2005P - Prediction of response and identification of mechanisms of resistance to neoadjuvant chemotherapy according to molecular subtypes in muscle-invasive bladder carcinoma

Background

Neoadjuvant chemotherapy (NACT) followed by cystectomy is the current standard treatment for muscle-invasive bladder carcinoma (MIBC). However, benefit of this treatment significantly differs between patients, and we lack reliable and validated predictive factors of response to NACT.

Methods

Fifty-eight FFPE samples from MIBC patients obtained at the time of transurethral resection (TURB) were analyzed, together with thirty cystectomy samples from patients that did not respond to NACT. Protein networks using probabilistic graphical models (PGM) were built using protein expression data. The resulting networks were divided into functional nodes with an overrepresented function using DAVID webtool.

Results

Three groups with different proteomics profiles were identified using a hierarchical clustering. Cluster 1 was characterized by a higher expression of KRT20, a luminal-papillary biomarker (LP). Cluster 2 was characterized by a higher expression of KRT5, KRT6A, KRT14, and CD44, all basal MIBC biomarkers (B). Finally, Cluster 3 had a higher expression of PGM5, DES, and SGDC proteins, biomarkers of luminal-infiltrated and luminal (LiL). Several differential biological processes were identified between the three subtypes, being LP more metabolic and mitochondria active, B group with a higher activity of DNA replication and cell cycle, and LiL with a higher immune and cytoskeleton activity. The rate of pathologic complete response (pCR) in each group was as follows: LP 41%, B 53%, and LiL 36% To characterize mechanisms of resistance, a paired analysis of TURB and cystectomy samples of non-responders was performed. Cystectomy samples with invasive residual disease had an increase in cytoskeleton, extracellular matrix and collagen-lipoproteins activities comparing to TURB samples.

Conclusions

Rates of pCR to NACT varies according to MIBC molecular subtype, being the basal subtype (B), those with a higher activity of DNA replication and cell cycle, the subtype with a higher rate of pCR. Besides that, several biologic processes that experienced changes between TURB and cystectomy samples could be related with resistance to NACT.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This work was supported by EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union.

Disclosure

A. Pinto Marin: Financial Interests, Personal, Advisory Board: BMS, Roche, MSD, Pfizer, Astellas, MSD; Financial Interests, Personal, Invited Speaker: BMS, Roche, MSD, Astellas. All other authors have declared no conflicts of interest.