抗体药物偶联物在转移性乳腺癌治疗中的研究进展

doi:10.3760/cma.j.cn371439-20231130-00063

摘要/Abstract

摘要：

抗体药物偶联物（ADC）可通过连接子将细胞毒性药物和针对肿瘤细胞靶点的抗体相结合，实现肿瘤精准靶向化疗。人表皮生长因子受体（HER）2靶点ADC恩美曲妥珠单抗及德曲妥珠单抗疗效卓越，已被批准为HER2阳性转移性乳腺癌的标准二线治疗药物。滋养层细胞表面抗原-2靶点ADC戈沙妥珠单抗在转移性三阴性乳腺癌治疗中疗效显著。其他如连接蛋白4、间皮素、LIV-1、受体酪氨酸激酶样孤儿受体、HER3靶点ADC疗效尚可，前景广阔。进一步探讨ADC在转移性乳腺癌治疗中的研究进展，可为ADC的应用和开发提供思路。

关键词: 乳腺肿瘤, 肿瘤转移, 分子靶向治疗, 抗体药物偶联物

Abstract:

Antibody-drug conjugate （ADC） couplings enable precise tumor targeted chemotherapy by combining cytotoxic drugs with antibodies against tumor cell targets via a linker. Trastuzumab emtansine and trastuzumab deruxtecan targeting human epidermal growth factor receptor （HER）2 are effective and have been approved as the standard second-line treatment for HER2-positive metastatic breast cancer. Sacituzumab govitecan targeting trophoblast cell surface antigen-2 has achieved remarkable efficacy in the treatment of metastatic triple-negative breast cancer. Other ADC that targeting Nectin-4， mesothelin， LIV-1， receptor tyrosine kinase-like orphan receptor， HER3， and other targets have reasonable efficacy and broad prospects. Further discussion on the research progress of ADC in the treatment of metastatic breast cancer can provide ideas for the application and development of ADC.

Key words: Breast neoplasms, Neoplasm metastasis, Molecular targeted therapy, Antibody-drug conjugate

王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.

Wang Ying, Liu Nan, Guo Bing. Advances of antibody-drug conjugate in the therapy of metastatic breast cancer[J]. Journal of International Oncology, 2024, 51(6): 364-369.

参考文献 37

[1]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: global statistics for 2020 and 2040[J]. Breast, 2022, 66: 15-23. DOI: 10.1016/j.breast.2022.08.010. pmid: 36084384
[3]	Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer[J]. Lancet, 2019, 394(10200): 793-804. DOI: 10.1016/S0140-6736(19)31774-X. pmid: 31478503
[4]	Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2017, 18(6): 732-742. DOI: 10.1016/S1470-2045(17)30312-1.
[5]	Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial[J]. Lancet Oncol, 2017, 18(6): 743-754. DOI: 10.1016/S1470-2045(17)30313-3.
[6]	Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase Ⅲ MARIANNE study[J]. J Clin Oncol, 2017, 35(2): 141-148. DOI: 10.1200/JCO.2016.67.4887.
[7]	Perez EA, Barrios C, Eiermann W, 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[J]. Cancer, 2019, 125(22): 3974-3984. DOI: 10.1002/cncr.32392. pmid: 31318460
[8]	Seagen Inc. A study of tucatinib vs. placebo in combination with ado-trastuzumab emtansine (T-DM1) for patients with advanced or metastatic HER2⁺ breast cancer[EB/OL]. [2023-12-30]. https://clinicaltrials.gov/search?cond=NCT03975647.
[9]	Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer[J]. N Engl J Med, 2020, 382(7): 610-621. DOI: 10.1056/NEJMoa1914510.
[10]	André F, Hee Park Y, Kim SB, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-breast02): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet, 2023, 401(10390): 1773-1785. DOI: 10.1016/S0140-6736(23)00725-0.
[11]	Hurvitz SA, Hegg R, Chung WP, 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[J]. Lancet, 2023, 401(10371): 105-117. DOI: 10.1016/S0140-6736(22)02420-5.
[12]	Gampenrieder SP, Rinnerthaler G, Tinchon C, et al. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-registry[J]. Breast Cancer Res, 2021, 23(1): 112. DOI: 10.1186/s13058-021-01492-x. pmid: 34906198
[13]	Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study[J]. Lancet Oncol, 2017, 18(11): 1512-1522. DOI: 10.1016/S1470-2045(17)30604-6.
[14]	Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1): 9-20. DOI: 10.1056/NEJMoa2203690.
[15]	Astra Z. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer[EB/OL]. [2023-12-30]. https://clinicaltrials.gov/search?cond=NCT04494425.
[16]	Zhang J, Liu R, Gao S, et al. Phase Ⅰ study of A166, an antibody-drug conjugate in advanced HER2-expressing solid tumours[J]. NPJ Breast Cancer, 2023, 9(1): 28. DOI: 10.1038/s41523-023-00522-5. pmid: 37072437
[17]	Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer[J]. N Engl J Med, 2021, 384(16): 1529-1541. DOI: 10.1056/NEJMoa2028485.
[18]	Rugo HS, Bardia A, Marmé F, 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[J]. Lancet, 2023, 402(10411): 1423-1433. DOI: 10.1016/S0140-6736(23)01245-X. pmid: 37633306
[19]	Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells[J]. Mol Cancer Ther, 2021, 20(12): 2329-2340. DOI: 10.1158/1535-7163.MCT-21-0206.
[20]	Bardia A, Krop IE, Kogawa T, et al. Datopotamab deruxtecan in advanced or metastatic HR⁺/HER2^- and triple-negative breast cancer: results from the phase Ⅰ TROPION-PanTumor01 study[J]. J Clin Oncol, 2024, 23: JCO2301909. DOI: 10.1200/JCO.23.01909.
[21]	Schmid P, Wysocki PJ, Ma CX, et al. Datopotamab deruxtecan (Dato-DXd)+durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ⅰb/Ⅱ study[J]. Ann Oncol, 2023, 34: S337. DOI: 10.1016/j.annonc.2023.09.556.
[22]	Liang K, Mei S, Gao X, et al. Dynamics of endocytosis and degradation of antibody-drug conjugate T-DM1 in HER2 positive cancer cells[J]. Drug Des Devel Ther, 2021, 15: 5135-5150. DOI: 10.2147/DDDT.S344052.
[23]	Rigby M, Bennett G, Chen L, et al. BT8009; a Nectin-4 targeting bicycle toxin conjugate for treatment of solid tumors[J]. Mol Cancer Ther, 2022, 21(12): 1747-1756. DOI: 10.1158/1535-7163.MCT-21-0875.
[24]	Wang H, Sun D, Chen J, et al. Nectin-4 has emerged as a compelling target for breast cancer[J]. Eur J Pharmacol, 2023, 960: 176129. DOI: 10.1016/j.ejphar.2023.176129.
[25]	Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial[J]. Lancet Oncol, 2021, 22(6): 872-882. DOI: 10.1016/S1470-2045(21)00094-2.
[26]	M-Rabet M, Cabaud O, Josselin E, et al. Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer[J]. Ann Oncol, 2017, 28(4): 769-776. DOI: 10.1093/annonc/mdw678. pmid: 27998973
[27]	Einama T, Yamagishi Y, Takihata Y, et al. Co-expression of mesothelin and CA125/MUC16 is a prognostic factor for breast cancer, especially in luminal-type breast cancer patients[J]. Biomark Res, 2021, 9(1): 78. DOI: 10.1186/s40364-021-00335-3.
[28]	Hassan R, Blumenschein GR Jr, Moore KN, et al. First-in-human, multicenter, phase Ⅰ dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors[J]. J Clin Oncol, 2020, 38(16): 1824-1835. DOI: 10.1200/JCO.19.02085.
[29]	de Nonneville A, Finetti P, Boudin L, et al. Prognostic and predictive value of LIV1 expression in early breast cancer and by molecular subtype[J]. Pharmaceutics, 2023, 15(3): 938. DOI: 10.3390/pharmaceutics15030938.
[30]	Sussman D, Smith LM, Anderson ME, et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer[J]. Mol Cancer Ther, 2014, 13(12): 2991-3000. DOI: 10.1158/1535-7163.MCT-13-0896. pmid: 25253783
[31]	Saravanan R, Balasubramanian V, Swaroop Balamurugan SS, et al. Zinc transporter LIV1: a promising cell surface target for triple negative breast cancer[J]. J Cell Physiol, 2022, 237(11): 4132-4156. DOI: 10.1002/jcp.30880. pmid: 36181695
[32]	Irmer B, Efing J, Reitnauer LE, et al. Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression[J]. Cell Commun Signal, 2023, 21(1): 171. DOI: 10.1186/s12964-023-01186-1. pmid: 37430307
[33]	Zhang S, Zhang H, Ghia EM, et al. Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody[J]. Proc Natl Acad Sci U S A, 2019, 116(4): 1370-1377. DOI: 10.1073/pnas.1816262116.
[34]	Tolcher AW, Meric-Bernstam F, McKean M, et al. NBE-002: a novel anthracycline-based antibody-drug conjugate (ADC) targe-ting ROR1 for the treatment of advanced solid tumors—a phase 1/2 clinical trial[J]. J Clin Oncol, 2021, 39(15_suppl): TPS1108-TPS1108. DOI: 10.1200/JCO.2021.39.15_suppl.TPS1108.
[35]	Menck K, Heinrichs S, Wlochowitz D, et al. WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer[J]. J Exp Clin Cancer Res, 2021, 40(1): 395. DOI: 10.1186/s13046-021-02187-z. pmid: 34911552
[36]	Hanker AB, Brown BP, Meiler J, et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity[J]. Cancer Cell, 2021, 39(8): 1099-1114.e8. DOI: 10.1016/j.ccell.2021.06.001. pmid: 34171264
[37]	Krop IE, Masuda N, Mukohara T, 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]. J Clin Oncol, 2023, 41(36): 5550-5560. DOI: 10.1200/JCO.23.00882.