index (ADI) at the census block group level using data from the Census Bureau’s American Community Survey. Associations between ADI and survival were estimated using Cox proportional hazards mixed-effects models accounting for geographic grouping and adjusting for demographic, clinical, and treatment factors. Among all participants, an increase in ADI quartile was associated with increased overall mortality for all four cancer sites in multivariable models adjusting for race, age at diagnosis, stage, treatment, and Gleason score (prostate only). When stratifying by race, these associations remained among breast (NHW: Hazard Ratio (HR)=1.10, 95% Confidence Interval (CI) 1.05-1.15, p<0.0001; NHB: HR=1.14, 95% CI 1.05-1.23, p<0.0001), prostate (NHW: HR=1.14, 95% CI 1.09-1.20, p<0.0001; NHB: HR=1.08, 95% CI 1.01-1.16, p<0.0001), and lung cancer (NHW: HR=1.05, 95% CI 1.03-1.08, p<0.0001; NHB: HR=1.05, 95% CI 0.99-1.11, p=0.069), while the ADI-mortality association for colorectal cancer cases appears to be restricted only to NHWs (NHW: HR=1.09, 95% CI 1.05-1.14, p<0.0001; NHB: HR=1.05, 95% CI 0.98-1.12, p=0.15). Associations of cancer-specific mortality were like those of overall mortality, with a few exceptions including Hormone Receptor (HmR)+/HER2-specific mortality which was only significant in NHW women (HR=1.09, 95% CI 0.99-1.20, p=0.077), while HmR+/HER2+-specific mortality was consistent for NHW (HR=1.23, 95% CI 1.01-1.49, p=0.037) and NHB women (HR=1.21, 95% CI 0.84-1.75, p=0.31). Adjustment for ADI substantially attenuated the effects of race on overall mortality for all cancer types, except lung cancer, and significantly attenuated the effect of race on overall mortality for overall breast (proportion attenuated=54%, 95% CI 33-92%, p<0.0001), HmR+/HER2- breast (proportion attenuated=45%, 95% CI 19-113%, p<0.0001), and prostate cancer (proportion attenuated=54%, 95% CI 33-96%, p<0.0001); and attenuated the effects of race on cancer-specific survival only for overall breast (proportion attenuated=40%, 95% CI 16% to 87%, p<0.0001) and marginally for HmR+/HER2- breast cancer (proportion attenuated=24%, 95% CI -4% to 78%, p=0.094). Area-level socioeconomic disadvantage is related to the risk of cancer mortality in a racially diverse population and impacts the role of racial differences in cancer mortality. Citation Format: Natalie G. Snider, Theresa Hastert, Mrudula Nair, Madhav KC, Julie Ruterbusch, Ann Schwartz, Ed Peters, Elena Stoffel, Laura Rozek, Kristen Purrington. Evaluating racial disparities in cancer survivorship via the role of area-level socioeconomic disadvantage in metropolitan Detroit [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A019.
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