Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer
by
, , , , , , , , , and
Alejandra Bernardini
1,2,3
,
Marta Dueñas
1,2,3,
María Cruz Martín-Soberon
1,4,
Carolina Rubio
1,2,3,
Cristian Suarez-Cabrera
1,2,3,
Raquel Ruiz-Palomares
1,2,
Ester Munera-Maravilla
1,2,3,
Sara Lázaro
2,
Iris Lodewijk
1,2,3,
Daniel Rueda
1,
David Gómez-Sánchez
1,
Teresa Alonso-Gordoa
5,
Javier Puente
6,
Álvaro Pinto
7,
Pilar González-Peramato
7,
Carlos Aguado
6,
Mercedes Herrera
4,
Flora López
4,
Victor M. G. Martinez
1,2,3,
Lucía Morales
1,2, 
Daniel Castellano
1,3,4,
Jesús M. Paramio
1,2,3,*
and
Guillermo de Velasco
1,4,*add
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1
Instituto de Investigación i+12, Hospital University “12 de Octubre”, 28040 Madrid, Spain
2
Unidad de Oncología Molecular, CIEMAT, 28045 Madrid, Spain
3
Centro de Investigacion en Red de Cáncer CIBERONC, 28029 Madrid, Spain
4
Departamento de Oncología Médica, Hospital 12 de Octubre, 28040 Madrid, Spain
5
Departamento de Oncología Médica, Hospital Ramón y Caja, 28034 Madrid, Spain
6
Departamento de Oncología Médica, Hospital Clínico San Carlos, 28040 Madrid, Spain
7
Departamento de Oncología Médica, Hospital La Paz, 28046 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(2), 378; https://doi.org/10.3390/cancers14020378
Submission received: 30 November 2021
/
Revised: 28 December 2021
/
Accepted: 29 December 2021
/
Published: 13 January 2022
Simple Summary
Few metastatic urothelial cancer patients achieve durable clinical benefit with vinflunine. Predictive biomarkers to help to identify better treatment strategies are extremely needed. The objective of this study was to identify molecular differences between extreme responders to vinflunine in urothelial cancer. Genomic and immune markers are potentially useful identifying patients that may achieve greater benefit with vinflunine.
Abstract
Background and Aims: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Methods: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Results: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Conclusions: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
Keywords:
urothelial cancer; bladder; vinflunine; biomarkers; immune signatures
