Reply to Joep J. de Jong and Ewan A. Gibb’s Letter to the Editor re: Gottfrid Sjödahl, Johan Abrahamsson, Karin Holmsten, et al. Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2021.10.035. Neoadjuvant Chemotherapy Response in Muscle-invasive Bladder Cancer: Differences in Intrinsic Biology or Subtyping Nomenclature?

Background: Neoadjuvant chemotherapy (NAC) improves survival in responder patients. However, for non-responders, the treatment represents an ineffective exposure to chemotherapy and its potential adverse events. Predicting the response to treatment is a major issue in the therapeutic management of patients, particularly for patients with muscle-invasive bladder cancer. Methods: Tissue samples of trans-urethral resection of bladder tumor collected at the diagnosis time, were analyzed by mid-infrared imaging. A sequence of spectral data processing was implemented for automatic recognition of informative pixels and scoring each pixel according to a continuous scale (from 0 to 10) associated with the response to NAC. The ground truth status of the responder or non-responder was based on histopathological examination of the samples. Results: Although the TMA spots of tumors appeared histologically homogeneous, the infrared approach highlighted spectral heterogeneity. Both the quantification of this heterogeneity and the scoring of the NAC response at the pixel level were used to construct sensitivity and specificity maps from which decision criteria can be extracted to classify cancerous samples. Conclusions: This proof-of-concept appears as the first to evaluate the potential of the mid-infrared approach for the prediction of response to neoadjuvant chemotherapy in MIBC tissues.

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Apparent plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.433 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 433-433

Author(s):

Roland Seiler ◽

Ewan Gibb ◽

Natalie Qiqi Wang ◽

Htoo Zarni Oo ◽

Hung-Ming Lam ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Molecular Subtypes ◽

Invasive Bladder Cancer ◽

Consensus Clustering ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

433 Background: After cisplatin-based neoadjuvant chemotherapy (NAC) almost two thirds of patients have residual muscle-invasive bladder cancer (MIBC) present at radical cystectomy (RC). The alterations induced by NAC in these cisplatin-resistant tumors remain largely unstudied. Here, we aim to investigate the characteristics of cisplatin-resistant tumors. Methods: RC 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. In addition, the tumor bed (scar tissue) of 21 post-NAC RC specimens with no residual tumor was profiled. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry (KRT5/6, GATA3, KI67 and CD8) were used to confirm tissue sampling and gene expression analysis. Results: Unsupervised consensus clustering yielded four distinct consensus clusters (CC). Consistent basal-(CC1) and luminal-like (CC2) phenotype similar to pre-NAC subtyping was observed in 42% of cases. One third of cases became immune-infiltrated (CC3) in the post-NAC setting but lacked basal and luminal markers. These tumors expressed a strong T-cell signature, chemokine signaling and checkpoint molecules. Conversely, CC4 was associated with healing/scarring. This ‘scar-like’ character of CC4 was consistent with the scar samples. Despite being pathological non-responders, the relative risk of death for CC4 was 2.8 and 3 times less than CC2-Luminal (p = 0.038) and CC3-Infiltrated (p = 0.018), respectively. Luminal-like pre-NAC samples were more likely to adopt a scar-like character (CC4) in the post-NAC setting, while the basal-like tumors were more likely to develop luminal features (CC2). Conclusions: This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Clinical trials are necessary to test the impact of these molecular subtypes with respect to selection of adjuvant and salvage treatments. Post-NAC immune infiltration could have implications for subsequent immunotherapy.

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