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
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 predictiv...
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BMC
2025-03-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01946-y |
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| author | Rebecca Dent Javier Cortés Yeon Hee Park Eva Muñoz-Couselo Sung-Bae Kim Joohyuk Sohn Seock-Ah Im Esther Holgado Theodoros Foukakis Sherko Kümmel Jennifer Yearley Anran Wang Michael Nebozhyn Lingkang Huang Razvan Cristescu Petar Jelinic Vassiliki Karantza Peter Schmid |
| author_facet | Rebecca Dent Javier Cortés Yeon Hee Park Eva Muñoz-Couselo Sung-Bae Kim Joohyuk Sohn Seock-Ah Im Esther Holgado Theodoros Foukakis Sherko Kümmel Jennifer Yearley Anran Wang Michael Nebozhyn Lingkang Huang Razvan Cristescu Petar Jelinic Vassiliki Karantza Peter Schmid |
| author_sort | Rebecca Dent |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4b4962b9db324675a0d0e9eac3dbd9f3 |
| institution | DOAJ |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Breast Cancer Research |
| spelling | doaj-art-4b4962b9db324675a0d0e9eac3dbd9f32025-08-20T03:02:19ZengBMCBreast Cancer Research1465-542X2025-03-0127111210.1186/s13058-024-01946-yMolecular 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 studyRebecca Dent0Javier Cortés1Yeon Hee Park2Eva Muñoz-Couselo3Sung-Bae Kim4Joohyuk Sohn5Seock-Ah Im6Esther Holgado7Theodoros Foukakis8Sherko Kümmel9Jennifer Yearley10Anran Wang11Michael Nebozhyn12Lingkang Huang13Razvan Cristescu14Petar Jelinic15Vassiliki Karantza16Peter Schmid17Division of Medical Oncology, National Cancer Centre SingaporeVall d´Hebron Institute of Oncology (VHIO)Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of MedicineVall d´Hebron Institute of Oncology (VHIO)Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of MedicineDepartment of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of MedicineMedical Oncology Service, Ramón y Cajal University HospitalDepartment of Oncology-Pathology, Karolinska Comprehensive Cancer Center, Karolinska Institute and Breast Cancer Centre, Cancer Theme, Karolinska University HospitalInterdisciplinary Breast Unit, Essen-Mitte Clinics, Essen, and Charité–Universitätsmedizin BerlinMerck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Centre for Experimental Cancer Medicine, Barts Cancer InstituteAbstract 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.https://doi.org/10.1186/s13058-024-01946-yImmunohistochemistryTriple-negative breast cancerTumor microenvironment |
| spellingShingle | Rebecca Dent Javier Cortés Yeon Hee Park Eva Muñoz-Couselo Sung-Bae Kim Joohyuk Sohn Seock-Ah Im Esther Holgado Theodoros Foukakis Sherko Kümmel Jennifer Yearley Anran Wang Michael Nebozhyn Lingkang Huang Razvan Cristescu Petar Jelinic Vassiliki Karantza Peter Schmid 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 Breast Cancer Research Immunohistochemistry Triple-negative breast cancer Tumor microenvironment |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Immunohistochemistry Triple-negative breast cancer Tumor microenvironment |
| url | https://doi.org/10.1186/s13058-024-01946-y |
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