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中华临床医师杂志(电子版) ›› 2021, Vol. 15 ›› Issue (10) : 735 -739. doi: 10.3877/cma.j.issn.1674-0785.2021.10.004

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HER2低表达乳腺癌及抗体偶联药物诊治进展
邬茜1, 辛灵1, 刘倩1, 刘荫华1,()   
  1. 1. 100034 北京,北京大学第一医院乳腺疾病中心
  • 收稿日期:2021-08-26 出版日期:2021-10-15
  • 通信作者: 刘荫华

Advances in diagnosis and treatment of HER2-low breast cancer and antibody drug conjugates

Qian Wu1, Ling Xin1, Qian Liu1, Yinhua Liu1,()   

  1. 1. Breast Disease Center, Peking University First Hospital, Beijing 100034, China
  • Received:2021-08-26 Published:2021-10-15
  • Corresponding author: Yinhua Liu
引用本文:

邬茜, 辛灵, 刘倩, 刘荫华. HER2低表达乳腺癌及抗体偶联药物诊治进展[J]. 中华临床医师杂志(电子版), 2021, 15(10): 735-739.

Qian Wu, Ling Xin, Qian Liu, Yinhua Liu. Advances in diagnosis and treatment of HER2-low breast cancer and antibody drug conjugates[J]. Chinese Journal of Clinicians(Electronic Edition), 2021, 15(10): 735-739.

DS-8201相关研究显示,经过多线解救治疗疾病进展的晚期人表皮生长因子受体2(HER2)低表达乳腺癌患者可以通过新型HER2抗体偶联药物(ADC)治疗达到临床显著获益。该结论不仅进一步细化了乳腺癌分类治疗理念,也引发了重新定义HER2表达状态标准的思考。同时,深入新型ADC药物研发工作正在成为新的热点问题而受到临床广泛关注。本文在复习HER2低表达乳腺癌研究历史及ADC药物研发现状的基础上,结合笔者研究数据,探讨HER2低表达乳腺癌临床病理特征及诊治进展。

Studies about DS-8201 have shown that patients who had advanced human epidermal growth factor receptor 2 (HER2)-low breast cancer refractory to standard therapies can achieve clinically significant benefits by novel HER2 antibody-drug conjugate (ADC). This conclusion not only further refines the classification of breast cancer, but also triggers the consideration of redefining the criteria for HER2 expression status. At the same time, in-depth research and development of novel ADCs is becoming a new hot issue and has received much clinical attention. In this paper, on the basis of reviewing the research history of HER2-low breast cancer and the current status of ADCs research and development, combined with our research data, we explore the clinicopathological features, diagnosis and treatment progress of HER2-low breast cancer.

表1 抗体偶联药物在HER2低表达乳腺癌中开展的相关临床试验
药物 试验号 分期 样本量(例) 人群 药物组合
DS-8201a NCT02564900 Ⅰb期 292 HER2阳性/低表达、晚期、后线 DS-8201a
DS-8201a NCT04132960 Ⅱ期 186 HER2过表达/低表达/无表达、晚期、后线 DS-8201a
DS-8201a NCT03734029(DESTINY-Breast04) Ⅲ期 557 HER2低表达、晚期、后线 DS-8201a vs 医生选择治疗(2∶1)
DS-8201a NCT04494425(DESTINY-Breast06) Ⅲ期 850 HER2低表达、激素受体阳性、晚期、后线 T-DXd vs 研究者选择化疗
DS-8201a NCT03523572 Ⅰb期 99 HER2阳性/低表达、晚期、后线 DS-8201a+纳武单抗
DS-8201a NCT04556773(DESTINY-Breast08) Ⅰb期 185 HER2低表达、晚期、后线

T-DXd+卡培他滨;

T-DXd+度伐单抗+紫杉醇;

T-DXd+Capivasertib;

T-DXd+阿那曲唑;

T-DXd+氟维司群

DS-8201a NCT04042701 Ⅰb期 115 HER2阳性/低表达、晚期、后线 T-DXd+帕博利珠单抗
DS-8201a NCT04553770 Ⅱ期 88 HER2低表达、激素受体阳性、早期、新辅助 DS-8201a vs DS-8201a+阿那曲唑
RC48-ADC NCT03052634 Ⅰb期 121 HER2阳性/低表达、晚期、后线 RC48-ADC
RC48-ADC NCT04400695 Ⅲ期 366 HER2低表达、晚期、后线 RC48-ADC vs 医生选择治疗
MRG002 NCT04742153 Ⅱ期 66 HER2低表达、晚期、后线 MRG002
SYD985 NCT02277717 Ⅰ期 185 HER2低表达、晚期、后线 SYD985
SYD985 NCT04602117 Ⅰ/Ⅰb期 27 HER2阳性或低表、晚期、后线 SYD985+紫杉醇
SYD985 NCT04235101 Ⅰ期 120 HER2阳性/低表达、晚期、后线 SYD985+尼拉帕利
ARX788 NCT02512237 Ⅰ期 80 HER2低表达、晚期、后线 ARX788
ARX788 NCT03255070 Ⅰ期 190 IHC 2+/ISH-、晚期、后线 ARX788
PF-06804103 NCT03284723 Ⅰ期 148 IHC 2+/ISH-、晚期、后线

PF-06804103;

PF-06804103+来曲唑+帕博西尼

FS-1502 NCT03944499 Ⅰ期 92 HER2低表达、晚期、后线 FS-1502
XMT-1522 NCT02952729 Ⅰ期 120 HER2低表达、晚期、后线 XMT-1522
1
Schneeweiss A, Park-Simon TW, Albanell J, et al. Phase Ⅰb study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer [J]. Invest New Drugs, 2018, 36(5): 848.
2
Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update [J]. J Clin Oncol, 2013, 31(31): 3997.
3
Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer [J]. J Clin Oncol, 2010, 28(16): 2784.
4
Wolff AC, Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update [J]. J Clin Oncol, 2018, 36(20): 2105.
5
Banerji U, Van Herpen CML, Saura C, et al. Trastuzumab Duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study [J]. Lancet Oncol, 2019, 20(8): 1124.
6
Clifton GT, Hale D, Vreeland TJ, et al. Results of a randomized phase Ⅱb trial of nelipepimut-S + Trastuzumab versus Trastuzumab to prevent recurrences in patients with high-risk HER2 low-expressing breast cancer [J]. Clin Cancer Res, 2020, 26(11): 2515.
7
Mittendorf EA, Lu B, Melisko M, et al. Efficacy and safety analysis of nelipepimut-S vaccine to prevent breast cancer recurrence: a randomized, multicenter, phase Ⅲ clinical trial [J]. Clin Cancer Res, 2019, 25(14): 4248.
8
Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of Trastuzumab Deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ⅰb study [J]. J Clin Oncol, 2020, 38(17): 1887.
9
Pondé N, Aftimos P, Piccart M. Antibody-drug conjugates in breast cancer: a comprehensive review [J]. Curr Treat Options Oncol, 2019, 20(5): 37.
10
Rinnerthaler G, Gampenrieder SP, Greil R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer [J]. Int J Mol Sci, 2019, 20(5): 1115.
11
Clifton GT, Peace KM, Holmes JP, et al. Initial safety analysis of a randomized phase Ⅱ trial of nelipepimut-S + GM-CSF and Trastuzumab compared to Trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors [J]. Clin Immunol, 2019, 201: 48.
12
Schalper KA, Kumar S, Hui P, et al. A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria [J]. Arch Pathol Lab Med, 2014, 138(2): 213.
13
Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47/NRG oncology phase Ⅲ randomized trial comparing adjuvant chemotherapy with or without Trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2 [J]. J Clin Oncol, 2020, 38(5): 444.
14
Gianni L, Lladó A, Bianchi G, et al. Open-label, phase Ⅱ, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer [J]. J Clin Oncol, 2010, 28(7): 1131.
15
Lanbein K, Van Bockstal M, Vandemeale L, et al. Distinguishing score 0 from score 1+ in HER2 immunohistochemistry-negative breast cancer: clinical and pathobiological relevance [J]. Am J Clin Pathol, 2013, 140(4): 561.
16
Press MF, Slamon DJ, Flom KJ, et al. Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens [J]. J Clin Oncol, 2002, 20(14): 3095.
17
Jacquemier J, Spyratos F, Esterni B, et al. SISH/CISH or qPCR as alternative techniques to FISH for determination of HER2 amplification status on breast tumors core needle biopsies: a multicenter experience based on 840 cases [J]. BMC Cancer, 2013, 13: 351.
18
Van Der Lee MM, Groothuis PG, Ubink R, et al. The Preclinical profile of the duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers [J]. Mol Cancer Ther, 2015, 14(3): 692.
19
Takegawa N, Tsurutani J, Kawakami H, et al. [fam-] Trastuzumab Deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification [J]. Int J Cancer, 2019, 145(12): 3414.
20
Baehner FL, Achacoso N, Maddala T, et al. Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories [J]. J Clin Oncol, 2010, 28(28): 4300.
21
Lehmann-che J, Amira-bouhidel F, Turpin E, et al. Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches [J]. Br J Cancer, 2011, 104(11): 1739.
22
Dabbs DJ, Klein ME, Mohsin SK, et al. High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the oncotype DX test: an independent quality assurance study [J]. J Clin Oncol, 2011, 29(32): 4279.
23
Noske A, Loibl S, Darb-Esfahani S, et al. Comparison of different approaches for assessment of HER2 expression on protein and mRNA level: prediction of chemotherapy response in the neoadjuvant Gepar Trio trial (NCT00544765) [J]. Breast Cancer Res Treat, 2011, 126(1): 109.
24
Tang Y, Tang F, Yang Y, et al. Real-time analysis on drug-antibody ratio of antibody-drug conjugates for synthesis, process optimization, and quality control [J]. Sci Rep, 2017, 7(1): 7763.
25
Krop IE, Beeram M, Modi S, et al. Phase Ⅰ study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer [J]. J Clin Oncol, 2010, 28(16): 2698.
26
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.
27
Von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for residual invasive HER2-positive breast cancer [J]. N Engl J Med, 2019, 380(7): 617.
28
Burris HA, Rugo HS, Vukelja SJ, et al. Phase Ⅱ study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy [J]. J Clin Oncol, 2011, 29(4): 398.
29
Krop IE, Lorusso P, Miller KD, et al. A phase Ⅱ study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine [J]. J Clin Oncol, 2012, 30(26): 3234.
30
Perez EA, Hurvitz SA, Amler LC, et al. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase Ⅱ study of patients with previously untreated HER2-positive metastatic breast cancer [J]. Breast Cancer Res, 2014, 16(3): R50.
31
Baselga J, Lewis Phillips GD, Verma S, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase Ⅲ study of Trastuzumab Emtansine in HER2-positive metastatic breast cancer [J]. Clin Cancer Res, 2016, 22(15): 3755.
32
Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1 [J]. Clin Cancer Res, 2016, 22(20): 5097.
33
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.
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