Review Article| Volume 37, ISSUE 1, P151-167, February 2023

Current and Emerging Role of Antibody–Drug Conjugates in HER2-Negative Breast Cancer


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Hematology/Oncology Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aiko N.
        • Ellisen L.W.
        • Chabner B.
        • et al.
        Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments.
        Targeted Oncol. 2017; 12: 719-739
        • Drago J.Z.
        • Modi S.
        • Chandarlapaty S.
        Unlocking the Potential of Antibody-Drug Conjugates for Cancer Therapy.
        Nature Reviews. 2021; 18: 327-344
        • Hamblett K.J.
        • Senter P.D.
        • Chace D.F.
        • et al.
        Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate.
        Clin Cancer Res. 2004; 10: 7063-7070
        • Xiuxia S.
        • Ponte J.F.
        • Yoder N.C.
        • et al.
        Effects of Drug–Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody–Maytansinoid Conjugates.
        Bioconjug Chem. 2017; 28: 1371-1381
        • Nareshkumar J.
        • Smith S.W.
        • Ghone S.
        • et al.
        Current ADC Linker Chemistry.
        Pharm Res. 2015; 32: 3526-3540
        • Yusuke O.
        • Hagihara K.
        • Oitate M.
        • et al.
        Bystander Killing Effect of DS-8201a, a Novel Anti-Human Epidermal Growth Factor Receptor 2 Antibody-Drug Conjugate, in Tumors with Human Epidermal Growth Factor Receptor 2 Heterogeneity.
        Cancer Sci. 2016; 107: 1039-1046
        • Shanu M.
        • Park H.
        • Murthy R.K.
        • et al.
        Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study.
        J Clin Oncol. 2020; 38: 1887-1896
        • Staudacher A.H.
        • Brown M.P.
        Antibody Drug Conjugates and Bystander Killing: Is Antigen-Dependent Internalisation Required?.
        Br J Cancer. 2017; 117: 1736-1742
        • Shanu M.
        • Jacot W.
        • Yamashita T.
        • et al.
        Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
        N Engl J Med. 2022; 387: 9-20
        • Okeley N.M.
        • Miyamoto J.B.
        • Zhang X.
        • Alley Stephen C.
        Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate.
        Clin Cancer Res. 2010; 16 (): 888-897
        • Olga A.
        • Whiteman K.R.
        • Bartle L.M.
        • et al.
        IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.
        Mol Cancer Ther. 2015;
        • Aditya B.
        • Mayer I.A.
        • Vahdat L.T.
        • et al.
        Sacituzumab Govitecan-Hziy in Refractory Metastatic Triple-Negative Breast Cancer.
        N Engl J Med. 2019; 380: 741-751
        • Neelima V.
        • Bardia A.
        Targeted Therapy for Metastatic Triple Negative Breast Cancer: The next Frontier in Precision Oncology.
        Oncotarget. 2017; 8: 106167-106168
        • Bardia A.
        • Messersmith W.A.
        • Kio E.A.
        • et al.
        Sacituzumab Govitecan, a Trop-2-Directed Antibody-Drug Conjugate, for Patients with Epithelial Cancer: Final Safety and Efficacy Results from the Phase I/II IMMU-132-01 Basket Trial.
        Ann Oncol. 2021; 32: 746-756
        • Aditya B.
        • Mayer I.A.
        • Diamond ., J.R.
        • et al.
        Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.
        J Clin Oncol. 2017; 35: 2141-2148
        • Aditya B.
        Datopotamab deruxtecan (Dato-DXd), a TROP.
        Ann Oncol. 2021; 32: S60-S78
        • Aditya B.
        • Tolaney S.M.
        • Loirat D.
        • et al.
        Sacituzumab Govitecan (SG) versus Treatment of Physician’s Choice (TPC) in Patients (pts) with Previously Treated, Metastatic Triple-Negative Breast Cancer (mTNBC): Final Results from the Phase 3 ASCENT Study.
        J Clin Oncol. 2022; 40: 1071
        • Aditya B.
        • Coates J.T.
        • Spring L.
        • et al.
        Abstract 2638: Sacituzumab Govitecan, Combination with PARP Inhibitor, Talazoparib, in Metastatic Triple-Negative Breast Cancer (TNBC): Translational Investigation.
        Cancer Res. 2022; 82: 2638
        • Rugo H.S.
        • Bardia A.
        • Marmé F.
        • et al.
        Primary Results from TROPiCS-02: A Randomized Phase 3 Study of Sacituzumab Govitecan (SG) versus Treatment of Physician’s Choice (TPC) in Patients (Pts) with Hormone receptor–positive/HER2-Negative (HR+/HER2-) Advanced Breast Cancer.
        J Clin Oncol. 2022; 40 (LBA1001–LBA1001)
        • National Comprehensive Cancer Network
        Breast Cancer (Version 4.2022).
        (Available at:) (Accessed July 21, 2022)
        • Ian K.
        • Juric D.
        • Shimizu T.
        • et al.
        Abstract GS1-05: Datopotamab Deruxtecan in Advanced/metastatic HER2- Breast Cancer: Results from the Phase 1 TROPION-PanTumor01 Study.
        Cancer Res. 2022; 82 (GS1–05)
        • Krop I.E.
        • Masuda N.
        • Mukohara T.
        • et al.
        Results from the Phase 1/2 Study of Patritumab Deruxtecan, a HER3-Directed Antibody-Drug Conjugate (ADC), in Patients with HER3-Expressing Metastatic Breast Cancer (MBC).
        J Clin Oncol. 2022; 40: 1002
        • Barroso-Sousa R.
        • Tolaney S.M.
        Clinical Development of New Antibody–Drug Conjugates in Breast Cancer: To Infinity and Beyond.
        BioDrugs. 2021; 35: 159-174
        • Wim D.
        • Ubink R.
        • van der Lee M.
        • et al.
        Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform.
        Mol Cancer Ther. 2014; 13: 2618-2629
        • Udai B.
        • van Herpen C.M.L.
        • Saura C.
        • et al.
        Trastuzumab Duocarmazine in Locally Advanced and Metastatic Solid Tumours and HER2-Expressing Breast Cancer: A Phase 1 Dose-Escalation and Dose-Expansion Study.
        Lancet Oncol. 2019; 20: 1124-1135
        • Alessandro R.
        • ACusmai
        • Acquafredda S.
        • et al.
        Ladiratuzumab Vedotin for Metastatic Triple Negative Cancer: Preliminary Results, Key Challenges, and Clinical Potential.
        Expert Opin Investig Drugs. 2022; 31: 495-498
        • Modi S.
        • Pusztai L.
        • Forero A.
        • et al.
        Abstract PD3-14: Phase 1 Study of the Antibody-Drug Conjugate SGN-LIV1A in Patients with Heavily Pretreated Triple-Negative Metastatic Breast Cancer.
        Cancer Res. 2018; 78 (PD3–14)
        • Meisel J.L.
        • Pluard T.J.
        • Vinayak S.
        • et al.
        Phase 1b/2 Study of Ladiratuzumab Vedotin (LV) in Combination with Pembrolizumab for First-Line Treatment of Triple-Negative Breast Cancer (SGNLVA-002, Trial in Progress).
        J Clin Oncol. 2022; 40: TPS1127
        • Han H.S.
        • Alemany C.A.
        • Brown-Glaberman U.A.
        • et al.
        SGNLVA-002: Single-Arm, Open Label Phase Ib/II Study of Ladiratuzumab Vedotin (LV) in Combination with Pembrolizumab for First-Line Treatment of Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer.
        J Clin Oncol. 2019; 37: TPS1110
        • Qin L.
        • Zhang R.
        • Yan H.
        • et al.
        Prognostic Significance of HER3 in Patients with Malignant Solid Tumors.
        Oncotarget. 2017; 8: 67140-67151
        • Heather S.
        • Hanssen A.
        • Loges S.
        • et al.
        EGFR and HER3 Expression in Circulating Tumor Cells and Tumor Tissue from Non-Small Cell Lung Cancer Patients.
        Scientific Rep. 2019; 9: 7406
        • Jänne P.A.
        • Baik C.
        • Wu-Chou S.
        • et al.
        Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer.
        Cancer Discov. 2022; 12: 74-89
        • Smith L.M.
        • Willmore E.
        • Austin C.A.
        • et al.
        The Novel poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons by Increasing the Persistence of DNA Strand Breaks.
        Clin Cancer Res. 2005; 11: 8449-8457
        • Znojek P.
        • Willmore E.
        • Curtin N.J.
        Preferential Potentiation of Topoisomerase I Poison Cytotoxicity by PARP Inhibition in S Phase.
        Br J Cancer. 2014; 111: 1319-1326
        • Yap T.A.
        • Hamilton E.
        • Bauer T.
        • et al.
        Phase Ib SEASTAR Study: Combining Rucaparib and Sacituzumab Govitecan in Patients With Cancer With or Without Mutations in Homologous Recombination Repair Genes.
        JCO Precision Oncol. 2022; 6: e2100456
        • LoRusso P.M.
        • Li J.
        • Burger A.
        • et al.
        Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors.
        Clin Cancer Res. 2016; 22: 3227-3237
        • Kummar S.
        • Chen A.
        • Ji J.
        • et al.
        Phase I Study of PARP Inhibitor ABT-888 in Combination with Topotecan in Adults with Refractory Solid Tumors and Lymphomas.
        Cancer Res. 2011; 71: 5626-5634
        • Redman J.M.
        • Hill E.M.
        • AlDeghaither D.
        • et al.
        Mechanisms of Action of Therapeutic Antibodies for Cancer.
        Mol Immunol. 2015; 67: 28-45
        • Garrido-Castro A.C.
        • Keenan T.E.
        • Li T.
        • et al.
        Saci-IO TNBC: Randomized Phase II Trial of Sacituzumab Govitecan (SG) +/- Pembrolizumab in PD-L1– Metastatic Triple-Negative Breast Cancer (mTNBC).
        J Clin Oncol. 2021; 39: TPS1106
        • Laura S.
        • Tolaney S.M.
        • Desai N.V.
        • et al.
        Phase 2 Study of Response-Guided Neoadjuvant Sacituzumab Govitecan (IMMU-132) in Patients with Localized Triple-Negative Breast Cancer: Results from the NeoSTAR Trial.
        J Clin Oncol. 2022; 40: 512
        • Marmé F.
        • Hanusch C.
        • Furlanetto J.
        • et al.
        58O Safety Interim Analysis (SIA) of the Phase III Postneoadjuvant SASCIA Study Evaluating Sacituzumab Govitecan (SG) in Patients with Primary HER2-Negative Breast Cancer (BC) at High Relapse Risk after Neoadjuvant Treatment.
        Ann Oncol. 2022;
        • Frederik M.
        • Stickeler E.
        • Furlanetto J.
        • et al.
        Phase III Postneoadjuvant Study Evaluating Sacituzumab Govitecan, an Antibody Drug Conjugate in Primary HER2-Negative Breast Cancer Patients with High Relapse Risk after Standard Neoadjuvant Treatment: SASCIA.
        J Clin Oncol. 2021; 39: TPS602
        • Dario T.
        • Curigliano G.
        Accelerating Progress in Early Triple-Negative Breast Cancer: A Viewpoint on Antibody-Drug Conjugates, Back from St Gallen Breast Cancer Conference 2021.
        Breast. 2022; 62: S54-S57
        • Coates J.T.
        • Sun S.
        • Leshchiner I.
        • et al.
        Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.
        Cancer Discov. 2021; 11: 2436-2445
        • Nagayama A.
        • Vidula N.
        • Ellisen L.
        • et al.
        Novel Antibody-Drug Conjugates for Triple Negative Breast Cancer.
        Ther Adv Med Oncol. 2020; 12 (1758835920915980)
        • Mosele M.F.
        • Lusque A.
        • Dieras V.
        • et al.
        LBA1 Unraveling the Mechanism of Action and Resistance to Trastuzumab Deruxtecan (T-DXd): Biomarker Analyses from Patients from DAISY Trial.” Annals of.
        (Available at:)