Prognostic difference between early breast cancer patients with HER2-low and HER2-zero status: A multicenter cohort study using propensity-score matched analysis

Prognostic difference between early breast cancer patients with HER2-low and HER2-zero status: A multicenter cohort study using propensity-score matched analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Prognostic difference between early breast cancer patients with HER2-low and HER2-zero status: A multicenter cohort study using propensity-score matched analysis Min Sung Chung, Chihwan CHA, Kyung Eun Kim, Jungbin Kim, Eunhae Um, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5235910/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2025 Read the published version in npj Breast Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background Since the approval of the trastuzumab deruxtecan for human epidermal growth factor receptor 2 (HER2)-low breast cancer, evidence suggests that low-HER2 expression may affect prognosis; however, it remains unclear how HER2-low subtype affects outcomes. Thus, this study aimed to investigate the differences in prognosis between patients with HER2-low and HER2-zero status. Methods This retrospective cohort study conducted at multi-institution included 1,627 patients diagnosed with HER2-low or HER2-zero breast cancer (stages I–III). For comparing outcomes between two groups, the survival analysis after propensity score matching was used. Survival outcomes including distant recurrence-free survival, and overall survival were evaluated using the Kaplan–Meier analyses. Results After propensity score matching, 445 patients with HER2-low and 707 patients with HER2-zero status were included. Among them, 914 (79.3%) and 238 (20.7%) patients had hormone receptor-positive and -negative disease. Median follow-up was 92.7 months. Locoregional recurrence-free survival and distant recurrence-free survival were comparable between patients with HER2-low and HER2-zero status ( p = 0.872, p = 0.746, respectively). HER2-low status did not affect overall survival. However, in a subgroup with lymph node metastases, patients with HER2-low status showed better recurrence-free survival compared with that of patients with HER2-zero status ( p = 0.033). Conclusions In this study, survival outcomes were comparable between patients with HER2-low and HER2-zero breast cancer. Additionally, patients with HER2-low status showed better survival outcomes compared with those with HER2-zero in the subgroup with lymph node metastasis. Further studies are needed to examine the biological mechanism underlying these prognostic differences. Health sciences/Oncology/Cancer/Breast cancer Biological sciences/Cancer/Breast cancer Figures Figure 1 Figure 2 Figure 3 Background Breast cancer with the low expression of human epidermal growth factor receptor 2 (HER2) has been previously classified as luminal or triple negative subtype, but the low HER2 expression has not been considered in treatment selection. With the emergence of novel anti-HER2 antibody–drug conjugates (trastuzumab deruxtecan, T-Dxd), clinical trial results 1 have suggested that HER2-low positive breast cancer may be a clinically and biologically distinct disease entity 2 – 4 . Some previous studies have reported on the prognostic implication of low HER2 expression; however, their findings were inconsistent, and the evidence remains insufficient to draw any conclusions 5 – 8 . Pooled analysis using previous prospective data by Denkert et al. showed that patients with HER2-low positive breast cancer had significantly better survival outcomes than those with HER2-zero (immunohistochemistry score of 0, no staining) breast cancer 9 . However, another nationwide study of more than 30,000 patients reported comparable overall survival (OS) outcomes for patients with HER2-low and HER2-zero breast cancer 10 . It remains unclear how low HER2 expression affects survival outcomes in patients with breast cancer. Additional evidence is required to elucidate the contribution of this factor to prognostication in this patient group. This study aimed to investigate the differences in survival outcomes between patients with HER2-low and HER2-zero breast cancer types, using propensity-score matching. The secondary aim of this study was to examine factors associated with survival in patients with HER2-low status. Methods Patients with primary breast cancer who underwent curative surgery between January 2012 and December 2017 were retrospectively identified from four institutions in South Korea. The inclusion criteria comprised patients aged 18–75 years with invasive breast cancer (pT1-3, N0-3). The exclusion criteria were patients with de novo metastasis and those with pregnancy-associated breast cancer. The primary outcomes of interest in this study were locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), recurrence-free survival (RFS), and OS, which were compared between the patient groups. LRRFS was defined as the duration from diagnosis until the development of a recurrence in the breast or chest wall and/or regional lymph nodes on the side previously affected by cancer. DRFS was defined as the duration from diagnosis until the development of a recurrence in a distant organ. RFS was defined as the duration from diagnosis until any type of disease recurrence was detected. OS was defined as the duration from diagnosis until death. Data on demographics such as age at the time of surgery, menopause status, date of diagnosis, and family history were collected. Pathologic information, including disease stage, tumor size, number of metastatic lymph nodes, histologic grade, Ki-67, hormone receptor (HR) status, and HER2 status, was documented. Surgical details, such as surgery date, the type of surgery performed (breast conserving surgery or mastectomy), any axillary surgery (no axillary surgery, sentinel lymph node biopsy alone, or axillary lymph node dissection), and post-operative complications, were recorded. Furthermore, we documented additional treatments received, including neoadjuvant or adjuvant chemotherapy, hormone therapy, target therapy, and radiation therapy. All instances of breast cancer recurrence, including locoregional recurrence, distant recurrence, and recurrence-free survival, were recorded during the follow-up period. The patient selection process is summarized in Fig. 1 . HER2-low breast cancer was defined as the breast cancer with immunohistochemistry (IHC) 1+, or 2 + and in-situ hybridization (ISH)-negative status. Among 1,794 patients diagnosed with primary breast cancer between January 1, 2012, and December 31, 2017, those with ductal carcinoma in situ and insufficient survival data were excluded. Finally, 1,152 patients were included in the analysis, including 707 patients with HER2-zero status and 445 patients with HER2-low status, after 1:2 propensity score matching. This study was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2022-12-034), and followed the Declaration of Helsinki that protect human subjects in medical research. Statistical analyses The clinicopathological characteristics were compared between two groups using the Student’s t-test, chi-square test and Fisher’s exact test. To mitigate the effects of any selection bias due to the retrospective nature of the study, propensity score matching with the greedy nearest neighbor method was used for all covariates to adjust for confounding factors in each group. The covariates were age, pathologic tumor stage, pathologic nodal stage, hormone receptor status, histologic grade and adjuvant treatment (hormone therapy, radiation therapy, and chemotherapy. Each treated unit was matched with one control unit (1:2 greedy nearest neighbor matching method). After propensity score matching, the chi-square test, Fisher exact test, and t -test were performed to assess the balance between the two groups. The caliper was set to 0.01, maintaining the absolute value of the difference in logits of propensity scores at ≤ 0.01. Survival curves were estimated using the Kaplan–Meier method, and the log-rank test was used to compare LRRFS, DRFS, RFS, and OS rates between two groups. To calculate the hazard ratio for survival outcomes, along with the corresponding 95% confidence interval (CI), we conducted the Cox proportional hazards regression analysis. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Results We retrospectively collected information on 1,627 patients with primary breast cancer with HER2-low or HER2-zero status. Before propensity score matching, there was no difference in age at diagnosis or TNM stage between two groups. However, patients with HER2-zero showed lesser HR positive tumor ( p = 0.010) and higher histologic tumor grade ( p = 0.005); they received more chemotherapy ( p < 0.001) and less hormone therapy (p = 0.012), compared with their counterparts (eTable 1). After adjusting for confounding factors using 1:2 propensity score matching, 445 (38.6%) patients with HER2-low status and 707 (61.4%) patients with HER2-zero status were included in the analysis (Table 1 ). Clinicopathologic variables including age, tumor stage, nodal stage, HR status, and histologic grade were well-balanced between the two groups. Furthermore, the rates of chemotherapy, radiotherapy, and hormone therapy were comparable between the groups. The mean age of the patients in the HER2-low status group was 51.4 years, and most of them had a tumor size < 2 cm; additionally, a quarter of them had a poor tumor grade, and 89.9% received chemotherapy. Table 1 Comparison of clinicopathologic factors based on HER2 status after 1:2 propensity score matching Variables All patients (N = 1,152) p HER2-zero (N = 707) HER2-low (N = 445) Age, years (mean ± SD) 50.9 ± 10.6 51.4 ± 10.0 0.469 Breast surgery 0.153 Breast conservation 421 (59.5) 274 (61.6) Mastectomy 286 (40.5) 169 (38.0) Unknown - 2 (0.4) Pathologic tumor stage 0.999 T1 417 (59.0) 262 (58.9) T2 255 (36.1) 161 (36.2) T3 35 (4.9) 22 (4.9) Pathologic nodal stage 0.952 N0 478 (67.6) 305 (68.5) N1 149 (21.1) 94 (21.1) N2 45 (6.4) 27 (6.1) N3 35 (4.9) 19 (4.3) Hormone receptor status 0.556 Positive 557 (78.8) 357 (80.2) Negative 150 (21.2) 88 (19.8) Histologic grade 0.638 1 158 (22.3) 88 (19.8) 2 327 (46.3) 217 (48.8) 3 187 (26.4) 114 (25.6) Unknown 35 (5.0) 26 (5.8) Chemotherapy 0.101 Yes 655 (92.6) 400 (89.9) No 52 (7.4) 45 (10.1) Radiotherapy 0.728 Yes 482 (68.2) 299 (67.2) No 225 (31.8) 146 (32.8) Hormone therapy 0.862 Yes 545 (77.1) 345 (77.5) No 162 (22.9) 100 (22.5) *Variables are indicated as frequency (%) or mean ± standard deviation (SD) **Age, pathologic tumor stage, pathologic nodal stage, histologic grade, hormone receptor status, chemotherapy, radiotherapy, and hormone therapy were adjusted using propensity score matching. HER2, human epidermal growth factor receptor 2 In the matched cohort, 914 (79.3%) patients had HR-positive breast cancer, and 238 (20.7%) had HR-negative cancer. The clinicopathological characteristics of the patients in the HER2-low and HER2-zero groups, stratified by HR status, were comparable (eTable 2). In the HR-positive / HER2-low subgroup (n = 357), approximately 40% of patients had a tumor size > 2 cm, and 30.5% had nodal metastasis, while 89.1% and 91.0% received chemotherapy and hormone therapy, respectively. In the HR-negative / HER2-low subgroup (n = 88), approximately 46.6% of patients had a tumor size > 2 cm, and 35.2% of patients had a nodal metastasis, while nearly all of them (93.2%) received chemotherapy. The use of adjuvant treatments did not differ between patients according to HER2 status and either HR-positive or HR-negative breast cancer. Survival outcomes according to HER2 status The median follow-up time was 92.7 months (range, 0.3–273.1 months). During the follow-up period, 79 and 68 cases of recurrence and death from any cause, respectively, were observed in the matched cohort. The 5-year OS rates for patients with HER2-low and HER2-zero were 95.4% and 97.6%, respectively. The corresponding 5-year disease-free survival rates were 96.6% and 95.0%, respectively. The Kaplan–Meier survival curves revealed no differences in OS, RFS, LRRFS, or DRFS rates between the groups ( p = 0.293, p = 0.080, p = 0.872, p = 0.746, respectively) (Fig. 2 ). The Cox regression analysis results showed that HER2-low status did not affect survival outcomes (OS: hazard ratio, 1.298; 95% CI, 0.798–2.112; p = 0.294, RFS: hazard ratio, 0.639; 95% CI, 0.386–1.059; p = 0.082) (Table 2 ). Table 2 Cox regression analysis of HER2 expression for survival outcomes in matched patients HR (95% CI) p Death 1.298 (0.798–2.112) 0.294 RFS 0.639 (0.386–1.059) 0.082 LRRFS 1.049 (0.585–1.884) 0.872 DRFS 0.929 (0.593–1.454) 0.746 *Hazard ratio (HR) is calculated for patients with HER2-low status based on HER2-zero status CI, confidence interval; HER2, human epidermal growth factor receptor 2; RFS, recurrence-free survival; LRRFS, locoregional recurrence-free survival; DRFS, distant recurrence-free survival The HR-status was not associated with survival outcomes in either the HER2-low or HER2-zero group. Among patient with HR-positive subtype, the Kaplan–Meier survival curves revealed no differences in OS, RFS, LRRFS, or DRFS rates between the groups ( p = 0.484, p = 0.065, p = 0.996, p = 0.630, respectively, eFigure 1). Among patient with HR-negative subtype, there was no statistical difference in survival curves as well (eFigure 2). Similarly, in Cox regression analyses, the HER2-low status did not affect prognosis in subgroups according to the HR-status (eTable 3). Additionally, the cohort was divided into subgroups based on lymph node metastasis. Among 369 patients with lymph node metastasis, the RFS rates of patients with HER2-low status were higher than those of patients with HER2-zero status ( p = 0.033, Fig. 3 ). Discussion Since the phase 3 clinical trial DESTINY-Breast 04 demonstrated the efficacy of T-Dxd in the treatment of metastatic HER2-low breast cancer, several studies have investigated the prognostic implications of HER2-low status 11 – 14 . However, evidence has been inconsistent, and the impact of HER2-low status on outcomes remains unclear. Thus, this study aimed to examine the survival outcomes of patients with HER-low status after propensity score matching, showing comparable long-term outcomes in patients with HER2-low and HER2-zero status. Additionally, patients with HER2-low status showed better survival outcomes compared with those with HER2-zero in the subgroup with lymph node metastasis. Our findings are in line with those of previous studies. A nationwide study using a large retrospective registry dataset reported that OS rates were comparable between these groups 10 . However, some evidence suggests that breast cancer-specific survival rates may be better in patients with HER2-low status, especially those in the HR-negative subgroup, than in their counterparts. Nevertheless, this nationwide study lacked recurrence data and did not adjust for confounders, despite the risk of selection bias. Additionally, it had missing data on some prognostic variables included in multivariate analysis. In contrast, the present study analyzed long-term survival and disease recurrence data after adjusting several confounding factors. Subgroup analysis among patients with lymph node metastasis demonstrated that patients with HER2-low status had better RFS than patients with HER2-zero, suggesting that the clinical impact of low HER2 expression may differ depending on lymph node status. These results are consistent with those of previous studies. Mutai et al., in a study of 608 patients with HR-positive breast cancer, reported that HER2-low status was associated with improved OS and RFS rates compared with those associated with HER-zero status in patients with high genomic risk 13 . Other studies have suggested that HER2-low status may be associated with a better prognosis compared with that associated with HER2-negative status in high-risk tumors, such as HR-negative tumors without a pathological complete response after neoadjuvant therapy, or those treated without any adjuvant therapy 15 . The mechanisms of these effects remain unclear and may be linked to some biological differences. However, improved outcomes may be achieved without anti-HER2 therapy, suggesting that HER2-low status may be a biological marker rather than an oncogenic driver in these subgroups. Gene expression analysis by Schettini et al. showed that proliferation-related genes were significantly downregulated, and luminal-related genes were upregulated in HER2-low breast cancer 4 . In addition, several pathologic characteristics related to reduced tumor aggressiveness, such as low Ki-67 labeling index, low tumor grade, and absence of lymphatic invasion, have been associated with HER2-low breast cancer 16 – 18 . As we lacked the relevant data, we could not test this hypothesis. Further research, including studies using in-depth molecular profiling and functional genomic analysis, is required to elucidate these effects. In a study by Park et al., oncologic outcomes differed according to menopausal status among patients with HR-positive/HER2-low status 19 . Among postmenopausal patients with breast cancer, RFS and OS rates were higher in the HER2-low subgroup than in the HER2-zero subgroup. The authors proposed that the main cause of this difference in prognosis was the late recurrence in the luminal subtype. However, herein, after adjusting for patient age and endocrine therapy using propensity score matching, no difference in survival outcomes was observed between patients with the HER2-low and HER2-zero status. Moreover, the HER2-low status did not seem to affect disease prognosis in the subgroups defined by HR expression. Further studies are needed to understand outcome patterns according to HER2-low status. Our study had some limitations. First, this was a retrospective study, likely subject to selection bias. To overcome the limitations of retrospective analyses, we conducted propensity score matching by adjusting for several important prognostic factors, helping address the limitations of some previous studies. Second, data on the HER2 status were based on local pathology reports, and no central confirmation of pathological assessment was performed. Although all participating institutions adhered to the guidelines of the American Society of Clinical Oncology/College of American Pathologists, the reproducibility of the reported results, especially those for immunohistochemistry scores of 0 or 1+, is not guaranteed. Third, in the matched sample, over 85% of all patients had received systemic chemotherapy. This skew may have affected the reported estimates, affecting generalizability of the findings to patients that do not undergo chemotherapy. Conclusions In conclusion, our study reported comparable survival outcomes between patients with HER2-low and HER2-zero breast cancer. In the subgroup with lymph node metastasis, the HER2-low status was associated with better survival outcomes than those with HER2-zero status. Further studies are needed to reveal the biological mechanisms underlying this prognostic difference between HER2-low and HER2-zero status. Abbreviations DRFS distant recurrence-free survival HER2 human epidermal growth factor receptor 2 HR hormone receptor IHC immunohistochemistry ISH in-situ hybridization LRRFS locoregional recurrence-free survival OS overall survival RFS recurrence-free survival Declarations Ethics approval and consent to participate: This study was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2022-12-034), and followed the Declaration of Helsinki that protect human subjects in medical research. Consent for publication: Not applicable Data availability: Research data that support the findings of this study are securely stored in an institutional repository and are available to share from the corresponding author upon reasonable request. Competing interests: The authors declare no conflict of interest. Author contributions Concept and design: CDC, MSC Acquisition, analysis, or interpretation of data: KEK, JK, EU, JL, GG, JIK Drafting of the manuscript: CDC, MSC Statistical analysis: NC Supervision: CDC, MSC Acknowledgements: This study was supported by the research fund of Hanyang University (HY- 02300000003523). The authors would like to thank Editage (www.editage.co.kr) for English language editing. References Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 387, 9–20, doi: 10.1056/NEJMoa2203690 (2022). Agostinetto, E. et al. HER2-Low Breast Cancer: Molecular Characteristics and Prognosis. Cancers (Basel) 13, doi: 10.3390/cancers13112824 (2021). Zhang, G. 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 20, 142, doi: 10.1186/s12916-022-02346-9 (2022). Schettini, F. et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5235910","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":371886079,"identity":"b6978aea-3661-448e-961f-f4e57c48a69f","order_by":0,"name":"Min Sung 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Gwak","email":"","orcid":"","institution":"Breast cancer center, Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University,","correspondingAuthor":false,"prefix":"","firstName":"Geumhee","middleName":"","lastName":"Gwak","suffix":""},{"id":371886087,"identity":"a785874a-9007-4ee4-96d7-c8accd08149f","order_by":8,"name":"Jae Il Kim","email":"","orcid":"","institution":"Department of Surgery, Inje University Ilsan Paik Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Il","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2024-10-10 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2","display":"","copyAsset":false,"role":"figure","size":364154,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/2d5ca0d70ce4ec0f3f99c3cd.jpg"},{"id":69437872,"identity":"f38266e1-4652-4fdf-86c4-96a9f9013f17","added_by":"auto","created_at":"2024-11-20 10:52:08","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":268751,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/389572cc7a46eb857906a886.jpg"},{"id":79333311,"identity":"5b7dce17-bee5-4e2f-a72b-a9245b914ada","added_by":"auto","created_at":"2025-03-27 07:12:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1566158,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/191d6091-57b1-4ab0-a5da-6f8d73ae91d9.pdf"},{"id":69437875,"identity":"950fe379-5dee-456d-9935-882de762d60b","added_by":"auto","created_at":"2024-11-20 10:52:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28786,"visible":true,"origin":"","legend":"","description":"","filename":"eTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/4267a682398f71b9b47e247d.docx"},{"id":69437876,"identity":"719052cb-55b6-4dcb-a589-bed2218b51c7","added_by":"auto","created_at":"2024-11-20 10:52:08","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":352554,"visible":true,"origin":"","legend":"","description":"","filename":"Fige1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/555d0481af4083b0a937923d.jpg"},{"id":69439125,"identity":"f0d69d85-b940-4c02-87eb-b1365c5d8dd3","added_by":"auto","created_at":"2024-11-20 11:00:08","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":351266,"visible":true,"origin":"","legend":"","description":"","filename":"Fige2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5235910/v1/96c7236856497bb50517cb52.jpg"}],"financialInterests":"(Not answered)","formattedTitle":"Prognostic difference between early breast cancer patients with HER2-low and HER2-zero status: A multicenter cohort study using propensity-score matched analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eBreast cancer with the low expression of human epidermal growth factor receptor 2 (HER2) has been previously classified as luminal or triple negative subtype, but the low HER2 expression has not been considered in treatment selection. With the emergence of novel anti-HER2 antibody\u0026ndash;drug conjugates (trastuzumab deruxtecan, T-Dxd), clinical trial results \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e have suggested that HER2-low positive breast cancer may be a clinically and biologically distinct disease entity \u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSome previous studies have reported on the prognostic implication of low HER2 expression; however, their findings were inconsistent, and the evidence remains insufficient to draw any conclusions \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Pooled analysis using previous prospective data by Denkert et al. showed that patients with HER2-low positive breast cancer had significantly better survival outcomes than those with HER2-zero (immunohistochemistry score of 0, no staining) breast cancer \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. However, another nationwide study of more than 30,000 patients reported comparable overall survival (OS) outcomes for patients with HER2-low and HER2-zero breast cancer \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt remains unclear how low HER2 expression affects survival outcomes in patients with breast cancer. Additional evidence is required to elucidate the contribution of this factor to prognostication in this patient group. This study aimed to investigate the differences in survival outcomes between patients with HER2-low and HER2-zero breast cancer types, using propensity-score matching. The secondary aim of this study was to examine factors associated with survival in patients with HER2-low status.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatients with primary breast cancer who underwent curative surgery between January 2012 and December 2017 were retrospectively identified from four institutions in South Korea. The inclusion criteria comprised patients aged 18\u0026ndash;75 years with invasive breast cancer (pT1-3, N0-3). The exclusion criteria were patients with \u003cem\u003ede novo\u003c/em\u003e metastasis and those with pregnancy-associated breast cancer. The primary outcomes of interest in this study were locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), recurrence-free survival (RFS), and OS, which were compared between the patient groups. LRRFS was defined as the duration from diagnosis until the development of a recurrence in the breast or chest wall and/or regional lymph nodes on the side previously affected by cancer. DRFS was defined as the duration from diagnosis until the development of a recurrence in a distant organ. RFS was defined as the duration from diagnosis until any type of disease recurrence was detected. OS was defined as the duration from diagnosis until death.\u003c/p\u003e \u003cp\u003eData on demographics such as age at the time of surgery, menopause status, date of diagnosis, and family history were collected. Pathologic information, including disease stage, tumor size, number of metastatic lymph nodes, histologic grade, Ki-67, hormone receptor (HR) status, and HER2 status, was documented. Surgical details, such as surgery date, the type of surgery performed (breast conserving surgery or mastectomy), any axillary surgery (no axillary surgery, sentinel lymph node biopsy alone, or axillary lymph node dissection), and post-operative complications, were recorded. Furthermore, we documented additional treatments received, including neoadjuvant or adjuvant chemotherapy, hormone therapy, target therapy, and radiation therapy. All instances of breast cancer recurrence, including locoregional recurrence, distant recurrence, and recurrence-free survival, were recorded during the follow-up period.\u003c/p\u003e \u003cp\u003eThe patient selection process is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. HER2-low breast cancer was defined as the breast cancer with immunohistochemistry (IHC) 1+, or 2\u0026thinsp;+\u0026thinsp;and in-situ hybridization (ISH)-negative status. Among 1,794 patients diagnosed with primary breast cancer between January 1, 2012, and December 31, 2017, those with ductal carcinoma \u003cem\u003ein situ\u003c/em\u003e and insufficient survival data were excluded. Finally, 1,152 patients were included in the analysis, including 707 patients with HER2-zero status and 445 patients with HER2-low status, after 1:2 propensity score matching.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis study was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2022-12-034), and followed the Declaration of Helsinki that protect human subjects in medical research.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe clinicopathological characteristics were compared between two groups using the Student\u0026rsquo;s t-test, chi-square test and Fisher\u0026rsquo;s exact test. To mitigate the effects of any selection bias due to the retrospective nature of the study, propensity score matching with the greedy nearest neighbor method was used for all covariates to adjust for confounding factors in each group. The covariates were age, pathologic tumor stage, pathologic nodal stage, hormone receptor status, histologic grade and adjuvant treatment (hormone therapy, radiation therapy, and chemotherapy. Each treated unit was matched with one control unit (1:2 greedy nearest neighbor matching method). After propensity score matching, the chi-square test, Fisher exact test, and \u003cem\u003et\u003c/em\u003e-test were performed to assess the balance between the two groups. The caliper was set to 0.01, maintaining the absolute value of the difference in logits of propensity scores at \u0026le;\u0026thinsp;0.01.\u003c/p\u003e \u003cp\u003eSurvival curves were estimated using the Kaplan\u0026ndash;Meier method, and the log-rank test was used to compare LRRFS, DRFS, RFS, and OS rates between two groups. To calculate the hazard ratio for survival outcomes, along with the corresponding 95% confidence interval (CI), we conducted the Cox proportional hazards regression analysis. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe retrospectively collected information on 1,627 patients with primary breast cancer with HER2-low or HER2-zero status. Before propensity score matching, there was no difference in age at diagnosis or TNM stage between two groups. However, patients with HER2-zero showed lesser HR positive tumor (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) and higher histologic tumor grade (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005); they received more chemotherapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and less hormone therapy (p\u0026thinsp;=\u0026thinsp;0.012), compared with their counterparts (eTable 1).\u003c/p\u003e \u003cp\u003eAfter adjusting for confounding factors using 1:2 propensity score matching, 445 (38.6%) patients with HER2-low status and 707 (61.4%) patients with HER2-zero status were included in the analysis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Clinicopathologic variables including age, tumor stage, nodal stage, HR status, and histologic grade were well-balanced between the two groups. Furthermore, the rates of chemotherapy, radiotherapy, and hormone therapy were comparable between the groups. The mean age of the patients in the HER2-low status group was 51.4 years, and most of them had a tumor size\u0026thinsp;\u0026lt;\u0026thinsp;2 cm; additionally, a quarter of them had a poor tumor grade, and 89.9% received chemotherapy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of clinicopathologic factors based on HER2 status after 1:2 propensity score matching\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAll patients (N\u0026thinsp;=\u0026thinsp;1,152)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHER2-zero\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;707)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHER2-low\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;445)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.4\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast conservation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e421 (59.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e274 (61.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e286 (40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e169 (38.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic tumor stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e417 (59.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e262 (58.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (36.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e161 (36.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic nodal stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.952\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e478 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e305 (68.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e149 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone receptor status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e557 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e357 (80.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistologic grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e327 (46.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e217 (48.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e187 (26.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e655 (92.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e400 (89.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.728\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e482 (68.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e299 (67.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e225 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.862\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e545 (77.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e345 (77.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162 (22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Variables are indicated as frequency (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e**Age, pathologic tumor stage, pathologic nodal stage, histologic grade, hormone receptor status, chemotherapy, radiotherapy, and hormone therapy were adjusted using propensity score matching.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHER2, human epidermal growth factor receptor 2\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the matched cohort, 914 (79.3%) patients had HR-positive breast cancer, and 238 (20.7%) had HR-negative cancer. The clinicopathological characteristics of the patients in the HER2-low and HER2-zero groups, stratified by HR status, were comparable (eTable 2). In the HR-positive / HER2-low subgroup (n\u0026thinsp;=\u0026thinsp;357), approximately 40% of patients had a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;2 cm, and 30.5% had nodal metastasis, while 89.1% and 91.0% received chemotherapy and hormone therapy, respectively. In the HR-negative / HER2-low subgroup (n\u0026thinsp;=\u0026thinsp;88), approximately 46.6% of patients had a tumor size\u0026thinsp;\u0026gt;\u0026thinsp;2 cm, and 35.2% of patients had a nodal metastasis, while nearly all of them (93.2%) received chemotherapy. The use of adjuvant treatments did not differ between patients according to HER2 status and either HR-positive or HR-negative breast cancer.\u003c/p\u003e\n\u003ch3\u003eSurvival outcomes according to HER2 status\u003c/h3\u003e\n\u003cp\u003eThe median follow-up time was 92.7 months (range, 0.3\u0026ndash;273.1 months). During the follow-up period, 79 and 68 cases of recurrence and death from any cause, respectively, were observed in the matched cohort. The 5-year OS rates for patients with HER2-low and HER2-zero were 95.4% and 97.6%, respectively. The corresponding 5-year disease-free survival rates were 96.6% and 95.0%, respectively. The Kaplan\u0026ndash;Meier survival curves revealed no differences in OS, RFS, LRRFS, or DRFS rates between the groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.293, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.080, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.872, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.746, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The Cox regression analysis results showed that HER2-low status did not affect survival outcomes (OS: hazard ratio, 1.298; 95% CI, 0.798\u0026ndash;2.112; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.294, RFS: hazard ratio, 0.639; 95% CI, 0.386\u0026ndash;1.059; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.082) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox regression analysis of HER2 expression for survival outcomes in matched patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.298 (0.798\u0026ndash;2.112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.639 (0.386\u0026ndash;1.059)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLRRFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.049 (0.585\u0026ndash;1.884)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDRFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.929 (0.593\u0026ndash;1.454)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.746\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Hazard ratio (HR) is calculated for patients with HER2-low status based on HER2-zero status\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eCI, confidence interval; HER2, human epidermal growth factor receptor 2; RFS, recurrence-free survival; LRRFS, locoregional recurrence-free survival; DRFS, distant recurrence-free survival\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe HR-status was not associated with survival outcomes in either the HER2-low or HER2-zero group. Among patient with HR-positive subtype, the Kaplan\u0026ndash;Meier survival curves revealed no differences in OS, RFS, LRRFS, or DRFS rates between the groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.484, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.065, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.996, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.630, respectively, eFigure 1). Among patient with HR-negative subtype, there was no statistical difference in survival curves as well (eFigure 2).\u003c/p\u003e \u003cp\u003eSimilarly, in Cox regression analyses, the HER2-low status did not affect prognosis in subgroups according to the HR-status (eTable 3).\u003c/p\u003e \u003cp\u003eAdditionally, the cohort was divided into subgroups based on lymph node metastasis. Among 369 patients with lymph node metastasis, the RFS rates of patients with HER2-low status were higher than those of patients with HER2-zero status (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince the phase 3 clinical trial DESTINY-Breast 04 demonstrated the efficacy of T-Dxd in the treatment of metastatic HER2-low breast cancer, several studies have investigated the prognostic implications of HER2-low status \u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. However, evidence has been inconsistent, and the impact of HER2-low status on outcomes remains unclear. Thus, this study aimed to examine the survival outcomes of patients with HER-low status after propensity score matching, showing comparable long-term outcomes in patients with HER2-low and HER2-zero status. Additionally, patients with HER2-low status showed better survival outcomes compared with those with HER2-zero in the subgroup with lymph node metastasis.\u003c/p\u003e \u003cp\u003eOur findings are in line with those of previous studies. A nationwide study using a large retrospective registry dataset reported that OS rates were comparable between these groups \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, some evidence suggests that breast cancer-specific survival rates may be better in patients with HER2-low status, especially those in the HR-negative subgroup, than in their counterparts. Nevertheless, this nationwide study lacked recurrence data and did not adjust for confounders, despite the risk of selection bias. Additionally, it had missing data on some prognostic variables included in multivariate analysis. In contrast, the present study analyzed long-term survival and disease recurrence data after adjusting several confounding factors.\u003c/p\u003e \u003cp\u003eSubgroup analysis among patients with lymph node metastasis demonstrated that patients with HER2-low status had better RFS than patients with HER2-zero, suggesting that the clinical impact of low HER2 expression may differ depending on lymph node status. These results are consistent with those of previous studies. Mutai et al., in a study of 608 patients with HR-positive breast cancer, reported that HER2-low status was associated with improved OS and RFS rates compared with those associated with HER-zero status in patients with high genomic risk \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Other studies have suggested that HER2-low status may be associated with a better prognosis compared with that associated with HER2-negative status in high-risk tumors, such as HR-negative tumors without a pathological complete response after neoadjuvant therapy, or those treated without any adjuvant therapy \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The mechanisms of these effects remain unclear and may be linked to some biological differences. However, improved outcomes may be achieved without anti-HER2 therapy, suggesting that HER2-low status may be a biological marker rather than an oncogenic driver in these subgroups. Gene expression analysis by Schettini et al. showed that proliferation-related genes were significantly downregulated, and luminal-related genes were upregulated in HER2-low breast cancer \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In addition, several pathologic characteristics related to reduced tumor aggressiveness, such as low Ki-67 labeling index, low tumor grade, and absence of lymphatic invasion, have been associated with HER2-low breast cancer \u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. As we lacked the relevant data, we could not test this hypothesis. Further research, including studies using in-depth molecular profiling and functional genomic analysis, is required to elucidate these effects.\u003c/p\u003e \u003cp\u003eIn a study by Park et al., oncologic outcomes differed according to menopausal status among patients with HR-positive/HER2-low status \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Among postmenopausal patients with breast cancer, RFS and OS rates were higher in the HER2-low subgroup than in the HER2-zero subgroup. The authors proposed that the main cause of this difference in prognosis was the late recurrence in the luminal subtype. However, herein, after adjusting for patient age and endocrine therapy using propensity score matching, no difference in survival outcomes was observed between patients with the HER2-low and HER2-zero status. Moreover, the HER2-low status did not seem to affect disease prognosis in the subgroups defined by HR expression. Further studies are needed to understand outcome patterns according to HER2-low status.\u003c/p\u003e \u003cp\u003eOur study had some limitations. First, this was a retrospective study, likely subject to selection bias. To overcome the limitations of retrospective analyses, we conducted propensity score matching by adjusting for several important prognostic factors, helping address the limitations of some previous studies. Second, data on the HER2 status were based on local pathology reports, and no central confirmation of pathological assessment was performed. Although all participating institutions adhered to the guidelines of the American Society of Clinical Oncology/College of American Pathologists, the reproducibility of the reported results, especially those for immunohistochemistry scores of 0 or 1+, is not guaranteed. Third, in the matched sample, over 85% of all patients had received systemic chemotherapy. This skew may have affected the reported estimates, affecting generalizability of the findings to patients that do not undergo chemotherapy.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our study reported comparable survival outcomes between patients with HER2-low and HER2-zero breast cancer. In the subgroup with lymph node metastasis, the HER2-low status was associated with better survival outcomes than those with HER2-zero status. Further studies are needed to reveal the biological mechanisms underlying this prognostic difference between HER2-low and HER2-zero status.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDRFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edistant recurrence-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHER2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman epidermal growth factor receptor 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehormone receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmunohistochemistry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eISH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ein-situ hybridization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLRRFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elocoregional recurrence-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erecurrence-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2022-12-034), and followed the Declaration of Helsinki that protect human subjects in medical research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e Research data that support the findings of this study are securely stored in an institutional repository and are available to share from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: CDC, MSC\u003c/p\u003e\n\u003cp\u003eAcquisition, analysis, or interpretation of data: KEK, JK, EU, JL, GG, JIK\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript:\u0026nbsp;CDC, MSC\u003c/p\u003e\n\u003cp\u003eStatistical analysis: NC\u003c/p\u003e\n\u003cp\u003eSupervision: CDC, MSC\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThis study was supported by the research fund of Hanyang University (HY- 02300000003523). The authors would like to thank Editage (www.editage.co.kr) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eModi, S. \u003cem\u003eet al.\u003c/em\u003e Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 387, 9\u0026ndash;20, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2203690\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2203690\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgostinetto, E. \u003cem\u003eet al.\u003c/em\u003e HER2-Low Breast Cancer: Molecular Characteristics and Prognosis. 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S. \u003cem\u003eet al.\u003c/em\u003e Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res 24, 22, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13058-022-01519-x\u003c/span\u003e\u003cspan address=\"10.1186/s13058-022-01519-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeiffer, D. S. \u003cem\u003eet al.\u003c/em\u003e Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database. 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Comparison of HER2-zero and HER2-low in terms of clinicopathological factors and survival in early-stage breast cancer: A systematic review and meta-analysis. Cancer Treat Rev 115, 102538, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ctrv.2023.102538\u003c/span\u003e\u003cspan address=\"10.1016/j.ctrv.2023.102538\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark, W. K. \u003cem\u003eet al.\u003c/em\u003e The Impact of HER2-Low Expression on Oncologic Outcomes in Hormone Receptor-Positive Breast Cancer. Cancers (Basel) 15, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers15225361\u003c/span\u003e\u003cspan address=\"10.3390/cancers15225361\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-breast-cancer","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjbcancer","sideBox":"Learn more about [npj Breast Cancer](http://www.nature.com/npjbcancer/)","snPcode":"41523","submissionUrl":"https://mts-npjbcancer.nature.com/","title":"npj Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5235910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5235910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSince the approval of the trastuzumab deruxtecan for human epidermal growth factor receptor 2 (HER2)-low breast cancer, evidence suggests that low-HER2 expression may affect prognosis; however, it remains unclear how HER2-low subtype affects outcomes. Thus, this study aimed to investigate the differences in prognosis between patients with HER2-low and HER2-zero status.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study conducted at multi-institution included 1,627 patients diagnosed with HER2-low or HER2-zero breast cancer (stages I\u0026ndash;III). For comparing outcomes between two groups, the survival analysis after propensity score matching was used. Survival outcomes including distant recurrence-free survival, and overall survival were evaluated using the Kaplan\u0026ndash;Meier analyses.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAfter propensity score matching, 445 patients with HER2-low and 707 patients with HER2-zero status were included. Among them, 914 (79.3%) and 238 (20.7%) patients had hormone receptor-positive and -negative disease. Median follow-up was 92.7 months. Locoregional recurrence-free survival and distant recurrence-free survival were comparable between patients with HER2-low and HER2-zero status (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.872, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.746, respectively). HER2-low status did not affect overall survival. However, in a subgroup with lymph node metastases, patients with HER2-low status showed better recurrence-free survival compared with that of patients with HER2-zero status (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this study, survival outcomes were comparable between patients with HER2-low and HER2-zero breast cancer. Additionally, patients with HER2-low status showed better survival outcomes compared with those with HER2-zero in the subgroup with lymph node metastasis. Further studies are needed to examine the biological mechanism underlying these prognostic differences.\u003c/p\u003e","manuscriptTitle":"Prognostic difference between early breast cancer patients with HER2-low and HER2-zero status: A multicenter cohort study using propensity-score matched analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 10:52:03","doi":"10.21203/rs.3.rs-5235910/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-12-16T05:50:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-12-07T17:27:53+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-12-07T16:45:09+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-12-03T16:54:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-12-02T20:20:19+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-10-29T17:47:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-21T21:03:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-21T11:15:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Breast Cancer","date":"2024-10-17T03:20:46+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-10-14T09:55:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-breast-cancer","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjbcancer","sideBox":"Learn more about [npj Breast Cancer](http://www.nature.com/npjbcancer/)","snPcode":"41523","submissionUrl":"https://mts-npjbcancer.nature.com/","title":"npj Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"898ff395-45de-425d-80d9-7c06a8412b46","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39578489,"name":"Health sciences/Oncology/Cancer/Breast cancer"},{"id":39578490,"name":"Biological sciences/Cancer/Breast cancer"}],"tags":[],"updatedAt":"2025-03-27T07:11:59+00:00","versionOfRecord":{"articleIdentity":"rs-5235910","link":"https://doi.org/10.1038/s41523-025-00737-8","journal":{"identity":"npj-breast-cancer","isVorOnly":false,"title":"npj Breast Cancer"},"publishedOn":"2025-03-26 04:00:00","publishedOnDateReadable":"March 26th, 2025"},"versionCreatedAt":"2024-11-20 10:52:03","video":"","vorDoi":"10.1038/s41523-025-00737-8","vorDoiUrl":"https://doi.org/10.1038/s41523-025-00737-8","workflowStages":[]},"version":"v1","identity":"rs-5235910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5235910","identity":"rs-5235910","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}