Clinical and Histopathological Profile of Breast Cancer Based on HER2 Stratification ASCO/CAP 2018: Analysis of HER2-Positive, Negative, Low, and Ultralow
Main Article Content
Introduction. The emerging classification of HER2-low and HER2-ultralow breast cancer subtypes has important treatment implications, especially after the introduction of trastuzumab deruxtecan, which is effective in tumors exhibiting low levels of HER2 expression. However, data from Indonesia are still limited. This study aimed to characterize the clinicopathological features of Invasive Breast Cancer (IBC) according to the ASCO/CAP 2018 HER2 classification and to determine the proportion of HER2-negative patients who can be further categorized as HER2-low or HER2-ultralow. Methods. This retrospective descriptive-analytical study involved 50 patients diagnosed with IBC who underwent HER2 immunohistochemical evaluation at Mohammad Hoesin General Hospital, Palembang, in February 2023. The variables analyzed were age, ER/PR status, Ki-67 index, tumor-infiltrating lymphocytes (TILs), lymphovascular invasion (LVI), histological grade, and tumor subtype. Results. Of the 50 patients, 16 (32%) were categorized as HER2-positive and 34 (68%) were categorized as HER2-negative. Among the HER2-negative group, 10 patients (35.7%) were HER2-low and 5 patients (17.8%) were HER2-ultralow. The majority of patients were aged 40 years or older and ER-positive. A high Ki-67 index was observed in 84% of cases. Most tumors were grade II–III and of the NST subtype. No significant differences were observed between the HER2-low and HER2-ultralow groups (p>0.05). Conclusion. A considerable proportion of HER2-negative IBCs are categorized as HER2-low or HER2-ultralow. These findings highlight the importance of accurate HER2 assessment to identify patients who may benefit from antibody–drug conjugate therapy and to advance precision medicine in breast cancer management in Indonesia.
2. Lamb CA, Vanzulli SI, Lanari C. Hormone receptors in breast cancer: More than estrogen receptors. Medicina (B Aires). 2019;79(6–1):540–5.
3. Wolff AC, Elizabeth Hale Hammond M, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, 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. Journal of Clinical Oncology. 2018;36(20):2105–22.
4. Franchina M, Pizzimenti C, Fiorentino V, Martini M, Ricciardi GRR, Silvestris N, et al. Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes. Int J Mol Sci. 2023;24(16).
5. Ullah A, Singla RK, Cao D, Chen B, Shen B. Age-related and postmenopausal breast cancer progression and treatment management: The significance of pro-inflammatory cytokines and CXC chemokines. Genes Dis. 2025;12(5):101606.
6. Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci. 2023 Apr 6;24(7):6834.
7. Martin EM, Orlando KA, Yokobori K, Wade PA. The estrogen receptor/GATA3/FOXA1 transcriptional network: lessons learned from breast cancer. Curr Opin Struct Biol. 2021 Dec;71:65–70.
8. Cheng X. A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes (Basel). 2024;15(7).
9. Aman NA, Doukoure B, Koffi KD, Koui BS, Traore ZC, Kouyate M, et al. HER2 overexpression and correlation with other significant clinicopathologic parameters in Ivorian breast cancer women. BMC Clin Pathol. 2019 Dec 17;19(1):1.
10. Hohmann L, Sigurjonsdottir K, Campos AB, Nacer DF, Veerla S, Rosengren F, et al. Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer. Nat Commun. 2025 Mar 5;16(1):2208.
11. Hu Y, Jones D, Zhao W, Tozbikian G, Wesolowski R, Parwani A V., et al. Incidence, Clinicopathologic Features, HER2 Fluorescence In Situ Hybridization Profile, and Oncotype DX Results of Human Epidermal Growth Factor Receptor 2-Low Breast Cancers: Experience From a Single Academic Center. Modern Pathology. 2023 Jul;36(7):100164.
12. Shen G, Zhao F, Huo X, Ren D, Du F, Zheng F, et al. Meta-Analysis of HER2-Enriched Subtype Predicting the Pathological Complete Response Within HER2-Positive Breast Cancer in Patients Who Received Neoadjuvant Treatment. Front Oncol. 2021 Jul 23;11.
13. He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021 Dec 16;6(1):425.
14. Li Y, Wang C, Huang T, Yu X, Tian B. The role of cancer-associated fibroblasts in breast cancer metastasis. Front Oncol. 2023 Jul 11;13.
15. Yang X, Rao J, Yang W, Shui R. Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy. Target Oncol. 2018 Dec 7;13(6):757–67.
16. Monteran L, Erez N. The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment. Front Immunol. 2019 Aug 2;10.
17. Cheng X. A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes (Basel). 2024 Jul 11;15(7):903.
18. Kuhn E, Gambini D, Despini L, Asnaghi D, Runza L, Ferrero S. Updates on Lymphovascular Invasion in Breast Cancer. Biomedicines. 2023 Mar 21;11(3):968.
19. Schettini F, Pascual T, Conte B, Chic N, Brasó-Maristany F, Galván P, et al. HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis. Cancer Treat Rev. 2020 Mar;84:101965.
20. Shashikumar HB, Sindhushree N, Ramakrishna M, Fathima Shihana Hameed. The study of the correlation of estrogen receptor, progesterone receptor, and HER2 receptor status in breast cancer and its incidence in a tertiary center hospital in South India. Asian J Med Sci. 2022;13(7):87–91.
21. Liang Q, Ma D, Gao RF, Yu KD. Effect of Ki-67 Expression Levels and Histological Grade on Breast Cancer Early Relapse in Patients with Different Immunohistochemical-based Subtypes. Sci Rep. 2020 May 6;10(1):7648.
