The impact of the immunological context on outcomes of solid cancer patients treated with genotype-matched targeted therapies: a comprehensive review.
Mubarak, O Middleton, G W
Mubarak, O
Middleton, G W
Affiliation
University Hospitals Birmingham NHS Foundation Trust; University of Birmingham
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Publication date
2025-03-19
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Abstract
Background: Outcomes with genotype-matched targeted therapy in solid cancer patients are heterogeneous: some have exceptional responses, whereas others have primary progression. This review explores the immunobiological features which may underlie this differential response.
Methods: We conducted a literature review of studies assessing the impact of immune context following searches on Web of Science, Medline and Embase. Relevant outcomes include response, progression-free survival and overall survival. Data were extracted from multivariate analysis, univariate analysis or directly from Kaplan-Meier curves. Meta-analyses were carried out where three or more studies analysed the same immune factor for the same cancer type. The remaining studies were analysed descriptively.
Results: In the adjuvant setting, assessment of the immune context does not highlight a group failing to derive benefit for the use of dabrafenib/trametinib after resection of BRAFV600E melanoma. Differential gene expression in exceptional responders show enrichment of genes associated with immune activation. BRAFV600E colorectal cancer patients with high cytolytic scores benefit from the addition of MEK inhibition whereas those with low scores fare better without. High programmed death-ligand 1 (PD-L1) expression is predictive of inferior outcomes to epidermal growth factor receptor (EGFR), ALK and G12C tyrosine kinase inhibitors. EGFR-mutant patients with high CD8+ T cells and PD-L1 positivity have very poor outcomes. Stromal tumour-infiltrating lymphocytes predict for efficacy of stromal-poor tumours in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with short-course adjuvant trastuzumab. High immune metagene and single immune gene expression are predictive of benefit for chemotherapy plus trastuzumab, but not chemotherapy alone. The addition of pertuzumab or lapatanib appears to be beneficial in those with immune non-enriched microenvironments. High major histocompatibility complex (MHC)-I is negatively predictive and high MHC-II is positively predictive of outcomes with trastuzumab-based therapy.
Conclusions: To our knowledge, this is the first review assessing immunological context as a biomarker for targeted therapy. The results of this review represent an important resource to aid future translational studies in advancing stratified precision medicine oncology.
Citation
Mubarak O, Middleton GW. The impact of the immunological context on outcomes of solid cancer patients treated with genotype-matched targeted therapies: a comprehensive review. Ann Oncol. 2025 Jul;36(7):737-748. doi: 10.1016/j.annonc.2025.03.007. Epub 2025 Mar 19.
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Article