Construction and validation of a gene expression classifier to predict immunotherapy response in primary triple-negative breast cancer
Ensenyat Méndez, Miquel (Institut d'Investigació Sanitària Illes Balears)
Orozco, Javier I. J. (Providence Saint John's Health Center)
Llinàs-Arias, Pere (Institut d'Investigació Sanitària Illes Balears)
Íñiguez-Muñoz, Sandra (Institut d'Investigació Sanitària Illes Balears)
Baker, Jennifer L. (David Geffen School of Medicine at UCLA. Department of Surgery)
Salomon, Matthew P. (University of Southern California (USC). Department of Medicine)
Martí, Mercè (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
DiNome, Maggie L. (Duke University School of Medicine. Department of Surgery)
Cortés, Javier (Universidad Europea de Madrid. Departamento de Medicina)
Marzese, Diego (Institut d'Investigació Sanitària Illes Balears)
Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia

Date:	2023
Abstract:	Immune checkpoint inhibitors (ICI) improve clinical outcomes in triple-negative breast cancer (TNBC) patients. However, a subset of patients does not respond to treatment. Biomarkers that show ICI predictive potential in other solid tumors, such as levels of PD-L1 and the tumor mutational burden, among others, show a modest predictive performance in patients with TNBC. We built machine learning models based on pre-ICI treatment gene expression profiles to construct gene expression classifiers to identify primary TNBC ICI-responder patients. This study involved 188 ICI-naïve and 721 specimens treated with ICI plus chemotherapy, including TNBC tumors, HR+/HER2− breast tumors, and other solid non-breast tumors. The 37-gene TNBC ICI predictive (TNBC-ICI) classifier performs well in predicting pathological complete response (pCR) to ICI plus chemotherapy on an independent TNBC validation cohort (AUC = 0. 86). The TNBC-ICI classifier shows better performance than other molecular signatures, including PD-1 (PDCD1) and PD-L1 (CD274) gene expression (AUC = 0. 67). Integrating TNBC-ICI with molecular signatures does not improve the efficiency of the classifier (AUC = 0. 75). TNBC-ICI displays a modest accuracy in predicting ICI response in two different cohorts of patients with HR + /HER2- breast cancer (AUC = 0. 72 to pembrolizumab and AUC = 0. 75 to durvalumab). Evaluation of six cohorts of patients with non-breast solid tumors treated with ICI plus chemotherapy shows overall poor performance (median AUC = 0. 67). TNBC-ICI predicts pCR to ICI plus chemotherapy in patients with primary TNBC. The study provides a guide to implementing the TNBC-ICI classifier in clinical studies. Further validations will consolidate a novel predictive panel to improve the treatment decision-making for patients with TNBC. Triple-Negative Breast Cancer (TNBC) is an aggressive type of breast cancer, responsible for a substantial burden of breast cancer-related deaths. In recent years, immunotherapy, a therapy that triggers the patient's immune system to attack the tumor, has arisen as a promising treatment in various cancers, including TNBC. However, a subset of patients with TNBC does not respond to this treatment. Here, we employed advanced computational techniques to predict response to immunotherapy plus chemotherapy in patients with primary TNBC. Our method is more accurate than using other existing markers, such as PD-L1, but is not very accurate in patients with non-TNBC breast cancers or non-breast cancers. This method could potentially be used to better select patients for immunotherapy, upfront, avoiding the side effects and costs of treating patients in which immunotherapy might not work. Ensenyat-Mendez et al. construct a gene expression-based machine learning classifier to predict the response of triple-negative breast cancer to immune checkpoint inhibition combined with chemotherapy. Predictive performance of the 37-gene classifier is better than that of PD-1 or PD-L1.
Grants:	Instituto de Salud Carlos III CPII22/00004 Instituto de Salud Carlos III CD22/00026 Instituto de Salud Carlos III PI22/01496
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cancer immunotherapy ; Predictive markers ; Breast cancer
Published in:	Communications Medicine, Vol. 3 (July 2023) , art. 93, ISSN 2730-664X

DOI: 10.1038/s43856-023-00311-y
PMID: 37430006

8 p, 1.9 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles