Age-, sex-, and race-related differences in outcomes of patients with muscle-invasive bladder cancer treated with radical cystectomy: The role of biology versus access to standard medical care.
Authors: Sood Akshay , Sjödahl Gottfrid , Duan Zhigang , Zhao Hui , Lobo Niyati , Hensley Patrick J. , Bree Kelly K. , Giordano Sharon H. , Ross Jeffrey S. , Kamat Ashish M. 
Published: June 2023

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Background: It remains unclear whether the poor outcomes associated with older age, female sex, and African-American (AA) race in patients with muscle-invasive bladder cancer (MIBC) treated with surgery are due to differential access to standard medical care or intrinsic differences in tumor biology. Methods: We designed an integrative study using two complementary datasets to answer our question. We used the SEER-Medicare MIBC dataset (n=2,327) to evaluate the real-world differences in survival outcomes among patients of female v male sex, AA v Caucasian race, and older v younger age before and after adjusting for demographic, tumor, treatment, and access-to-care factors. Next, we used The Cancer Genome Atlas (TCGA) project’s MIBC dataset (n=410) to evaluate the biological differences in molecular profiles of bladder tumors in these patient groups. Biological endpoints examined included DNA-level genomic alterations, mRNA expression subtypes, and RPPA-derived proteomic profiles, and clinical endpoints assessed included unadjusted and adjusted cancer-specific mortality (CSM) outcomes. Multivariable GLM, multivariate MMLR, and Fine-Gray competing-risk models were used. Results: Population-level analysis demonstrated that patients of female sex (10-y CSM: 51.3% v 43.8%, Gray’s p<0.001), AA race (10-y CSM: 56.2% v 46.1%, Gray’s p=0.022) and older age (10-y CSM: 47.8% >=81 y v 44.1% <=70 y, Gray’s p=0.032) had worse CSM at presentation. In adjusted analyses, however, only female sex remained associated with worse CSM (HR=1.17, p=0.028). The TCGA analysis revealed that advanced age was associated with increased total mutational burden and neoantigen load, both of which have been associated with improved survival. No other age-related differences were seen in other DNA alterations, mRNA expression subtype distribution, or RPPA proteomic cluster profiles. Similarly, no racial differences were observed in molecular alterations either at the DNA-, RNA-, or protein-level. However, females were noted to have adverse molecular profiles across all levels of molecular expression i.e. DNA-, RNA-, and proteomic-level. Specifically, females were noted to have lower total mutational burden (in stage 3-4 cancers, median 170 v 240, p=0.01), lower neoantigen load (in stage 3-4 cancers, median 382 v 551, p<0.01), higher Msig2 DNA mutational signature (in stage 3-4 cancers, 65.3% v 50.5%, p=0.04), higher basal/sq mRNA subtype (in stage 3-4 cancers, 52% v 34.2%, p=0.02), and lower RPPA cluster1 subtype (in stage 2 cancers, 15.2% v 36%, p<0.01). Conclusions: Our findings suggest that the poor outcomes seen among patients of AA race and older age in the real-world are likely driven by multilevel biases in healthcare delivery, while in women they may be a result of a combination of biological and access-to-care factors.