OtherPerspective
Open Access

Antibody-drug conjugates in breast cancer: advances and prospects

Zhiqiang Shi, Yongjin Lu, Qiuchen Zhao, Yongsheng Wang and Pengfei Qiu
Cancer Biology & Medicine February 2025, 22 (2) 83-92; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0486

References

  1. 1.↵
    2. Bray F,
    3. Laversanne M,
    4. Sung H,
    5. Ferlay J,
    6. Siegel RL,
    7. Soerjomataram I, et al.
    Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74: 229–63.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Joubert N,
    3. Beck A,
    4. Dumontet C,
    5. Denevault-Sabourin C.
    Antibody-drug conjugates: the last decade. Pharmaceuticals (Basel). 2020; 13: 245.
    OpenUrlPubMed
  3. 3.↵
    2. Schlam I,
    3. Moges R,
    4. Morganti S,
    5. Tolaney SM,
    6. Tarantino P.
    Next-generation antibody-drug conjugates for breast cancer: moving beyond HER2 and TROP2. Crit Rev Oncol Hematol. 2023; 190: 104090.
  4. 4.↵
    2. Verma S,
    3. Miles D,
    4. Gianni L,
    5. Krop IE,
    6. Welslau M,
    7. Baselga J, et al.
    Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367: 1783–9.
    OpenUrlCrossRefPubMedWeb of Science
  5. 5.↵
    2. Hurvitz SA,
    3. Hegg R,
    4. Chung WP,
    5. Im SA,
    6. Jacot W,
    7. Ganju V, et al.
    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. 2023; 401: 105–17.
    OpenUrlCrossRefPubMed
  6. 6.↵
    2. Harbeck N,
    3. Ciruelos E,
    4. Jerusalem G,
    5. Müller V,
    6. Niikura N,
    7. Viale G, et al.
    Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024; 30: 3717–27.
    OpenUrlPubMed
  7. 7.↵
    2. Rugo HS,
    3. Bardia A,
    4. Marmé F,
    5. Cortés J,
    6. Schmid P,
    7. Loirat D, et al.
    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. Lancet. 2023; 402: 1423–33.
    OpenUrlPubMed
  8. 8.↵
    2. Bardia A,
    3. Rugo HS,
    4. Tolaney SM,
    5. Loirat D,
    6. Punie K,
    7. Oliveira M, et al.
    Final results from the randomized phase III ASCENT clinical trial in metastatic triple-negative breast cancer and association of outcomes by human epidermal growth factor receptor 2 and trophoblast cell surface antigen 2 expression. J Clin Oncol. 2024; 42: 1738–44.
    OpenUrlPubMed
  9. 9.↵
    2. Xu B,
    3. Wang S,
    4. Yan M,
    5. Sohn J,
    6. Li W,
    7. Tang J, et al.
    Sacituzumab govitecan in HR+HER2− metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024; 30: 3709–16.
    OpenUrlPubMed
  10. 10.↵
    2. Xu B,
    3. Ma F,
    4. Wang T,
    5. Wang S,
    6. Tong Z,
    7. Li W, et al.
    A phase IIb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments. Int J Cancer. 2023; 152: 2134–44.
    OpenUrlPubMed
  11. 11.↵
    2. von Minckwitz G,
    3. Huang CS,
    4. Mano MS,
    5. Loibl S,
    6. Mamounas EP,
    7. Untch M, et al.
    Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019; 380: 617–28.
    OpenUrlCrossRefPubMed
  12. 12.↵
    Daiichi Sankyo. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05) [ClinicalTrials.gov ID]. Available from: https://clinicaltrials.gov/study/NCT04622319, 2024.
  13. 13.↵
    2. Gianni L,
    3. Pienkowski T,
    4. Im YH,
    5. Tseng LM,
    6. Liu MC,
    7. Lluch A, et al.
    5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016; 17: 791–800.
    OpenUrlCrossRefPubMed
  14. 14.↵
    AstraZeneca. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer [ClinicalTrials.gov ID]. Available from: https://clinicaltrials.gov/study/NCT05113251, 2024.
  15. 15.↵
    2. Spring LM,
    3. Tolaney SM,
    4. Fell G,
    5. Bossuyt V,
    6. Abelman RO,
    7. Wu B, et al.
    Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial. Ann Oncol. 2024; 35: 293–301.
    OpenUrlPubMed
  16. 16.↵
    2. Modi S,
    3. Jacot W,
    4. Yamashita T,
    5. Sohn J,
    6. Vidal M,
    7. Tokunaga E, et al.
    Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022; 387: 9–20.
    OpenUrlCrossRefPubMed
  17. 17.↵
    2. Bardia A,
    3. Hu X,
    4. Dent R,
    5. Yonemori K,
    6. Barrios CH,
    7. O’Shaughnessy JA, et al.
    Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024; 391: 2110–22.
    OpenUrlPubMed
  18. 18.↵
    2. Dieci MV,
    3. Miglietta F,
    4. Griguolo G,
    5. Guarneri V.
    Biomarkers for HER2-positive metastatic breast cancer: beyond hormone receptors. Cancer Treat Rev. 2020; 88: 102064.
  19. 19.
    2. Koyama K,
    3. Ishikawa H,
    4. Abe M,
    5. Shiose Y,
    6. Ueno S,
    7. Qiu Y, et al.
    Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression. PLoS One. 2022; 17: e0267027.
  20. 20.
    2. Alves FR,
    3. Gil L,
    4. Vasconcelos de Matos L,
    5. Baleiras A,
    6. Vasques C,
    7. Neves MT, et al.
    Impact of human epidermal growth factor receptor 2 (HER2) low status in response to neoadjuvant chemotherapy in early breast cancer. Cureu. 2022; 14: e22330.
  21. 21.↵
    2. Tarantino P,
    3. Jin Q,
    4. Tayob N,
    5. Jeselsohn RM,
    6. Schnitt SJ,
    7. Vincuilla J, et al.
    Prognostic and biologic significance of ERBB2-low expression in early-stage breast cancer. JAMA Oncol. 2022; 8: 1177–83.
    OpenUrlPubMed
  22. 22.↵
    2. Cherifi F,
    3. Da Silva A,
    4. Johnson A,
    5. Blanc-Fournier C,
    6. Abramovici O,
    7. Broyelle A, et al.
    HELENA: HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer. BMC Cancer. 2022; 22: 1081.
    OpenUrlCrossRefPubMed
  23. 23.↵
    2. Filho OM,
    3. Viale G,
    4. Stein S,
    5. Trippa L,
    6. Yardley DA,
    7. Mayer IA, et al.
    Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov. 2021; 11: 2474–87.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    2. Phillips GD,
    3. Fields CT,
    4. Li G,
    5. Dowbenko D,
    6. Schaefer G,
    7. Miller K, et al.
    Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res. 2014; 20: 456–68.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    2. Bon G,
    3. Pizzuti L,
    4. Laquintana V,
    5. Loria R,
    6. Porru M,
    7. Marchiò C, et al.
    Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER study. J Exp Clin Cancer Res. 2020; 39: 279.
    OpenUrlPubMed
  26. 26.↵
    2. Mosele F,
    3. Deluche E,
    4. Lusque A,
    5. Le Bescond L,
    6. Filleron T,
    7. Pradat Y, et al.
    Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023; 29: 2110–20.
    OpenUrlCrossRefPubMed
  27. 27.↵
    2. Sung M,
    3. Tan X,
    4. Lu B,
    5. Golas J,
    6. Hosselet C,
    7. Wang F, et al.
    Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1). Mol Cancer Ther. 2018; 17: 243–53.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    2. Nilsson MB,
    3. Poteete A,
    4. Udagawa H,
    5. Yu XX,
    6. He JQ,
    7. Le XN, et al.
    Trastuzumab deruxtecan resistance is associated with reduced responsiveness to topoisomerase inhibitors (payload resistance) but no reduction in sensitivity to HER2 tyrosine kinase inhibitors. 2023 AACR. Cancer Res. 2023; 83: Abstract 383.
  29. 29.↵
    2. Coates JT,
    3. Sun S,
    4. Leshchiner I,
    5. Thimmiah N,
    6. Martin EE,
    7. McLoughlin D, 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: 2436–45.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    2. López-Miranda E,
    3. Pérez-García JM,
    4. Di Cosimo S,
    5. Brain E,
    6. Ravnik M,
    7. Escrivá-de-Romaní S, et al.
    Trastuzumab emtansine plus non-pegylated liposomal doxorubicin in HER2-positive metastatic breast cancer (Thelma): a single-arm, multicenter, phase Ib trial. Cancers (Basel). 2020; 12: 3509.
    OpenUrlPubMed
  31. 31.↵
    2. Krop IE,
    3. Modi S,
    4. LoRusso PM,
    5. Pegram M,
    6. Guardino E,
    7. Althaus B, et al.
    Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res. 2016; 18: 34.
    OpenUrlPubMed
  32. 32.↵
    2. Krop IE,
    3. Im SA,
    4. Barrios C,
    5. Bonnefoi H,
    6. Gralow J,
    7. Toi M, et al.
    Trastuzumab emtansine plus pertuzumab versus taxane plus trastuzumab plus pertuzumab after anthracycline for high-risk human epidermal growth factor receptor 2-positive early breast cancer: the phase Ⅲ KAITLIN study. J Clin Oncol. 2022; 40: 438–48.
    OpenUrlPubMed
  33. 33.
    2. Hurvitz SA,
    3. Martin M,
    4. Jung KH,
    5. Huang CS,
    6. Harbeck N,
    7. Valero V, et al.
    Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE study. J Clin Oncol. 2019; 37: 2206–16.
    OpenUrlCrossRefPubMed
  34. 34.↵
    2. Perez EA,
    3. Barrios C,
    4. Eiermann W,
    5. Toi M,
    6. Im YH,
    7. Conte P, et al.
    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: 3974–84.
    OpenUrlPubMed
  35. 35.↵
    2. Andre F,
    3. Hamilton EP,
    4. Loi S,
    5. Anders CK,
    6. Schmid P,
    7. Stroyakovskiy D, et al.
    DESTINY-Breast07: dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 1009.
  36. 36.↵
    AstraZeneca. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09) [ClinicalTrials.gov ID]. Available https://clinicaltrials.gov/study/NCT04784715, 2024.
  37. 37.↵
    2. Hurvitz S,
    3. Loi S,
    4. O’shaughnessy J,
    5. Okines A,
    6. Tolaney S,
    7. Sohn JH, et al.
    HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. 2024; 84: SABCS GS01-10.
  38. 38.↵
    2. Freedman RA,
    3. Heiling HM,
    4. Li T,
    5. Trapani D,
    6. Tayob N,
    7. Smith KL, et al.
    Neratinib and ado-trastuzumab-emtansine for pre-treated and untreated HER2-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium Trial 022. Ann Oncol. 2024; 35: 993–1002.
    OpenUrlPubMed
  39. 39.↵
    2. Emens LA,
    3. Esteva FJ,
    4. Beresford M,
    5. Saura C,
    6. De Laurentiis M,
    7. Kim SB, et al.
    Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020; 21: 1283–95.
    OpenUrlCrossRefPubMed
  40. 40.↵
    2. Roche HL.
    A study of trastuzumab emtansine in combination with atezolizumab or placebo as a treatment for participants with human epidermal growth factor 2 (HER2)-positive and programmed death-ligand 1 (PD-L1)-positive locally advanced (LABC) or metastatic breast cancer (MBC) (KATE3) [ClinicalTrials.gov ID]. Available from: https://clinicaltrials.gov/study/NCT04740918, 2024.
  41. 41.↵
    2. Garido-Castrot AC,
    3. Kim SE,
    4. Desrosiers J,
    5. Nanda R,
    6. Carey LA,
    7. Clark AS, et al.
    SACI-0 HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract LBA1004.
  42. 42.↵
    2. Khoury K,
    3. Meisel JL,
    4. Yau C,
    5. Rugo HS,
    6. Nanda R,
    7. Davidian M, et al.
    Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nat Med. 2024; 30: 3728–36.
    OpenUrlPubMed
  43. 43.↵
    2. Shatsky RA,
    3. Trivedi MS,
    4. Yau C,
    5. Nanda R,
    6. Rugo HS,
    7. Davidian M, et al.
    Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nat Med. 2024; 30: 3737–47.
    OpenUrlPubMed
  44. 44.↵
    AstraZeneca. A phase III randomised study to evaluate Dato-DXd and durvalumab for neoadjuvant/adjuvant treatment of triple-negative or hormone receptor-low/HER2-negative breast cancer [ClinicalTrials.gov ID]. Available from: https://clinicaltrials.gov/study/NCT06112379, 2024.
  45. 45.↵
    2. Hu XC,
    3. Wang LP,
    4. Zhang J,
    5. Zhang QY,
    6. Ouyang QC,
    7. Wang XJ, et al.
    ACE-Breast-02: a pivotal phase II/III trial of ARX788, a novel anti-HER2 antibody-drug conjugate (ADC), versus lapatinib plus capecitabine for HER2+ advanced breast cancer (ABC). 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 1020.
  46. 46.↵
    2. Bardia A,
    3. Jhaveri K,
    4. Im SA,
    5. Pernas S,
    6. De Laurentiis M,
    7. Wang S, et al.
    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 Oncol. 2025; 43: 285–96.
    OpenUrlPubMed
  47. 47.↵
    2. Jhaveri K,
    3. Bardia A,
    4. Im S,
    5. Simon SP,
    6. Laurentiis MD,
    7. Wang S, et al.
    LBA2 – Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in pretreated, inoperable/metastatic HR+/HER2− breast cancer (BC): additional safety analysis from TROPION-Breast01. 2024 ESMO BC. Ann Oncol. 2024; 9: 1–47.
    OpenUrl
  48. 48.↵
    2. Pernas S,
    3. Im S,
    4. Hattori M,
    5. Xu BH,
    6. Wang SS,
    7. Lu YS, et al.
    Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer: patient-reported outcomes (PROs) from theTROPION-Breast01 study. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 1006.
  49. 49.↵
    2. Xu BH,
    3. Yin YM,
    4. Fan Y,
    5. Ouyang QC,
    6. Song LH,
    7. Wang XJ, et al.
    Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): results from the phase III OptiTROP-Breast01 study. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 104.
  50. 50.↵
    2. Krop IE,
    3. Masuda N,
    4. Mukohara T,
    5. Takahashi S,
    6. Nakayama T,
    7. Inoue K, et al.
    Patritumab deruxtecan (HER3-DXd), a human epidermal growth factor receptor 3-directed antibody-drug conjugate, in patients with previously treated human epidermal growth factor receptor 3-expressing metastatic breast cancer: a multicenter, phase I/II trial. J Clin Oncol. 2023; 41: 5550–60.
    OpenUrlPubMed
  51. 51.↵
    2. Pistilli B,
    3. Ibrahimi N,
    4. Lacroix-Triki M,
    5. Vicier C,
    6. Frenel JS,
    7. D’Hondt V, et al.
    340O – Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 study of patritumab deruxtecan (HER3-DXd) in patients (pts) with HR+/HER2− advanced breast cancer (ABC). 2024 ESMO. Ann Oncol. 2024; 35: S357–405.
    OpenUrl
  52. 52.↵
    2. Giordano A,
    3. Awan AA,
    4. Bruce JY,
    5. Rugo HS,
    6. Diamond JR,
    7. Novik Y, et al.
    Enfortumab vedotin in the HR+/HER2− and triple-negative breast cancer cohorts of EV-202. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 1005.
  53. 53.↵
    2. Liu XJ,
    3. Zhang J,
    4. Shen L,
    5. Liu JQ,
    6. Huang J,
    7. Zhuang ZX, et al.
    Evaluation of the safety, pharmacokinetics, and efficacy of JSKN003 in patients with advanced solid tumors: a phase I/II clinical study. 2024 ASCO. J Clin Oncol. 2024; 42: Abstract 3031.
Back to top

In this issue

Print
Download PDF
Email Article
Citation Tools

Jump to section

Subjects