{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:06:22Z","timestamp":1790723182676,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objective: The clinical success of novel antibody-drug conjugates has led to the identification of a new subgroup within traditionally HER2-negative breast cancers, termed \u2018HER2-low.\u2019 The aim of this study was to investigate the clinicopathological differences between HER2-low and HER2-negative groups in neoadjuvant-naive primary breast cancer patients, with a specific focus on stromal tumor-infiltrating lymphocyte (sTIL) density. Materials and Methods: The study included 731 neoadjuvant-naive invasive breast cancer patients. Tumors were classified as HER2-negative (IHC 0) and HER2-low (IHC 1+ or 2+\/ISH-negative). sTIL levels were evaluated following the International TILs Working Group guidelines. Results: The HER2-low group (38.7%) demonstrated significantly higher histological grade (p = 0.033) and higher sTIL density (p = 0.006) compared to the HER2-negative group. A stepwise increase in sTIL rates was observed parallel to the HER2 immunohistochemical score (0 \u2192 1+ \u2192 2+) (p = 0.015). The HER2-low\/hormone receptor (HR)-negative subgroup exhibited the highest sTIL density (median 35%). No statistically significant difference in overall or disease-free survival was found between the groups. Conclusions: HER2-low breast cancers were associated with a more immunogenic tumor microenvironment compared to HER2-negative tumors. This robust immune infiltration may offset the higher histological grade observed in the HER2-low cohort, potentially explaining the comparable survival outcomes. These findings provide a biological rationale for exploring the synergy between novel antibody\u2013drug conjugates and immune checkpoint inhibitors, particularly in the highly immunogenic HER2-low\/HR-negative subgroup.<\/jats:p>","DOI":"10.3390\/medicina62050826","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparison of Stromal Tumor-Infiltrating Lymphocyte (sTIL) Levels and Clinicopathological Features in Neoadjuvant-Naive HER2-Low and HER2-Negative Primary Breast Cancers"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-6105","authenticated-orcid":false,"given":"M\u00fcmin","family":"Emiro\u011flu","sequence":"first","affiliation":[{"name":"Department of Pathology, Elaz\u0131\u011f Fethi Sekin City Hospital, Elaz\u0131\u011f 23100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra Canan","family":"Kelten Talu","sequence":"additional","affiliation":[{"name":"Department of Pathology, UHS Izmir Faculty of Medicine, Izmir Tepecik Education and Research Hospital, Izmir 35020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem","family":"Karaali","sequence":"additional","affiliation":[{"name":"Department of General Surgery, UHS Izmir Faculty of Medicine, Izmir Tepecik Education and Research Hospital, Izmir 35020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7698-3574","authenticated-orcid":false,"given":"Ol\u00e7un \u00dcmit","family":"\u00dcnal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, UHS Faculty of Medicine, Izmir City Hospital, Izmir 35540, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-5923","authenticated-orcid":false,"given":"Mihriban","family":"Erdo\u011fan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, UHS Faculty of Medicine, Izmir City Hospital, Izmir 35540, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xu, H., Han, Y., Wu, Y., Wang, Y., Li, Q., Zhang, P., Yuan, P., Luo, Y., Fan, Y., and Chen, S. (2022). Clinicopathological Characteristics and Prognosis of HER2-Low Early-Stage Breast Cancer: A Single-Institution Experience. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.906011"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S1470-2045(21)00301-6","article-title":"Clinical and molecular characteristics of HER2-low-positive breast cancer: Pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials","volume":"22","author":"Denkert","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41379-022-01019-5","article-title":"HER2-low breast cancers: Incidence, HER2 staining patterns, clinicopathologic features, MammaPrint and BluePrint genomic profiles","volume":"35","author":"Zhang","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"700","DOI":"10.4143\/crt.2023.1138","article-title":"HER2-Low Breast Cancer: Now and in the Future","volume":"56","author":"Kang","year":"2024","journal-title":"Cancer Res. Treat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1001\/jamaoncol.2022.7476","article-title":"Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database","volume":"9","author":"Peiffer","year":"2023","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13058-021-01492-x","article-title":"Landscape of HER2-low metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-Registry","volume":"23","author":"Gampenrieder","year":"2021","journal-title":"Breast Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jacot, W., Maran-Gonzalez, A., Massol, O., Sorbs, C., Mollevi, C., Guiu, S., Boissi\u00e8re-Michot, F., and Ramos, J. (2021). Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers. Cancers, 13.","DOI":"10.3390\/cancers13236059"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Agostinetto, E., Rediti, M., Fimereli, D., Debien, V., Piccart, M., Aftimos, P., Sotiriou, C., and de Azambuja, E. (2021). HER2-Low Breast Cancer: Molecular Characteristics and Prognosis. Cancers, 13.","DOI":"10.3390\/cancers13112824"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13058-024-01783-z","article-title":"HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer: Are they connected?","volume":"26","author":"Ende","year":"2024","journal-title":"Breast Cancer Res."},{"key":"ref_10","unstructured":"WHO Classification of Tumours Editorial Board (2026). Breast Tumours in WHO Classification of Tumours Series, International Agency for Research on Cancer. [6th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s10549-023-07079-8","article-title":"Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients","volume":"202","author":"Chen","year":"2023","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e470","DOI":"10.1016\/j.clbc.2023.07.007","article-title":"Tumor-Infiltrating Lymphocytes in HER2-Low Breast Cancer","volume":"23","author":"Fernandes","year":"2023","journal-title":"Clin. Breast Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41416-023-02287-x","article-title":"Anticipating changes in the HER2 status of breast tumours with disease progression\u2014Towards better treatment decisions in the new era of HER2-low breast cancers","volume":"129","author":"Bergeron","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41523-022-00434-w","article-title":"HER2-low-positive breast cancer: Evolution from primary tumor to residual disease after neoadjuvant treatment","volume":"8","author":"Miglietta","year":"2022","journal-title":"npj Breast Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1200\/JOP.18.00206","article-title":"HER2 Testing in Breast Cancer: American Society of Clinical Oncology\/College of American Pathologists Clinical Practice Guideline Focused Update Summary","volume":"14","author":"Wolff","year":"2018","journal-title":"J. Oncol. Pract."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1200\/JCO.19.02309","article-title":"Estrogen and progesterone receptor testing in breast cancer: ASCO\/CAP guideline update","volume":"38","author":"Allison","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/annonc\/mdu450","article-title":"The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014","volume":"26","author":"Salgado","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16264","DOI":"10.1002\/cam4.6290","article-title":"Clinical characteristics, tumor-infiltrating lymphocytes, and prognosis in HER2-low breast cancer: A comparison study with HER2-zero and HER2-positive disease","volume":"12","author":"Lu","year":"2023","journal-title":"Cancer Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rodrigues, P.R., Lopes-Concei\u00e7\u00e3o, L., Sousa, V., Coutada, A., Bento, M.J., Coimbra, N., Leal, C., Pereira, D., and Ferreira, A.M. (2025). The clinicopathological characteristics, oncologic outcomes and costs of \u201cHER2-low\u201d early breast cancer compared to HER2-zero and HER2-positive: A single-centre retrospective analysis. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1579602"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103666","DOI":"10.1016\/j.breast.2023.103666","article-title":"Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy","volume":"73","author":"Shao","year":"2023","journal-title":"Breast"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Takada, K., Kashiwagi, S., Nishikawa, M., Kochi, A., Watanabe, C., Kinoshita, H., Ogisawa, K., Shibutani, M., and Morisaki, T. (2025). Clinical characteristics and prognostic impact of HER2-ultralow breast cancer and tumor-infiltrating lymphocytes (TILs). BMC Cancer, 25.","DOI":"10.1186\/s12885-025-15255-w"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41523-020-00208-2","article-title":"Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer","volume":"7","author":"Schettini","year":"2021","journal-title":"npj Breast Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1200\/JCO.19.02488","article-title":"HER2-Low Breast Cancer: Pathological and Clinical Landscape","volume":"38","author":"Tarantino","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13058-023-01639-y","article-title":"Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low","volume":"25","author":"Hu","year":"2023","journal-title":"Breast Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sanomachi, T., Okuma, H.S., Kitadai, R., Kawachi, A., Yazaki, S., Tokura, M., Arakaki, M., Saito, A., Kita, S., and Yamamoto, K. (2023). Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1157789"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1007\/s12094-025-03921-1","article-title":"Prognostic and recurrence risk predictive values of tumor infiltrating lymphocytes in HER2-low breast cancer","volume":"27","author":"Song","year":"2025","journal-title":"Clin. Transl. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"oyaf054","DOI":"10.1093\/oncolo\/oyaf054","article-title":"Tumor-infiltrating lymphocytes as predictive biomarkers in neoadjuvant treatment of HER2-positive breast cancer","volume":"30","author":"Bal","year":"2025","journal-title":"Oncologist"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1007\/s12282-021-01303-3","article-title":"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","volume":"29","author":"Horisawa","year":"2021","journal-title":"Breast Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4048\/jbc.2024.0223","article-title":"Differences in HER2-0 and HER2-low Breast Cancer: Androgen Receptor and Programmed Death Ligand 1 as Predictive Factors","volume":"28","author":"Zhang","year":"2025","journal-title":"J. Breast Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Miligy, I.M., Badr, N., Stevens, A., Spooner, D., Awasthi, R., Mir, Y., Khurana, A., Sharma, V., Chandaran, U., and Rakha, E.A. (2024). Pathological Changes Following Neoadjuvant Endocrine Therapy (NAET): A Multicentre Study of 391 Breast Cancers. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137381"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"75","DOI":"10.5114\/wo.2024.139375","article-title":"High tumour-infiltrating lymphocytes correlate with distinct gene expression profile and favourable survival in single hormone receptor-positive breast cancer","volume":"28","author":"Ciarka","year":"2024","journal-title":"Wspolczesna Onkol. Oncol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/826\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T14:19:12Z","timestamp":1777472352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":31,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["medicina62050826"],"URL":"https:\/\/doi.org\/10.3390\/medicina62050826","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,27]]}}}