DNA Repair Pathway Alterations in Bladder Cancer

Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy

ATM Deficiency Confers Specific Therapeutic Vulnerabilities in Bladder Cancer

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer

Relative Timing of Radiotherapy and Androgen Deprivation for Prostate Cancer and Implications for Treatment During the COVID-19 Pandemic

This cohort study uses National Cancer Database data from 2004 to 2014 to examine the association between overall survival and timing of radiotherapy relative to androgen deprivation therapy in patients with prostate cancer

Doublecortin Expression in Prostate Adenocarcinoma and Neuroendocrine Tumors

Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and histologic grade and clinical outcome. We sought to evaluate the relationship between DCX expression and these variables in human prostate cancer. DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC) and compared across disease states, histologic grades, and clinical outcomes. Biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and overall survival (OS) were analyzed using Cox proportional hazards. DCX expression was not significantly different among normal prostate (n = 29), primary prostate cancer (n = 131), and metastases (n = 19) and did not increase with grade in a large cohort of radical prostatectomy samples (n = 17,967). Those with DCX expression above and below the median did not have significant differences in BRFS (HR 1.15 [95% confidence interval, 0.88-1.49], P = .31), MFS (HR 1.2 [0.84-1.7], P = .3), or OS (HR 1.15 [0.7-1.84], P = .56). In a cohort with untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n = 10) compared with grade group 5 prostate adenocarcinoma (n = 110) (P = .007). Similarly, in 2 cohorts with mCRPC (n = 290), DCX expression was higher in lesions with neuroendocrine features compared with adenocarcinoma (P < .001). Contrary to recent data using mouse models, DCX expression did not differ by disease state or outcome and did not increase with grade in a large data set of patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine histology, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX and its clinical significance in prostate cancer