Immunohistochemistry-based molecular subtyping in muscle-invasive bladder cancer: Predicting response to neoadjuvant chemotherapy.

Abstract

e16590 Background: Muscle-invasive bladder cancer (MIBC) presents a heterogeneous response to perioperative chemotherapy, with significant variability in outcomes. Several molecular classifications have been proposed, but two main subtypes—luminal and basal/squamous—are widely recognized. Immunohistochemistry using GATA3 and CK 5/6 can identify these subtypes in over 80% of cases, as shown in previous studies. This study examines the role of this approach to assess the relationship between molecular subtypes and response to neoadjuvant chemotherapy in MIBC. Methods: This retrospective longitudinal study included 68 patients diagnosed with non-metastatic MIBC treated with cisplatinum-based neoadjuvant chemotherapy at Hospital Reina Sofía from 2014 to 2023. Tumors were classified into luminal (GATA3+, CK 5/6−), basal/squamous (GATA3−, CK 5/6+), or double-positive (GATA3+, CK 5/6+) subtypes. Clinical and pathological data, including overall survival (OS), disease-free survival (DFS), and pathological response, were analyzed using Kaplan-Meier curves, log-rank tests, and Chi square tests. Results: Among the 68 patients treated with neoadjuvant chemotherapy, 13 (19.1%) were classified as luminal, 5 (7.4%) as basal/squamous, and 50 (73.5%) as double-positive. Patients with luminal tumors demonstrated significantly higher 5-year DFS and OS compared to those with double-positive tumors (5-year DFS: 91.7% vs. 50,7%, p = 0.021; 5-year OS: 100% vs. 60,5%, p = 0.016), median follow-up period of 40 months. Pathological complete response (pT0) was observed in 7/13 (53.8%) luminal tumors compared to 15/50 (30.0%) double-positive tumors, although the difference was not statistically significant (p = 0.190). Additionally, 9/13 (69.2%) luminal tumors achieved tumor downstaging ( < pT2) versus 20/50 (40.0%) double-positive tumors (p = 0.060). The basal subtype (n = 5; 7.4%) was excluded from survival and pathological response analyses due to its low representation in the sample. Conclusions: The luminal subtype showed superior outcomes in terms of pathological response, DFS, and OS compared to double-positive tumors. The prevalence of the double-positive subtype raises questions about the ability of immunohistochemistry to fully capture the heterogeneity of molecular subtypes. Further studies incorporating advanced molecular techniques are warranted to validate these results and refine their clinical application. Clinical and pathologic characteristics according to molecular subtype. Luminal Double-positive n 13 50 Age Mean (sd) 64.38 (9.17) 67.42 (7.85) Performance status (%) ECOG 0 11 (84.6) 37 (74) ECOG 1 2 (15.4) 13 (26) Pathological tumor stage (%) pT0 7 (53.8) 15 (30) pT1 2 (15.4) 5 (10) ≥pT2 4 (30.8) 30 (60) Pathological lymph node stage (%) pN0 13 (100) 41 (82) pN1-3 0 (0) 9 (18)