ABSTRACT
BACKGROUND: Studies have linked pre-existing kidney disease (KD) to higher rates of mortality due to coronavirus disease 2019 (COVID-19) infection. In the rural Midwest, where KD is prevalent, the impact of COVID-19 has been significant in a population that includes many patients on Medicare or Medicaid. METHODS: A retrospective cohort study was performed assessing patients with acute kidney injury (AKI), chronic kidney disease (CKD) and end stage renal disease (ESRD), with and without COVID-19. International Classification of Diseases 10th Revision codes were submitted by physicians into Freeman Health System's Electronic Medical Records and gathered from April 2020 to January 2021. The data were analyzed and compared to determine whether the mortality rate in patients with varying stages of KD and COVID-19 was higher than the mortality rate in patients with KD alone, excluding variables such as sex and age. RESULTS: The 95% confidence interval (CI) of the mortality rate of patients with COVID-19 and any degree of KD, encompassing both AKI and CKD, was between 30.21% and 37.63%. This metric was significantly higher than the 95% CI of COVID-19 infection (6.70%-9.96%, p<0.0001) or KD alone (10.89%-13.01%, p<0.0001). Within those with COVID-19 and KD, the highest rate of mortality was in patients with AKI (38.13% and 49.02%). There was not sufficient statistical support in our sample to assert that COVID-19 increased mortality in ESRD patients. CONCLUSIONS: Based on our results, patients with KD and COVID-19 are at higher risk for mortality when compared to patients with KD alone. Further studies are warranted into individual comorbidities affecting KD patient outcomes with COVID-19.
ABSTRACT
PURPOSE: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER+ breast cancer. EXPERIMENTAL DESIGN: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance. RESULTS: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3 amplifications or FGFR2 mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor. CONCLUSIONS: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors.
Subject(s)
Breast Neoplasms/drug therapy , Fibroblast Growth Factor 3/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Adult , Aged , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Fulvestrant/administration & dosage , Fulvestrant/adverse effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Middle Aged , Mutation/genetics , Neoplasm Metastasis , Piperazines/administration & dosage , Piperazines/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Receptors, Estrogen/genetics , Exome Sequencing , Xenograft Model Antitumor AssaysABSTRACT
Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.
