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Clinical Trial
. 2025 Mar 11;27(1):35.
doi: 10.1186/s13058-024-01946-y.

Molecular determinants of response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer: exploratory analysis of the open-label, multicohort phase 1b KEYNOTE-173 study

Rebecca Dent  1 , Javier Cortés  2   3   4 , Yeon Hee Park  5 , Eva Muñoz-Couselo  2   6 , Sung-Bae Kim  7 , Joohyuk Sohn  8 , Seock-Ah Im  9 , Esther Holgado  10 , Theodoros Foukakis  11 , Sherko Kümmel  12 , Jennifer Yearley  13 , Anran Wang  13 , Michael Nebozhyn  13 , Lingkang Huang  13 , Razvan Cristescu  13 , Petar Jelinic  13 , Vassiliki Karantza  13 , Peter Schmid  14
Affiliations
Clinical Trial

Molecular determinants of response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer: exploratory analysis of the open-label, multicohort phase 1b KEYNOTE-173 study

Rebecca Dent et al. Breast Cancer Res. .

Abstract

Background: The multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response.

Methods: Cell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures using RNA sequencing) and pathologic complete response (pCR).

Results: At baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c+ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63-1.00), CD11c+/MHCII+/CD163-/CD68- cells (DC: 0.76; 95% CI, 0.53-0.99), CD11c+/MHCII-/CD163-/CD68- cells (nonactivated/immature DC: 0.80; 95% CI 0.54-1.00), and CD11c+/CD163+ cells (M2 macrophage: 0.77; 95% CI 0.55-0.99). Other associations with pCR included baseline CD11c+/MHCII-/CD163-/CD68- (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51-1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52-0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on TcellinfGEP was 0.55 (95% CI 0.25-0.85); when detrended by TcellinfGEP, AUROC varied for the non-TcellinfGEP signatures. TcellinfGEP expression trended higher in responders than in nonresponders when evaluating pCR.

Conclusions: Myeloid cell populations within the tumor compartment at baseline and TcellinfGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy.

Trial registration: ClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.

Keywords: Immunohistochemistry; Triple-negative breast cancer; Tumor microenvironment.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution. The study was conducted in accordance with the protocol, its amendments, the ethical principles originating from the Declaration of Helsinki, and Good Clinical Practice guidelines. Written informed consent was provided by all patients before enrollment. Competing interests: RD reports grants or contracts from AstraZeneca and Roche; consulting fees from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Novartis, Pfizer, and Roche; honoraria from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Novartis, Pfizer, and Roche; support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Novartis, and Roche; and participation on data safety monitoring boards or advisory boards for AstraZeneca, Daiichi Sankyo, Eisai, MSD, Novartis, and Roche. JC reports consulting fees from AbbVie, AstraZeneca, Bioasis, BioInvent, Boehringer Ingelheim, BridgeBio, Clovis Oncology, Daiichi Sankyo, Ellipses, Expres2ion Biotechnologies, GEMoaB, Gilead, Hibercell, Jazz Pharmaceuticals, Leuko, Lilly, Menarini, MSD, Reveal Genomics, Roche, Scorpion Therapeutics, Seattle Genetics, and Zymeworks; honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Stemline Therapeutics; travel, accommodation, and expenses from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, MSD, Novartis, Pfizer, Roche, and Stemline Therapeutics; patents (Pharmaceutical Combinations of a Pi3k Inhibitor and a Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED and Her2 as a Predictor of Response to Dual HER2 Blockade in the Absence of Cytotoxic Therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED); stock or stock options from MAJ3 Capital, Leuko (relative); and research funding to the institution from Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-LaRoche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, IQVIA, Queen Mary University of London, and Roche. YHP reports grants or contracts from AstraZeneca, Gencurix, Genome Insight, MSD, Novartis, Pfizer, and Roche; consulting fees from AstraZeneca, Daiichi Sankyo, Eisai, EVEREST, Gilead, Lilly, MENARINI, MSD, Novartis, Pfizer, and Roche; honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, and Roche; support for attending meetings and/or travel from AstraZeneca, Gilead, and Pfizer; participation on a data safety monitoring board or advisory board for AstraZeneca, Daiichi Sankyo, MENARINI, Novartis, Pfizer, and Roche; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Dong-A ST, Pfizer, Roche, and Sanofi. EM-C reports consulting fees from BMS, MSD, Novartis, Pierra Fabre, and Sanofi; honoraria from BMS, MSD, Novartis, Pierre Fabre, and Sanofi; and support for attending meetings and/or travel from MSD and Novartis. S-BK reports consulting fees from Ansol Bioscience, AstraZeneca, BeiGene, Dae Haw Pharmaceutical Co. Ltd, Daiichi Sankyo, ISU Abxis, Lilly, Novartis, and OBI Pharma; and stock or stock options in Genopeaks. JS reports research funding to their institution from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Seagen and stock or stock options in Daiichi Sankyo. S-AI reports grants or contracts from AstraZeneca, Boryung Pharm, Daewoong Pharm, Daiichi Sankyo, Eisai, Pfizer, and Roche and consulting fees from AstraZeneca, Bertis, Daiichi Sankyo, Eisai, GSK, Hanmi, Idience, Lilly, MSD, Novartis, Pfizer, and Roche. EH has nothing to disclose. TF reports grants or contracts for clinical trial support from AstraZeneca, Novartis, Pfizer, and Veracyte; royalties for authorship of two chapters from UpToDate; consulting or private fees from Affibody, Exact Sciences, and Veracyte; honoraria for lectures to their institution from AstraZeneca, Daiichi Sankyo, Gilead, Pfizer, and Roche; and participation on an advisory board in December 2020 and private fees from Novartis. SK reports consulting fees from Lilly, MSD, Pink, and Somatex-Hologic; honoraria from Agendia, Amgen, AstraZeneca, Daiichi Sankyo, Exact Science, Gilead, Lilly, MSD, Novartis, Pfizer, Roche Pharma and Diagnostics, Seagen, Somatex-Hologic, and Sonoscape; support for attending meetings and/or travel from Daiichi Sankyo, Gilead, and Roche; participants on a data safety monitoring board or advisory board and payment from Agendia, Amgen, AstraZeneca, Daiichi Sankyo, Exact Science, Gilead, Lilly, Novartis, Pfizer, Roche Pharma and Diagnostics, MSD, Seagen, Somatex-Hologic, and Sonoscape; and a leadership or fiduciary role (no payment) for ESMO and WSG. JY reports employment at MSD, USA; stock or stock options in Merck & Co., Inc., Rahway, NJ, USA; patents issued and being filed, but not directly related to the manuscript; and receipt of equipment, materials, drugs, medical writing, gifts, or other services for work conducted as a full-time employee at MSD. AW reports employment at MSD and stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. MN reports employment at MSD and stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. LH reports employment at MSD and stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. RC reports employment at MSD and stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. PJ reports employment at MSD and stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. VK reports employment at MSD; stock or stock options in Merck & Co., Inc., Rahway, NJ, USA; and support for attending meetings and/or travel from MSD. PS has nothing to disclose.

Figures

Fig. 1
Fig. 1
pCR based on immune subsets and spatial localization at baseline. A CD11c+ (macrophages and DCs); B CD11c+/MHCII+/CD163−/CD68− (DCs); C CD11c+/MHCII−/CD163−/CD68− (nonactivated/immature DCs); D CD11c+/CD163+ (M2 macrophages); and E CD11c/CD3 baseline ratio. Abbreviations: DC: dendritic cell; pCR: pathologic complete response; sqrt: square root
Fig. 2
Fig. 2
pCR based on T-cell population and spatial localization at baseline. A CD3+; B CD8+; and C CD8+/Granzyme B+/Ki67+. Abbreviation: pCR: pathologic complete response
Fig. 3
Fig. 3
CD163+/MHCII+ change from baseline detrended by baseline based on pCR and by spatial localization. Abbreviation: pCR: pathologic complete response
Fig. 4
Fig. 4
TcellinfGEP and non-TcellinfGEPa consensus signature score at baseline by A pCR and B ORR. Abbreviations: CR: complete response; EMT: epithelial mesenchymal transition; gMDSC: granulocytic myeloid-derived suppressor cell; mMDSC: monocytic myeloid-derived suppressor cell; ORR: objective response rate; pCR: pathologic complete response; PR: partial response; TcellinfGEP: T-cell–inflamed gene expression profile; TGFβ: transforming growth factor β. aDetrended by TcellinfGEP. bDetrended by mMDSC
Fig. 5
Fig. 5
TcellinfGEP and non-TcellinfGEP consensus signature score detrended change from baseline by A pCR and B ORR. Abbreviations: CR: complete response; EMT: epithelial mesenchymal transition; gMDSC: granulocytic myeloid-derived suppressor cell; mMDSC: monocytic myeloid-derived suppressor cell; ORR: objective response rate; pCR pathologic complete response; PR: partial response; TcellinfGEP: T-cell–inflamed gene expression profile; TGFβ: transforming growth factor β
See this image and copyright information in PMC

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