TROP2-targeting antibody–drug conjugates in breast cancer and ovarian carcinoma: therapeutic advances and resistance mechanisms

Abstract

Antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) have emerged as a promising therapeutic strategy for the treatment of triple-negative breast cancer (TNBC) and ovarian carcinoma, two malignancies characterized by poor prognosis and limited therapeutic options. ADCs are complex molecules that combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents, enabling selective delivery of drugs to tumor cells while minimizing systemic toxicity. Recent advances in ADC technology have led to the development of several TROP2-targeting agents, including sacituzumab govitecan and datopotamab deruxtecan, which have demonstrated significant efficacy and acceptable safety in patients with advanced or treatment-resistant TNBC and ovarian carcinoma. Clinical trials have reported improvements in progression-free and overall survival, as well as objective response rates, compared to standard therapies. However, emerging evidence indicates that both primary and acquired resistance mechanisms may limit the long-term efficacy of these agents. Current research efforts are focused on elucidating these resistance pathways, optimizing combination strategies with immunotherapy and targeted agents, and expanding the application of TROP2-targeting ADCs to other tumor types. The integration of biomarker-driven patient selection and next-generation ADC technologies offers new opportunities to overcome resistance and enhance clinical benefit. This review provides a comprehensive overview of the development, clinical implementation, and resistance mechanisms of TROP2-targeting ADCs in TNBC and ovarian carcinoma, underscoring their potential to reshape the therapeutic landscape of these challenging cancers.

Keywords

ADC resistance / TROP2 / breast cancer / ovarian carcinoma

References

[1] Long R,Tang G.Antibody-drug conjugates in cancer therapy: applications and future advances.Front Immunol2025;16:1516419 PMCID:PMC12133739

[2] Agelidis A,Jaloudi M.Triple-negative breast cancer on the rise: breakthroughs and beyond.Breast Cancer2025;17:523-9 PMCID:PMC12209529

[3] Zhu Y,Liu Y,Sun X.Prognostic value of systemic inflammatory markers in ovarian cancer: a PRISMA-compliant meta-analysis and systematic review.BMC Cancer2018;18:443 PMCID:PMC5907305

[4] Narayana RVL.Exploring the therapeutic use and outcome of antibody-drug conjugates in ovarian cancer treatment.Oncogene2025;44:2343-56 PMCID:PMC12229892

[5] Davis AA,Pereira PMR.Novel treatment approaches utilizing antibody-drug conjugates in breast cancer.NPJ Breast Cancer2025;11:42 PMCID:PMC12075872

[6] Zhang X,Na F.Evolution of TROP2: biological insights and clinical applications.Eur J Med Chem2025;296:117863

[7] Bujnak AC,Tewari K.Clinical applications of antibody drug conjugates for gynecologic malignancies: review of available medicines and emerging therapeutics.Gynecol Oncol2025;195:180-91

[8] Dri A,Bianchini G.Breaking barriers in triple negative breast cancer (TNBC) - unleashing the power of antibody-drug conjugates (ADCs).Cancer Treat Rev2024;123:102672

[9] Fenton MA,Graff SL.Sequencing antibody drug conjugates in breast cancer: exploring future roles.Curr Oncol2023;30:10211-23 PMCID:PMC10742750

[10] Gupta G,Pant K,Thapa R.Antibody-drug conjugates (ADCs): a novel therapy for triple-negative breast cancer (TNBC).Curr Cancer Drug Targets2025;25:108-12

[11] García-Illescas D,García-Durán C.The evolving landscape of antibody-drug conjugates in ovarian cancer: new drugs for a new era.Curr Opin Obstet Gynecol2024;36:104-11

[12] Veneziani AC,Oza AM.Antibody-drug conjugates: advancing from magic bullet to biological missile.Clin Cancer Res2024;30:1434-7

[13] Beck A,Dumontet C.Strategies and challenges for the next generation of antibody-drug conjugates.Nat Rev Drug Discov2017;16:315-37

[14] Younes A,Smith SE.Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma.J Clin Oncol2012;30:2183-9 PMCID:PMC3646316

[15] Dennis N,Livings C.Quality-adjusted time without symptoms or toxicity analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2- positive metastatic breast cancer patients based on secondary use of the DESTINY-Breast03 trial.Eur J Cancer2025;217:115192

[16] Wen M,Park Y,Gerber HP.Homogeneous antibody-drug conjugates with dual payloads: potential, methods and considerations.MAbs2025;17:2498162 PMCID:PMC12054377

[17] Murase Y,Ueda T.Mechanisms of resistance to antibody-drug conjugates in cancers.Respir Investig2025;63:693-8

[18] Saleh K,Khalife N.Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer.Cancer Drug Resist2024;7:22 PMCID:PMC11267152

[19] Loganzo F,Gerber HP.Mechanisms of resistance to antibody-drug conjugates.Mol Cancer Ther2016;15:2825-34

[20] Monteiro MR,Junior AADS.Antibody-drug conjugates in breast cancer: a comprehensive review of how to selectively deliver payloads.Breast Cancer2024;16:51-70 PMCID:PMC10909371

[21] García-Alonso S,Pandiella A.Resistance to antibody-drug conjugates.Cancer Res2018;78:2159-65

[22] Hafeez U,Gan HK.Antibody-drug conjugates for cancer therapy.Molecules2020;25:4764 PMCID:PMC7587605

[23] Li G,Shen BQ.Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells.Mol Cancer Ther2018;17:1441-53

[24] Larose ÉA,Yu S,Yi Z.Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing.Cancer Drug Resist2025;8:11 PMCID:PMC11977375

[25] Kinneer K,Tiberghien AC.SLC46A3 as a potential predictive biomarker for antibody-drug conjugates bearing noncleavable linked maytansinoid and pyrrolobenzodiazepine warheads.Clin Cancer Res2018;24:6570-82

[26] Coates JT,Leshchiner I.Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer.Cancer Discov2021;11:2436-45 PMCID:PMC8495771

[27] Glaviano A,Baird RD.Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.Drug Resist Updat2024;76:101103

[28] Haag P,Lindberg ML,Lewensohn R.Deficient activation of Bak and Bax confers resistance to gemtuzumab ozogamicin-induced apoptotic cell death in AML.Exp Hematol2009;37:755-66

[29] Zou Y,Chen B.crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.Drug Resist Updat2024;77:101126

[30] Rosen DB,Cordeiro JA.AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.PLoS One2013;8:e53518 PMCID:PMC3539972

[31] Zhang L.Metabolic control of CD8⁺ T cell fate decisions and antitumor immunity.Trends Mol Med2018;24:30-48

[32] Chen YF,Shao ZM.Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions.Cancer Commun2023;43:297-337 PMCID:PMC10009672

[33] Kepp O.Immunogenic cell death and bystander killing: expanding the therapeutic potential of modern antibody-drug conjugates.Oncoimmunology2025;14:2533488 PMCID:PMC12269677

[34] Bosch A,Zaragoza R,Lluch A.Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research.Cancer Treat Rev2010;36:206-15

[35] Guven DC,Kus F.Optimal adjuvant treatment strategies for TNBC patients with residual disease after neoadjuvant treatment.Expert Rev Anticancer Ther2023;23:1049-59

[36] Zou Y,Chen P.Clinical approaches to overcome PARP inhibitor resistance.Mol Cancer2025;24:156 PMCID:PMC12123805

[37] Gao Y,Wang CC.Novel ATR/PARP1 dual inhibitors demonstrate synergistic antitumor efficacy in triple-negative breast cancer models.Adv Sci2025;12:e01916 PMCID:PMC12362783

[38] Ye F,Li Y.Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer.Mol Cancer2023;22:105 PMCID:PMC10324146

[39] Gbadamosi MO,Makarem MS,Ohaegbulam AC.Chemoimmunomodulation in triple negative breast cancer: a key to maximizing anti-PD-1 chemoimmunotherapeutic efficacy.Oncoimmunology2025;14:2527303 PMCID:PMC12243914

[40] Bao W.Efficacy and safety of neoadjuvant chemotherapy containing anti-angiogenic drugs, immunotherapy, or PARP inhibitors for ovarian cancer.Crit Rev Oncol Hematol2024;194:104238

[41] Aslan M,Garcia-Marques FJ.Oncogene-mediated metabolic gene signature predicts breast cancer outcome.NPJ Breast Cancer2021;7:141 PMCID:PMC8553750

[42] Bignotti E,Calza S.Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients.Eur J Cancer2010;46:944-53

[43] Khan S,Bushara NZA.Targeting refractory triple-negative breast cancer with sacituzumab govitecan: a new era in precision medicine.Cells2024;13:2126 PMCID:PMC11674573

[44] Qureshi Z,Altaf F.Revolutionizing triple-negative metastatic breast cancer treatment: sacituzumab Govitecan’s role in advancing chemotherapy.Ann Med Surg2024;86:5314-9 PMCID:PMC11374285

[45] Rugo HS,Marmé F.Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.Lancet2023;402:1423-33

[46] Bardia A,Barrios C.275TiP ASCENT-03: phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in first-line (1L) metastatic triple-negative breast cancer (mTNBC).Ann Oncol2022;33:S663-4

[47] Marmé F,Furlanetto J.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 Oncol2022;33:S148-9

[48] Paz-Ares LG,Mountzios GS.Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study.J Clin Oncol2024;42:2860-72 PMCID:PMC11328920

[49] Santin AD,Spira A.Efficacy and safety of sacituzumab govitecan in patients with advanced solid tumors (TROPiCS-03): analysis in patients with advanced endometrial cancer.J Clin Oncol2024;42:3421-9 PMCID:PMC11458108

[50] Perrone E,Zeybek B.Preclinical activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) linked to the active metabolite of irinotecan (SN-38), in ovarian cancer.Front Oncol2020;10:118 PMCID:PMC7028697

[51] Greenman M,Demirkiran C,Santin AD.Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.Gynecol Oncol Rep2024;54:101459 PMCID:PMC11300917

[52] Bardia A,Kogawa T.Datopotamab deruxtecan in advanced or metastatic HR+/HER2- and triple-negative breast cancer: results from the phase I TROPION-PanTumor01 study.J Clin Oncol2024;42:2281-94 PMCID:PMC11210948

[53] Okajima D,Maejima T.Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells.Mol Cancer Ther2021;20:2329-40 PMCID:PMC9398094

[54] Schipilliti FM,Mazzuca F,Guven DC.Datopotamab deruxtecan: a novel antibody drug conjugate for triple-negative breast cancer.Heliyon2024;10:e28385 PMCID:PMC10981107

[55] Oaknin A,Rha S.714MO Datopotamab deruxtecan (Dato-DXd) in patients with endometrial (EC) or ovarian cancer (OC): results from the phase II TROPION-PanTumor03 study.Ann Oncol2024;35:S547-8

[56] Bardia A, Jhaveri K, Im SA, et al.; TROPION-Breast01 Investigators. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: primary results from TROPION-Breast01.J Clin Oncol2025;43:285-96 PMCID:PMC11771365

[57] Dent RA,Bachelot T.TROPION-Breast02: datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.Future Oncol2023;19:2349-59

[58] Cheng Y,Tian Q.Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132.Front Oncol2022;12:951589 PMCID:PMC9817100

[59] Lorusso D,Martin-Babau J.793TiP A phase III, randomized, open-label, multicenter study of sacituzumab tirumotecan (sac-TMT) monotherapy vs treatment of physician’s choice chemotherapy in patients with endometrial cancer who have received prior chemotherapy and immunotherapy: ENGOT-en23/GOG-3095/MK-2870-005.Ann Oncol2024;35:S592

[60] Ouyang Q,Liang Y.Results of a phase 1/2 study of sacituzumab tirumotecan in patients with unresectable locally advanced or metastatic solid tumors refractory to standard therapies.J Hematol Oncol2025;18:61 PMCID:PMC12142944

[61] Yap T,Bauer T.547P Rucaparib + sacituzumab govitecan (SG): initial data from the phase Ib/II SEASTAR study (NCT03992131).Ann Oncol2020;31:S476-7

[62] Bardia A,Thimmiah N.Antibody-drug conjugate sacituzumab govitecan enables a sequential TOP1/PARP inhibitor therapy strategy in patients with breast cancer.Clin Cancer Res2024;30:2917-24 PMCID:PMC11247314

[63] Seneviratne LC,Blau S.Trilaciclib combined with sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC): updated phase 2 safety and efficacy results.J Clin Oncol2024;42:1091

[64] Rainey N,Chiu J.A phase 2 randomized study of magrolimab combination therapy in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): ELEVATE-TNBC.J Clin Oncol2023;41:TPS1130

[65] Spring LM,Fell G.Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial.Ann Oncol2024;35:293-301

[66] Tolaney SM,Kalinsky K.Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study.J Clin Oncol2025;43:LBA109

[67] Tolaney SM,Takano T.OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.Future Oncol2024;20:2343-55 PMCID:PMC11520537

[68] Schmid P,De la Cruz Merino L.181O Interim analysis (IA) of the atezolizumab (atezo) + sacituzumab govitecan (SG) arm in patients (pts) with triple-negative breast cancer (TNBC) in MORPHEUS-pan BC: a phase Ib/II study of multiple treatment (tx) combinations in pts with locally advanced/metastatic BC (LA/mBC).ESMO Open2024;9:103203

[69] Sharma P,Yoder R.Results of a phase I study of alpelisib and sacituzumab govitecan (SG) in patients with HER2-negative metastatic breast cancer (MBC).J Clin Oncol2025;43:1094

[70] Kier MW,Blank SV.A single-center, open-label, single-arm, phase I study with dose expansion cohort of sacituzumab govitecan in combination with cisplatin for patients with platinum sensitive recurrent ovarian and endometrial cancer.J Clin Oncol2025;43:TPS5623

[71] Dowlati A,Lorusso P.439TiP AVZO-021-1001: a first-in-human open-label, multicenter phase I/II dose-escalation and expansion study evaluating AVZO-021 in adult patients with advanced solid tumors.Ann Oncol2024;35:S405

[72] Schmid P,Armstrong A.BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC) - initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd).J Clin Oncol2021;39:1023

[73] Bardia A,Albain K.TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.Ther Adv Med Oncol2024;16:17588359241248336 PMCID:PMC11057345

[74] Schmid P,O’Shaughnessy J.TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer.Ther Adv Med Oncol2025;17:17588359251327992 PMCID:PMC12035291

[75] McArthur HL,Dent R.TROPION-Breast04: a randomized phase III study of neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by adjuvant durvalumab versus standard of care in patients with treatment-naïve early-stage triple negative or HR-low/HER2- breast cancer.Ther Adv Med Oncol2025;17:17588359251316176 PMCID:PMC11800260

[76] Wang J,Huang Y.716MO Efficacy and safety of sacituzumab tirumotecan (sac-TMT) plus pembrolizumab in patients with recurrent or metastatic cervical cancer.Ann Oncol2024;35:S548-9