Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy

Abstract

PurposeNeoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with non-metastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC. Materials and MethodsFour bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex, and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan Meier (KM) curves. Cox proportional hazards (PH) models were used to evaluate the primary and secondary study endpoints of overall survival (OS) and cancer-specific survival (CSS), respectively. ResultsA total of 601 patients with MIBC were included, where 247 had been treated with NAC and RC and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and CSS at three years was 7% and 5%, respectively. After controlling for clinicopathologic variables, non-luminal tumors had greatest benefit from NAC with 10% greater OS at 3 years (71% vs 61%) while luminal tumors had minimal benefit (63% vs 65%) for NAC vs. non-NAC, respectively. ConclusionsIn patients with MIBC, a commercially available molecular subtyping assay revealed non-luminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.

Molecular Subtypes as a Basis for Stratified Use of Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer—A Narrative Review

“…Last year, Lotan and colleagues published a statistical meta-analysis of response and outcome for NAC-treated and untreated patients from four cohorts profiled with the Genomic Subtyping Classifier (GSC) [ 35 ], of which three were previously reported as original and full-length publications. The study included data on 247 stage cT2-4N0-3 patients treated with pre-operative chemotherapy and 354 stage cT1-4N0-3 patients who received RC without prior NAC treatment.…”

“…While this study adjusted for some variables, it selectively included clinical T1 tumors in the untreated arm and cases with known disseminated disease in the treated arm. Unfortunately, the authors did not report pathologic response information, which further urges caution given that they examined a commercially available biomarker (Decipher ® ) [ 35 ]. Finally, even if these reservations are ignored, the statistical significance of the main finding falls when patients treated with adjuvant chemotherapy are excluded from analysis, something that arguably should have been done from the beginning.…”

“…Second, analyses with the GSC classifier suggested better survival for the GSC-basal and an absence of survival benefit for the GSC-luminal subtypes. As with the SWOG S1314 trial, neither of the GSC subtyping studies detected a difference in response [ 34 , 35 ]. Third, the Taber et al and Sjödahl et al studies both showed that luminal-like subtypes (i.e., LundTax Uro and GU) and the Consensus stroma-rich subtype had better response rates and survival after NAC, compared to the poorly responding Ba/Sq subtype [ 20 , 36 ].…”

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

“…Similarly, genomic imbalances are widespread in muscle invasive bladder cancers, more frequently than lower grade/stage tumors ( Spasova et al, 2021 ). Understanding the genomic heterogeneity of muscle invasive bladder cancer is now being explored as a potential therapeutic response tool ( Lotan et al, 2021 ), an approach amenable to understanding the consequences of adhesion receptor phenotype heterogeneity.…”

This Month in Adult Urology

“…Lotan el al (page 541) in a multi-institutional study advance these objectives, evaluating a cohort of 601 patients with nonvariant muscle-invasive bladder cancer who underwent transcriptomic profiling based on a commercially available genomic classifier. 1 They found that neoadjuvant chemotherapy was associated with survival benefits in nonluminal subtypes, but not in luminal subtypes. The authors conclude that a genomic classifier may help identify patients with bladder cancer who would benefit most from neoadjuvant chemotherapy.…”