Research advances in targeted drug therapy and drug resistance mechanisms for breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YUAN Shuanglong ¹ , JIA Lizhou ² ,  ZHOU Yi ³

1. Department of Thyroid and Breast Surgery, Bayannur Hospital, Bayannur, Inner Mongolia 015000, P. R. China;
2. Central Laboratory, Bayannur Hospital, Bayannur, Inner Mongolia 015000, P. R. China;
3. Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P. R. China;

Corresponding author：

ZHOU Yi, Email: lubj2001@163.com

Keywords：

targeted therapy drugs; drug resistance mechanism; breast cancer; treatment strategy

DOI：

10.7507/1007-9424.202504123

Video：

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Objective To systematically elucidate the resistance mechanism of targeted drug therapy for breast cancer and to discuss the future direction of optimized treatment strategies. Method A literature review on targeted therapy for breast cancer had been conducted based on recent domestic and international researches. Results Contemporary breast cancer targeted therapies maincomprised human epidermal growth factor receptor 2 (HER2)-directed agents, CDK4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) / mechanistic target of rapamycin (mTOR) pathway blockers, poly (ADP-ribose) polymerase inhibitors, and immune checkpoint modulators, etc. While these agents conferred subtype-specific survival benefits, resistance developed through target mutations, compensatory signaling, epigenetic alterations, drug efflux pumps, etc. Emerging reversal drug resistance strategies involved dual-targeted approaches (such as trastuzumab in combination with pertuzumab), dynamic monitoring of drug-resistant gene mutations by liquid biopsy, epigenetic modulators, etc. Conclusions Drug resistance remains a key bottleneck limiting long-term efficacy of breast cancer targeted therapy. Future research should integrate multi-omics approaches to decipher tumor heterogeneity, implement combinatorial multi-target inhibition with real-time monitoring of multidimensional interventions, and leverage artificial intelligence to predict resistance evolution. This integrated strategy will enable personalized combination therapies, ultimately overcoming drug resistance and improving patient survival outcomes.

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1. 邬昊, 吕青. 全球及中国乳腺癌的流行病学趋势及防控启示: 2018–2022年《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(7): 796-802.
2. Maqsood Q, Khan MU, Fatima T, et al. Recent insights into breast cancer: molecular pathways, epigenetic regulation, and emerging targeted therapies. Breast Cancer (Auckl), 2025, 19: 11782234251355663. doi: 10.1177/11782234251355663.
3. 张一鸣, 田辛晨, 王宇飞, 等. 基于分子分型的乳腺癌中医精准辨治思路探讨. 北京中医药大学学报, 2023, 46(7): 1025-1031.
4. 杨晓静, 徐溢, 沈赞. 抗HER2靶向治疗的耐药机制及治疗新策略. 肿瘤, 2023, 43(7): 580-597.
5. Khan MM, Yalamarty SSK, Rajmalani BA, et al. Recent strategies to overcome breast cancer resistance. Crit Rev Oncol Hematol, 2024, 197: 104351. doi: 10.1016/j.critrevonc.2024.104351.
6. Ryspayeva D, Seyhan AA, MacDonald WJ, et al. Signaling pathway dysregulation in breast cancer. Oncotarget, 2025, 16: 168-201.
7. Singla H, Ludhiadch A, Kaur RP, et al. Recent advances in HER2 positive breast cancer epigenetics: susceptibility and therapeutic strategies. Eur J Med Chem, 2017, 142: 316-327.
8. 吴悠, 戴建国. HER2阳性乳腺癌靶向治疗的研究进展. 中国临床新医学, 2024, 17(10): 1183-1186.
9. Vega Cano KS, Marmolejo Castañeda DH, et al. Systemic therapy for HER2-positive metastatic breast cancer: current and future trends. Cancers (Basel), 2022, 15(1): 51. doi: 10.3390/cancers15010051.
10. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med, 2012, 366(2): 109-119.
11. 艾林, 张清媛. T-DM1治疗晚期HER2阳性乳腺癌耐药机制的研究进展. 现代肿瘤医学, 2025, 1-7.5-08-05.
12. Ma F, Yan M, Li W, et al. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): Randomised, double blind, multicentre, phase 3 trial. BMJ, 2023, 383: e076065. doi: 10.1136/bmj-2023-076065.
13. Cheng X, Sun Y, Highkin M, et al. Breast cancer mutations HER2V777L and PIK3CAH1047R activate the p21-CDK4/6-cyclin D1 axis to drive tumorigenesis and drug resistance. Cancer Res, 2023, 83(17): 2839-2857.
14. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2017, 18(12): 1688-1700.
15. 曹萌, 刘相麟, 刘喆赢, 等. 汉曲优^®与帕妥珠单抗联合化疗新辅助治疗HER-2阳性乳腺癌疗效和安全评价. 中国临床研究, 2022, 35(3): 319-324.
16. Copeland-Halperin RS, Liu JE, Yu AF. Cardiotoxicity of HER2-targeted therapies. Curr Opin Cardiol, 2019, 34(4): 451-458.
17. Chai M, Li L, Wu H, et al. Lung toxicity induced by anti-HER2 antibody-drug conjugates for breast cancer. Crit Rev Oncol Hematol, 2024, 195: 104274. doi: 10.1016/j.critrevonc.2024.104274.
18. De Sanctis R, Jacobs F, Benvenuti C, et al. From seaside to bedside: current evidence and future perspectives in the treatment of breast cancer using marine compounds. Front Pharmacol, 2022, 13: 909566. doi: 10.3389/fphar.2022.909566.
19. 谢宁, 刘斌亮, 欧阳取长. 晚期HR阳性/HER2阳性乳腺癌的治疗进展. 肿瘤药学, 2022, 12(6): 703-708.
20. 张智滔, 赵帅. 托瑞米芬联合他莫昔芬辅助治疗晚期乳腺癌的效果及对患者生存质量的影响. 临床合理用药杂志, 2022, 15(28): 96-98.
21. Olayoku FR, Verhoog NJD, Louw A. Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist. Front Pharmacol, 2023, 14: 1122031. doi: 10.3389/fphar.2023.1122031.
22. Robertson JF. Fulvestrant (Faslodex) —how to make a good drug better. Oncologist, 2007, 12(7): 774-784.
23. Martel S, Bruzzone M, Ceppi M, et al. Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. Cancer Treat Rev, 2018, 62: 123-132.
24. 陈飞, 程祺, 隋殿晶. CDK4/6抑制剂在乳腺癌治疗中的耐药机制. 中国老年学杂志, 2023, 43(19): 4858-4860.
25. 王晓稼, 王薇. HR阳性/HER2阴性乳腺癌CDK4/6抑制剂联合内分泌治疗—《中国临床肿瘤学会(CSCO)乳腺癌诊疗指南(2022版)》解读. 浙江医学, 2022, 44(24): 2595-2599.
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