The long and winding road to biomarkers for immunotherapy: a retrospective analysis of samples from patients with triple-negative breast cancer treated with pembrolizumab.

BACKGROUND

Immune checkpoint blockade (ICB) in combination with chemotherapy improves outcome of patients with triple-negative breast cancer (TNBC) in metastatic and early settings. The identification of predictive biomarkers able to guide treatment decisions is challenging and currently limited to programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) in the advanced setting, with several limitations.

MATERIALS AND METHODS

We carried out a retrospective analysis of clinical-pathological and molecular characteristics of tumor samples from 11 patients with advanced TNBC treated with single-agent pembrolizumab participating in two early-phase clinical trials: KEYNOTE-012 and KEYNOTE-086. Clinical, imaging, pathological [i.e. tumor-infiltrating lymphocytes (TILs), PD-L1 status], RNA sequencing, and whole-exome sequencing data were analyzed. We compared our results with publicly available transcriptomic data from TNBC cohorts from TCGA and METABRIC.

RESULTS

Response to pembrolizumab was heterogeneous: two patients experienced exceptional long-lasting responses, six rapid progressions, and three relatively slower disease progression. Neither PD-L1 nor stromal TILs were significantly associated with response to treatment. Increased TMB values were observed in tumor samples from exceptional responders compared to the rest of the cohort (P = 3.4 × 10

CONCLUSIONS

The wide spectrum of clinical responses to ICB supports that TNBC is a heterogeneous disease. Tumors with high TMB respond better to ICB. However, the optimal cut-off of 10 mutations (mut)/megabase (Mb) may not reflect the complexity of all tumor subtypes, despite its approval as a tumor-agnostic biomarker. Further studies are required to better elucidate the relevance of the tumor microenvironment and its components as potential predictive biomarkers in the context of ICB.

Informations de copyright

Copyright © 2024. Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Disclosure LB: investigator-initiated trial (funds paid to institution): AstraZeneca. Advisory boards: Domain Therapeutics, iTEOS Therapeutics. Travel grant from GILEAD. AG: travel grant from AstraZeneca, advisory board (to the institution): Daiichi Sankyo, Eli Lilly. EA: consultancy fees/honoraria: Eli Lilly, Sandoz, AstraZeneca. Research grant from Gilead to the institution. Support for attending medical conferences from: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca. JS: permanent member of the Scientific Advisory Board and owns stocks of Surface Oncology, is member of the Scientific Advisory Board of Tarus Therapeutics, and is a member of the Scientific Advisory Board of Domain Therapeutics. CS: Advisory board (receipt of honoraria or consultations fees): Astellas, Cepheid, Vertex, Seattle genetics, Puma, Amgen, Exact Sciences; Participation in company sponsored speaker’s bureau: Eisai, Prime Oncology, Teva, Foundation Medicine, Exact Sciences; other support (travel, accommodation expenses): Roche, Genentech, Pfizer. All other authors have declared no conflicts of interest.