Clinicopathologic features and prognosis of breast cancer patients with low human epidermal growth factor receptor<b>-</b>2 expression_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Xinpei ¹ , LUO Yinyi ¹ ,  WANG Shiming ²

1. The First Clinical College of Shanxi Medical University, Taiyuan 030000, P. R. China;
2. Department of Breast Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030000, P. R. China;

Corresponding author：

WANG Shiming, Email: wangshimingSX@sina.com

Keywords：

breast cancer; low human epidermal growth factor receptor-2 expression; clinicopathologic features; prognosis

DOI：

10.7507/1007-9424.202302001

Video：

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Objective To analyze the clinicopathologic features and prognosis of breast cancer patients with low human epidermal growth factor receptor-2 (HER2) expression. Methods The breast cancer patients underwent initially surgical resection in the First Hospital of Shanxi Medical University from October 2015 to October 2017 and met the criterion of this study were retrospectively gathered. Based on the immunohistochemical / in situ hybridization detection results, the patients were divided into three subtypes of HER2 zero, low, and positive expressions, and the differences in the clinicopathologic characteristics, overall survival (OS) and disease-free survival (DFS) of the three subtypes of breast cancer patients were compared. At the same time, the risk factors affecting the OS and DFS of breast cancer patients with low HER2 expression were analyzed. Results A total of 315 eligible patients were gathered in this study, including 68 patients with HER2 zero expression, 121 patients with low HER2 expression, and 126 patients with positive HER2 expression. There were no statistic differences in the menstrual status, T stage, and histological classification between the breast cancer patients with low HER2 and positive HER2 expressions (P>0.05), but the proportions of the patients with lymph node metastasis, histological grade Ⅲ, negative hormone receptor (HR) and high Ki67 expression in the low HER2 expression patients were lower than those in the positive HER2 expression patients. And compared with HER2 zero expression breast cancer patients, the proportions of premenopausal / perimenopausal, T2–4, N1–3, histological grade Ⅱ, ductal carcinoma, negative HR, and low Ki67 expression patients in the breast cancer patients with low HER2 expression were higher (P<0.05). While the survival curves of OS and DFS by Kaplan-Meier method had no statistic differences among the three subtypes of the breast cancer patients (χ²=0.070, P=0.966; χ²=0.362, P=0.835). The multivariate analysis results by Cox proportional hazards regression found that the low HER2 expression breast cancer patients with histological grade Ⅲ and negative HR had the higher risks of OS and DFS shortening (P<0.05). In addition, the risk of DFS shortening in the patients with T stage 2–4 and N stage 1–3 was increased (P<0.05). Conclusions From the results of this study, breast cancer patients with low HER2 expression is different from the other two subtypes of breast cancer in terms of clinicopathologic characteristics. However, there are no statistical significances in comparing the OS and DFS of three types of breast cancer patients, but it is found that histological grading and HR are related to the OS and DFS of breast cancer patients with low HER2 expression, and it is also found that T stage and N stage are related to the DFS of breast cancer patients with low HER2 expression, so more attentions should be paid to the treatment plans.

Citation： WU Xinpei, LUO Yinyi, WANG Shiming. Clinicopathologic features and prognosis of breast cancer patients with low human epidermal growth factor receptor-2 expression. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(6): 691-697. doi: 10.7507/1007-9424.202302001 Copy

1.	Loibl S, Gianni L. HER2-positive breast cancer. Lancet, 2017, 389(10087): 2415-2429.
2.	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.
3.	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.
4.	Xu Z, Guo D, Jiang Z, et al. Novel HER2-targeting antibody-drug conjugates of trastuzumab beyond T-DM1 in breast cancer: trastuzumab deruxtecan (DS-8201a) and (Vic-) trastuzumab duocarmazine (SYD985). Eur J Med Chem, 2019, 183: 111682. doi: 10.1016/j.ejmech.2019.111682.
5.	Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN guidelines insights breast cancer, version 1. 2016. J Natl Compr Canc Netw, 2015, 13(12): 1475-1485.
6.	Jiao DC, Zhu JJ, Qin L, et al. Clinical practice guidelines for modified radical mastectomy of breast cancer: Chinese Society of Breast Surgery (CSBrs) practice guidelines 2021. Chin Med J (Engl), 2021, 134(8): 895-897.
7.	Giuliano AE, Edge SB, Hortobagyi GN. Eighth edition of the AJCC cancer staging manual: breast cancer. Ann Surg Oncol, 2018, 25(7): 1783-1785.
8.	Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. Ⅰ. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology, 1991, 19(5): 403-410.
9.	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 Clin Oncol, 2013, 31(31): 3997-4013.
10.	Fitzgibbons PL, Dillon DA, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med, 2014, 138(5): 595-601.
11.	Pondé N, Brandão M, El-Hachem G, et al. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev, 2018, 67: 10-20.
12.	Andersson M, Lidbrink E, Bjerre K, et al. Phase Ⅲ randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol, 2011, 29(3): 264-271.
13.	Awada A, Colomer R, Inoue K, et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial. JAMA Oncol, 2016, 2(12): 1557-1564.
14.	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. J Clin Oncol, 2018, 36(20): 2105-2122.
15.	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.
16.	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.
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.	Rossi V, Sarotto I, Maggiorotto F, et al. Moderate immunohisto-chemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist, 2012, 17(11): 1418-1425.
19.	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. doi: 10.1016/j.clbc.2019.07.013.
20.	Zhang G, Ren C, Li C, et al. Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status. BMC Med, 2022, 20(1): 142. doi: 10.1186/s12916-022-02346-9.
21.	Tarantino P, Jin Q, Tayob N, et al. Prognostic and biologic significance of ERBB2-low expression in early-stage breast cancer. JAMA Oncol, 2022, 8(8): 1177-1183.
22.	Xin L, Wu Q, Zhan C, et al. Multicenter study of the clinicopathological features and recurrence risk prediction model of early-stage breast cancer with low-positive human epidermal growth factor receptor 2 expression in China (Chinese Society of Breast Surgery 021). Chin Med J (Engl), 2022, 135(6): 697-706.
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.	Di Fiore PP, Pierce JH, Kraus MH, et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science, 1987, 237(4811): 178-182.
25.	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.
26.	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.
27.	Mutai R, Barkan T, Moore A, et al. Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer. Breast, 2021, 60: 62-69.
28.	Li Y, Abudureheiyimu N, Mo H, et al. In real life, low-level HER2 expression may be associated with better outcome in HER2-negative breast cancer: a study of the National Cancer Center, China. Front Oncol, 2022, 11: 774577. doi: 10.3389/fonc.2021.774577.
29.	Yu KD, Jiang YZ, Chen S, et al. Effect of large tumor size on cancer-specific mortality in node-negative breast cancer. Mayo Clin Proc, 2012, 87(12): 1171-1180.
30.	Crowe JP Jr, Gordon NH, Shenk RR, et al. Primary tumor size. Relevance to breast cancer survival. Arch Surg, 1992, 127(8): 910-915.
31.	Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24 740 breast cancer cases. Cancer, 1989, 63(1): 181-187.
32.	Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4): 207. doi: 10.1186/bcr2607.
33.	Rakha EA, El-Sayed ME, Lee AH, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol, 2008, 26(19): 3153-3158.
34.	Grann VR, Troxel AB, Zojwalla NJ, et al. Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer, 2005, 103(11): 2241-2251.
35.	Kwast AB, Voogd AC, Menke-Pluijmers MB, et al. Prognostic factors for survival in metastatic breast cancer by hormone receptor status. Breast Cancer Res Treat, 2014, 145(2): 503-511.
36.	Kolarova I, Dusek L, Ryska A, et al. Impact of hormone receptor status on the behaviour of HER2+ breast cancer. In Vivo, 2020, 34(6): 3441-3449.

1. Loibl S, Gianni L. HER2-positive breast cancer. Lancet, 2017, 389(10087): 2415-2429.
2. 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.
3. 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.
4. Xu Z, Guo D, Jiang Z, et al. Novel HER2-targeting antibody-drug conjugates of trastuzumab beyond T-DM1 in breast cancer: trastuzumab deruxtecan (DS-8201a) and (Vic-) trastuzumab duocarmazine (SYD985). Eur J Med Chem, 2019, 183: 111682. doi: 10.1016/j.ejmech.2019.111682.
5. Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN guidelines insights breast cancer, version 1. 2016. J Natl Compr Canc Netw, 2015, 13(12): 1475-1485.
6. Jiao DC, Zhu JJ, Qin L, et al. Clinical practice guidelines for modified radical mastectomy of breast cancer: Chinese Society of Breast Surgery (CSBrs) practice guidelines 2021. Chin Med J (Engl), 2021, 134(8): 895-897.
7. Giuliano AE, Edge SB, Hortobagyi GN. Eighth edition of the AJCC cancer staging manual: breast cancer. Ann Surg Oncol, 2018, 25(7): 1783-1785.
8. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. Ⅰ. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology, 1991, 19(5): 403-410.
9. 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 Clin Oncol, 2013, 31(31): 3997-4013.
10. Fitzgibbons PL, Dillon DA, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med, 2014, 138(5): 595-601.
11. Pondé N, Brandão M, El-Hachem G, et al. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev, 2018, 67: 10-20.
12. Andersson M, Lidbrink E, Bjerre K, et al. Phase Ⅲ randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol, 2011, 29(3): 264-271.
13. Awada A, Colomer R, Inoue K, et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial. JAMA Oncol, 2016, 2(12): 1557-1564.
14. 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. J Clin Oncol, 2018, 36(20): 2105-2122.
15. 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.
16. 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.
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. Rossi V, Sarotto I, Maggiorotto F, et al. Moderate immunohisto-chemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist, 2012, 17(11): 1418-1425.
19. 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. doi: 10.1016/j.clbc.2019.07.013.
20. Zhang G, Ren C, Li C, et al. Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status. BMC Med, 2022, 20(1): 142. doi: 10.1186/s12916-022-02346-9.
21. Tarantino P, Jin Q, Tayob N, et al. Prognostic and biologic significance of ERBB2-low expression in early-stage breast cancer. JAMA Oncol, 2022, 8(8): 1177-1183.
22. Xin L, Wu Q, Zhan C, et al. Multicenter study of the clinicopathological features and recurrence risk prediction model of early-stage breast cancer with low-positive human epidermal growth factor receptor 2 expression in China (Chinese Society of Breast Surgery 021). Chin Med J (Engl), 2022, 135(6): 697-706.
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. Di Fiore PP, Pierce JH, Kraus MH, et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science, 1987, 237(4811): 178-182.
25. 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.
26. 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.
27. Mutai R, Barkan T, Moore A, et al. Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer. Breast, 2021, 60: 62-69.
28. Li Y, Abudureheiyimu N, Mo H, et al. In real life, low-level HER2 expression may be associated with better outcome in HER2-negative breast cancer: a study of the National Cancer Center, China. Front Oncol, 2022, 11: 774577. doi: 10.3389/fonc.2021.774577.
29. Yu KD, Jiang YZ, Chen S, et al. Effect of large tumor size on cancer-specific mortality in node-negative breast cancer. Mayo Clin Proc, 2012, 87(12): 1171-1180.
30. Crowe JP Jr, Gordon NH, Shenk RR, et al. Primary tumor size. Relevance to breast cancer survival. Arch Surg, 1992, 127(8): 910-915.
31. Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24 740 breast cancer cases. Cancer, 1989, 63(1): 181-187.
32. Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4): 207. doi: 10.1186/bcr2607.
33. Rakha EA, El-Sayed ME, Lee AH, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol, 2008, 26(19): 3153-3158.
34. Grann VR, Troxel AB, Zojwalla NJ, et al. Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer, 2005, 103(11): 2241-2251.
35. Kwast AB, Voogd AC, Menke-Pluijmers MB, et al. Prognostic factors for survival in metastatic breast cancer by hormone receptor status. Breast Cancer Res Treat, 2014, 145(2): 503-511.
36. Kolarova I, Dusek L, Ryska A, et al. Impact of hormone receptor status on the behaviour of HER2+ breast cancer. In Vivo, 2020, 34(6): 3441-3449.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Clinicopathologic features and prognosis of breast cancer patients with low human epidermal growth factor receptor-2 expression

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