Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer.

Abstract

PURPOSE:

After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied.

EXPERIMENTAL DESIGN:

Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis.

RESULTS:

Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar-like tumors had the most favorable prognosis.

CONCLUSIONS:

This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.

• Authors: Roland Seiler, Ewan A Gibb, Natalie Q Wang, Htoo Zarni Oo, Hung-Ming Lam, Kim E van Kessel, Charlotte S Voskuilen, Brian Winters, Nicholas Erho, Mandeep M Takhar, James Douglas, Funda Vakar-Lopez, Simon J Crabb, Bas W G van Rhijn, Elisabeth E Fransen van de Putte, Ellen C Zwarthoff, George N Thalmann, Elai Davicioni, Joost L Boormans, Marc Dall'Era, Michiel S van der Heijden, Jonathan L Wright, Peter C Black
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 16 Pg. 5082-5093 (08 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30224344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Neoplasm Proteins
• Cisplatin

Topics

• Aged
• Biomarkers, Tumor (genetics)
• Cisplatin (administration & dosage, adverse effects)
• Cystectomy
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy (adverse effects)
• Neoplasm Proteins (genetics)
• Urinary Bladder Neoplasms (drug therapy, genetics, pathology, surgery)