Survival analysis of adjuvant endocrine therapy in HER2 positive early breast cancer patients with low ER positivity

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While endocrine therapy (ET) is standard for ER-positive disease, its benefit in ER-low tumors, particularly with concurrent HER2 overexpression, is less established. Methods: We conducted a retrospective cohort study using Taiwan’s national cancer registry, identifying 10,408 patients with HER2-positive early breast cancer diagnosed between 2011 and 2019. Of these, 1436 (15.48%) had low ER positivity. Patients were stratified by ER level (1–9% vs. ≥10%) and ET use. Overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS) were evaluated via Kaplan-Meier and Cox regression analyses. Progesterone receptor (PR) status was also assessed. Results: Adjuvant ET significantly improved OS, BCSS, and RFS in both ER subgroups (all p < 0.05). In ER-low patients, ET was associated with improved OS (90.16% vs. 85.55%, p = 0.0082), BCSS (93.91% vs. 89.71%, p = 0.0047), and RFS (91.24% vs. 88.21%, p = 0.0316). On multivariate analysis, PR positivity—not ER level—was an independent predictor of improved outcomes. Notably, PR-positive, ER-low patients had better OS with ET (92.08% vs. 86.69%, p = 0.0216). Conclusion: Adjuvant ET provides meaningful survival benefits in HER2-positive early breast cancer with low ER expression, particularly in PR-positive tumors. Despite this, 41.92% of eligible ER-low patients did not receive ET, highlighting a treatment gap. PR status may guide ET decisions, supporting individualized treatment approaches. low ER positivity HER2 positivity survival early breast cancer endocrine therapy Figures Figure 1 Figure 2 Figure 3 Implications for Practice Adjuvant endocrine therapy (ET) improves survival in HER2-positive early breast cancer patients with low ER expression, especially when PR is positive. PR status should be considered a key biomarker to guide ET decisions in this subgroup. Despite clear benefits, over 40% of eligible patients do not receive ET in Taiwan, indicating a treatment gap. Clinicians should incorporate PR assessment and consider ET in ER-low, HER2-positive patients to optimize individualized care and improve outcomes. Introduction Breast cancer remains one of the most prevalent malignancies globally 1 , encompassing a variety of immunohistochemical subtypes with distinct biological behaviors and therapeutic responses. 2–5 Among these, human epidermal growth factor receptor 2 (HER2)-positive breast cancer is recognized for its aggressive clinical course, and the advent of HER2-targeted therapies has significantly improved outcomes. 6–8 Endocrine therapy (ET) is standard for hormone receptor–positive early breast cancer, typically prescribed for tumors expressing estrogen receptor (ER) or progesterone receptor (PR). However, the crosstalk between ER and HER2 signaling pathways can induce endocrine resistance, highlighting the need for combined treatment strategies, as supported by the ASCO guidelines and reinforced by trials like ADAPT showing improved responses when HER2 blockade is paired with ET 9 10 However, when HER2 positivity is coupled with low ER expression (1–9%), treatment strategies become more complex and require careful consideration. 11,12 Adjuvant ET in patients with early-stage, HER2-positive breast cancer exhibiting low ER expression represents a clinically nuanced and evolving area of oncologic management. While a low ER positive status used to raise questions regarding the efficacy of ET, emerging evidence suggests a potential benefit, particularly when integrated with HER2-targeted therapies 13,14 . A prospective cohort study by Xie et al. demonstrated improved breast cancer-specific survival (BCCS) with adjuvant ET, most notably with aromatase inhibitors (AIs) or sequential tamoxifen followed by AIs, even among patients with low ER-positive, HER2-positive disease. 15 The findings support the judicious use of ET in this subset of patients, with careful consideration of regimen selection to optimize clinical outcomes. Despite the central role of endocrine treatment in ER-positive breast cancers, its benefit in ER-low tumors, especially those that also overexpress HER2, still remains contentious. For example, a large cohort study conducted in China reported that although patients with low ER expression received ET, no significant improvement in relapse-free survival (RFS) was observed. 11 This finding suggested that the biological behavior of HER2-positive, low ER-expressing tumors may necessitate a departure from conventional endocrine therapy and prompt the use of more targeted approaches. Further prospective cohort studies and meta-analyses have underscored the need for individualized treatment regimens that take into account both HER2 and ER status. Although some evidence suggests limited ET benefits in this setting, definitive conclusions remain elusive, underscoring the need for further investigation. This study critically evaluates adjuvant ET’s role in HER2-positive, low ER early breast cancer, aiming to clarify its clinical impact and guide optimized treatment strategies. Materials and Methods Ethical approval and informed consent The data for this study was derived from the Taiwan Cancer Registry—Long Form system 16 , which includes records of women diagnosed with breast cancer in Taiwan. The research protocol was approval from the institutional review board (IRB-TPEVGH protocol no. 2024-06-007B). Given the retrospective and anonymized nature of the study, informed consent was waived. Patients’ selection Early breast cancer patients with HER2-positive status (defined as HER2 3+ or HER2 2+ with Fluorescence in situ hybridization [FISH] positivity) and ER-positive status (defined as ER>=1%) were enrolled in this study, from 2011 to 2019. These patients were retrospectively followed for a mean period of 6 years, from 2011 to 2017. According to the ASCO guidelines, ER positivity of 1-9% was classified as low ER status. In this study, patients were grouped into either ER ≥10% and ER 1-9%. Adjuvant endocrine therapy was defined as the administration of tamoxifen or aromatase inhibitors (AIs), including letrozole, anastrozole, and exemestane, following curative surgery. In addition to ER grouping, various clinical features, including PR status, tumor grade, pathological stage, surgical procedure, radiotherapy, chemotherapy, targeted therapy, and whether patients received adjuvant endocrine therapy or not, were recorded and extracted. We compared the characteristics of patients with and without adjuvant ET among the cohort of HER2-positive early breast cancer patients with low ER expression. Survival analysis Overall survival (OS) was defined as the duration from diagnosis to death from any cause, while BCSS referred to the period from diagnosis to death specifically attributable to breast cancer. RFS was the interval from diagnosis to the occurrence of the first recurrence or death, whichever occurred first. Censored date of the study was set to 2017. We conducted a series of survival analyses, with a mean follow-up period extending up to 6 years, to compare the outcomes of adjuvant ET in HER2-positive early breast cancer patients with ER positivity of ≥10% and ER positivity of 1-9%. Additionally, we evaluated the impact of PR on survival outcomes in HER2-positive early breast cancer patients with low ER status. Among PR-positive and PR-negative patients, survival outcomes were further compared, stratified by the conduct of adjuvant ET. Primary and secondary endpoints The primary endpoint was to assess the survival outcomes, including OS, BCSS, and RFS, in HER2-positive early breast cancer patients with low ER positivity, with or without adjuvant ET. The secondary endpoint was the prognostic role of PR in HER2-positive early breast cancer patients. Statistical analyses Statistical analyses were conducted using Statistical Product and Service Solutions (SPSS) version 26.0 software (SPSS Inc., IBM, Armonk, NY, USA). Survival durations were estimated employing the Kaplan-Meier method, with comparisons made using the log-rank test. For multivariable analysis, Cox's proportional hazards model was utilized. Statistical significance was defined as a p-value of less than 0.05. Results This study enrolled 10,408 early HER2-positive and ER-positive breast cancer patients. Among these, 1,436 (15.48%) had low ER positivity (1–9%), and 7,838 (84.52%) had ER positivity ≥10% ( Table 1 ). Table 1. The characteristics of early breast cancer patients with HER2-positivity. ER 1-9% ER>=10% Total p -value ER positivity 1436 (15.48%) 7838 (84.52%) 9274 PR Negative 719 (50.07%) 1443 (18.41%) 2162 <.0001 Positive 717 (49.93%) 6395 (81.59%) 7112 Grading 1 50 (3.48%) 778 (9.93%) 828 <.0001 2 581 (40.46%) 4280 (54.60%) 4861 3 805 (56.06%) 2780 (35.47%) 3585 Staging 0 229 (15.95%) 922 (11.76%) 1151 <.0001 1 472 (32.87%) 2765 (35.28%) 3237 2 498 (34.68%) 2966 (37.84%) 3464 3 237 (16.50%) 1185 (15.12%) 1422 Operation Negative 8 (0.56%) 51 (0.65%) 59 0.6818 Positive 1428 (99.44%) 7787 (99.35%) 9215 Radiotherapy Negative 704 (49.03%) 3353 (42.78%) 4057 <.0001 Positive 732 (50.97%) 4485 (57.22%) 5217 Chemotherapy Negative 391 (27.23%) 2251 (28.72%) 2642 0.2499 Positive 1045 (72.77%) 5587 (71.28%) 6632 Target therapy Negative 668 (46.52%) 3712 (47.46%) 4380 0.5573 Positive 768 (53.48%) 4126 (52.64%) 4894 Endocrine therapy Negative 602 (41.92%) 694 (8.85%) 1296 <.0001 Positive 834 (58.08%) 7144 (91.15%) 7978 In the ER ≥10% group, 81.59% were progesterone receptor (PR) positive, compared to 49.93% in the ER 1–9% group. Tumor grade III predominated in the ER-low group (56.06%), whereas grade II was most common in the ER ≥10% group (54.60%). Most patients were diagnosed at stage II in both groups (34.68% in ER-low, 37.84% in ER ≥10%). Nearly all patients underwent curative surgery (99.44% ER-low, 99.35% ER ≥10%). Radiotherapy was administered to 50.97% of ER-low and 57.22% of ER ≥10% patients. Chemotherapy was given to 72.77% of ER-low and 71.28% of ER ≥10%. Targeted therapy rates were comparable (53.48% ER-low, 52.64% ER ≥10%). Notably, 91.15% of ER ≥10% patients received adjuvant endocrine therapy (ET), while only 58.08% of ER-low patients received ET. Among ER-low patients, those receiving adjuvant ET were more often PR positive (54.56%) than those who did not receive ET (43.85%). Grade III tumors were prevalent regardless of ET status (53.84% with ET, 59.14% without). Most patients receiving ET were diagnosed at stage I (36.09%), whereas stage II predominated in those without ET (34.88%). Mean ages were similar (54.32 ± 10.23 years with ET; 55.33 ± 10.66 years without). Radiotherapy was more frequent among ET recipients (56.24% vs. 43.69%). Chemotherapy rates were nearly identical (72.78% vs. 72.76%), and targeted therapy was slightly lower in ET recipients (51.32%) compared to non-recipients (56.48%) ( Table 2 ). Table 2. The characteristics of HER2-positivity in early breast cancer patients with low ER positivity. ER 1-9% Endocrine therapy (+) Endocrine therapy (-) p -value PR Negative 379 (45.44%) 338 (56.15%) <.0001 Positive 455 (54.56%) 264 (43.85%) Grade 1 40 (4.80%) 10 (1.66%) 0.0024 2 345 (41.37%) 236 (39.20%) 3 449 (53.84%) 356 (59.14%) Staging 0 121 (14.51%) 108 (17.94%) 0.0070 1 301 (36.09%) 171 (28.41%) 2 288 (34.53%) 210 (34.88%) 3 124 (14.87%) 113 (18.77%) Age 54.32 + 10.23 55.33 + 10.66 0.2745 Radiotherapy Negative 365 (43.76%) 339 (56.31%) <.0001 Positive 469 (56.24%) 263 (43.69%) Chemotherapy Negative 227 (27.22%) 164 (27.24%) 0.9919 Positive 607 (72.78%) 438 (72.76%) Target therapy Negative 406 (48.68%) 262 (43.52%) 0.0531 Positive 428 (51.32%) 340 (56.48%) Survival analyses revealed significantly higher overall survival (OS) in patients receiving adjuvant ET across ER groups. In the ER ≥10% cohort, OS was 92.32% with ET versus 83.98% without ( p < 0.0001, Figure 1a ). Similarly, ER-low patients showed improved OS with ET (90.16% vs. 85.55%, p = 0.0082, Figure 1b ). Within the ER-low group, PR positivity correlated with better OS irrespective of ET (89.54% vs. 86.91%, p = 0.0295, Figure 1c ). Among PR-positive patients, ET further improved OS (92.08% vs. 86.69%, p = 0.0216, Figure 1d ). Conversely, in PR-negative ER-low patients, ET showed a non-significant trend toward improved OS (88.55% vs. 84.09%, p = 0.0649, Figure 1e ). Breast cancer-specific survival (BCSS) also favored ET recipients in both ER ≥10% (95.27% vs. 87.07%, p < 0.0001, Figure 2a ) and ER-low groups (93.91% vs. 89.71%, p = 0.0047, Figure 2b ). However, BCSS did not differ significantly by PR status within the ER-low subgroup regardless of ET (92.63% vs. 91.71%, p = 0.2384, Figure 2c ). Recurrence-free survival (RFS) was significantly better with ET in both ER ≥10% (94.24% vs. 86.44%, p < 0.0001, Figure 3a ) and ER-low patients (91.24% vs. 88.21%, p = 0.0316, Figure 3b ). No significant RFS differences were observed between PR-positive and PR-negative ER-low patients irrespective of ET (89.26% vs. 90.67%, p = 0.8142, Figure 3c ). Multivariate Cox regression confirmed that PR positivity, cancer stage, and receipt of endocrine, chemotherapy, radiotherapy, and targeted therapies were significantly associated with improved OS, BCSS, and RFS. Tumor grade was prognostic for BCSS and RFS. Importantly, low ER positivity was not an independent prognostic factor, whereas PR positivity remained consistently prognostic across outcomes ( Table 3 ). Table 3. Multivariate analysis for OS, BCSS, and RFS by using Cox's proportional hazards model. OS Hazard ratio [ 95% CI ] BCSS Hazard ratio [ 95% CI ] RFS Hazard ratio [ 95% CI ] Low ER positivity 1.094 [0.904-1.324] 0.987 [0.772-1.260 ] 1.105 [0.896-1.363] PR positivity 0.745* [0.637-0.871] 0.789* [0.643-0.969] 0.780* [0.653-0.933] Grade Grade 2 0.996 [0.756-1.312] 1.330 [0.863-2.051] 1.933 [1.272-2.937] Grade 3 1.142 [0.861-1.515] 1.671 [1.079-2.587] 2.228 [1.458-3.403] Staging Stage1 2.648 [1.820-3.853] 3.117 [1.695-5.731] 2.462 [1.618-3.746] Stage2 9.002 [6.250-12.966] 11.243 [6.218-20.328] 5.019 [3.288-7.660] Stage3* 22.849 [15.731-33.187] 31.210 [17.179-56.701] 12.542 [8.128-19.352] Operation 2.214 [0.826-5.938] 1.569 [0.501-4.915] 0.723 [0.358-1.462] Radiotherapy 0.685* [0.588-0.797] 0.759* [0.623-0.925] 0.655* [0.552-0.776] Chemotherapy 0.360* [0.297-0.437] 0.494* [0.377-0.647] 0.611* [0.480-0.778] Endocrine therapy 0.598* [0.501-0.713] 0.461* [0.371-0.573] 0.555* [0.457-0.676] Target therapy 0.840 [0.704-1.002] 0.859 [0.685-1.076] 1.038 [0.851-1.266] CI= Confidence interval * p -value <0.05 In summary, among early HER2-positive breast cancer patients with low ER expression, adjuvant ET significantly improved OS, BCSS, and RFS. Nonetheless, 41.9% of ER-low patients did not receive ET, representing a missed opportunity for survival benefit. Additionally, PR-positive, ER-low patients experienced the greatest OS improvement with ET, highlighting the importance of PR status in guiding therapy decisions. Discussion Recent evidence elucidates the intricate crosstalk between ER and HER2 signaling pathways, supporting dual blockade strategies in breast cancer co-expressing hormone receptors and HER2. 17,18 The ExteNET trial further underscores this interaction, demonstrating the clinical benefit of targeting both pathways in HER2- and ER-positive disease. 19 Nonetheless, endocrine therapy carries a substantial burden of adverse effects—such as depression, vasomotor symptoms, vaginal dryness, and arthralgia—which compromise quality of life and contribute to high discontinuation rates (31–73%) before the recommended five-year duration. 20,21 This raises a critical clinical question: in HER2-positive breast cancer patients with low ER expression (1–9%), can ET be omitted without undermining treatment efficacy? Our study highlights this clinical uncertainty, showing that 41.92% of Taiwanese patients with HER2-positive early breast cancer and low ER positivity did not receive adjuvant ET. This variability reflects ongoing debate and lack of consensus on ET’s role in this subgroup. A prospective cohort study by Xie et al. (2022) found improved BCSS with ET in 407 women with low ER-positive disease, particularly among HER2-positive patients. 15 Similarly, Choong et al. reported worse OS with omission of ET in low-ER early breast cancer, independent of PR, HER2, or Ki-67 status. 14 Conversely, Wang, Li et al. observed no significant difference in five-year RFS between ET-treated and untreated patients in a Chinese cohort. 11 Our analysis demonstrates that adjuvant ET significantly improves OS, BCSS, and RFS in HER2-positive early breast cancer with low ER expression. This aligns with ASCO guidelines defining ER positivity at ≥ 1%, and supports using the 1% ER cutoff to guide ET decisions. 22 These findings reinforced the critical role of ER expression in guiding ET decisions and were consistent with existing literature. Importantly, 41.92% of patients with low ER expression in our cohort did not receive ET—indicating a missed opportunity to optimize survival. Clinicopathologic differences between ER ≥ 10% and ER 1–9% groups were significant ( p < 0.0001), including tumor grade, stage, radiotherapy, and PR positivity (Table 1 ). The ER-low group had a predominance of grade III tumors (56.06%), while grade II predominated in ER ≥ 10% (54.60%). Stage distribution showed higher proportions of stage 0 and stage III disease in the low ER group. Notably, fewer ER-low patients received adjuvant radiotherapy (50.97% vs. 57.22%). Within the ER-low subgroup, those receiving ET had less advanced disease and higher PR positivity compared to those without ET (Table 2 ). These differences might result from inherent variations in tumor biology, while selection bias due to sample size disparity could not be totally excluded. PR status was markedly different between groups: 49.93% PR-positive in ER-low versus 81.59% in ER ≥ 10% tumors. Within the ER-low cohort, PR positivity was significantly higher in ET recipients ( p < 0.0001), highlighting PR’s potential predictive role beyond ER levels. Previous studies have demonstrated that PR signaling exerts a critical modulatory effect on estrogen receptor alpha (ERα) activity within the breast cancer microenvironment, influencing both tumor biology and therapeutic responsiveness. 23–26 Prior research suggests PR expression enhances response to adjuvant ET, while low PR may contribute to tamoxifen resistance. 27–30 In our cohort, PR-positive, ER-low patients receiving ET had significantly better OS (92.08% vs. 86.69%, p = 0.0216), whereas PR-negative patients showed a non-significant trend favoring ET (88.55% vs. 84.09%, p = 0.0649). No significant differences were observed in BCSS or RFS by PR status within this subgroup. These findings echo those of Bardou et al., who identified PR positivity as an independent predictor of ET benefit, with concordant ER/PR-positive tumors deriving superior survival improvements compared to discordant cases. 31 Lashen et al. further proposed a 10% PR positivity cutoff to refine prognostication. 32 Multivariate analysis in our study revealed that low ER expression was not an independent prognostic factor for OS, BCSS, or RFS, whereas PR positivity consistently predicted improved outcomes. Other significant prognostic factors included tumor stage, radiotherapy, chemotherapy, and ET receipt. These results parallel the meta-analysis by Boland et al., encompassing 13,667 patients, which linked PR negativity with poorer OS and disease-free survival. 33 In summary, adjuvant ET confers survival benefits in HER2-positive early breast cancer irrespective of ER expression level. The substantial proportion (41.92%) of ER-low patients in Taiwan not receiving ET represents a critical gap in care that should be addressed through clinician-led counseling to optimize treatment uptake. PR positivity may serve as a key biomarker to identify ER-low patients most likely to benefit from ET, supporting its integration into therapeutic decision-making. Limitations of this study include its retrospective design, which inherently risks selection bias. The relatively smaller ER-low cohort limits statistical power and subgroup robustness. Additionally, data on duration and specific ET regimens were unavailable, restricting evaluation of treatment heterogeneity’s impact on outcomes. Conclusions In conclusion, this real-world dataset from Taiwan provides valuable insight on the use of adjuvant ET in patients with HER2-positive early breast cancer and ER-low status. Despite demonstrating survival benefits, approximately 41.92% of patients with ER expression of 1–9% did not receive adjuvant ET. These findings highlighted the need to actively consider and discuss ET for these patients to improve treatment outcomes. This study offered real world evidence in survival data to support clinicians and patients in making more informed evidence through shared decision-making. Abbreviations ER: Estrogen receptor PR: Progesterone-receptor HER2: Human epidermal growth factor receptor 2 FISH: Fluorescence in situ hybridization ET: Endocrine therapy OS: Overall survival BCSS: Breast cancer-specific survival RFS: Recurrence-free survival Declarations Ethical approval and consent to participate This study has been approved by the Taipei Veterans General Hospital (TPEVGH) ethics committee. The research protocol was approval from the institutional review board (IRB-TPEVGH protocol no. 2024-06-007B). Given the retrospective and anonymized nature of the study, informed consent was waived. Consent for publication Not applicable. Availability of supporting data Data for this study were obtained from the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan (URL:// https://dep.mohw.gov.tw/DOS/cp-5119-59201-113.html). All data generated or analyzed during this study are included in this published article and its supplementary information files. Conflicts of interest The authors declare no competing interests. Funding This work was supported in part by IRB-TPEVGH protocol no. 2024-06-007B. Author contributions Hsuan-Hsuan Yu (conceptualization; writing—original draft), Deanna Gracia (data curation; formal analysis; investigation), Chan-Heng Ho (data curation; formal analysis; investigation), Hao-Yang Chen (data curation; formal analysis; investigation), Ling-Ming Tseng (funding acquisition; investigation), Ta-Chung Chao (funding acquisition; investigation), and Chi-Cheng Huang (conceptualization; formal analysis; methodology; supervision). Acknowledgments The authors gratefully acknowledge the Taiwan Clinical Oncology Research Foundation, Melissa Lee Cancer Foundation, and Dr. Morris Chang for their generous support and assistance throughout this study. References Siegel RL, Miller KD, Fuchs HE, Jemal AJCacjfc. Cancer statistics, 2022. 2022;72(1):7-33. Reis‐Filho J, Lakhani SR. Breast cancer special types: why bother? The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland . 2008;216(4):394-398. Gallager HS. 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Drug Des Devel Ther . 2022;16:305-314. doi:10.2147/dddt.S336643 Thomas C, Gustafsson J-Å. Progesterone receptor-estrogen receptor crosstalk: a novel insight. Trends in Endocrinology & Metabolism . 2015;26(9):453-454. Huggins RJ, Greene GL. ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation. NPJ Breast Cancer . 2023;9(1):96. Chakravorty G, Ahmad S, Godbole MS, Gupta S, Badwe RA, Dutt A. Deciphering the mechanisms of action of progesterone in breast cancer. Oncotarget . 2023;14:660. Yao N, Song Z, Wang X, Yang S, Song H. Prognostic impact of progesterone receptor status in Chinese estrogen receptor positive invasive breast cancer patients. Journal of breast cancer . 2017;20(2):160-169. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol . May 15 2003;21(10):1973-9. doi:10.1200/jco.2003.09.099 Lashen AG, Toss MS, Mongan NP, Green AR, Rakha EA. The clinical value of progesterone receptor expression in luminal breast cancer: A study of a large cohort with long-term follow-up. Cancer . Apr 15 2023;129(8):1183-1194. doi:10.1002/cncr.34655 Boland MR, Ryan É J, Dunne E, Aherne TM, Bhatt NR, Lowery AJ. Meta-analysis of the impact of progesterone receptor status on oncological outcomes in oestrogen receptor-positive breast cancer. Br J Surg . Jan 2020;107(1):33-43. doi:10.1002/bjs.11347 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Breast Cancer Research → Version 1 posted Editorial decision: Revision requested 12 Aug, 2025 Reviews received at journal 05 Aug, 2025 Reviews received at journal 30 Jul, 2025 Reviewers agreed at journal 29 Jun, 2025 Reviewers agreed at journal 27 Jun, 2025 Reviewers invited by journal 27 Jun, 2025 Editor assigned by journal 19 Jun, 2025 Submission checks completed at journal 19 Jun, 2025 First submitted to journal 14 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6896091","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":477976163,"identity":"5addfb6d-bf6f-4288-99b8-d1014f29695b","order_by":0,"name":"Hsuan-Hsuan Yu","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hsuan-Hsuan","middleName":"","lastName":"Yu","suffix":""},{"id":477976164,"identity":"a21f089e-1367-4cc9-873f-3553f06b780c","order_by":1,"name":"Deanna Gracia","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Deanna","middleName":"","lastName":"Gracia","suffix":""},{"id":477976165,"identity":"46d061af-d649-45b6-bead-42e5ecf7daa9","order_by":2,"name":"Ta-Chung Chao","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ta-Chung","middleName":"","lastName":"Chao","suffix":""},{"id":477976166,"identity":"dd49e1e4-04ea-4c7f-b1d9-c2064bc419fa","order_by":3,"name":"Chan-Heng Ho","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Chan-Heng","middleName":"","lastName":"Ho","suffix":""},{"id":477976167,"identity":"849fd5cf-d9e9-49dc-9f24-7ecaff9e680b","order_by":4,"name":"Hao-Yang Chen","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Hao-Yang","middleName":"","lastName":"Chen","suffix":""},{"id":477976168,"identity":"768464e8-c3ae-437a-b90b-5ede29dd6024","order_by":5,"name":"Ling-Ming Tseng","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ling-Ming","middleName":"","lastName":"Tseng","suffix":""},{"id":477976169,"identity":"ac55e203-2e15-4962-ae1f-1bfbca8811f8","order_by":6,"name":"Chi-Cheng Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYDACCcYGZiCVYH/g8AEQV4Z4LQwHjyWAuDxEaGFggGg5fMYAxCeshX92c/Pngoo7eYxtZz6/ulFjwcPAfvjoBryW3DnYJj3jzLNiZp6z26xzjgEdxpOWdgOfFgOJxDZm3rbDiW0SZ7cZ57ABtUjwmBHS0vyZ99/hxB75N8+Mc/4Rp6VBmrfhcOIMhjPMj3PbiNAicSOxTZrn2OHEDQzHzJhz+yR42Aj5hX9G+uPPPDUgLYcff875VifHz374GF4tyIBNAkwSqxwEmD+QonoUjIJRMApGDgAAfU1M3lFOYPMAAAAASUVORK5CYII=","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chi-Cheng","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2025-06-15 02:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6896091/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6896091/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13058-025-02157-9","type":"published","date":"2025-12-29T15:57:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85826081,"identity":"efa0f8eb-3805-439e-9277-ca271458875b","added_by":"auto","created_at":"2025-07-02 07:11:55","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":128591,"visible":true,"origin":"","legend":"\u003cp\u003eThe overall survivals of early breast cancer with HER2-positive.\u003c/p\u003e\n\u003cp\u003e(1a). The OS of HER2-positive early breast cacner with ER\u0026gt;=10% group. The OS rate was significantly higher in those with adjuvant ET compared to those without (92.32% vs. 83.98%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001). (1b). The OS of HER2-positive early breast cacner with ER 1-9% group. Similarly, the adjuvant ET group was associated with a statistically better outcome in OS (90.16% vs. 85.55%, \u003cem\u003ep\u003c/em\u003e = 0.0082). (1c). The OS of HER2-positive early breast cacner with ER 1-9% group. PR positivity was associated with a significantly better OS (89.54% vs. 86.91%, \u003cem\u003ep\u003c/em\u003e = 0.0295). (1d). The OS of HER2-positive early breast cacner with ER 1-9% and PR positivity. Those with PR positivity receiving adjuvant ET had a significantly better OS than those without (92.08% vs. 86.69%, \u003cem\u003ep\u003c/em\u003e = 0.0216). (1e). The OS of HER2-positive early breast cacner with ER 1-9% and PR-negative. Among PR-negative and ER-low patients, adjuvant ET showed an insignificant better OS (88.55% vs. 84.09%, \u003cem\u003ep\u003c/em\u003e= 0.0649).\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6896091/v1/2d47157a39726995658fdeb0.jpg"},{"id":85828234,"identity":"b5fd0889-b30b-446d-b900-a5e121be49f4","added_by":"auto","created_at":"2025-07-02 07:27:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":81823,"visible":true,"origin":"","legend":"\u003cp\u003eThe breast cancer-specific survivals of early breast cancer with HER2-positive.\u003c/p\u003e\n\u003cp\u003e(2a). The BCSS of HER2-positive early breast cacner with ER\u0026gt;=10% group. Patients receiving adjuvant ET demonstrated significantly better outcomes compared to those who did not (95.27% vs. 87.07%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001). (2b). The BCSS of HER2-positive early breast cacner with ER 1-9% group. Patients receiving adjuvant ET also demonstrated significantly better outcomes (93.91% vs. 89.71%, \u003cem\u003ep \u003c/em\u003e= 0.0047). (2c). The BCSS of HER2-positive early breast cacner with ER 1-9% group comparing PR status. No significant difference in BCSS was observed between dichotomous PR status (92.63% vs. 91.71%, \u003cem\u003ep\u003c/em\u003e = 0.2384).\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6896091/v1/b919fe2d6c1718af0d906a56.jpg"},{"id":85826086,"identity":"416a3f3b-9560-4368-b382-f256377d6fe6","added_by":"auto","created_at":"2025-07-02 07:11:55","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83696,"visible":true,"origin":"","legend":"\u003cp\u003eThe recurrence-free survivals of early breast cancer with HER2-positive.\u003c/p\u003e\n\u003cp\u003e(3a). The RFS of HER2-positive early breast cacner with ER\u0026gt;=10% group. Patients who received adjuvant ET also demonstrated significantly better outcomes than those without (94.24% vs. 86.44%, \u003cem\u003ep\u003c/em\u003e\u0026lt; 0.0001). (3b). The RFS of HER2-positive early breast cacner with ER 1-9% group. Patients who received adjuvant ET also demonstrated significantly better outcomes than those without (91.24% vs. 88.21%, \u003cem\u003ep\u003c/em\u003e = 0.0316). (3c). The RFS of HER2-positive early breast cacner with ER 1-9% group. No difference in RFS was observed between PR positive and PR negative status (89.26% vs. 90.67%, \u003cem\u003ep\u003c/em\u003e = 0.8142).\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6896091/v1/ab840c7121d7e86cf7f2aaa5.jpg"},{"id":99545575,"identity":"8136c765-1b73-487e-adb9-1b305bc613e1","added_by":"auto","created_at":"2026-01-05 16:08:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1232586,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6896091/v1/ced6074f-1b6f-4a08-8b51-e3577ab6dc84.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Survival analysis of adjuvant endocrine therapy in HER2 positive early breast cancer patients with low ER positivity","fulltext":[{"header":"Implications for Practice","content":"\u003cp\u003eAdjuvant endocrine therapy (ET) improves survival in HER2-positive early breast cancer patients with low ER expression, especially when PR is positive. PR status should be considered a key biomarker to guide ET decisions in this subgroup. Despite clear benefits, over 40% of eligible patients do not receive ET in Taiwan, indicating a treatment gap. Clinicians should incorporate PR assessment and consider ET in ER-low, HER2-positive patients to optimize individualized care and improve outcomes.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eBreast cancer remains one of the most prevalent malignancies globally \u003csup\u003e1\u003c/sup\u003e, encompassing a variety of immunohistochemical subtypes with distinct biological behaviors and therapeutic responses. \u003csup\u003e2\u0026ndash;5\u003c/sup\u003e Among these, human epidermal growth factor receptor 2 (HER2)-positive breast cancer is recognized for its aggressive clinical course, and the advent of HER2-targeted therapies has significantly improved outcomes. \u003csup\u003e6\u0026ndash;8\u003c/sup\u003e Endocrine therapy (ET) is standard for hormone receptor\u0026ndash;positive early breast cancer, typically prescribed for tumors expressing estrogen receptor (ER) or progesterone receptor (PR). However, the crosstalk between ER and HER2 signaling pathways can induce endocrine resistance, highlighting the need for combined treatment strategies, as supported by the ASCO guidelines and reinforced by trials like ADAPT showing improved responses when HER2 blockade is paired with ET \u003csup\u003e9 10\u003c/sup\u003e However, when HER2 positivity is coupled with low ER expression (1\u0026ndash;9%), treatment strategies become more complex and require careful consideration. \u003csup\u003e11,12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAdjuvant ET in patients with early-stage, HER2-positive breast cancer exhibiting low ER expression represents a clinically nuanced and evolving area of oncologic management. While a low ER positive status used to raise questions regarding the efficacy of ET, emerging evidence suggests a potential benefit, particularly when integrated with HER2-targeted therapies \u003csup\u003e13,14\u003c/sup\u003e. A prospective cohort study by Xie et al. demonstrated improved breast cancer-specific survival (BCCS) with adjuvant ET, most notably with aromatase inhibitors (AIs) or sequential tamoxifen followed by AIs, even among patients with low ER-positive, HER2-positive disease. \u003csup\u003e15\u003c/sup\u003e The findings support the judicious use of ET in this subset of patients, with careful consideration of regimen selection to optimize clinical outcomes.\u003c/p\u003e \u003cp\u003eDespite the central role of endocrine treatment in ER-positive breast cancers, its benefit in ER-low tumors, especially those that also overexpress HER2, still remains contentious. For example, a large cohort study conducted in China reported that although patients with low ER expression received ET, no significant improvement in relapse-free survival (RFS) was observed. \u003csup\u003e11\u003c/sup\u003e This finding suggested that the biological behavior of HER2-positive, low ER-expressing tumors may necessitate a departure from conventional endocrine therapy and prompt the use of more targeted approaches.\u003c/p\u003e \u003cp\u003eFurther prospective cohort studies and meta-analyses have underscored the need for individualized treatment regimens that take into account both HER2 and ER status. Although some evidence suggests limited ET benefits in this setting, definitive conclusions remain elusive, underscoring the need for further investigation.\u003c/p\u003e \u003cp\u003e This study critically evaluates adjuvant ET\u0026rsquo;s role in HER2-positive, low ER early breast cancer, aiming to clarify its clinical impact and guide optimized treatment strategies.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical approval and informed consent\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for this study was derived from the Taiwan Cancer Registry—Long Form system \u003csup\u003e16\u003c/sup\u003e, which includes records of women diagnosed with breast cancer in Taiwan. The research protocol was approval from the institutional review board (IRB-TPEVGH protocol no. 2024-06-007B). Given the retrospective and anonymized nature of the study, informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients’ selection\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEarly breast cancer patients with HER2-positive status (defined as HER2 3+ or HER2 2+ with Fluorescence in situ hybridization [FISH] positivity) and ER-positive status (defined as ER\u0026gt;=1%) were enrolled in this study, from 2011 to 2019. These patients were retrospectively followed for a mean period of 6 years, from 2011 to 2017. According to the ASCO guidelines, ER positivity of 1-9% was classified as low ER status. In this study, patients were grouped into either ER ≥10% and ER 1-9%. Adjuvant endocrine therapy was defined as the administration of tamoxifen or aromatase inhibitors (AIs), including letrozole, anastrozole, and exemestane, following curative surgery.\u003c/p\u003e\n\u003cp\u003eIn addition to ER grouping, various clinical features, including PR status, tumor grade, pathological stage, surgical procedure, radiotherapy, chemotherapy, targeted therapy, and whether patients received adjuvant endocrine therapy or not, were recorded and extracted. We compared the characteristics of patients with and without adjuvant ET among the cohort of HER2-positive early breast cancer patients with low ER expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSurvival analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival (OS) was defined as the duration from diagnosis to death from any cause, while BCSS referred to the period from diagnosis to death specifically attributable to breast cancer. RFS was the interval from diagnosis to the occurrence of the first recurrence or death, whichever occurred first. Censored date of the study was set to 2017.\u003c/p\u003e\n\u003cp\u003eWe conducted a series of survival analyses, with a mean follow-up period extending up to 6 years, to compare the outcomes of adjuvant ET in HER2-positive early breast cancer patients with ER positivity of ≥10% and ER positivity of 1-9%. Additionally, we evaluated the impact of PR on survival outcomes in HER2-positive early breast cancer patients with low ER status. Among PR-positive and PR-negative patients, survival outcomes were further compared, stratified by the conduct of adjuvant ET.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary and secondary endpoints\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was to assess the survival outcomes, including OS, BCSS, and RFS, in HER2-positive early breast cancer patients with low ER positivity, with or without adjuvant ET. The secondary endpoint was the prognostic role of PR in HER2-positive early breast cancer patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using Statistical Product and Service Solutions (SPSS) version 26.0 software (SPSS Inc., IBM, Armonk, NY, USA). Survival durations were estimated employing the Kaplan-Meier method, with comparisons made using the log-rank test. For multivariable analysis, Cox's proportional hazards model was utilized. Statistical significance was defined as a p-value of less than 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study enrolled 10,408 early HER2-positive and ER-positive breast cancer patients. Among these, 1,436 (15.48%) had low ER positivity (1\u0026ndash;9%), and 7,838 (84.52%) had ER positivity \u0026ge;10% (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 1. The characteristics of early breast cancer patients with HER2-positivity.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eER 1-9%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eER\u0026gt;=10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eER positivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e1436 (15.48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e7838 (84.52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e9274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e719 (50.07%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e1443 (18.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e2162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e717 (49.93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e6395 (81.59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e7112\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrading\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e50 (3.48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e778 (9.93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e828\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e581 (40.46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e4280 (54.60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e4861\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e805 (56.06%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e2780 (35.47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e3585\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e229 (15.95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e922 (11.76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e472 (32.87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e2765 (35.28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e3237\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e498 (34.68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e2966 (37.84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e3464\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e237 (16.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e1185 (15.12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1422\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOperation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e8 (0.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e51 (0.65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.6818\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1428 (99.44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e7787 (99.35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e9215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e704 (49.03%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e3353 (42.78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e4057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e732 (50.97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e4485 (57.22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e5217\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e391 (27.23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e2251 (28.72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e2642\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.2499\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1045 (72.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e5587 (71.28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e6632\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTarget therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e668 (46.52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e3712 (47.46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e4380\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.5573\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e768 (53.48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e4126 (52.64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e4894\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e602 (41.92%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e694 (8.85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1296\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e834 (58.08%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e7144 (91.15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e7978\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIn the ER \u0026ge;10% group, 81.59% were progesterone receptor (PR) positive, compared to 49.93% in the ER 1\u0026ndash;9% group. Tumor grade III predominated in the ER-low group (56.06%), whereas grade II was most common in the ER \u0026ge;10% group (54.60%). Most patients were diagnosed at stage II in both groups (34.68% in ER-low, 37.84% in ER \u0026ge;10%). Nearly all patients underwent curative surgery (99.44% ER-low, 99.35% ER \u0026ge;10%). Radiotherapy was administered to 50.97% of ER-low and 57.22% of ER \u0026ge;10% patients. Chemotherapy was given to 72.77% of ER-low and 71.28% of ER \u0026ge;10%. Targeted therapy rates were comparable (53.48% ER-low, 52.64% ER \u0026ge;10%). Notably, 91.15% of ER \u0026ge;10% patients received adjuvant endocrine therapy (ET), while only 58.08% of ER-low patients received ET.\u003c/p\u003e\n\u003cp\u003eAmong ER-low patients, those receiving adjuvant ET were more often PR positive (54.56%) than those who did not receive ET (43.85%). Grade III tumors were prevalent regardless of ET status (53.84% with ET, 59.14% without). Most patients receiving ET were diagnosed at stage I (36.09%), whereas stage II predominated in those without ET (34.88%). Mean ages were similar (54.32 \u0026plusmn; 10.23 years with ET; 55.33 \u0026plusmn; 10.66 years without). Radiotherapy was more frequent among ET recipients (56.24% vs. 43.69%). Chemotherapy rates were nearly identical (72.78% vs. 72.76%), and targeted therapy was slightly lower in ET recipients (51.32%) compared to non-recipients (56.48%) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 2. The characteristics of HER2-positivity in early breast cancer patients with low ER positivity.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"585\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 585px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eER 1-9%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 201px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine therapy (+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine therapy (-)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e379 (45.44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e338 (56.15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e455 (54.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e264 (43.85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e40 (4.80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e10 (1.66%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e345 (41.37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e236 (39.20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e449 (53.84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e356 (59.14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e121 (14.51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e108 (17.94%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e301 (36.09%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e171 (28.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e288 (34.53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e210 (34.88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e124 (14.87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e113 (18.77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e54.32 \u003cu\u003e+\u003c/u\u003e 10.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e55.33 \u003cu\u003e+\u003c/u\u003e 10.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.2745\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e365 (43.76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e339 (56.31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e469 (56.24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e263 (43.69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e227 (27.22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e164 (27.24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.9919\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e607 (72.78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e438 (72.76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTarget therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e406 (48.68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e262 (43.52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0531\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e428 (51.32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003e340 (56.48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSurvival analyses revealed significantly higher overall survival (OS) in patients receiving adjuvant ET across ER groups. In the ER \u0026ge;10% cohort, OS was 92.32% with ET versus 83.98% without (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001, \u003cstrong\u003eFigure 1a\u003c/strong\u003e). Similarly, ER-low patients showed improved OS with ET (90.16% vs. 85.55%, \u003cem\u003ep\u003c/em\u003e = 0.0082, \u003cstrong\u003eFigure 1b\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWithin the ER-low group, PR positivity correlated with better OS irrespective of ET (89.54% vs. 86.91%, \u003cem\u003ep\u003c/em\u003e = 0.0295, \u003cstrong\u003eFigure 1c\u003c/strong\u003e). Among PR-positive patients, ET further improved OS (92.08% vs. 86.69%, \u003cem\u003ep\u003c/em\u003e = 0.0216, \u003cstrong\u003eFigure 1d\u003c/strong\u003e). Conversely, in PR-negative ER-low patients, ET showed a non-significant trend toward improved OS (88.55% vs. 84.09%, \u003cem\u003ep\u003c/em\u003e = 0.0649,\u003cstrong\u003e\u0026nbsp;Figure 1e\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eBreast cancer-specific survival (BCSS) also favored ET recipients in both ER \u0026ge;10% (95.27% vs. 87.07%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001, \u003cstrong\u003eFigure 2a\u003c/strong\u003e) and ER-low groups (93.91% vs. 89.71%, \u003cem\u003ep\u003c/em\u003e = 0.0047, \u003cstrong\u003eFigure 2b\u003c/strong\u003e). However, BCSS did not differ significantly by PR status within the ER-low subgroup regardless of ET (92.63% vs. 91.71%, \u003cem\u003ep\u003c/em\u003e = 0.2384, \u003cstrong\u003eFigure 2c\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eRecurrence-free survival (RFS) was significantly better with ET in both ER \u0026ge;10% (94.24% vs. 86.44%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001, \u003cstrong\u003eFigure 3a\u003c/strong\u003e) and ER-low patients (91.24% vs. 88.21%, \u003cem\u003ep\u003c/em\u003e = 0.0316, \u003cstrong\u003eFigure 3b\u003c/strong\u003e). No significant RFS differences were observed between PR-positive and PR-negative ER-low patients irrespective of ET (89.26% vs. 90.67%, \u003cem\u003ep\u003c/em\u003e = 0.8142, \u003cstrong\u003eFigure 3c\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMultivariate Cox regression confirmed that PR positivity, cancer stage, and receipt of endocrine, chemotherapy, radiotherapy, and targeted therapies were significantly associated with improved OS, BCSS, and RFS. Tumor grade was prognostic for BCSS and RFS. Importantly, low ER positivity was not an independent prognostic factor, whereas PR positivity remained consistently prognostic across outcomes (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 3. Multivariate analysis for OS, BCSS, and RFS by using Cox\u0026apos;s proportional hazards model.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHazard ratio\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[ 95% CI ]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCSS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHazard ratio\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[ 95% CI ]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRFS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHazard ratio\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[ 95% CI ]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow ER positivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.094\u003c/p\u003e\n \u003cp\u003e[0.904-1.324]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.987\u003c/p\u003e\n \u003cp\u003e[0.772-1.260 ]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.105\u003c/p\u003e\n \u003cp\u003e[0.896-1.363]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePR positivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.745*\u003c/p\u003e\n \u003cp\u003e[0.637-0.871]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.789*\u003c/p\u003e\n \u003cp\u003e[0.643-0.969]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.780*\u003c/p\u003e\n \u003cp\u003e[0.653-0.933]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.996\u003c/p\u003e\n \u003cp\u003e[0.756-1.312]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1.330\u003c/p\u003e\n \u003cp\u003e[0.863-2.051]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.933\u003c/p\u003e\n \u003cp\u003e[1.272-2.937]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.142\u003c/p\u003e\n \u003cp\u003e[0.861-1.515]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1.671\u003c/p\u003e\n \u003cp\u003e[1.079-2.587]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.228\u003c/p\u003e\n \u003cp\u003e[1.458-3.403]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eStage1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.648\u003c/p\u003e\n \u003cp\u003e[1.820-3.853]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e3.117\u003c/p\u003e\n \u003cp\u003e[1.695-5.731]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.462\u003c/p\u003e\n \u003cp\u003e[1.618-3.746]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eStage2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e9.002\u003c/p\u003e\n \u003cp\u003e[6.250-12.966]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e11.243\u003c/p\u003e\n \u003cp\u003e[6.218-20.328]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e5.019\u003c/p\u003e\n \u003cp\u003e[3.288-7.660]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eStage3*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e22.849\u003c/p\u003e\n \u003cp\u003e[15.731-33.187]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e31.210\u003c/p\u003e\n \u003cp\u003e[17.179-56.701]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12.542\u003c/p\u003e\n \u003cp\u003e[8.128-19.352]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOperation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.214\u003c/p\u003e\n \u003cp\u003e[0.826-5.938]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1.569\u003c/p\u003e\n \u003cp\u003e[0.501-4.915]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.723\u003c/p\u003e\n \u003cp\u003e[0.358-1.462]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.685*\u003c/p\u003e\n \u003cp\u003e[0.588-0.797]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.759*\u003c/p\u003e\n \u003cp\u003e[0.623-0.925]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.655*\u003c/p\u003e\n \u003cp\u003e[0.552-0.776]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.360*\u003c/p\u003e\n \u003cp\u003e[0.297-0.437]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.494*\u003c/p\u003e\n \u003cp\u003e[0.377-0.647]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.611*\u003c/p\u003e\n \u003cp\u003e[0.480-0.778]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.598*\u003c/p\u003e\n \u003cp\u003e[0.501-0.713]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.461*\u003c/p\u003e\n \u003cp\u003e[0.371-0.573]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.555*\u003c/p\u003e\n \u003cp\u003e[0.457-0.676]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTarget therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.840\u003c/p\u003e\n \u003cp\u003e[0.704-1.002]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.859\u003c/p\u003e\n \u003cp\u003e[0.685-1.076]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.038\u003c/p\u003e\n \u003cp\u003e[0.851-1.266]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI= Confidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003ep\u003c/em\u003e-value \u0026lt;0.05\u003c/p\u003e\n\u003cp\u003eIn summary, among early HER2-positive breast cancer patients with low ER expression, adjuvant ET significantly improved OS, BCSS, and RFS. Nonetheless, 41.9% of ER-low patients did not receive ET, representing a missed opportunity for survival benefit. Additionally, PR-positive, ER-low patients experienced the greatest OS improvement with ET, highlighting the importance of PR status in guiding therapy decisions.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecent evidence elucidates the intricate crosstalk between ER and HER2 signaling pathways, supporting dual blockade strategies in breast cancer co-expressing hormone receptors and HER2.\u003csup\u003e17,18\u003c/sup\u003e The ExteNET trial further underscores this interaction, demonstrating the clinical benefit of targeting both pathways in HER2- and ER-positive disease. \u003csup\u003e19\u003c/sup\u003e Nonetheless, endocrine therapy carries a substantial burden of adverse effects\u0026mdash;such as depression, vasomotor symptoms, vaginal dryness, and arthralgia\u0026mdash;which compromise quality of life and contribute to high discontinuation rates (31\u0026ndash;73%) before the recommended five-year duration. \u003csup\u003e20,21\u003c/sup\u003e This raises a critical clinical question: in HER2-positive breast cancer patients with low ER expression (1\u0026ndash;9%), can ET be omitted without undermining treatment efficacy?\u003c/p\u003e \u003cp\u003eOur study highlights this clinical uncertainty, showing that 41.92% of Taiwanese patients with HER2-positive early breast cancer and low ER positivity did not receive adjuvant ET. This variability reflects ongoing debate and lack of consensus on ET\u0026rsquo;s role in this subgroup. A prospective cohort study by Xie et al. (2022) found improved BCSS with ET in 407 women with low ER-positive disease, particularly among HER2-positive patients.\u003csup\u003e15\u003c/sup\u003e Similarly, Choong et al. reported worse OS with omission of ET in low-ER early breast cancer, independent of PR, HER2, or Ki-67 status.\u003csup\u003e14\u003c/sup\u003e Conversely, Wang, Li et al. observed no significant difference in five-year RFS between ET-treated and untreated patients in a Chinese cohort.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur analysis demonstrates that adjuvant ET significantly improves OS, BCSS, and RFS in HER2-positive early breast cancer with low ER expression. This aligns with ASCO guidelines defining ER positivity at \u0026ge;\u0026thinsp;1%, and supports using the 1% ER cutoff to guide ET decisions.\u003csup\u003e22\u003c/sup\u003e These findings reinforced the critical role of ER expression in guiding ET decisions and were consistent with existing literature. Importantly, 41.92% of patients with low ER expression in our cohort did not receive ET\u0026mdash;indicating a missed opportunity to optimize survival.\u003c/p\u003e \u003cp\u003eClinicopathologic differences between ER\u0026thinsp;\u0026ge;\u0026thinsp;10% and ER 1\u0026ndash;9% groups were significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), including tumor grade, stage, radiotherapy, and PR positivity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The ER-low group had a predominance of grade III tumors (56.06%), while grade II predominated in ER\u0026thinsp;\u0026ge;\u0026thinsp;10% (54.60%). Stage distribution showed higher proportions of stage 0 and stage III disease in the low ER group. Notably, fewer ER-low patients received adjuvant radiotherapy (50.97% vs. 57.22%). Within the ER-low subgroup, those receiving ET had less advanced disease and higher PR positivity compared to those without ET (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These differences might result from inherent variations in tumor biology, while selection bias due to sample size disparity could not be totally excluded.\u003c/p\u003e \u003cp\u003ePR status was markedly different between groups: 49.93% PR-positive in ER-low versus 81.59% in ER\u0026thinsp;\u0026ge;\u0026thinsp;10% tumors. Within the ER-low cohort, PR positivity was significantly higher in ET recipients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), highlighting PR\u0026rsquo;s potential predictive role beyond ER levels.\u003c/p\u003e \u003cp\u003ePrevious studies have demonstrated that PR signaling exerts a critical modulatory effect on estrogen receptor alpha (ERα) activity within the breast cancer microenvironment, influencing both tumor biology and therapeutic responsiveness. \u003csup\u003e23\u0026ndash;26\u003c/sup\u003e Prior research suggests PR expression enhances response to adjuvant ET, while low PR may contribute to tamoxifen resistance. \u003csup\u003e27\u0026ndash;30\u003c/sup\u003e In our cohort, PR-positive, ER-low patients receiving ET had significantly better OS (92.08% vs. 86.69%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0216), whereas PR-negative patients showed a non-significant trend favoring ET (88.55% vs. 84.09%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0649). No significant differences were observed in BCSS or RFS by PR status within this subgroup.\u003c/p\u003e \u003cp\u003eThese findings echo those of Bardou et al., who identified PR positivity as an independent predictor of ET benefit, with concordant ER/PR-positive tumors deriving superior survival improvements compared to discordant cases. \u003csup\u003e31\u003c/sup\u003e Lashen et al. further proposed a 10% PR positivity cutoff to refine prognostication. \u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMultivariate analysis in our study revealed that low ER expression was not an independent prognostic factor for OS, BCSS, or RFS, whereas PR positivity consistently predicted improved outcomes. Other significant prognostic factors included tumor stage, radiotherapy, chemotherapy, and ET receipt. These results parallel the meta-analysis by Boland et al., encompassing 13,667 patients, which linked PR negativity with poorer OS and disease-free survival.\u003csup\u003e33\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn summary, adjuvant ET confers survival benefits in HER2-positive early breast cancer irrespective of ER expression level. The substantial proportion (41.92%) of ER-low patients in Taiwan not receiving ET represents a critical gap in care that should be addressed through clinician-led counseling to optimize treatment uptake. PR positivity may serve as a key biomarker to identify ER-low patients most likely to benefit from ET, supporting its integration into therapeutic decision-making.\u003c/p\u003e \u003cp\u003eLimitations of this study include its retrospective design, which inherently risks selection bias. The relatively smaller ER-low cohort limits statistical power and subgroup robustness. Additionally, data on duration and specific ET regimens were unavailable, restricting evaluation of treatment heterogeneity\u0026rsquo;s impact on outcomes.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this real-world dataset from Taiwan provides valuable insight on the use of adjuvant ET in patients with HER2-positive early breast cancer and ER-low status. Despite demonstrating survival benefits, approximately 41.92% of patients with ER expression of 1\u0026ndash;9% did not receive adjuvant ET. These findings highlighted the need to actively consider and discuss ET for these patients to improve treatment outcomes. This study offered real world evidence in survival data to support clinicians and patients in making more informed evidence through shared decision-making.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eER: Estrogen receptor\u003c/p\u003e\n\u003cp\u003ePR: Progesterone-receptor\u003c/p\u003e\n\u003cp\u003eHER2: Human epidermal growth factor receptor 2\u003c/p\u003e\n\u003cp\u003eFISH: Fluorescence in situ hybridization\u003c/p\u003e\n\u003cp\u003eET: Endocrine therapy\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBCSS: Breast cancer-specific survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRFS: Recurrence-free survival\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the Taipei Veterans General Hospital (TPEVGH) ethics committee. The research protocol was approval from the institutional review board (IRB-TPEVGH protocol no. 2024-06-007B). Given the retrospective and anonymized nature of the study, informed consent was waived.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData for this study were obtained from the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan (URL:// https://dep.mohw.gov.tw/DOS/cp-5119-59201-113.html). All data generated or analyzed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by IRB-TPEVGH protocol no. 2024-06-007B.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHsuan-Hsuan Yu (conceptualization; writing\u0026mdash;original draft), Deanna Gracia (data curation; formal analysis; investigation), Chan-Heng Ho (data curation; formal analysis; investigation), Hao-Yang Chen (data curation; formal analysis; investigation), Ling-Ming Tseng (funding acquisition; investigation), Ta-Chung Chao (funding acquisition; investigation), and Chi-Cheng Huang (conceptualization; formal analysis; methodology; supervision).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge the Taiwan Clinical Oncology Research Foundation, Melissa Lee Cancer Foundation, and Dr. Morris Chang for their generous support and assistance throughout this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal AJCacjfc. 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Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis. \u003cem\u003eESMO Open\u003c/em\u003e. Apr 2021;6(2):100088. doi:10.1016/j.esmoop.2021.100088\u003c/li\u003e\n\u003cli\u003eFusco N, Viale G. The \u0026ldquo;lows\u0026rdquo;: Update on ER-low and HER2-low breast cancer. \u003cem\u003eThe Breast\u003c/em\u003e. 2024:103831. \u003c/li\u003e\n\u003cli\u003eChoong GMY, Hoskin TL, Boughey JC, Ingle JN, Goetz MP. The impact of adjuvant endocrine therapy (AET) omission in ER-low (1-10%) early-stage breast cancer. American Society of Clinical Oncology; 2024.\u003c/li\u003e\n\u003cli\u003eXie Y, Yang L, Wu Y, Zheng H, Gou Q. Adjuvant endocrine therapy in patients with estrogen receptor-low positive breast cancer: A prospective cohort study. \u003cem\u003eBreast\u003c/em\u003e. Dec 2022;66:89-96. doi:10.1016/j.breast.2022.09.008\u003c/li\u003e\n\u003cli\u003eThe Health and Welfare Database Manual. 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The Role of Progesterone Receptors in Breast Cancer. \u003cem\u003eDrug Des Devel Ther\u003c/em\u003e. 2022;16:305-314. doi:10.2147/dddt.S336643\u003c/li\u003e\n\u003cli\u003eThomas C, Gustafsson J-\u0026Aring;. Progesterone receptor-estrogen receptor crosstalk: a novel insight. \u003cem\u003eTrends in Endocrinology \u0026amp; Metabolism\u003c/em\u003e. 2015;26(9):453-454. \u003c/li\u003e\n\u003cli\u003eHuggins RJ, Greene GL. ER\u0026alpha;/PR crosstalk is altered in the context of the ER\u0026alpha; Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation. \u003cem\u003eNPJ Breast Cancer\u003c/em\u003e. 2023;9(1):96. \u003c/li\u003e\n\u003cli\u003eChakravorty G, Ahmad S, Godbole MS, Gupta S, Badwe RA, Dutt A. Deciphering the mechanisms of action of progesterone in breast cancer. \u003cem\u003eOncotarget\u003c/em\u003e. 2023;14:660. \u003c/li\u003e\n\u003cli\u003eYao N, Song Z, Wang X, Yang S, Song H. Prognostic impact of progesterone receptor status in Chinese estrogen receptor positive invasive breast cancer patients. \u003cem\u003eJournal of breast cancer\u003c/em\u003e. 2017;20(2):160-169. \u003c/li\u003e\n\u003cli\u003eBardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. May 15 2003;21(10):1973-9. doi:10.1200/jco.2003.09.099\u003c/li\u003e\n\u003cli\u003eLashen AG, Toss MS, Mongan NP, Green AR, Rakha EA. The clinical value of progesterone receptor expression in luminal breast cancer: A study of a large cohort with long-term follow-up. \u003cem\u003eCancer\u003c/em\u003e. Apr 15 2023;129(8):1183-1194. doi:10.1002/cncr.34655\u003c/li\u003e\n\u003cli\u003eBoland MR, Ryan \u0026Eacute; J, Dunne E, Aherne TM, Bhatt NR, Lowery AJ. 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Jan 2020;107(1):33-43. doi:10.1002/bjs.11347\u003c/li\u003e\n\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":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"low ER positivity, HER2 positivity, survival, early breast cancer, endocrine therapy","lastPublishedDoi":"10.21203/rs.3.rs-6896091/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6896091/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOptimal treatment strategies for early-stage human epidermal growth factor receptor 2 (HER2) positive breast cancer with low estrogen receptor (ER) expression (1–9%) remain unclear. While endocrine therapy (ET) is standard for ER-positive disease, its benefit in ER-low tumors, particularly with concurrent HER2 overexpression, is less established.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective cohort study using Taiwan’s national cancer registry, identifying 10,408 patients with HER2-positive early breast cancer diagnosed between 2011 and 2019. Of these, 1436 (15.48%) had low ER positivity. Patients were stratified by ER level (1–9% vs. ≥10%) and ET use. Overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS) were evaluated via Kaplan-Meier and Cox regression analyses. Progesterone receptor (PR) status was also assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdjuvant ET significantly improved OS, BCSS, and RFS in both ER subgroups (all p \u0026lt; 0.05). In ER-low patients, ET was associated with improved OS (90.16% vs. 85.55%, p = 0.0082), BCSS (93.91% vs. 89.71%, p = 0.0047), and RFS (91.24% vs. 88.21%, p = 0.0316). On multivariate analysis, PR positivity—not ER level—was an independent predictor of improved outcomes. Notably, PR-positive, ER-low patients had better OS with ET (92.08% vs. 86.69%, p = 0.0216).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdjuvant ET provides meaningful survival benefits in HER2-positive early breast cancer with low ER expression, particularly in PR-positive tumors. Despite this, 41.92% of eligible ER-low patients did not receive ET, highlighting a treatment gap. PR status may guide ET decisions, supporting individualized treatment approaches.\u003c/p\u003e","manuscriptTitle":"Survival analysis of adjuvant endocrine therapy in HER2 positive early breast cancer patients with low ER positivity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 07:11:51","doi":"10.21203/rs.3.rs-6896091/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-12T04:40:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-05T15:33:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-30T05:41:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153882126088583023389458811710651102582","date":"2025-06-29T14:30:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306553110050693054056195127653696443060","date":"2025-06-27T15:50:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-27T14:20:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-19T13:45:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-19T13:26:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research","date":"2025-06-15T02:18:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a55ac4d-7499-400c-9116-f416ff1dc30d","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:07:04+00:00","versionOfRecord":{"articleIdentity":"rs-6896091","link":"https://doi.org/10.1186/s13058-025-02157-9","journal":{"identity":"breast-cancer-research","isVorOnly":false,"title":"Breast Cancer Research"},"publishedOn":"2025-12-29 15:57:54","publishedOnDateReadable":"December 29th, 2025"},"versionCreatedAt":"2025-07-02 07:11:51","video":"","vorDoi":"10.1186/s13058-025-02157-9","vorDoiUrl":"https://doi.org/10.1186/s13058-025-02157-9","workflowStages":[]},"version":"v1","identity":"rs-6896091","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6896091","identity":"rs-6896091","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}