Antibody-Drug Conjugates in Breast Cancer: The Road Towards Biologically-Informed Selection and Sequencing

Overview

Journal Curr Oncol Rep

Publisher Current Science

Date 2025 Jan 9

PMID 39786525

Authors

Tess A OMeara

Paolo Tarantino

Stefania Morganti

Ilana Schlam

Ana C Garrido-Castro

Sara M Tolaney

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: In this review, we discuss evidence supporting the use of antibody-drug conjugates (ADCs) in breast cancer treatment, describe novel ADCs and combination regimens under development, and examine our current understanding of resistance mechanisms and biomarkers to guide ADC selection and sequencing.

Recent Findings: Three ADCs have proven benefit in patients with metastatic breast cancer: trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG). There are over two hundred investigational ADCs on the horizon, as pre-clinical studies work to identify novel ADC targets and structures. In this new frontier, translational efforts are underway to personalize the use of ADCs, including refining HER2 quantification and elucidating genetic, epigenetic, and post-translational mechanisms of resistance. ADCs have provided important treatment options for patients with breast cancer. As patients become eligible for more than one ADC, there is an unmet need to identify the appropriate timing and sequence of these therapies to maximize their efficacy.

References

Fu Z, Li S, Han S, Shi C, Zhang Y . Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022; 7(1):93. PMC: 8941077. DOI: 10.1038/s41392-022-00947-7. View

Khongorzul P, Ling C, Ullah Khan F, Ihsan A, Zhang J . Antibody-Drug Conjugates: A Comprehensive Review. Mol Cancer Res. 2019; 18(1):3-19. DOI: 10.1158/1541-7786.MCR-19-0582. View

Xiao T, Ali S, Mata D, Lohmann A, Blanchette P . Antibody-Drug Conjugates in Breast Cancer: Ascent to Destiny and Beyond-A 2023 Review. Curr Oncol. 2023; 30(7):6447-6461. PMC: 10378319. DOI: 10.3390/curroncol30070474. View

Peddi P, Hurvitz S . Trastuzumab emtansine: the first targeted chemotherapy for treatment of breast cancer. Future Oncol. 2013; 9(3):319-26. PMC: 3860880. DOI: 10.2217/fon.13.7. View

Verma S, Miles D, Gianni L, Krop I, Welslau M, Baselga J . Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367(19):1783-91. PMC: 5125250. DOI: 10.1056/NEJMoa1209124. View

Perez E, Barrios C, Eiermann W, Toi M, Im Y, Conte P . Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Cancer. 2019; 125(22):3974-3984. DOI: 10.1002/cncr.32392. View

Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T . 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(7):1039-46. PMC: 4946713. DOI: 10.1111/cas.12966. View

Modi S, Saura C, Yamashita T, Park Y, Kim S, Tamura K . Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019; 382(7):610-621. PMC: 7458671. DOI: 10.1056/NEJMoa1914510. View

Hurvitz S, Hegg R, Chung W, Im S, Jacot W, Ganju V . Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022; 401(10371):105-117. DOI: 10.1016/S0140-6736(22)02420-5. View

10.

Cortes J, Hurvitz S, Im S, Iwata H, Curigliano G, Kim S . Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024; 30(8):2208-2215. PMC: 11333275. DOI: 10.1038/s41591-024-03021-7. View

11.

Holthuis E, Vondeling G, Kuiper J, Dezentje V, Rosenlund M, Overbeek J . Real-world data of HER2-low metastatic breast cancer: A population based cohort study. Breast. 2022; 66:278-284. PMC: 9663525. DOI: 10.1016/j.breast.2022.11.003. View

12.

Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E . Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387(1):9-20. PMC: 10561652. DOI: 10.1056/NEJMoa2203690. View

13.

Franchina M, Pizzimenti C, Fiorentino V, Martini M, Ricciardi G, Silvestris N . Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes. Int J Mol Sci. 2023; 24(16). PMC: 10454084. DOI: 10.3390/ijms241612795. View

14.

Bardia A, Hu X, Dent R, Yonemori K, Barrios C, OShaughnessy J . Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024; 391(22):2110-2122. DOI: 10.1056/NEJMoa2407086. View

15.

Mosele F, Deluche E, Lusque A, Le Bescond L, Filleron T, Pradat Y . Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023; 29(8):2110-2120. PMC: 10427426. DOI: 10.1038/s41591-023-02478-2. View

16.

Tarantino P, Gandini S, Nicolo E, Trillo P, Giugliano F, Zagami P . Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022; 163:35-43. DOI: 10.1016/j.ejca.2021.12.022. View

17.

Geukens T, De Schepper M, Richard F, Maetens M, Van Baelen K, Mahdami A . Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer. Eur J Cancer. 2023; 188:152-160. DOI: 10.1016/j.ejca.2023.04.026. View

18.

Kopp A, Hofsess S, Cardillo T, Govindan S, Donnell J, Thurber G . Antibody-Drug Conjugate Sacituzumab Govitecan Drives Efficient Tissue Penetration and Rapid Intracellular Drug Release. Mol Cancer Ther. 2022; 22(1):102-111. PMC: 9812893. DOI: 10.1158/1535-7163.MCT-22-0375. View

19.

Rugo H, Bardia A, Marme F, Cortes J, Schmid P, Loirat D . Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022; 40(29):3365-3376. DOI: 10.1200/JCO.22.01002. View

20.

Iwai T, Sugimoto M, Wakita D, Yorozu K, Kurasawa M, Yamamoto K . Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies. Oncotarget. 2018; 9(59):31411-31421. PMC: 6101148. DOI: 10.18632/oncotarget.25830. View