Clinicopathological features of breast cancer with low HER2 expression and analysis of factors related to the efficacy of neoadjuvant chemotherapy_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YI Qiao ,  ZUO Huaiquan

Department of General Surgery (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan Treatment Center for Gynaecologic and Breast Diseases (Breast Surgery), Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

ZUO Huaiquan, Email: z13982405295@163.com

Keywords：

breast cancer; low expression of human epidermal growth factor receptor 2; clinicopathological features; neoadjuvant chemotherapy; pathological complete response

DOI：

10.7507/1007-9424.202202007

Video：

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Objective To investigate the clinicopathological characteristics of HER2 protein expression in different degrees in human epidermal growth factor receptor 2 (HER2) negative breast cancer and the factors related to the efficacy of neoadjuvant chemotherapy in breast cancer with low HER2 expression. Methods The clinicopathological data of 161 patients with HER2-negative breast cancer who received neoadjuvant chemotherapy in the Department of Breast Surgery, Affiliated Hospital of Southwest Medical University from March 2019 to March 2022 were retrospectively collected. The difference of clinical and pathological characteristics of patients with different levels of HER2 protein expression were analyzed, and the factors influencing the pathological complete remission (pCR) rate of breast cancer patients with low HER2 expression after neoadjuvant chemotherapy with unconditional logistic regression model were analyzed. Results Among 161 HER2 negative breast cancer patients, 108 cases were low HER2 expression, accounting for 67.1%. Compared with those with zero expression of HER2 [immunohistochemistry (IHC) 0], the patients with low HER2 expression had higher axillary lymph node metastasis rate (P=0.048), lower histological grade (P=0.006), and higher proportion of positive hormone receptor expression (P<0.001). There was no significant difference in pCR rate among the HER2 IHC 0, IHC 1+ and IHC 2+ / in situ hybridization (ISH)– (P=0.099) , and the pCR rate of low expression of HER2 was lower than that of zero expression of HER2 in the general population and Luminal subgroup, and the difference was statistically significant (P<0.05). There was no significant difference in triple negative breast cancer subgroup (P=0.814). The logistic regression analysis showed that age, histological grade and estrogen receptor expression status were independent influencing factors for pCR rate after neoadjuvant chemotherapy with low HER2 expression (P<0.05). Conclusions Different degrees of HER2 protein expressions in patients with HER2-negative breast cancer have unique clinicopathological characteristics. The pCR rate of neoadjuvant chemotherapy in patients with low HER2-expression breast cancer is lower than that in patients with zero HER2-expression breast cancer. Age, histological grade and estrogen receptor expression status are independent factors influencing the pCR rate of neoadjuvant chemotherapy in patients with low HER2-expression breast cancer.

Citation： YI Qiao, ZUO Huaiquan. Clinicopathological features of breast cancer with low HER2 expression and analysis of factors related to the efficacy of neoadjuvant chemotherapy. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(9): 1213-1219. doi: 10.7507/1007-9424.202202007 Copy

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. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up^†. Ann Oncol, 2019, 30(8): 1194-1220.
3.	Choong GM, Cullen GD, O’Sullivan CC. Evolving standards of care and new challenges in the management of HER2-positive breast cancer. CA Cancer J Clin, 2020, 70(5): 355-374.
4.	Sapino A, Goia M, Recupero D, et al. Current challenges for HER2 testing in diagnostic pathology: state of the art and controversial issues. Front Oncol, 2013, 3: 129.
5.	Wolff AC, Hammond MEH, 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. Arch Pathol Lab Med, 2018, 142(11): 1364-1382.
6.	Onsum MD, Geretti E, Paragas V, et al. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol, 2013, 183(5): 1446-1460.
7.	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 Clin Oncol, 2020, 38(17): 1887-1896.
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10.	中国临床肿瘤学会乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会. 人表皮生长因子受体2阳性乳腺癌临床诊疗专家共识(2021版). 中华医学杂志, 2021, 101(17): 1226-1231.
11.	中国癌协会乳腺癌专业委员会. 中国抗癌办会乳腺癌诊治指南与规范(2019年版). 中国癌症杂志, 2019, 29(8): 609-680.
12.	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 Clin Oncol, 2012, 30(26): 3234-3241.
13.	Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase Ⅱstudy 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 Clin Oncol, 2011, 29(4): 398-405.
14.	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. Clin Cancer Res, 2016, 22(15): 3755-3763.
15.	Kim SB, Wildiers H, Krop IE, et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase Ⅲ study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int J Cancer, 2016, 139(10): 2336-2342.
16.	Lee CK, Davies L, Gebski VJ, et al. Serum human epidermal growth factor 2 extracellular domain as a predictive biomarker for lapatinib treatment efficacy in patients with advanced breast cancer. J Clin Oncol, 2016, 34(9): 936-944.
17.	Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol, 2020, 38(17): 1951-1962.
18.	Shui R, Liang X, Li X, et al. Hormone receptor and human epidermal growth factor receptor 2 detection in invasive breast carcinoma: a retrospective study of 12 467 patients from 19 Chinese representative clinical centers. Clin Breast Cancer, 2020, 20(1): e65-e74.
19.	Lambein K, Van Bockstal M, Vandemaele L, et al. Distinguishing score 0 from score 1+ in HER2 immunohistochemistry-negative breast cancer: clinical and pathobiological relevance. Am J Clin Pathol, 2013, 140(4): 561-566.
20.	Ho-Pun-Cheung A, Bazin H, Boissière-Michot F, et al. Quantification of HER1, HER2 and HER3 by time-resolved Förster resonance energy transfer in FFPE triple-negative breast cancer samples. Br J Cancer, 2020, 122(3): 397-404.
21.	Jensen K, Krusenstjerna-Hafstrøm R, Lohse J, et al. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin-fixed, paraffin-embedded specimens: analytical performance measuring HER2. Mod Pathol, 2017, 30(2): 180-193.
22.	Modi S, Glass B, Prakash A, et al. Artificial intelligence analysis of advanced breast cancer patients from a phase I trial of trastuzumab deruxtecan (T-DxD): HER2 and histopathology features as predictors of clinical benefit. 2020ESMO. Abstract 286P. https://www.annalsofoncology.org/article/S0923-7534(20)40384-9/fulltext.
23.	Schettini F, Chic N, Brasó-Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer, 2021, 7(1): 1. doi: 10.1038/s41523-020-00208-2.
24.	Dehghani M, Keshavarz P, Talei A, et al. The effects of low HER2/neu expression on the clinicopathological characteristics of triple-negative breast cancer patients. Asian Pac J Cancer Prev, 2020, 21(10): 3027-3032.
25.	Plasilova ML, Hayse B, Killelea BK, et al. Features of triple-negative breast cancer: Analysis of 38 813 cases from the national cancer database. Medicine (Baltimore), 2016, 95(35): e4614. doi: 10.1097/MD.0000000000004614.
26.	Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol, 2021, 22(8): 1151-1161.
27.	Reinert T, Sartori GP, Souza AAB et al . Abstract PS4-22: Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer. Cancer Res, https://aacrjournals.org/ cancerres/ article/81/4_Supplement/PS4-22/648803/Abstract-PS4-22-Prevalence-of-HER2-low-and-HER2.
28.	de Moura Leite L, Cesca MG, Tavares MC, et al. HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer. Breast Cancer Res Treat, 2021, 190(1): 155-163.

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. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up^†. Ann Oncol, 2019, 30(8): 1194-1220.
3. Choong GM, Cullen GD, O’Sullivan CC. Evolving standards of care and new challenges in the management of HER2-positive breast cancer. CA Cancer J Clin, 2020, 70(5): 355-374.
4. Sapino A, Goia M, Recupero D, et al. Current challenges for HER2 testing in diagnostic pathology: state of the art and controversial issues. Front Oncol, 2013, 3: 129.
5. Wolff AC, Hammond MEH, 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. Arch Pathol Lab Med, 2018, 142(11): 1364-1382.
6. Onsum MD, Geretti E, Paragas V, et al. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol, 2013, 183(5): 1446-1460.
7. 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 Clin Oncol, 2020, 38(17): 1887-1896.
8. 中国抗癌协会乳腺癌专业委员会. 中国抗癌协会乳腺癌诊治指南与规范(2021年版). 中国癌症杂志, 2021, 31(10): 954-1040.
9. 李健斌, 江泽飞. 2021年中国临床肿瘤学会乳腺癌诊疗指南更新要点解读. 中华医学杂志, 2021, 101(24): 1835-1838.
10. 中国临床肿瘤学会乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会. 人表皮生长因子受体2阳性乳腺癌临床诊疗专家共识(2021版). 中华医学杂志, 2021, 101(17): 1226-1231.
11. 中国癌协会乳腺癌专业委员会. 中国抗癌办会乳腺癌诊治指南与规范(2019年版). 中国癌症杂志, 2019, 29(8): 609-680.
12. 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 Clin Oncol, 2012, 30(26): 3234-3241.
13. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase Ⅱstudy 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 Clin Oncol, 2011, 29(4): 398-405.
14. 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. Clin Cancer Res, 2016, 22(15): 3755-3763.
15. Kim SB, Wildiers H, Krop IE, et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase Ⅲ study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int J Cancer, 2016, 139(10): 2336-2342.
16. Lee CK, Davies L, Gebski VJ, et al. Serum human epidermal growth factor 2 extracellular domain as a predictive biomarker for lapatinib treatment efficacy in patients with advanced breast cancer. J Clin Oncol, 2016, 34(9): 936-944.
17. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol, 2020, 38(17): 1951-1962.
18. Shui R, Liang X, Li X, et al. Hormone receptor and human epidermal growth factor receptor 2 detection in invasive breast carcinoma: a retrospective study of 12 467 patients from 19 Chinese representative clinical centers. Clin Breast Cancer, 2020, 20(1): e65-e74.
19. Lambein K, Van Bockstal M, Vandemaele L, et al. Distinguishing score 0 from score 1+ in HER2 immunohistochemistry-negative breast cancer: clinical and pathobiological relevance. Am J Clin Pathol, 2013, 140(4): 561-566.
20. Ho-Pun-Cheung A, Bazin H, Boissière-Michot F, et al. Quantification of HER1, HER2 and HER3 by time-resolved Förster resonance energy transfer in FFPE triple-negative breast cancer samples. Br J Cancer, 2020, 122(3): 397-404.
21. Jensen K, Krusenstjerna-Hafstrøm R, Lohse J, et al. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin-fixed, paraffin-embedded specimens: analytical performance measuring HER2. Mod Pathol, 2017, 30(2): 180-193.
22. Modi S, Glass B, Prakash A, et al. Artificial intelligence analysis of advanced breast cancer patients from a phase I trial of trastuzumab deruxtecan (T-DxD): HER2 and histopathology features as predictors of clinical benefit. 2020ESMO. Abstract 286P. https://www.annalsofoncology.org/article/S0923-7534(20)40384-9/fulltext.
23. Schettini F, Chic N, Brasó-Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer, 2021, 7(1): 1. doi: 10.1038/s41523-020-00208-2.
24. Dehghani M, Keshavarz P, Talei A, et al. The effects of low HER2/neu expression on the clinicopathological characteristics of triple-negative breast cancer patients. Asian Pac J Cancer Prev, 2020, 21(10): 3027-3032.
25. Plasilova ML, Hayse B, Killelea BK, et al. Features of triple-negative breast cancer: Analysis of 38 813 cases from the national cancer database. Medicine (Baltimore), 2016, 95(35): e4614. doi: 10.1097/MD.0000000000004614.
26. Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol, 2021, 22(8): 1151-1161.
27. Reinert T, Sartori GP, Souza AAB et al . Abstract PS4-22: Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer. Cancer Res, https://aacrjournals.org/ cancerres/ article/81/4_Supplement/PS4-22/648803/Abstract-PS4-22-Prevalence-of-HER2-low-and-HER2.
28. de Moura Leite L, Cesca MG, Tavares MC, et al. HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer. Breast Cancer Res Treat, 2021, 190(1): 155-163.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Clinicopathological features of breast cancer with low HER2 expression and analysis of factors related to the efficacy of neoadjuvant chemotherapy

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