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 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 research. Results Contemporary breast cancer targeted therapies mainly comprised human epidermal growth factor receptor 2 (HER2)-directed agents, CDK4/6 inhibitors, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin pathway blockers, poly (ADP-ribose) polymerase inhibitors, and immune checkpoint modulators, etc. While these agents had conferred subtype-specific survival benefits, resistance developed through target mutations, compensatory signaling, epigenetic alterations, drug efflux pumps, among other mechanisms. Emerging strategies for reversing drug resistance included 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 is expected to enable personalized combination therapies, ultimately overcoming drug resistance and improving patient survival outcomes.

Citation： YUAN Shuanglong, JIA Lizhou, ZHOU Yi. Research advances in targeted drug therapy and drug resistance mechanisms for breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(9): 1181-1188. doi: 10.7507/1007-9424.202504123 Copy

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1. 鄔昊, 呂青. 全球及中國乳腺癌的流行病學趨勢及防控啟示: 2018–2022年《全球癌癥統計報告》解讀. 中國普外基礎與臨床雜志, 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. 張一鳴, 田辛晨, 王宇飛, 等. 基于分子分型的乳腺癌中醫精準辨治思路探討. 北京中醫藥大學學報, 2023, 46(7): 1025-1031.
4. 楊曉靜, 徐溢, 沈贊. 抗HER2靶向治療的耐藥機制及治療新策略. 腫瘤, 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. 吳悠, 戴建國. HER2陽性乳腺癌靶向治療的研究進展. 中國臨床新醫學, 2024, 17(10): 1183-1186.
9. Vega Cano KS, Marmolejo Casta?eda 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, 張清媛. T-DM1治療晚期HER2陽性乳腺癌耐藥機制的研究進展. 現代腫瘤醫學, 2025: 1-7. [2025-08-05].
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, 劉相麟, 劉喆贏, 等. 漢曲優^?與帕妥珠單抗聯合化療新輔助治療HER-2陽性乳腺癌療效和安全評價. 中國臨床研究, 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. 謝寧, 劉斌亮, 歐陽取長. 晚期HR陽性/HER2陽性乳腺癌的治療進展. 腫瘤藥學, 2022, 12(6): 703-708.
20. 張智滔, 趙帥. 托瑞米芬聯合他莫昔芬輔助治療晚期乳腺癌的效果及對患者生存質量的影響. 臨床合理用藥雜志, 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. 陳飛, 程祺, 隋殿晶. CDK4/6抑制劑在乳腺癌治療中的耐藥機制. 中國老年學雜志, 2023, 43(19): 4858-4860.
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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research advances in targeted drug therapy and drug resistance mechanisms for breast cancer

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