ONCOLOGY / CLINICAL RESEARCH
HER2-low status in breast cancer: clinicopathological factors and prognostic value
More details
Hide details
1
Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland
Submission date: 2024-11-22
Final revision date: 2025-02-27
Acceptance date: 2025-03-09
Online publication date: 2025-04-27
Corresponding author
Joanna Huszno
Maria Sklodowska-Curie
National Research
Institute of Oncology
Gliwice Branch, Poland
KEYWORDS
TOPICS
ABSTRACT
Introduction:
This study aimed to assess the prognostic importance of HER2-low status in breast cancer (BC). Additionally, we compared the HER2-low subgroup (defined as HER2-low1+; HER2-low2+/ISH(-)) with HER2-zero and HER2-positive subgroups according to clinical, histopathological, and molecular characteristics.
Material and methods:
The study analyzed the medical records of BC patients treated at the National Institute of Oncology in Gliwice, Poland, between 2002 and 2018. HER2 overexpression was assessed in postoperative specimens or samples obtained via core needle biopsy.
Results:
Of the 657 tumors, 176 (27%) tumors were classified as HER2-low BC, 248 (38%) as HER2-zero and 233 (35%) as HER2-positive tumors. BC patients with HER2-low tumors were more likely to have hormone receptor-positive (HR+) status compared to those with HER2-zero tumors (82.4% vs. 62.1%, p < 0.001). Specifically, patients with HER2-low1+ tumors had a higher frequency of HR+ status versus both HER2-zero and HER2-positive tumors. Similarly, patients with HER2-low2+/ISH(-) tumors were more frequently characterized as HR+ compared to HER2-zero and HER2-positive patients. In the subgroup of patients with estrogen receptor negative tumors, overall survival (OS) was slightly worse than for those with HER2-low status compared to HER2-zero patients (5-year OS 72.6% vs. 86.7%, p = 0.074). Non-significantly poorer OS was noted in HER2-low1+ patients with negative prognostic factors, including HR-, progesterone receptor-negative, grade 3, and larger tumors.
Conclusions:
HER2-low status was associated with worse OS in breast cancer patients with certain negative prognostic factors compared with HER2-zero status. Additionally, HER2-low1+ and HER2-low2+/ISH(-) subgroups predominantly exhibited HR+ status.
REFERENCES (45)
1.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177-82.
2.
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-92.
3.
Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21: 519-30.
4.
Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389: 1195-205.
5.
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747-52.
6.
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: 1364-82.
7.
Antonio C, Wolff M, Elizabeth H, 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. Arch Pathol Lab Med 2014; 138: 241-56.
8.
Zhang H, Peng Y. Current biological, pathological and clinical landscape of HER2-low breast cancer. Cancers 2022; 15: 126.
9.
Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol 2020; 38: 1951-62.
10.
Petrelli F, Rea C, Parati MC, et al. Prognostic value of HER2-low satus in ER+ early breast cancer: a systematic review and meta-analysis. Anticancer Res 2023; 43: 4303-13.
11.
Fehrenbacher L, Cecchini RS, Geyer CE Jr, 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 2019; 38: 444-53.
12.
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: 1151-61.
13.
Abbasvandi F, Bayat M, Akbari A, et al. Tumor characteristics and survival rate of HER2-low breast cancer patients: a retrospective cohort study. Sci Rep 2023; 13: 16719.
14.
Agostinetto E, Rediti M, Fimereli D, et al. HER2-low breast cancer: molecular characteristics and prognosis. Cancers 2021; 13: 2824.
15.
Liu CG, Li Y, Ma T, et al. Clinicopathological characteristics and prognosis of early-stage HER2 low-expression breast cancer: a single-center retrospective study. Front Oncol 2023; 13: 1130734.
16.
Yang X, Li Y, Lu X, et al. Clinicopathological features and prognosis of patients with HER2-low breast cancer. BMC Cancer 2023; 23: 914.
17.
Hein A, Hartkopf AD, Emons J, et al. Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status. Eur J Cancer 2021; 155: 1-12.
18.
Tan RSYC, Ong WS, Lee KH, et al. HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med 2022; 20: 105.
19.
Horisawa N, Adachi Y, Takatsuka D, et al. The frequency of low HER2 expression in breast cancer and a comparison of prognosis between patients with HER2-low and HER2-negative breast cancer by HR status. Breast Cancer 2022; 29: 234-41.
20.
Ignatov T, Eggemann H, Burger E, et al. Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade. Breast Cancer Res Treat 2015; 151: 357-64.
21.
Rossi V, Sarotto I, Maggiorotto F, et al. Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplifcation is a negative prognostic factor in early breast cancer. Oncologist 2012; 17: 1418-25.
22.
Allison KH, Hammond EH, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update. Arch Pathol Labor Med 2020; 144: 545-63.
23.
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: 1887.
24.
Giuliani S, Ciniselli ChM, Leonardi E, et al. In a cohort of breast cancer screened patients the proportion of HER2 positive cases is lower than that earlier reported and pathological characteristics differ between HER2 3+ and HER2 2+/Her2 amplifed cases. Virchows Arch 2016; 469: 45-50.
25.
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: 1151-61.
26.
Miglietta F, Griguolo G, Bottosso M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer 2021; 7: 137.
27.
Khalil MA, Habibian L, Martin C, et al. Landscape of HER2-low breast cancer: Insights from a six-year study on prevalence and clinicopathological characteristics. Ann Diagn Pathol 2024; 72: 152326.
28.
Sato A, Maeda Y, Matsumoto A, Ikeda T, Jinno H. Clinicopathological features and prognosis of breast cancer with low HER2 status evaluated by fluorescence in situ hybridization. Oncol Letter 2025; 29: 92.
29.
Bergeron A, Bertaut A, Beltjens F, et al. Anticipating changes in the HER2 status of breast tumours with disease progression – towards better treatment decisions in the new era of HER2-low breast cancers. Br J Cancer 2023; 129: 122-34.
30.
Yang M, Sun J, Liu L, et al. Clinicopathological characteristics of HER2 low breast cancer: a retrospective study. Sci Rep 2023; 13: 12382.
31.
Li Y, Tsang JY, Tam F, Loong T, Tse GM. Comprehensive characterization of HER2-low breast cancers: implications in prognosis and treatment. EbioMedicine 2023; 91: 104571.
32.
de Nonneville A, Houvenaeghel G, Cohen M, et al. Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers. Eur J Cancer 2022; 176: 181-8.
33.
Zhang H, Katerji H, Turner BM, et al. HER2-low breast cancers: incidence, HER2 staining patterns, clinicopathological features, MammaPrint and BluePrint genomic profiles. Mol Pathol 2022; 35: 1075-82.
34.
Schettini F, Braso-Maristany F, Kuderer NM, Prat A. A perspective on the development and lack of interchangeability of the breast cancer intrinsic subtypes. NPJ Breast Cancer 2022; 8: 85.
35.
Ignatov A, Lempfer S, Mészáros J, Eggemann H. Prognostic impact of HER2 low status in male breast cancer: prospective cohort analysis. Cancers 2024; 16: 3399.
36.
Tarantino P, Viale G, Press MF, et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer. Ann Oncol 2023; 34: 645-59.
37.
Won HS, Ahn J, Kim Y, et al. Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res 2022; 24: 22.
38.
da Silva JL, de Souza Carvalho G, de Albuquerque LZ, et al. Exploring real-world HER2-low data in early-stage triple-negative breast cancer: insights and implications. Breast Cancer 2023; 15: 337-47.
39.
Molinelli C, Jacobs F, Agostinetto E, et al. Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis. ESMO Open 2023; 8: 101592.
40.
Ma Y, Jiao D, Zhang J, et al. HER2-low status was associated with better breast cancer-specific survival in early-stage triple-negative breast cancer. Oncologist 2024; 29: e309-18.
41.
Zattarin E, Presti D, Mariani L, et al. Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors. Breast Cancer 2023; 9: 27.
42.
Guven DC, Sahin TK. The association between HER2 low status and survival in patients with metastatic breast cancer treated with Cyclin dependent kinases 4 and 6 inhibitors: a systematic review and meta analysis. Breast Cancer Res Treat 2024; 204: 443-52.
43.
Xu H, Han Y, Wu Y, et al. Clinicopathological characteristics and prognosis of HER2-low early-stage breast cancer: a single-institution experience. Front Oncol 2022; 12: 906011.
44.
Park WK, Nam SJ, Kim SW, et al. The impact of HER2-low expression on oncologic outcomes in hormone receptor-positive breast cancer. Cancers 2023; 15: 5361.
45.
Şen GA, Aydın E, Guliyev M, et al. The impact of HER2-low status on pathological complete response and disease-free survival in early-stage breast cancer. BMC Cancer 2024; 24: 1311.