Synapse - Natural history and genomic landscape of chemotherapy-resistant muscle-invasive bladder cancer

Natural history and genomic landscape of chemotherapy-resistant muscle-invasive bladder cancer Journal Article

Authors:	Lenis, A. T.; Whiting, K.; Ravichandran, V.; Tallman, J. E.; Alam, S. M.; Chu, C. E.; De Jesus Escano, M.; Bochner, E.; Katims, A.; Reisz, P. A.; Truong, H.; Clinton, T. N.; Telis, L.; Dason, S.; McPherson, V.; Teo, M. Y.; Funt, S.; Aggen, D.; Goh, A. C.; Donahue, T. F.; Cha, E. K.; Donat, S. M.; Herr, H. W.; Dalbagni, G.; Schultz, N.; Berger, M. F.; Bajorin, D. F.; Rosenberg, J. E.; Bochner, B. H.; Ostrovnaya, I.; Al-Ahmadie, H.; Solit, D. B.; Iyer, G.; Pietzak, E. J.
Article Title:	Natural history and genomic landscape of chemotherapy-resistant muscle-invasive bladder cancer
Abstract:	PURPOSEPatients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials.METHODSData were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients.RESULTSLymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P =.021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors.CONCLUSIONAlthough chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease. © American Society of Clinical Oncology.
Keywords:	cancer chemotherapy; cancer survival; aged; major clinical study; clinical feature; cancer recurrence; cisplatin; gemcitabine; recurrence risk; cohort analysis; retrospective study; cystectomy; genomics; dna damage response; kaplan meier method; recurrence free survival; clinical outcome; demographics; muscle invasive bladder cancer; lymph vessel metastasis; human; male; female; article; whole exome sequencing
Journal Title:	JCO Precision Oncology
Volume:	8
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2024-09-01
Start Page:	e2300274
Language:	English
DOI:	10.1200/po.23.00274
PUBMED:	38691813
PROVIDER:	scopus
PMCID:	PMC11310921
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85200458290&doi=10.1200%2fPO.23.00274&partnerID=40&md5=3ea86604d11d8baed5c0e07fe17a190a
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF; MSK corresponding author is Eugene Pietzak -- Source: Scopus