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      Resistance to antibody‐drug conjugates in breast cancer: mechanisms and solutions

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          Abstract

          Antibody‐drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer. Currently, there are two ADCs approved for the treatment of human epidermal growth factor receptor 2‐positive breast cancer, one for triple‐negative breast cancer, and multiple investigational ADCs in clinical trials. However, drug resistance has been noticed in clinical use, especially in trastuzumab emtansine. Here, the mechanisms of ADC resistance are summarized into four categories: antibody‐mediated resistance, impaired drug trafficking, disrupted lysosomal function, and payload‐related resistance. To overcome or prevent resistance to ADCs, innovative development strategies and combination therapy options are being investigated. Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

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          Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

          Gunter von Minckwitz, Chiun-Sheng Huang, Max S Mano … (2018)
          Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
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            Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance

            Sreya Bagchi, Robert Yuan, Edgar Engleman (2021)
            Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs—which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)—quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome.
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              Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

              Shanu Modi, Cristina Saura, Toshinari Yamashita … (2019)
              Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
              Article 0 comments Cited 658 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ke‐Da Yu:
                ORCID: https://orcid.org/0000-0002-2883-1282
                yukeda@fudan.edu.cn , yukeda@163.com
                Journal
                Journal ID (nlm-ta): Cancer Commun (Lond)
                Journal ID (iso-abbrev): Cancer Commun (Lond)
                Journal ID (doi): 10.1002/(ISSN)2523-3548
                Journal ID (publisher-id): CAC2
                Title: Cancer Communications
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2523-3548
                Publication date (Electronic): 10 November 2022
                Publication date Collection: March 2023
                Volume: 43
                Issue: 3 ( doiID: 10.1002/cac2.v43.3 )
                Pages: 297-337
                Affiliations
                [ 1 ] Department of Breast Surgery Fudan University Shanghai Cancer Center Shanghai 200032 P. R. China
                [ 2 ] Shanghai Medical College Fudan University Shanghai 200032 P. R. China
                [ 3 ] Department of Breast Surgery First Affiliated Hospital of China Medical University Shenyang Liaoning 110001 P. R. China
                Author notes
                [*] [* ] Correspondence

                Ke‐Da Yu, MD, Ph.D., Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China.

                Email: yukeda@ 123456fudan.edu.cn , yukeda@ 123456163.com

                Author information
                https://orcid.org/0000-0002-2883-1282
                Article
                Publisher ID: CAC212387
                DOI: 10.1002/cac2.12387
                PMC ID: 10009672
                PubMed ID: 36357174
                SO-VID: 40ac4d41-84d7-40fb-b6e4-3cb796005cb7
                Copyright © © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date revision received : 13 July 2022
                Date received : 18 May 2022
                Date accepted : 26 October 2022
                Page count
                Figures: 3, Tables: 4, Pages: 41, Words: 17384
                Categories
                Subject: Review
                Subject: Review
                Custom metadata
                source-schema-version-number 2.0
                cover-date March 2023
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023

                Keywords: antibody‐drug conjugate,breast cancer,drug resistance,combination therapy,predictive biomarker
                Data availability:
                Keywords: antibody‐drug conjugate, breast cancer, drug resistance, combination therapy, predictive biomarker

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