Research progress of HER2 gene expression in evaluating targeted therapy effect for patients with HER2-positive breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LU Xiaoyang , FENG Jing ,  ZHOU Yi

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：

human epidermal growth factor receptor 2; copy number; trastuzumab; circulating tumour DNA

DOI：

10.7507/1007-9424.202106105

Video：

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Objective To summarize the correlation between human epidermal growth factor receptor 2 (HER2) gene expression and the efficacy of targeted therapy for patients with HER2-positive breast cancer, and to summarize the new progress in the study of HER2 gene copy number. Method The relevant literatures on researches of targeted therapy effectiveness for patients with HER2-positive breast cancer were retrieved and reviewed. Results HER2 gene copy number and HER2/centromere on chromosome 17 (CEP17) ratio were related to the prognosis of patients with HER2-positive breast cancer, and circulating tumor DNA sequencing was expected to be a predictive indicator of targeted therapy effectiveness. Conclusion Higher copy number of HER2 gene might be associated with a better prognosis of HER2-positive breast cancer, and HER2/CEP17 ratio and circulating tumour DNA are of some significances in evaluating treatment response of trastuzumab for patients with HER2-positive breast cancer.

Citation： LU Xiaoyang, FENG Jing, ZHOU Yi. Research progress of HER2 gene expression in evaluating targeted therapy effect for patients with HER2-positive breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(5): 683-687. doi: 10.7507/1007-9424.202106105 Copy

1.	Wild CP, Weiderpass E, Stewart BW. World cancer report: cancer research for cancer prevention. Lyon: International Agency for Research on Cancer, 2020.
2.	Kreutzfeldt J, Rozeboom B, Dey N, et al. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res, 2020, 10(4): 1045-1067.
3.	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)乳腺癌诊疗指南2020. 北京: 人民卫生出版社, 2020.
4.	Nami B, Maadi H, Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers (Basel), 2018, 10(10): 342. doi: 10.3390/cancers10100342.
5.	Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 1987, 235(4785): 177-182.
6.	Early Breast Cancer Trialists’ Collaborative group (EBCTCG). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol, 2021, 22(8): 1139-1150.
7.	Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol, 2014, 15(6): 640-647.
8.	Miglietta F, Dieci MV, Griguolo G, et al. Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer. Cancer Treat Rev, 2021, 98: 102222. doi: 10.1016/j.ctrv.2021.102222.
9.	Adamczyk A, Kruczak A, Harazin-Lechowska A, et al. Relationship between HER2 gene status and selected potential biological features related to trastuzumab resistance and its influence on survival of breast cancer patients undergoing trastuzumab adjuvant treatment. Onco Targets Ther, 2018, 11: 4525-4535.
10.	Biserni GB, Engstrøm MJ, Bofin AM. HER2 gene copy number and breast cancer-specific survival. Histopathology, 2016, 69(5): 871-879.
11.	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 Clin Oncol, 2020, 38(5): 444-453.
12.	Wang X, Teng X, Ding W, et al. A clinicopathological study of 30 breast cancer cases with a HER2/CEP17 ratio of ≥2.0 but an average HER2 copy number of < 4.0 signals per cell. Mod Pathol, 2020, 33(8): 1557-1562.
13.	Borley A, Mercer T, Morgan M, et al. Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network. Br J Cancer, 2014, 110(8): 2139-2143.
14.	Meisel JL, Zhao J, Suo A, et al. Clinicopathologic factors associated with response to neoadjuvant anti-HER2-directed chemotherapy in HER2-positive breast cancer. Clin Breast Cancer, 2020, 20(1): 19-24.
15.	Zhao J, Krishnamurti U, Zhang C, et al. HER2 immunohistochemistry staining positivity is strongly predictive of tumor response to neoadjuvant chemotherapy in HER2 positive breast cancer. Pathol Res Pract, 2020, 216(11): 153155. doi: 10.1016/j.prp.2020.153155.
16.	Veeraraghavan J, De Angelis C, Mao R, et al. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann Oncol, 2019, 30(6): 927-933.
17.	Wang Y, Singh K, Dizon D, et al. Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer. Breast Cancer Res Treat, 2021, 186(3): 667-676.
18.	Rakha EA, Miligy IM, Quinn CM, et al. Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases. Br J Cancer, 2021, 124(11): 1836-1842.
19.	Xuan Q, Ji H, Tao X, et al. Quantitative assessment of HER2 amplification in HER2-positive breast cancer: its association with clinical outcomes. Breast Cancer Res Treat, 2015, 150(3): 581-588.
20.	Wu Z, Xu S, Zhou L, et al. Clinical significance of quantitative HER2 gene amplification as related to its predictive value in breast cancer patients in neoadjuvant setting. Onco Targets Ther, 2018, 11: 801-808.
21.	Bates M, Sperinde J, Köstler WJ, et al. Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. Ann Oncol, 2011, 22(9): 2014-2020.
22.	周宇婷, 谭秋雯, 吕青. HER2阳性乳腺癌曲妥珠单抗耐药机理的研究进展. 中国普外基础与临床杂志, 2016, 23(10): 1280-1284.
23.	Filho OM, Viale G, Stein S, 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(10): 2474-2487.
24.	Rosenberg CL. Polysomy 17 and HER-2 amplification: true, true, and unrelated. J Clin Oncol, 2008, 26(30): 4856-4858.
25.	Greenwell K, Hussain L, Lee D, et al. Complete pathologic response rate to neoadjuvant chemotherapy increases with increasing HER2/CEP17 ratio in HER2 overexpressing breast cancer: analysis of the National Cancer Database (NCDB). Breast Cancer Res Treat, 2020, 181(2): 249-254.
26.	Singer CF, Tan YY, Fitzal F, et al. Pathological complete response to neoadjuvant trastuzumab is dependent on HER2/CEP17 ratio in HER2-amplified early breast cancer. Clin Cancer Res, 2017, 23(14): 3676-3683.
27.	Lee HJ, Seo AN, Kim EJ, et al. HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer. Am J Clin Pathol, 2014, 142(6): 755-766.
28.	Lee K, Kim HJ, Jang MH, et al. Centromere 17 copy number gain reflects chromosomal instability in breast cancer. Sci Rep, 2019, 9(1): 17968. doi: 10.1038/s41598-019-54471-w.
29.	Kogawa T, Fujii T, Wu J, et al. Prognostic value of HER2 to CEP17 ratio on fluorescence in situ hybridization ratio in patients with nonmetastatic HER2-positive inflammatory and noninflammatory breast cancer treated with neoadjuvant chemotherapy with or without trastuzumab. Oncologist, 2020, 25(6): e909-e919.
30.	Kogawa T, Fouad TM, Liu DD, et al. High HER2/centromeric probe for chromosome 17 fluorescence in situ hybridization ratio predicts pathologic complete response and survival outcome in patients receiving neoadjuvant systemic therapy with trastuzumab for HER2-overexpressing locally advanced breast cancer. Oncologist, 2016, 21(1): 21-27.
31.	Blanton KC, Deal AM, Kaiser-Rogers KA, et al. Clinicopathologic features of breast cancer reclassified as HER2-amplified by fluorescence in situ hybridization with alternative chromosome 17 probes. Ann Diagn Pathol, 2020, 48: 151576. doi: 10.1016/j.anndiagpath.2020.151576.
32.	Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol, 2020, 21(10): 1296-1308.
33.	Guan X, Liu B, Niu Y, et al. Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer. Breast, 2020, 49: 261-266.
34.	汤蕾, 符德元. 循环肿瘤 DNA 在乳腺癌早期诊断中的临床应用进展. 中国普外基础与临床杂志, 2021, 28(8): 1086-1090.
35.	Ho D, Huang J, Chapman JW, et al. Impact of serum HER2, TIMP-1,and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab). Breast Cancer Res Treat, 2017, 164(3): 571-580.
36.	Ran R, Huang W, Liu Y, et al. Prognostic value of plasma HER2 gene copy number in HER2-positive metastatic breast cancer treated with first-line trastuzumab. Onco Targets Ther, 2020, 13: 4385-4395.
37.	Zhang P, Xiao J, Ruan Y, et al. Monitoring value of serum HER2 as a predictive biomarker in patients with metastatic breast cancer. Cancer Manag Res, 2020, 12: 4667-4675.

1. Wild CP, Weiderpass E, Stewart BW. World cancer report: cancer research for cancer prevention. Lyon: International Agency for Research on Cancer, 2020.
2. Kreutzfeldt J, Rozeboom B, Dey N, et al. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res, 2020, 10(4): 1045-1067.
3. 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)乳腺癌诊疗指南2020. 北京: 人民卫生出版社, 2020.
4. Nami B, Maadi H, Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers (Basel), 2018, 10(10): 342. doi: 10.3390/cancers10100342.
5. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 1987, 235(4785): 177-182.
6. Early Breast Cancer Trialists’ Collaborative group (EBCTCG). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol, 2021, 22(8): 1139-1150.
7. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol, 2014, 15(6): 640-647.
8. Miglietta F, Dieci MV, Griguolo G, et al. Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer. Cancer Treat Rev, 2021, 98: 102222. doi: 10.1016/j.ctrv.2021.102222.
9. Adamczyk A, Kruczak A, Harazin-Lechowska A, et al. Relationship between HER2 gene status and selected potential biological features related to trastuzumab resistance and its influence on survival of breast cancer patients undergoing trastuzumab adjuvant treatment. Onco Targets Ther, 2018, 11: 4525-4535.
10. Biserni GB, Engstrøm MJ, Bofin AM. HER2 gene copy number and breast cancer-specific survival. Histopathology, 2016, 69(5): 871-879.
11. 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 Clin Oncol, 2020, 38(5): 444-453.
12. Wang X, Teng X, Ding W, et al. A clinicopathological study of 30 breast cancer cases with a HER2/CEP17 ratio of ≥2.0 but an average HER2 copy number of < 4.0 signals per cell. Mod Pathol, 2020, 33(8): 1557-1562.
13. Borley A, Mercer T, Morgan M, et al. Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network. Br J Cancer, 2014, 110(8): 2139-2143.
14. Meisel JL, Zhao J, Suo A, et al. Clinicopathologic factors associated with response to neoadjuvant anti-HER2-directed chemotherapy in HER2-positive breast cancer. Clin Breast Cancer, 2020, 20(1): 19-24.
15. Zhao J, Krishnamurti U, Zhang C, et al. HER2 immunohistochemistry staining positivity is strongly predictive of tumor response to neoadjuvant chemotherapy in HER2 positive breast cancer. Pathol Res Pract, 2020, 216(11): 153155. doi: 10.1016/j.prp.2020.153155.
16. Veeraraghavan J, De Angelis C, Mao R, et al. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann Oncol, 2019, 30(6): 927-933.
17. Wang Y, Singh K, Dizon D, et al. Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer. Breast Cancer Res Treat, 2021, 186(3): 667-676.
18. Rakha EA, Miligy IM, Quinn CM, et al. Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases. Br J Cancer, 2021, 124(11): 1836-1842.
19. Xuan Q, Ji H, Tao X, et al. Quantitative assessment of HER2 amplification in HER2-positive breast cancer: its association with clinical outcomes. Breast Cancer Res Treat, 2015, 150(3): 581-588.
20. Wu Z, Xu S, Zhou L, et al. Clinical significance of quantitative HER2 gene amplification as related to its predictive value in breast cancer patients in neoadjuvant setting. Onco Targets Ther, 2018, 11: 801-808.
21. Bates M, Sperinde J, Köstler WJ, et al. Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. Ann Oncol, 2011, 22(9): 2014-2020.
22. 周宇婷, 谭秋雯, 吕青. HER2阳性乳腺癌曲妥珠单抗耐药机理的研究进展. 中国普外基础与临床杂志, 2016, 23(10): 1280-1284.
23. Filho OM, Viale G, Stein S, 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(10): 2474-2487.
24. Rosenberg CL. Polysomy 17 and HER-2 amplification: true, true, and unrelated. J Clin Oncol, 2008, 26(30): 4856-4858.
25. Greenwell K, Hussain L, Lee D, et al. Complete pathologic response rate to neoadjuvant chemotherapy increases with increasing HER2/CEP17 ratio in HER2 overexpressing breast cancer: analysis of the National Cancer Database (NCDB). Breast Cancer Res Treat, 2020, 181(2): 249-254.
26. Singer CF, Tan YY, Fitzal F, et al. Pathological complete response to neoadjuvant trastuzumab is dependent on HER2/CEP17 ratio in HER2-amplified early breast cancer. Clin Cancer Res, 2017, 23(14): 3676-3683.
27. Lee HJ, Seo AN, Kim EJ, et al. HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer. Am J Clin Pathol, 2014, 142(6): 755-766.
28. Lee K, Kim HJ, Jang MH, et al. Centromere 17 copy number gain reflects chromosomal instability in breast cancer. Sci Rep, 2019, 9(1): 17968. doi: 10.1038/s41598-019-54471-w.
29. Kogawa T, Fujii T, Wu J, et al. Prognostic value of HER2 to CEP17 ratio on fluorescence in situ hybridization ratio in patients with nonmetastatic HER2-positive inflammatory and noninflammatory breast cancer treated with neoadjuvant chemotherapy with or without trastuzumab. Oncologist, 2020, 25(6): e909-e919.
30. Kogawa T, Fouad TM, Liu DD, et al. High HER2/centromeric probe for chromosome 17 fluorescence in situ hybridization ratio predicts pathologic complete response and survival outcome in patients receiving neoadjuvant systemic therapy with trastuzumab for HER2-overexpressing locally advanced breast cancer. Oncologist, 2016, 21(1): 21-27.
31. Blanton KC, Deal AM, Kaiser-Rogers KA, et al. Clinicopathologic features of breast cancer reclassified as HER2-amplified by fluorescence in situ hybridization with alternative chromosome 17 probes. Ann Diagn Pathol, 2020, 48: 151576. doi: 10.1016/j.anndiagpath.2020.151576.
32. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol, 2020, 21(10): 1296-1308.
33. Guan X, Liu B, Niu Y, et al. Longitudinal HER2 amplification tracked in circulating tumor DNA for therapeutic effect monitoring and prognostic evaluation in patients with breast cancer. Breast, 2020, 49: 261-266.
34. 汤蕾, 符德元. 循环肿瘤 DNA 在乳腺癌早期诊断中的临床应用进展. 中国普外基础与临床杂志, 2021, 28(8): 1086-1090.
35. Ho D, Huang J, Chapman JW, et al. Impact of serum HER2, TIMP-1,and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab). Breast Cancer Res Treat, 2017, 164(3): 571-580.
36. Ran R, Huang W, Liu Y, et al. Prognostic value of plasma HER2 gene copy number in HER2-positive metastatic breast cancer treated with first-line trastuzumab. Onco Targets Ther, 2020, 13: 4385-4395.
37. Zhang P, Xiao J, Ruan Y, et al. Monitoring value of serum HER2 as a predictive biomarker in patients with metastatic breast cancer. Cancer Manag Res, 2020, 12: 4667-4675.

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Research progress of HER2 gene expression in evaluating targeted therapy effect for patients with HER2-positive breast cancer

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