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Clinical Research and Public HealthIn-Press PreviewClinical ResearchOncology Open Access | 10.1172/JCI205962

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple negative breast cancer CALGB40603 (Alliance)

Patrick D. Rädler,1 Brooke M. Felsheim,1 Aranzazu Fernandez-Martinez,2 Adam D. Pfefferle,1 Michele C. Hayward,1 Baljit Singh,3 William Sikov,4 Lisa A. Carey,1 and Charles M. Perou1

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Rädler, P. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Felsheim, B. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Fernandez-Martinez, A. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Pfefferle, A. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Hayward, M. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Singh, B. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Sikov, W. in: PubMed | Google Scholar

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Carey, L. in: PubMed | Google Scholar |

1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America

2IHU-National PRecISion Medicine Center in Oncology, Institut Gustave Roussy, Villejuif, France

3White Plains Hospital, White Plains, United States of America

4Program in Women's Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America

Find articles by Perou, C. in: PubMed | Google Scholar |

Published August 4, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI205962.
Copyright © 2026, Rädler et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 4, 2026 - Version history
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Abstract

Background: Despite therapeutic advances in the early-stage triple negative breast cancer (TNBC) setting, residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and is a major obstacle to improving patient outcomes. Methods: To better characterize RD and identify survival associated features, we performed comprehensive transcriptomic profiling of 340 pre-treatment stage II/III TNBCs and 70 matched post-treatment RD samples from the randomized CALGB 40603 (Alliance) Phase 2 clinical trial. Preclinical treatment strategies mimicking RD patients were explored using Antibody Drug Conjugate (ADC) treatment in patient derived xenograft (PDX) mouse models. Results: Our study shows that prognostic genomic features measured prior to treatment may differ from prognostic features measured after treatment from RD specimens. Specifically, we identified that patients with a genomic PAM50 subtype of Basal-like in RD specimens have a poor survival outcome and their matching pre-treatment tumors are characterized by elevated chromosomal amplifications of oncogenic drivers (i.e., MYC, CDK6, and CCND1) as well as significantly reduced B- and T-cell expression features. Paired analyses of Basal-like RD and matched pre-treatment tumors reveal further lymphocyte depletion in the RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a Basal-like and conventional chemotherapy-resistant PDX model, resembling Basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response. Conclusion: RD biology differs from pre-treatment tumors, with Basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Pre-clinical modeling suggests that this high-risk group may benefit from adjuvant ADC therapy. Trial registration: ClinicalTrials.gov NCT00861705 Funding: National Cancer Institute (NCI) U10CA180821 (Alliance for Clinical Trials in Oncology) NCI U24CA176171 (Alliance for Clinical Trials in Oncology) NCI UG1CA233373 (Alliance for Clinical Trials in Oncology) NCI Breast SPORE program P50-CA058223 (CMP) Susan G. Komen SAC-160074 (CMP, PDR) Breast Cancer Research Foundation BCRF-23-127 (CMP) NCI R01-CA229409 (CMP) UNC LCCC Triple Negative Breast Cancer Center (CMP)

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