Impact of Squamous Histology on Clinical Outcomes and Molecular Profiling in Metastatic Urothelial Carcinoma PatientsTreated With Immune Checkpoint Inhibitors or Enfortumab Vedotin - Beyond the Abstract
However, patients with predominant variant histology are frequently excluded from UC clinical trials, and outcomes in the subset of patients who have at least a component of variant histology have not generally been reported. To better define the prognostic significance of UCS in the era of novel systemic therapies for UC, we undertook a retrospective analysis of patients with UCS or pure UC (pUC) treated with an ICI and/or EV at a high-volume academic center. Treatment outcomes were compared across the two histologic subtypes.
A total of 160 patients (40 UCS, 120 pUC) were identified for this analysis. Among 151 patients treated with an ICI (38 UCS, 113 pUC), patients with UCS were older, had lower baseline hemoglobin and albumin levels, and higher neutrophil-to-lymphocyte ratio compared to patients with pUC. No significant differences in baseline characteristics were observed between the two groups at the time of EV initiation, though fewer patients were included in this analysis (n=37; 12 UCS, 25 pUC). In terms of relevant outcomes, among the 151 patients treated with an ICI, patients with UCS (n=38) were found to have a shorter mPFS (1.9 vs 4.8 months, p<0.01) and mOS (9.2 vs 20.7 months, p<0.01) relative to those with pUC (n=113). Among the 37 patients treated with EV (12 UCS, 25 pUC), UCS patients similarly had a lower ORR (17% vs 70%, p<0.01) and shorter mPFS (3.4 vs 15.8 months, p<0.01) relative to pUC patients.
To investigate potential molecular drivers of these differential outcomes, next-generation sequencing results were also compared across patients with UCS and pUC. In this analysis, UCS samples were found to be enriched for CDKN2A, CDKN2B, and PIK3CA alterations, while pUC samples were enriched for ERBB2 alterations. No significant differences were seen between tumor mutation burden (TMB) and PD-L1 expression status, although these data were available for some patients (53% and 34% of cases, respectively).
Several factors may have contributed to the inferior outcomes seen with these newer treatments for patients with urothelial carcinoma and at least a component of squamous differentiation, relative to patients with a pure urothelial histology. The presence of clinical characteristics at baseline that are known to be poor prognostic markers, such as NLR and lower Hgb and albumin, may have accounted for the inferior responses to ICI therapy seen among patients with UCS. Prior analyses have additionally shown lower levels of Nectin-4 expression in basal/squamous molecular subtypes of muscle invasive bladder cancer and mUC, as well as inferior responses to EV in tumors with a lower level of Nectin-4 expression, which may explain the lower response rate to EV among patients with UCS relative to pUC.
Overall, these findings suggest that despite the recent therapeutic advances in the management of mUC, the presence of squamous differentiation remains a characteristic associated with adverse prognosis and leads to inferior responses to these more novel therapies such as ICIs and ADCs. There are several limitations to this study, including the single-center, retrospective nature of this analysis, and lack of additional relevant biomarker data (e.g. TMB and PD-L1 status) for many patients. Despite these caveats, the results highlight a higher-risk subset of patients with mUC who have squamous differentiation and an important unmet clinical need for additional therapeutic options in this patient population. These hypothesis-generating findings additionally warrant further prospective validation in larger cohorts of UCS patients treated with ICI- or EV-containing regimens.
Written by: Ivan de Kouchkovsky, MD, Tanya Jindal, BS, BA, & Vadim S Koshkin, MD
University of California San Francisco, San Francisco, CA
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