Novel Prognostic Stratification and Therapeutic Implications in T1N0M0 Breast Cancer: Insights from a Multi-Center Chinese Cohort

Novel Prognostic Stratification and Therapeutic Implications in T1N0M0 Breast Cancer: Insights from a Multi-Center Chinese Cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Novel Prognostic Stratification and Therapeutic Implications in T1N0M0 Breast Cancer: Insights from a Multi-Center Chinese Cohort linlin sun, Xiaopei Dong, Hua Yang, Yingjian Sha, Xiaodong Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6348915/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Early-stage breast cancer (T1N0M0 BC) generally has a favorable prognosis, but relapse risks persist over time. The role of adjuvant systemic treatments (AST) for tumors ≤ 10 mm remains debated. Given the limited availability of robust prospective data, retrospective studies play a crucial role in guiding clinical decision-making. Methods: This multicenter retrospective study included 1,733 invasive T1N0M0 breast cancer patients treated at two Chinese centers (1998–2018). Patients with neoadjuvant chemotherapy or unknown estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status were excluded. Primary endpoint was disease-free survival (DFS); secondary endpoints included distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS). Survival outcomes across four molecular subtypes (ER, PR, HER2-defined) were analyzed using Kaplan–Meier and Cox models. Tumor size thresholds for AST benefit were determined via maximally selected rank statistics. Results: This study evaluated 1,733 T1N0M0 breast cancer patients, with HR+/HER2 − as the most common subtype (56.9%), followed by HR+/HER2+ (12.6%), HR-/HER2+ (10.8%), and triple-negative (19.7%). Molecular subtypes showed significant prognostic stratification (10-year DFS: 84.0% for HR+/HER2- vs 73.4% for HR-/HER2+, P < 0.001). AST demonstrated significant overall benefit (DFS HR = 0.33, 95% CI: 0.24–0.45, P < 0.001), with consistent improvements in DRFS, BCSS, and OS (all P < 0.01). Subtype-specific thresholds were identified: no AST benefit for HR+/HER2 − tumors < 10 mm ( P = 0.33 for endocrine therapy); significant DFS improvement for HER2 + tumors ≥ 8 mm receiving trastuzumab (HR = 0.37, 95% CI: 0.14–0.77, P = 0.018); and for triple-negative tumors ≥ 9 mm (HR = 0.38, 95% CI: 0.21–0.74, P = 0.002). Conclusion: This study highlights the prognostic heterogeneity of T1N0M0 breast cancer and identifies high-risk subgroups that benefit from AST. Integrating molecular and clinicopathologic features supports a more personalized approach to early-stage breast cancer treatment. T1N0M0 Breast Cancer Adjuvant Systemic Therapy Prognostic Heterogeneity Molecular Subtypes Personalized Treatment Strategies Figures Figure 1 Figure 2 Figure 3 Figure 4 Background The widespread adoption of mammographic screening over recent decades has revolutionized early breast cancer detection, particularly for stage I tumors (T1, ≤ 20 mm) [ 1 , 2 ]. While these small, node-negative malignancies demonstrate generally favorable outcomes, with cancer-specific survival rates exceeding 90% over 5 to 10 years[ 3 – 5 ], they present a paradoxical clinical challenge. In a multicenter retrospective cohort study spearheaded by G. Houvenaeghel et al., the recurrence rates for T1N0M0 breast cancer were 6% at 5 years and increased to 16.2% at 10 years[ 4 ]. This persistent risk trajectory persists even among the smallest tumors, as evidenced by a 4,113-patient cohort showing 97% and 95% 5-year disease-free survival for T1a and T1b tumors respectively[ 6 ]. These outcomes underscore the continuous risk of late relapses in tumors initially deemed to have a favorable prognosis. The biological heterogeneity of these ostensibly low-risk tumors creates significant therapeutic dilemmas, which have not been well characterized for these early-stage cancers after initial local therapies[ 7 , 8 ]. Unlike their node-positive counterparts where adjuvant systemic therapy (AST) demonstrates clear benefit, the risk-benefit calculus for T1N0M0 tumors remains uncertain[ 6 , 9 ]. This evidence gap stems from the systematic exclusion of these patients from prospective randomized trials, forcing clinicians to rely on suboptimal evidence from retrospective analyses and expert consensus. Current practice patterns show striking variability, with AST routinely administered for tumors > 10 mm but remaining controversial for smaller lesions (≤ 10 mm)[ 10 – 12 ]. Emerging data highlight the critical prognostic influence of biological subtypes[ 6 , 7 , 13 , 14 ]. Patients with HER2-positive and triple-negative T1N0M0 tumors demonstrating significantly worse outcomes than hormone receptor-positive counterparts[ 4 , 15 , 16 ]. This molecular stratification has intensified debates regarding risk-adapted treatment intensification[ 6 , 17 , 18 ], particularly as contemporary genomic tools reveal substantial heterogeneity within traditional histopathological classifications. This multicenter retrospective analysis was designed to address these critical knowledge gaps by systematically evaluating disease characteristics, treatment patterns, and long-term outcomes across a large T1N0M0 cohort. By correlating clinicopathological features with survival endpoints, we aim to develop more precise prognostic models to guide AST decision-making in this clinically ambiguous population. Methods Study Population This multicenter study compiled longitudinal data from breast cancer (BC) patients treated at two Chinese institutions: Tianjin Medical University Cancer Institute (May 1998 - October 2018) and Affiliated Hospital of Hebei University (January 2016 - March 2018). Ethical approval was obtained with patient consent. Inclusion criteria were as follows: Female patients with primary invasive BC, tumor size ≤ 20 mm (T1), node-negative (N0) and metastasis-free (M0), and complete ER/PR/HER2 status documentation. Exclusion criteria are patients with Neoadjuvant chemotherapy recipients, unknown ER, PR, or HER2 status, and male patients or non-invasive subtypes Data collection Variables assessed were demographics (age, menopausal status), tumor characteristics (histological grade, size), biomarkers: HR status (nuclear staining of 1% or more for ER or PR was considered positive [19] ), HER2 status (HER2 positivity was ascertained using an immunohistochemical (IHC) score of 3+. In cases where the results were equivocal, fluorescence in situ hybridization was employed to confirm a HER2/CEP17 ratio exceeding 2.2 [20] ), and treatment modalities (surgery, adjuvant therapy). Four molecular subtypes were identified: HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-. Two independent physicians reviewed all pathology and survival data. Discrepancies were resolved by third-party adjudication. Primary endpoints including disease-free survival (DFS), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS). DFS was defined as the period from surgical intervention to local recurrence, distant metastasis, death, or last follow-up without relapse. DRFS encompassed the time from the initial diagnosis to distant recurrence or last follow-up. BCSS was the interval from the initial diagnosis to breast cancer-related death or last follow-up, while OS spanned from the initial diagnosis to death from any cause or last follow-up. Data analysis The study assessed categorical variables were analyzed using the chi-square test. Survival estimates for DFS, DRFS, BCSS, and OS were calculated via the Kaplan–Meier method, with the log-rank test assessing inter-group differences. The Cox proportional hazards model evaluated the prognostic impact of patient and tumor characteristics on these outcomes. Maximally selected rank statistics determined the optimal tumor size cutoff, dividing patients into two subgroups based on molecular subtypes for further analysis with multivariable Cox models. Statistical procedures and survival probability charts were executed using GraphPad Prism (version 10), and tumor size cutoffs were computed using R software version 4.3.3 (Bell Laboratories, Murray Hill, NJ). Hazard ratios (HR) were presented with 95% confidence intervals (CI), considering a P value of < 0.05 as statistically significant. Results Demographic and Tumor Characteristics We identified 1733 consecutive female patients with pT1N0M0 BC from Tianjin Medical University Cancer Institute (1511 patients) and Hospital and the Affiliated Hospital of Hebei University (222 patients). The median follow-up was 172 months (interquartile range, 107–203) for the Tianjin group and 85 months (interquartile range, 80–92) for the Hebei group. Upon applying identification rules for HR and HER2 status, 987 cases (56.9%) were classified as HR+/HER2-, 218 cases (12.6%) as HR+/HER2+, 187 cases (10.8%) as HR-/HER2+, and 341 cases (19.7%) as HR-/HER2-. Baseline clinicopathologic characteristics were compared across the molecular subtypes (Table S1). A notably higher prevalence of premenopausal status was observed in the HR+/HER2 + subgroup. The likelihood of undergoing lumpectomy was markedly lower among patients with HR-/HER2 + tumors, accounting for only 10.7% of cases within this subtype. The prevalence of invasive ductal carcinoma was elevated in HER2-positive subgroups relative to HER2-negative ones. Additionally, histological grade III tumors were less frequently observed in the HR+/HER2- subgroup compared to other subgroups. Tumor sizes exceeding 1.0 cm were most common, occurring in 60.1% of HR+/HER2-, 59.2% of HR+/HER2+, 57.8% of HR-/HER2+, and 68.9% of HR-/HER2- subgroups. Comprehensive adjuvant chemotherapy was administered to all patients with HER2-positive tumors within this study cohort. Survival outcomes The 5-year and 10-year survival rates for patients with T1N0M0 disease are detailed in Table S2. For the HR+/HER2- subgroup, the 5-year DFS, DRFS, BCSS, and OS rates exceeded 90%. In contrast, the HR-/HER2 + subgroup showed the lowest survival rates at 5 years, particularly for DFS. Over a 10-year period, the HR+/HER2- subtype demonstrated the most favorable outcomes, while the HR-/HER2 + subtype had the least favorable results among the four groups. Kaplan–Meier analysis revealed significant differences in survival among these groups (Figure. 1A-D, P < 0.001 for all). Univariate analysis indicated that lower histological grade (I or II), smaller tumor size (≤ 10 mm), and the use of adjuvant chemotherapy were associated with improved DFS, DRFS, BCSS, and OS (Table S3, P < 0.05 for all). Factors contributing to poorer DFS, DRFS, and BCSS included premenopausal status and younger age (≤ 40 years). However, for OS, being younger than 60 years correlated with better outcomes. The best prognoses in DRFS and BCSS were observed in patients with HR+/HER2- subtype. Multivariate analyses further substantiated that adjuvant chemotherapy was beneficial for DFS, DRFS, BCSS, and OS (Table 1, P < 0.001 for all). Factors such as being younger than 60 years, postmenopausal status, a lower histological grade (I or II), and a tumor size ≤ 5 mm were associated with improved OS ( P 5 mm were predictors of poorer prognoses in DRFS and BCSS. Additionally, younger patients (≤ 40 years) and those with a histological grade 3 were linked to worse DFS and DRFS. Moreover, tumors exceeding 10 mm and the HR-/HER2 + subtype were correlated with diminished DFS. Table 1 Hazard Ratios Quantifying the Multivariate Associations between Patient, Tumor, and Treatment Characteristics and Breast Cancer Events. DFS DRFS BCSS OS Variables HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P Molecular subtype HR + HER2- 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) HR + HER2+ 1.21 (0.84–1.71) .30 1.91 (1.29–2.77) < .001 1.70 (1.09–2.61) .017 1.744 (1.18–2.53) .004 HR-HER2+ 1.69 (1.18–2.39) .003 2.55 (1.70–3.77) < .001 2.66 (1.70–4.09) < .001 2.52 (1.71–3.66) < .001 HR-HER2- 1.02 (0.75–1.38) .896 1.29 (0.90–1.83) 0.16 1.46 (0.99–2.14) .054 1.56 (1.13–2.13) .007 Age ≤ 40 2.20 (1.38–3.52) < .001 2.15 (1.25–3.73) .006 1.47 (0.81–2.7) 0.21 0.38 (0.231–0.62) 40 to ≤ 60 1.32 (0.92–1.93) .14 1.29 (0.84–2.04) .26 0.96 (0.59–1.59) .88 0.25 (0.18–0.35) 60 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Menopausal status Premenopause 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Postmenopause 0.78 (0.59–1.01) .06 0.67 (0.49–0.92) < .001 0.54 (0.37–0.76) < .001 0.58 (0.41–0.81) .002 Surgery type Lumpectomy 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Mastectomy 0.87 (0.64–1.09) .39 0.89 (0.63–1.30) .54 0.89 (0.58–1.39) .59 0.72 (0.51–1.04) .07 Radiotherapy None 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Done 0.98 (0.68–1.40) .91 0.92 (0.61–1.37) .71 0.92 (0.56–1.46) .73 0.74 (0.47–1.13) .18 Histology Invasive ductal carcinoma 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Non-invasive ductal carcinoma 0.99 (0.68–1.40) .96 1.20 (0.79–1.75) .37 1.06 (0.67–1.60) .80 1.10 (0.77–1.52) .59 Histological grade other 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) III 2.03 (1.57–2.62) 5 to ≤ 10 1.80 (0.99–3.60) .07 3.84 (1.57–12.70) .010 11.68 (2.54–207.20) .015 5.26 (1.95–21.6) .005 > 10 to ≤ 20 2.93 (1.68–5.72) < .001 6.70 (2.83–21.80) .001 20.53 (4.59–361.50) .002 8.83 (3.36–35.79) < .001 Adjuvant chemotherapy None 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Done 0.33 (0.24–0.45) < .001 0.35 (0.25–0.52) < .001 0.32 (0.22–0.49) < .001 0.37 (0.27–0.51) < .001 Abbreviations: HR, hormone receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; HR, hazard ratio; P < 0.05 is statistically significant. Tumor size and survival across the molecular subtypes Figure. S1 illustrates the distribution of tumor sizes and the optimal cutoff points for predicting survival outcomes across the entire cohort and various tumor subtypes. The cutoff size for predicting DFS, DRFS, BCSS, and OS, was determined to be 10 mm for the whole population. For specific subtypes, the cutoff was 10 mm for HR+/HER2- tumors, 8 mm for HR+/HER2 + tumors, 7 mm for HR-/HER2 + tumors, and 9 mm for HR-/HER2- tumors. For HER2-positive diseases, including both HR+/HER2 + and HR-/HER2 + subtypes, the identified cutoff was 8 mm. The cutoffs were then examined in the cohort where it was derived (Figure. S2). Both univariate and multivariate analyses demonstrated that the administration of adjuvant chemotherapy did not enhance the prognosis for patients in the HR+/HER2- group with tumors < 10 mm (Figure. 2 and Table 2). Furthermore, after adjusting for additional prognostic factors, histological grade III was significantly correlated with poorer DFS and OS (HR for DFS = 5.580, 95% CI = 1.550–18.710, P = 0.006; HR for OS = 8.078, 95% CI = 2.132–33.990, P = 0.002). Conversely, postmenopausal status was associated with improved DFS, DRFS, BCSS, and OS in the HR+/HER2- group with tumors ≥ 10 mm. Additionally, age > 60 years was linked to poorer OS in this subgroup. Furthermore, adjuvant endocrine therapy was associated with a reduced likelihood of distant metastasis in patients with tumors ≥ 10 mm within the HR+/HER2- group, as detailed in Table 2. For tumors < 8 mm in HER2-enriched patients (HR+/HER2 + and HR-/HER2 + subtypes), adjuvant chemotherapy combined with trastuzumab did not yield better survival outcomes after adjusting for other prognostic factors. However, for tumors ≥ 0.8 cm, this treatment combination significantly improved DFS, DRFS, BCSS, and OS (Figure. 3 and Table 3). In triple-negative patients (HR−/HER2−) with tumors < 9 mm, adjuvant chemotherapy was not associated with improved survival outcomes (Figure. 4 and Table 4). However, for tumors ≥ 9 mm, adjuvant chemotherapy was beneficial for DFS, DRFS, BCSS, and OS. Additionally, for OS analysis, patients older than 60 years had a significantly higher risk compared to those 60 years or younger. Table 4 Hazard Ratios Quantifying the Multivariate Associations between Patients, Tumor, and Treatment Characteristics and Breast Cancer Events in HR-/HER2- (T < 9 mm) Breast Cancer and HR-/HER2- (≥ 9 mm) Breast Cancer. DFS DRFS BCSS OS Variables <9 mm ≥ 9 mm <9 mm ≥ 9 mm <9 mm ≥ 9 mm <9 mm ≥ 9 mm HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P Age, years ≤ 60 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) > 60 1.02 (0.49–2.05) 0.95 1.07 (0.45–2.40) .87 1.45 (0.56–3.53) .42 3.85 (2.00–7.69) < .001 Menopausal status Premenopause 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Postmenopause 0.44 (0.05–2.27) .36 0.88 (0.52–1.48) .64 0.78 (0.42–1.43) .42 0.62 (0.30–1.18) .16 0.70 (0.36–1.29) .27 Histological grade other 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) III 14.23 (2.02–190.60) .02 1.15 (0.72–1.86) .56 0.84 (0.50–2.49) .52 0.85 (0.49–1.49) .57 10.06 (0.45–657.80) .18 1.10 (0.69–1.79) .68 Adjuvant chemotherapy None 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Done 0.15 (0.02–1.44) .09 0.382 (0.21–0.74) .002 0.41 (0.21–0.86) .01 0.38 (0.19–0.85) .01 0.10 (0.003–1.28) .10 0.38 (0.22–0.73) .002 Abbreviations: HR, hormone receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; HR, hazard ratio; P < 0.05 is statistically significant. Discussion In this extensive study involving 1,733 patients with T1N0M0 BC, the overall prognosis was favorable across all subgroups. Patients with HR+/HER2- tumors experienced the most favorable outcomes, while those with HR-/HER2 + tumors had the poorest prognoses, aligning with previous research [4, 5, 8, 21–25] . However, it is important to note that, aside from the HR+/HER2- subgroup, the breast cancer-specific mortality rate was below 90% for the other three subtypes. This indicates a persistent risk of cancer-related mortality even in tumors typically classified as having a "good prognosis." Our study identified key prognostic factors including molecular subtype, age, menopausal status, tumor size, histological grade, and adjuvant chemotherapy. High-grade tumors and premenopausal status were associated with poorer outcomes, aligning with previous research [4, 26] . Age over 60 improved DFS and DRFS but reduced OS. Our findings also confirmed that age does not significantly impact breast cancer-specific survival, consistent with prior studies[ 16 , 27 ]. Younger patients tend to have cancers that exhibit more aggressive features and are more likely to relapse. Conversely, older patients are more likely to succumb to diseases other than cancer, such as comorbid conditions[ 27 ]. The efficacy of adjuvant systemic treatments in T1N0M0 BC is contentious, largely due to associated adverse effects[ 28 – 31 ]. Treatment benefits hinge on baseline prognosis and its impact on recurrence risk, which are influenced by tumor size and biological subtype[ 6 ]. Our data indicate that tumor size and subtype are independent survival factors in T1N0M0 BC. While prevailing studies typically classify T1a and T1b tumors together based on similar biological properties and prognoses[ 5 , 8 , 15 , 32 – 34 ], our findings reveal distinct survival differences between these subgroups. Furthermore, our findings indicate that patients with tumors smaller than established cutoffs demonstrated favorable prognoses across different tumor subtypes, regardless of whether they received adjuvant systemic treatments. This observation challenges the necessity of adjuvant systemic treatments for smaller tumors. The 2024 National Comprehensive Cancer Network (NCCN) guidelines recommend assessing a 21-gene recurrence score for HR+/HER2- T1N0M0 tumors to evaluate the necessity of chemotherapy, advocating its use for patients with intermediate or high scores. In the absence of such data, chemotherapy remains a consideration. Our findings indicate that tumors < 10 mm typically exhibit favorable prognoses without adjuvant chemotherapy, suggesting its potential redundancy in these cases. Moreover, while adjuvant endocrine therapy is associated with improved DFS and DRFS for tumors ≥ 9 mm, it does not independently influence prognosis for smaller tumors, recommending its application for T1b and T1c classifications. In HER2-positive tumor cases, the variability in prognostic outcomes and therapeutic benefits has led to uncertainty regarding the precise thresholds for recommending adjuvant chemotherapy, including trastuzumab. Current guidelines advocate for the consideration of trastuzumab-based chemotherapy in HER2-positive T1bN0 tumors. Our data, encompassing 405 HER2-positive patients, demonstrates that those with tumors under 10 mm gain no benefit from trastuzumab-based chemotherapy. Additionally, HR+/HER2 + BC patients present better prognoses and smaller tumor thresholds compared to HR-/HER2 + cases, indicating distinct subtypes within HER2-positive BC. This suggests that personalized adjuvant endocrine therapy could potentially improve outcomes for HR-positive patients. Finally, despite the historically poor outcomes associated with HR-/HER2- BC, our data indicate favorable results, with a 5-year overall survival rate exceeding 90%. The guidelines suggest the consideration of adjuvant chemotherapy for patients with triple-negative breast cancer (TNBC) presenting with T1bN0 tumors. However, our findings reveal that patients with tumors smaller than 9 mm cm do not benefit from adjuvant chemotherapy, suggesting adjuvant chemotherapy may not be necessary for smaller tumors in T1b BC. In summary, we suggest adjuvant systemic treatments for tumors meeting or exceeding established subtype-specific cutoffs. Personalized treatment recommendations are warranted for tumors below these thresholds. For low-risk patients with smaller tumors, adjuvant systemic treatments may be omitted, while high-risk patients, such as those with high histologic grade or younger age at diagnosis, may benefit from adjuvant systemic treatments, ensuring tailored and effective treatment strategies. Our study, conducted across multiple centers, was designed to eliminate variability in local oncology practice patterns. It benefits from a median follow-up period exceeding 10 years, enabling a comprehensive evaluation of the long-term outcomes associated with various treatment modalities. Furthermore, due to ongoing debates surrounding the recommendations for adjuvant systemic treatments for T1N0M0 BC, the distribution of treatment plans within the study cohort was heterogeneous. Our methodology, which involved treating tumor size as a continuous variable, provided robust statistical power sufficient to precisely delineate the tumor size thresholds applicable to different molecular subtypes. This approach facilitated the identification of patient cohorts that could potentially omit adjuvant systemic treatments without negatively impacting their survival outcomes. The findings of this study enhance our intricate comprehension of clinical outcomes as influenced by biological subtypes, tumor dimensions, and therapeutic strategies. They offer a fresh viewpoint for evaluating the advantages of adjuvant systemic treatments in patients with small, node-negative tumors, thereby facilitating more informed dialogues between patients and healthcare providers. Our data corroborate an outstanding prognosis across all subgroups, suggesting that patients with varying tumor subtypes might experience enhanced benefits from customized treatments tailored to specific tumor size cutoffs. However, the retrospective design of our study introduces inherent limitations, including unbalanced baseline characteristics and a non-randomized allocation of patients across treatment groups. We attempted to mitigate these limitations through multivariable analysis that included relevant prognostic factors. Additionally, due to rare endpoint events in HR-/HER2 + tumors < 7mm, subgroup analysis is impractical. HR-/HER2 + and HR+/HER2 + are thus combined for analysis. Further research is needed to define the optimal tumor size cutoff for adjuvant systemic treatments in lymph node-negative HR-/HER2 + BC and identify the best systemic treatment for tumors below this cutoff. Furthermore, the limited sample sizes in certain subgroups precluded further adjustments, resulting in wide confidence intervals for some outcome estimates. Finally, as all patients with HER2-positive tumors received adjuvant chemotherapy, it was not feasible to compare outcomes among those who did not receive chemotherapy, those who received chemotherapy only, and those who received combination therapy. Consequently, any comparisons between patients treated with chemotherapy, with or without trastuzumab, should be interpreted with caution. Despite these limitations, our findings provide robust evidence supporting the efficacy of adjuvant systemic treatments in patients with T1N0M0 BC, particularly for those with tumors at or above identified size thresholds. For tumors below these thresholds, adjuvant systemic treatments may be unnecessary. Future research should aim to refine management strategies for these patients, enhance methods for identifying those at the highest risk of recurrence, and minimize treatment-related toxicity. Conclusions The findings of this cohort study of patients withT1N0M0 breast cancer suggest that patients with different breast cancer subtypes meeting or exceeding established cutoffs should receive adjuvant systemic treatments, while adjuvant systemic treatments did not provide a survival benefit for tumors smaller than these cutoffs. More investigations, especially prospective studies, are necessary to support our findings. Abbreviations AST : Adjuvant systemic treatments BC : Breast cancer BCSS : Breast cancer-specific survival CI : Confidence intervals DFS : Disease-free survival DRFS : Distant recurrence-free survival ER : Estrogen receptor HER2 : Human epidermal growth factor receptor 2 HR : Hazard ratio IHC : immunohistochemical OS : overall survival PR : Progesterone receptor TNBC : Triple-negative breast cancer Declarations Ethics Approved by institutional review boards at both centers. Patient data were anonymized for analysis. Data Availability The data used for this study is from Tianjin Medical University Cancer Institute and Hospital and Affiliated Hospital of Hebei University. Investigators can access this data through a data use agreement with the two hospitals. Competing interests The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper. Funding Statement The study was supported by the Tianjin Science and Technology Commission (grant N: 18ZXXYSY00070), Tianjin Key Medical Discipline (Specialty) construction Project (grant N: TJYXZdXK-009a), and Science & Technology Development Fund of Tianjin Education Commission for Higher Education (grant N: 2021KJ191). Authors' contributions L.S.: Writing, Data curation, Conceptualization. X.D.: Writing – review & editing, Data curation. H.Y.: Writing – review & editing, Supervision. Y.S.: Writing – review & editing, Data curation. X.L.: Writing – review & editing, Supervision. W.M.: Writing – review & editing, Supervision. C.C.: Writing – review & editing, Supervision. Q.J.: Writing – review & editing, Supervision Y.S.: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Acknowledgements Not applicable. References Autier P, Boniol M, Middleton R, Dore JF, Hery C, Zheng T, Gavin A: Advanced breast cancer incidence following population-based mammographic screening . Ann Oncol 2011, 22 (8):1726-1735. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ et al : Effect of screening and adjuvant therapy on mortality from breast cancer . N Engl J Med 2005, 353 (17):1784-1792. Rosen PR, Groshen S, Saigo PE, Kinne DW, Hellman S: A long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma . J Clin Oncol 1989, 7 (3):355-366. Houvenaeghel G, Goncalves A, Classe JM, Garbay JR, Giard S, Charytensky H, Cohen M, Belichard C, Faure C, Uzan S et al : Characteristics and clinical outcome of T1 breast cancer: a multicenter retrospective cohort study . Ann Oncol 2014, 25 (3):623-628. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH, Rouzier R, Broglio KR, Hortobagyi GN, Valero V: Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma . J Clin Oncol 2007, 25 (31):4952-4960. Vaz-Luis I, Ottesen RA, Hughes ME, Mamet R, Burstein HJ, Edge SB, Gonzalez-Angulo AM, Moy B, Rugo HS, Theriault RL et al : Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study . J Clin Oncol 2014, 32 (20):2142-2150. Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, Wolmark N: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes . J Natl Cancer Inst 2001, 93 (2):112-120. Fehrenbacher L, Capra AM, Quesenberry CP, Jr., Fulton R, Shiraz P, Habel LA: Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: a cohort from an integrated health care delivery system . J Clin Oncol 2014, 32 (20):2151-2158. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I et al : Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer . N Engl J Med 2015, 372 (2):134-141. Gradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, Allison KH, Anderson B, Burstein HJ, Chew H et al : NCCN Guidelines(R) Insights: Breast Cancer, Version 4.2023 . J Natl Compr Canc Netw 2023, 21 (6):594-608. Curigliano G, Burstein HJ, Gnant M, Loibl S, Cameron D, Regan MM, Denkert C, Poortmans P, Weber WP, Thurlimann B et al : Understanding breast cancer complexity to improve patient outcomes: The St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023 . Ann Oncol 2023, 34 (11):970-986. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ, Panel m: Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009 . Ann Oncol 2009, 20 (8):1319-1329. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, Bellon JR, Wong JS, Smith BL, Harris JR: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy . J Clin Oncol 2008, 26 (14):2373-2378. Amar S, McCullough AE, Tan W, Geiger XJ, Boughey JC, McNeil RB, Coppola KE, McLaughlin SA, Palmieri FM, Perez EA: Prognosis and outcome of small (<=1 cm), node-negative breast cancer on the basis of hormonal and HER-2 status . Oncologist 2010, 15 (10):1043-1049. An X, Lei X, Huang R, Luo R, Li H, Xu F, Yuan Z, Wang S, de Nonneville A, Goncalves A et al : Adjuvant chemotherapy for small, lymph node-negative, triple-negative breast cancer: A single-center study and a meta-analysis of the published literature . Cancer 2020, 126 Suppl 16 :3837-3846. Zhang Q, He Y, Luo N, Patel SJ, Han Y, Gao R, Modak M, Carotta S, Haslinger C, Kind D et al : Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma . Cell 2019, 179 (4):829-845 e820. Parsons BM, Uprety D, Smith AL, Borgert AJ, Dietrich LL: A US Registry-Based Assessment of Use and Impact of Chemotherapy in Stage I HER2-Positive Breast Cancer . J Natl Compr Canc Netw 2018, 16 (11):1311-1320. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E et al : Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer . N Engl J Med 2017, 377 (2):122-131. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M et al : American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer . J Clin Oncol 2010, 28 (16):2784-2795. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P et al : Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update . J Clin Oncol 2013, 31 (31):3997-4013. Joensuu H, Pylkkanen L, Toikkanen S: Late mortality from pT1N0M0 breast carcinoma . Cancer 1999, 85 (10):2183-2189. Ichizawa N, Fukutomi T, Iwamoto E, Akashi-Tanaka S: Long-term results of T1a, T1b and T1c invasive breast carcinomas in Japanese women: validation of the UICC T1 subgroup classification . Jpn J Clin Oncol 2002, 32 (3):108-109. Kim RG, Kim EK, Kim HA, Koh JS, Kim MS, Kim KI, Lee JI, Moon NM, Ko E, Noh WC: Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience . Eur J Surg Oncol 2011, 37 (7):629-634. Garassino I, Gullo G, Orefice S, Tondulli L, Masci G, Salvini P, Eboli M, Di Tommaso L, Giordano L, Alloisio M et al : Outcome of T1N0M0 breast cancer in relation to St. Gallen risk assignment criteria for adjuvant therapy . Breast 2009, 18 (4):263-266. Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA: Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies . J Clin Oncol 2004, 22 (9):1630-1637. Thurell J, Manouchehri N, Fredriksson I, Wilking U, Bergh J, Ryden L, Koppert LB, Karsten MM, Kiani NA, Hedayati E: Risk-adjusted benchmarking of long-term overall survival in patients with HER2-positive early-stage Breast cancer: A Swedish retrospective cohort study . Breast 2023, 70 :18-24. Jenkins EO, Deal AM, Anders CK, Prat A, Perou CM, Carey LA, Muss HB: Age-specific changes in intrinsic breast cancer subtypes: a focus on older women . Oncologist 2014, 19 (10):1076-1083. Hassett MJ, O'Malley AJ, Pakes JR, Newhouse JP, Earle CC: Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer . J Natl Cancer Inst 2006, 98 (16):1108-1117. Kim H, Hong B, Kim S, Kang SM, Park J: Chemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review . Syst Rev 2024, 13 (1):167. Qureshi Z, Altaf F, Jamil A, Siddique R, Fatima E: Safety and Efficacy of Trastuzumab Deruxtecan for Metastatic HER2+ and HER2-low Breast Cancer: An Updated Systematic Review and Meta-Analysis of Clinical Trials . Am J Clin Oncol 2024. Milata JL, Otte JL, Carpenter JS: Oral Endocrine Therapy Nonadherence, Adverse Effects, Decisional Support, and Decisional Needs in Women With Breast Cancer . Cancer Nurs 2018, 41 (1):E9-E18. Sasada S, Kondo N, Hashimoto H, Takahashi Y, Terata K, Kida K, Sagara Y, Ueno T, Anan K, Suto A et al : Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer . Breast Cancer Res Treat 2023, 202 (3):473-483. Cabel L, Peron J, Cottu PH, Rodrigues MJ: Prognosis of t1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas . J Clin Oncol 2015, 33 (3):291. Ignatov T, Eggemann H, Burger E, Costa SD, Ignatov A: Management of small T1a/b breast cancer by tumor subtype . Breast Cancer Res Treat 2017, 163 (1):111-118. Table 2 and 3 Table 2 and 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.docx Table3.docx SDC1.pdf SDC2.pdf SDC3.pdf SDC4.pdf SDC5.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Dec, 2025 Reviews received at journal 22 Nov, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviews received at journal 27 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviewers invited by journal 04 May, 2025 Editor assigned by journal 02 Apr, 2025 Submission checks completed at journal 02 Apr, 2025 First submitted to journal 31 Mar, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6348915","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451790514,"identity":"b8c3081b-dbbb-4d3f-88e2-9f9f88f2f800","order_by":0,"name":"linlin sun","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"linlin","middleName":"","lastName":"sun","suffix":""},{"id":451790515,"identity":"65887e37-2de5-46f1-b9b6-41170571e447","order_by":1,"name":"Xiaopei Dong","email":"","orcid":"","institution":"Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaopei","middleName":"","lastName":"Dong","suffix":""},{"id":451790516,"identity":"1a7dcc5c-822d-4b7e-b119-d5188212346c","order_by":2,"name":"Hua Yang","email":"","orcid":"","institution":"Affiliated Hospital of Hebei University","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Yang","suffix":""},{"id":451790517,"identity":"d4b320d7-46d2-4e20-bc97-de259d65c2f0","order_by":3,"name":"Yingjian Sha","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingjian","middleName":"","lastName":"Sha","suffix":""},{"id":451790518,"identity":"ae61d4ef-758f-4e6d-a1ae-7140a68abd08","order_by":4,"name":"Xiaodong Liu","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Liu","suffix":""},{"id":451790519,"identity":"b1d6a7e1-af5e-4a58-b4b3-bfbcf925cf40","order_by":5,"name":"Wenjing Meng","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Meng","suffix":""},{"id":451790520,"identity":"acffdf7f-20bd-4c1f-9393-dde7b9b5c87a","order_by":6,"name":"Can Cui","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Can","middleName":"","lastName":"Cui","suffix":""},{"id":451790521,"identity":"61cde416-6322-40e8-94d5-b5be9f3d69f5","order_by":7,"name":"Junqi Si","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Junqi","middleName":"","lastName":"Si","suffix":""},{"id":451790522,"identity":"dfb9e865-8b2a-4aec-af29-2c8d8bc18ba1","order_by":8,"name":"ye Shi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYDACCcYGBiDi4WdgSAByD5CgRbKNeC1ADNTCYHAMzCVCi/zs5jaJjzsOyxjfb3i6mafmDgN/e3cCXi0Gdw62Sc48c5jH7BhD2m2eY88YJM6c3YBfi0RimzRvG1QLb8NhoEgufi3yM4Ba/gK1GLcRq4XhBlALI1CLARuxWgxuJDZb9ral80gcS0i7OefYYR6CfpGfkf7wxs82a3v+5jNpN97UHJbjb+8l4DAGBhYJCM2TACYJKQcB5g8Qmv0AMapHwSgYBaNgBAIAAvlNNlxu6s0AAAAASUVORK5CYII=","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":true,"prefix":"","firstName":"ye","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2025-04-01 03:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6348915/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6348915/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82310676,"identity":"cce942e3-c8e9-4c06-8d9e-50272b949690","added_by":"auto","created_at":"2025-05-09 01:53:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":353768,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Survival Curve of pT1N0M0 Breast Cancer Stratified by Molecular Subtype: (A) DFS in T1N0M0 HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- tumors; (B) DRFS in T1N0M0 HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- tumors; (C) BCSS in T1N0M0 HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- tumors; and (D) OS in T1N0M0 HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- tumors.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/793ec1f33f4de085b786dd50.png"},{"id":82310677,"identity":"98f181ea-9802-48cb-abba-4a7b8bc094ec","added_by":"auto","created_at":"2025-05-09 01:53:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":348961,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier Analyses of Survival According to Adjuvant Systemic Treatments in HR+/HER2- Breast Cancer: (a) DFS in Patients with Tumor Size \u0026lt;10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (b) DRFS in Patients with Tumor Size \u0026lt;10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (c) BCSS in Patients with Tumor Size \u0026lt;10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (d) OS in Patients With Tumor Size \u0026lt;10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (e) DFS in Patients with Tumor Size ≥10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (f) DRFS in Patients with Tumor Size ≥10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (g) BCSS in Patients with Tumor Size ≥10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (h) OS in Patients with Tumor Size ≥10 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/fd0acd3588a601d5a1b6b227.png"},{"id":82310693,"identity":"33497433-7d11-4c03-8d42-fc266b349f71","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":411599,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier Analyses of Survival According to Adjuvant Systemic Treatments in HER2+ Breast Cancer: (a) DFS in Patients with Tumor Size \u0026lt;8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (b) DRFS in Patients with Tumor Size \u0026lt;8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (c) BCSS in Patients with Tumor Size \u0026lt;8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (d) OS in Patients with Tumor Size \u0026lt;8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy With Trastuzumab; (e) DFS in Patients with Tumor Size ≥8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (f) DRFS in Patients with Tumor Size ≥8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (g) BCSS in Patients with Tumor Size ≥8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab; (h) OS in Patients with Tumor Size ≥8 mm Who Received Adjuvant Chemotherapy without Trastuzumab, and Adjuvant Chemotherapy with Trastuzumab.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/c31a178adf122d91fccb392f.png"},{"id":82310682,"identity":"b035cc35-1504-42e6-8611-8bfa6bebba01","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":371610,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier Analyses of Survival According to Adjuvant Systemic Treatments in HR-/HER2- Breast Cancer: (a) DFS in Patients with Tumor Size \u0026lt;9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (b) DRFS in Patients with Tumor Size \u0026lt;9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (c) BCSS in Patients with Tumor Size \u0026lt;9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (d) OS in Patients with Tumor Size \u0026lt;9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (e) DFS in Patients with Tumor Size ≥9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (f) DRFS in Patients with Tumor Size ≥9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (g) BCSS in Patients with Tumor Size ≥9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy; (h) OS in Patients with Tumor Size ≥9 mm Who Received No Adjuvant Chemotherapy, and Adjuvant Chemotherapy.\u003c/p\u003e\n\u003cp\u003eAbbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2; \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05 is Statistically Significant.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/199e53c1e6017c0dc4a1c8e8.png"},{"id":82312329,"identity":"0a2e6759-c774-4988-807b-e33397171a1a","added_by":"auto","created_at":"2025-05-09 02:09:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3910703,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/f4e4e70a-38f9-4a02-9e0f-ac98e455f548.pdf"},{"id":82310681,"identity":"f41a2485-3094-4101-a18f-5ee55ca9ec1c","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23316,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/cb8054077aa0eff90e4c739d.docx"},{"id":82311829,"identity":"505950ed-4174-4ba7-a145-8176a23919ee","added_by":"auto","created_at":"2025-05-09 02:01:09","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23291,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/0e211a363d590205213a3038.docx"},{"id":82310683,"identity":"9ae95422-5472-41b7-b6c7-a89ecb7e19ac","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":191559,"visible":true,"origin":"","legend":"","description":"","filename":"SDC1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/dd6b7a0a2f1fff3c8d471ffe.pdf"},{"id":82310687,"identity":"b5aae1c2-5e17-4da4-827a-788f08b44d7d","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":148771,"visible":true,"origin":"","legend":"","description":"","filename":"SDC2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/e072090aecbae5bd6121ea84.pdf"},{"id":82310695,"identity":"6d203ef8-81f2-4884-9117-78dbdf56a386","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":177598,"visible":true,"origin":"","legend":"","description":"","filename":"SDC3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/2672901b448ca44cb4a4df29.pdf"},{"id":82310689,"identity":"7508c59f-cada-4e56-827b-ce1acc7d7a7d","added_by":"auto","created_at":"2025-05-09 01:53:10","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":2821866,"visible":true,"origin":"","legend":"","description":"","filename":"SDC4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/ae6177d3953ae093d594eed0.pdf"},{"id":82311832,"identity":"0bd36536-d429-4d81-a80d-9b4826eb024d","added_by":"auto","created_at":"2025-05-09 02:01:11","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":684947,"visible":true,"origin":"","legend":"","description":"","filename":"SDC5.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6348915/v1/f01ea56e15d5e4cb71c116eb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel Prognostic Stratification and Therapeutic Implications in T1N0M0 Breast Cancer: Insights from a Multi-Center Chinese Cohort","fulltext":[{"header":"Background","content":"\u003cp\u003eThe widespread adoption of mammographic screening over recent decades has revolutionized early breast cancer detection, particularly for stage I tumors (T1, \u0026le;\u0026thinsp;20 mm) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While these small, node-negative malignancies demonstrate generally favorable outcomes, with cancer-specific survival rates exceeding 90% over 5 to 10 years[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], they present a paradoxical clinical challenge. In a multicenter retrospective cohort study spearheaded by G. Houvenaeghel et al., the recurrence rates for T1N0M0 breast cancer were 6% at 5 years and increased to 16.2% at 10 years[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This persistent risk trajectory persists even among the smallest tumors, as evidenced by a 4,113-patient cohort showing 97% and 95% 5-year disease-free survival for T1a and T1b tumors respectively[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These outcomes underscore the continuous risk of late relapses in tumors initially deemed to have a favorable prognosis.\u003c/p\u003e \u003cp\u003eThe biological heterogeneity of these ostensibly low-risk tumors creates significant therapeutic dilemmas, which have not been well characterized for these early-stage cancers after initial local therapies[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Unlike their node-positive counterparts where adjuvant systemic therapy (AST) demonstrates clear benefit, the risk-benefit calculus for T1N0M0 tumors remains uncertain[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This evidence gap stems from the systematic exclusion of these patients from prospective randomized trials, forcing clinicians to rely on suboptimal evidence from retrospective analyses and expert consensus. Current practice patterns show striking variability, with AST routinely administered for tumors\u0026thinsp;\u0026gt;\u0026thinsp;10 mm but remaining controversial for smaller lesions (\u0026le;\u0026thinsp;10 mm)[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmerging data highlight the critical prognostic influence of biological subtypes[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients with HER2-positive and triple-negative T1N0M0 tumors demonstrating significantly worse outcomes than hormone receptor-positive counterparts[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This molecular stratification has intensified debates regarding risk-adapted treatment intensification[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], particularly as contemporary genomic tools reveal substantial heterogeneity within traditional histopathological classifications.\u003c/p\u003e \u003cp\u003eThis multicenter retrospective analysis was designed to address these critical knowledge gaps by systematically evaluating disease characteristics, treatment patterns, and long-term outcomes across a large T1N0M0 cohort. By correlating clinicopathological features with survival endpoints, we aim to develop more precise prognostic models to guide AST decision-making in this clinically ambiguous population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThis multicenter study compiled longitudinal data from breast cancer (BC) patients treated at two Chinese institutions: Tianjin Medical University Cancer Institute (May 1998 - October 2018) and Affiliated Hospital of Hebei University (January 2016 - March 2018). Ethical approval was obtained with patient consent. Inclusion criteria were as follows: Female patients with primary invasive BC, tumor size\u0026thinsp;\u0026le;\u0026thinsp;20 mm (T1), node-negative (N0) and metastasis-free (M0), and complete ER/PR/HER2 status documentation. Exclusion criteria are patients with Neoadjuvant chemotherapy recipients, unknown ER, PR, or HER2 status, and male patients or non-invasive subtypes\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eVariables assessed were demographics (age, menopausal status), tumor characteristics (histological grade, size), biomarkers: HR status (nuclear staining of 1% or more for ER or PR was considered positive\u003csup\u003e[19]\u003c/sup\u003e), HER2 status (HER2 positivity was ascertained using an immunohistochemical (IHC) score of 3+. In cases where the results were equivocal, fluorescence in situ hybridization was employed to confirm a HER2/CEP17 ratio exceeding 2.2\u003csup\u003e[20]\u003c/sup\u003e), and treatment modalities (surgery, adjuvant therapy). Four molecular subtypes were identified: HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-. Two independent physicians reviewed all pathology and survival data. Discrepancies were resolved by third-party adjudication.\u003c/p\u003e \u003cp\u003ePrimary endpoints including disease-free survival (DFS), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS). DFS was defined as the period from surgical intervention to local recurrence, distant metastasis, death, or last follow-up without relapse. DRFS encompassed the time from the initial diagnosis to distant recurrence or last follow-up. BCSS was the interval from the initial diagnosis to breast cancer-related death or last follow-up, while OS spanned from the initial diagnosis to death from any cause or last follow-up.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eThe study assessed categorical variables were analyzed using the chi-square test. Survival estimates for DFS, DRFS, BCSS, and OS were calculated via the Kaplan\u0026ndash;Meier method, with the log-rank test assessing inter-group differences. The Cox proportional hazards model evaluated the prognostic impact of patient and tumor characteristics on these outcomes. Maximally selected rank statistics determined the optimal tumor size cutoff, dividing patients into two subgroups based on molecular subtypes for further analysis with multivariable Cox models. Statistical procedures and survival probability charts were executed using GraphPad Prism (version 10), and tumor size cutoffs were computed using R software version 4.3.3 (Bell Laboratories, Murray Hill, NJ). Hazard ratios (HR) were presented with 95% confidence intervals (CI), considering a \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 as statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003eDemographic and Tumor Characteristics\u003c/h2\u003e\n \u003cp\u003eWe identified 1733 consecutive female patients with pT1N0M0 BC from Tianjin Medical University Cancer Institute (1511 patients) and Hospital and the Affiliated Hospital of Hebei University (222 patients). The median follow-up was 172 months (interquartile range, 107–203) for the Tianjin group and 85 months (interquartile range, 80–92) for the Hebei group. Upon applying identification rules for HR and HER2 status, 987 cases (56.9%) were classified as HR+/HER2-, 218 cases (12.6%) as HR+/HER2+, 187 cases (10.8%) as HR-/HER2+, and 341 cases (19.7%) as HR-/HER2-. Baseline clinicopathologic characteristics were compared across the molecular subtypes (Table S1). A notably higher prevalence of premenopausal status was observed in the HR+/HER2 + subgroup. The likelihood of undergoing lumpectomy was markedly lower among patients with HR-/HER2 + tumors, accounting for only 10.7% of cases within this subtype. The prevalence of invasive ductal carcinoma was elevated in HER2-positive subgroups relative to HER2-negative ones. Additionally, histological grade III tumors were less frequently observed in the HR+/HER2- subgroup compared to other subgroups. Tumor sizes exceeding 1.0 cm were most common, occurring in 60.1% of HR+/HER2-, 59.2% of HR+/HER2+, 57.8% of HR-/HER2+, and 68.9% of HR-/HER2- subgroups. Comprehensive adjuvant chemotherapy was administered to all patients with HER2-positive tumors within this study cohort.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eSurvival outcomes\u003c/h2\u003e\n \u003cp\u003eThe 5-year and 10-year survival rates for patients with T1N0M0 disease are detailed in Table S2. For the HR+/HER2- subgroup, the 5-year DFS, DRFS, BCSS, and OS rates exceeded 90%. In contrast, the HR-/HER2 + subgroup showed the lowest survival rates at 5 years, particularly for DFS. Over a 10-year period, the HR+/HER2- subtype demonstrated the most favorable outcomes, while the HR-/HER2 + subtype had the least favorable results among the four groups. Kaplan–Meier analysis revealed significant differences in survival among these groups (Figure. 1A-D, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001 for all).\u003c/p\u003e\n \u003cp\u003eUnivariate analysis indicated that lower histological grade (I or II), smaller tumor size (≤ 10 mm), and the use of adjuvant chemotherapy were associated with improved DFS, DRFS, BCSS, and OS (Table S3, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 for all). Factors contributing to poorer DFS, DRFS, and BCSS included premenopausal status and younger age (≤ 40 years). However, for OS, being younger than 60 years correlated with better outcomes. The best prognoses in DRFS and BCSS were observed in patients with HR+/HER2- subtype.\u003c/p\u003e\n \u003cp\u003eMultivariate analyses further substantiated that adjuvant chemotherapy was beneficial for DFS, DRFS, BCSS, and OS (Table\u0026nbsp;1, P \u0026lt; 0.001 for all). Factors such as being younger than 60 years, postmenopausal status, a lower histological grade (I or II), and a tumor size ≤ 5 mm were associated with improved OS (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 for all). In contrast, HER2-positive tumors, premenopausal status, and a tumor size \u0026gt; 5 mm were predictors of poorer prognoses in DRFS and BCSS. Additionally, younger patients (≤ 40 years) and those with a histological grade 3 were linked to worse DFS and DRFS. Moreover, tumors exceeding 10 mm and the HR-/HER2 + subtype were correlated with diminished DFS.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eHazard Ratios Quantifying the Multivariate Associations between Patient, Tumor, and Treatment Characteristics and Breast Cancer Events.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDRFS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBCSS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMolecular subtype\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR + HER2-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR + HER2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.21\u003c/p\u003e\n \u003cp\u003e(0.84–1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.91\u003c/p\u003e\n \u003cp\u003e(1.29–2.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.70\u003c/p\u003e\n \u003cp\u003e(1.09–2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.744\u003c/p\u003e\n \u003cp\u003e(1.18–2.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR-HER2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.69\u003c/p\u003e\n \u003cp\u003e(1.18–2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.55\u003c/p\u003e\n \u003cp\u003e(1.70–3.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.66\u003c/p\u003e\n \u003cp\u003e(1.70–4.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.52\u003c/p\u003e\n \u003cp\u003e(1.71–3.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR-HER2-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003cp\u003e(0.75–1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.896\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.29\u003c/p\u003e\n \u003cp\u003e(0.90–1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003cp\u003e(0.99–2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.56\u003c/p\u003e\n \u003cp\u003e(1.13–2.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e≤ 40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.20\u003c/p\u003e\n \u003cp\u003e(1.38–3.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.15\u003c/p\u003e\n \u003cp\u003e(1.25–3.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.47\u003c/p\u003e\n \u003cp\u003e(0.81–2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003cp\u003e(0.231–0.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt; 40 to ≤ 60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.32\u003c/p\u003e\n \u003cp\u003e(0.92–1.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.29\u003c/p\u003e\n \u003cp\u003e(0.84–2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003cp\u003e(0.59–1.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003cp\u003e(0.18–0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt; 60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMenopausal status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePremenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostmenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003cp\u003e(0.59–1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003cp\u003e(0.49–0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003cp\u003e(0.37–0.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003cp\u003e(0.41–0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgery type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLumpectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMastectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003cp\u003e(0.64–1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003cp\u003e(0.63–1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003cp\u003e(0.58–1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003cp\u003e(0.51–1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003cp\u003e(0.68–1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003cp\u003e(0.61–1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003cp\u003e(0.56–1.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003cp\u003e(0.47–1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive ductal carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-invasive ductal carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003cp\u003e(0.68–1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.20\u003c/p\u003e\n \u003cp\u003e(0.79–1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003cp\u003e(0.67–1.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003cp\u003e(0.77–1.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.03\u003c/p\u003e\n \u003cp\u003e(1.57–2.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003cp\u003e(1.01–1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.28\u003c/p\u003e\n \u003cp\u003e(0.93–1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.37\u003c/p\u003e\n \u003cp\u003e(1.04–1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor size, mm\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e≤ 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt; 5 to ≤ 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.80\u003c/p\u003e\n \u003cp\u003e(0.99–3.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.84\u003c/p\u003e\n \u003cp\u003e(1.57–12.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.68\u003c/p\u003e\n \u003cp\u003e(2.54–207.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.26\u003c/p\u003e\n \u003cp\u003e(1.95–21.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt; 10 to ≤ 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.93\u003c/p\u003e\n \u003cp\u003e(1.68–5.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.70\u003c/p\u003e\n \u003cp\u003e(2.83–21.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.53\u003c/p\u003e\n \u003cp\u003e(4.59–361.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.83\u003c/p\u003e\n \u003cp\u003e(3.36–35.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjuvant chemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e(0.24–0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003cp\u003e(0.25–0.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003cp\u003e(0.22–0.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003cp\u003e(0.27–0.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eAbbreviations: HR, hormone receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; HR, hazard ratio; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 is statistically significant.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eTumor size and survival across the molecular subtypes\u003c/h3\u003e\n\u003cp\u003eFigure. S1 illustrates the distribution of tumor sizes and the optimal cutoff points for predicting survival outcomes across the entire cohort and various tumor subtypes. The cutoff size for predicting DFS, DRFS, BCSS, and OS, was determined to be 10 mm for the whole population. For specific subtypes, the cutoff was 10 mm for HR+/HER2- tumors, 8 mm for HR+/HER2 + tumors, 7 mm for HR-/HER2 + tumors, and 9 mm for HR-/HER2- tumors. For HER2-positive diseases, including both HR+/HER2 + and HR-/HER2 + subtypes, the identified cutoff was 8 mm. The cutoffs were then examined in the cohort where it was derived (Figure. S2).\u003c/p\u003e\n\u003cp\u003eBoth univariate and multivariate analyses demonstrated that the administration of adjuvant chemotherapy did not enhance the prognosis for patients in the HR+/HER2- group with tumors \u0026lt; 10 mm (Figure. 2 and Table\u0026nbsp;2). Furthermore, after adjusting for additional prognostic factors, histological grade III was significantly correlated with poorer DFS and OS (HR for DFS = 5.580, 95% CI = 1.550–18.710, \u003cem\u003eP\u003c/em\u003e = 0.006; HR for OS = 8.078, 95% CI = 2.132–33.990, \u003cem\u003eP\u003c/em\u003e = 0.002). Conversely, postmenopausal status was associated with improved DFS, DRFS, BCSS, and OS in the HR+/HER2- group with tumors ≥ 10 mm. Additionally, age \u0026gt; 60 years was linked to poorer OS in this subgroup. Furthermore, adjuvant endocrine therapy was associated with a reduced likelihood of distant metastasis in patients with tumors ≥ 10 mm within the HR+/HER2- group, as detailed in Table\u0026nbsp;2.\u003c/p\u003e\n\u003cdiv\u003e\n\u003c/div\u003e\n\u003cp\u003eFor tumors \u0026lt; 8 mm in HER2-enriched patients (HR+/HER2 + and HR-/HER2 + subtypes), adjuvant chemotherapy combined with trastuzumab did not yield better survival outcomes after adjusting for other prognostic factors. However, for tumors ≥ 0.8 cm, this treatment combination significantly improved DFS, DRFS, BCSS, and OS (Figure. 3 and Table\u0026nbsp;3).\u003c/p\u003e\n\u003cdiv\u003e\n\u003c/div\u003e\n\u003cp\u003eIn triple-negative patients (HR−/HER2−) with tumors \u0026lt; 9 mm, adjuvant chemotherapy was not associated with improved survival outcomes (Figure. 4 and Table\u0026nbsp;4). However, for tumors ≥ 9 mm, adjuvant chemotherapy was beneficial for DFS, DRFS, BCSS, and OS. Additionally, for OS analysis, patients older than 60 years had a significantly higher risk compared to those 60 years or younger.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eHazard Ratios Quantifying the Multivariate Associations between Patients, Tumor, and Treatment Characteristics and Breast Cancer Events in HR-/HER2- (T \u0026lt; 9 mm) Breast Cancer and HR-/HER2- (≥ 9 mm) Breast Cancer.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"17\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDRFS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eBCSS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e≥ 9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e≥ 9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e≥ 9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e≥ 9 mm\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e≤ 60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt; 60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003cp\u003e(0.49–2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003cp\u003e(0.45–2.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.45\u003c/p\u003e\n \u003cp\u003e(0.56–3.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.85\u003c/p\u003e\n \u003cp\u003e(2.00–7.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMenopausal status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePremenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostmenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003cp\u003e(0.05–2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003cp\u003e(0.52–1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003cp\u003e(0.42–1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003e(0.30–1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003cp\u003e(0.36–1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.23\u003c/p\u003e\n \u003cp\u003e(2.02–190.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003cp\u003e(0.72–1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003cp\u003e(0.50–2.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003cp\u003e(0.49–1.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.06\u003c/p\u003e\n \u003cp\u003e(0.45–657.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003cp\u003e(0.69–1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjuvant chemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003cp\u003e(0.02–1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003cp\u003e(0.21–0.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003cp\u003e(0.21–0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003cp\u003e(0.19–0.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003cp\u003e(0.003–1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003cp\u003e(0.22–0.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"17\"\u003eAbbreviations: HR, hormone receptor; HER2, human epidermal growth factor receptor 2; CI, confidence interval; HR, hazard ratio; P \u0026lt; 0.05 is statistically significant.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this extensive study involving 1,733 patients with T1N0M0 BC, the overall prognosis was favorable across all subgroups. Patients with HR+/HER2- tumors experienced the most favorable outcomes, while those with HR-/HER2\u0026thinsp;+\u0026thinsp;tumors had the poorest prognoses, aligning with previous research\u003csup\u003e[4, 5, 8, 21\u0026ndash;25]\u003c/sup\u003e. However, it is important to note that, aside from the HR+/HER2- subgroup, the breast cancer-specific mortality rate was below 90% for the other three subtypes. This indicates a persistent risk of cancer-related mortality even in tumors typically classified as having a \"good prognosis.\"\u003c/p\u003e \u003cp\u003eOur study identified key prognostic factors including molecular subtype, age, menopausal status, tumor size, histological grade, and adjuvant chemotherapy. High-grade tumors and premenopausal status were associated with poorer outcomes, aligning with previous research\u003csup\u003e[4, 26]\u003c/sup\u003e. Age over 60 improved DFS and DRFS but reduced OS. Our findings also confirmed that age does not significantly impact breast cancer-specific survival, consistent with prior studies[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Younger patients tend to have cancers that exhibit more aggressive features and are more likely to relapse. Conversely, older patients are more likely to succumb to diseases other than cancer, such as comorbid conditions[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe efficacy of adjuvant systemic treatments in T1N0M0 BC is contentious, largely due to associated adverse effects[\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Treatment benefits hinge on baseline prognosis and its impact on recurrence risk, which are influenced by tumor size and biological subtype[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our data indicate that tumor size and subtype are independent survival factors in T1N0M0 BC. While prevailing studies typically classify T1a and T1b tumors together based on similar biological properties and prognoses[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], our findings reveal distinct survival differences between these subgroups. Furthermore, our findings indicate that patients with tumors smaller than established cutoffs demonstrated favorable prognoses across different tumor subtypes, regardless of whether they received adjuvant systemic treatments. This observation challenges the necessity of adjuvant systemic treatments for smaller tumors.\u003c/p\u003e \u003cp\u003e The 2024 National Comprehensive Cancer Network (NCCN) guidelines recommend assessing a 21-gene recurrence score for HR+/HER2- T1N0M0 tumors to evaluate the necessity of chemotherapy, advocating its use for patients with intermediate or high scores. In the absence of such data, chemotherapy remains a consideration. Our findings indicate that tumors\u0026thinsp;\u0026lt;\u0026thinsp;10 mm typically exhibit favorable prognoses without adjuvant chemotherapy, suggesting its potential redundancy in these cases. Moreover, while adjuvant endocrine therapy is associated with improved DFS and DRFS for tumors\u0026thinsp;\u0026ge;\u0026thinsp;9 mm, it does not independently influence prognosis for smaller tumors, recommending its application for T1b and T1c classifications.\u003c/p\u003e \u003cp\u003eIn HER2-positive tumor cases, the variability in prognostic outcomes and therapeutic benefits has led to uncertainty regarding the precise thresholds for recommending adjuvant chemotherapy, including trastuzumab. Current guidelines advocate for the consideration of trastuzumab-based chemotherapy in HER2-positive T1bN0 tumors. Our data, encompassing 405 HER2-positive patients, demonstrates that those with tumors under 10 mm gain no benefit from trastuzumab-based chemotherapy. Additionally, HR+/HER2\u0026thinsp;+\u0026thinsp;BC patients present better prognoses and smaller tumor thresholds compared to HR-/HER2\u0026thinsp;+\u0026thinsp;cases, indicating distinct subtypes within HER2-positive BC. This suggests that personalized adjuvant endocrine therapy could potentially improve outcomes for HR-positive patients.\u003c/p\u003e \u003cp\u003eFinally, despite the historically poor outcomes associated with HR-/HER2- BC, our data indicate favorable results, with a 5-year overall survival rate exceeding 90%. The guidelines suggest the consideration of adjuvant chemotherapy for patients with triple-negative breast cancer (TNBC) presenting with T1bN0 tumors. However, our findings reveal that patients with tumors smaller than 9 mm cm do not benefit from adjuvant chemotherapy, suggesting adjuvant chemotherapy may not be necessary for smaller tumors in T1b BC.\u003c/p\u003e \u003cp\u003eIn summary, we suggest adjuvant systemic treatments for tumors meeting or exceeding established subtype-specific cutoffs. Personalized treatment recommendations are warranted for tumors below these thresholds. For low-risk patients with smaller tumors, adjuvant systemic treatments may be omitted, while high-risk patients, such as those with high histologic grade or younger age at diagnosis, may benefit from adjuvant systemic treatments, ensuring tailored and effective treatment strategies.\u003c/p\u003e \u003cp\u003e Our study, conducted across multiple centers, was designed to eliminate variability in local oncology practice patterns. It benefits from a median follow-up period exceeding 10 years, enabling a comprehensive evaluation of the long-term outcomes associated with various treatment modalities. Furthermore, due to ongoing debates surrounding the recommendations for adjuvant systemic treatments for T1N0M0 BC, the distribution of treatment plans within the study cohort was heterogeneous. Our methodology, which involved treating tumor size as a continuous variable, provided robust statistical power sufficient to precisely delineate the tumor size thresholds applicable to different molecular subtypes. This approach facilitated the identification of patient cohorts that could potentially omit adjuvant systemic treatments without negatively impacting their survival outcomes.\u003c/p\u003e \u003cp\u003eThe findings of this study enhance our intricate comprehension of clinical outcomes as influenced by biological subtypes, tumor dimensions, and therapeutic strategies. They offer a fresh viewpoint for evaluating the advantages of adjuvant systemic treatments in patients with small, node-negative tumors, thereby facilitating more informed dialogues between patients and healthcare providers. Our data corroborate an outstanding prognosis across all subgroups, suggesting that patients with varying tumor subtypes might experience enhanced benefits from customized treatments tailored to specific tumor size cutoffs.\u003c/p\u003e \u003cp\u003eHowever, the retrospective design of our study introduces inherent limitations, including unbalanced baseline characteristics and a non-randomized allocation of patients across treatment groups. We attempted to mitigate these limitations through multivariable analysis that included relevant prognostic factors. Additionally, due to rare endpoint events in HR-/HER2\u0026thinsp;+\u0026thinsp;tumors\u0026thinsp;\u0026lt;\u0026thinsp;7mm, subgroup analysis is impractical. HR-/HER2\u0026thinsp;+\u0026thinsp;and HR+/HER2\u0026thinsp;+\u0026thinsp;are thus combined for analysis. Further research is needed to define the optimal tumor size cutoff for adjuvant systemic treatments in lymph node-negative HR-/HER2\u0026thinsp;+\u0026thinsp;BC and identify the best systemic treatment for tumors below this cutoff. Furthermore, the limited sample sizes in certain subgroups precluded further adjustments, resulting in wide confidence intervals for some outcome estimates. Finally, as all patients with HER2-positive tumors received adjuvant chemotherapy, it was not feasible to compare outcomes among those who did not receive chemotherapy, those who received chemotherapy only, and those who received combination therapy. Consequently, any comparisons between patients treated with chemotherapy, with or without trastuzumab, should be interpreted with caution.\u003c/p\u003e \u003cp\u003eDespite these limitations, our findings provide robust evidence supporting the efficacy of adjuvant systemic treatments in patients with T1N0M0 BC, particularly for those with tumors at or above identified size thresholds. For tumors below these thresholds, adjuvant systemic treatments may be unnecessary. Future research should aim to refine management strategies for these patients, enhance methods for identifying those at the highest risk of recurrence, and minimize treatment-related toxicity.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe findings of this cohort study of patients withT1N0M0 breast cancer suggest that patients with different breast cancer subtypes meeting or exceeding established cutoffs should receive adjuvant systemic treatments, while adjuvant systemic treatments did not provide a survival benefit for tumors smaller than these cutoffs. More investigations, especially prospective studies, are necessary to support our findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAST\u003c/em\u003e\u003c/strong\u003e: Adjuvant systemic treatments\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBC\u003c/em\u003e\u003c/strong\u003e: Breast cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBCSS\u003c/em\u003e\u003c/strong\u003e: Breast cancer-specific survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCI\u003c/em\u003e\u003c/strong\u003e: Confidence intervals\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDFS\u003c/em\u003e\u003c/strong\u003e: Disease-free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDRFS\u003c/em\u003e\u003c/strong\u003e: Distant recurrence-free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eER\u003c/em\u003e\u003c/strong\u003e: Estrogen receptor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHER2\u003c/em\u003e\u003c/strong\u003e: Human epidermal growth factor receptor 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHR\u003c/em\u003e\u003c/strong\u003e: Hazard ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIHC\u003c/em\u003e\u003c/strong\u003e: immunohistochemical\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOS\u003c/em\u003e\u003c/strong\u003e: overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePR\u003c/em\u003e\u003c/strong\u003e: Progesterone receptor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTNBC\u003c/em\u003e\u003c/strong\u003e: Triple-negative breast cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproved by institutional review boards at both centers. Patient data were anonymized for analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used for this study is from Tianjin Medical University Cancer Institute and Hospital and Affiliated Hospital of Hebei University. Investigators can access this data through a data use agreement with the two hospitals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the Tianjin Science and Technology Commission (grant N: 18ZXXYSY00070), Tianjin Key Medical Discipline (Specialty) construction Project (grant N: TJYXZdXK-009a), and Science \u0026amp; Technology Development Fund of Tianjin Education Commission for Higher Education (grant N: 2021KJ191).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.S.: Writing, Data curation, Conceptualization. X.D.: Writing \u0026ndash; review \u0026amp; editing, Data curation. H.Y.: Writing \u0026ndash; review \u0026amp; editing, Supervision. Y.S.: Writing \u0026ndash; review \u0026amp; editing, Data curation. X.L.: Writing \u0026ndash; review \u0026amp; editing, Supervision. W.M.: Writing \u0026ndash; review \u0026amp; editing, Supervision. C.C.: Writing \u0026ndash; review \u0026amp; editing, Supervision. Q.J.: Writing \u0026ndash; review \u0026amp; editing, Supervision Y.S.: Writing \u0026ndash; review \u0026amp; editing, Supervision, Funding acquisition, Conceptualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAutier P, Boniol M, Middleton R, Dore JF, Hery C, Zheng T, Gavin A: \u003cstrong\u003eAdvanced breast cancer incidence following population-based mammographic screening\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2011, \u003cstrong\u003e22\u003c/strong\u003e(8):1726-1735.\u003c/li\u003e\n\u003cli\u003eBerry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEffect of screening and adjuvant therapy on mortality from breast cancer\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2005, \u003cstrong\u003e353\u003c/strong\u003e(17):1784-1792.\u003c/li\u003e\n\u003cli\u003eRosen PR, Groshen S, Saigo PE, Kinne DW, Hellman S: \u003cstrong\u003eA long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e1989, \u003cstrong\u003e7\u003c/strong\u003e(3):355-366.\u003c/li\u003e\n\u003cli\u003eHouvenaeghel G, Goncalves A, Classe JM, Garbay JR, Giard S, Charytensky H, Cohen M, Belichard C, Faure C, Uzan S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCharacteristics and clinical outcome of T1 breast cancer: a multicenter retrospective cohort study\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2014, \u003cstrong\u003e25\u003c/strong\u003e(3):623-628.\u003c/li\u003e\n\u003cli\u003eHanrahan EO, Gonzalez-Angulo AM, Giordano SH, Rouzier R, Broglio KR, Hortobagyi GN, Valero V: \u003cstrong\u003eOverall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2007, \u003cstrong\u003e25\u003c/strong\u003e(31):4952-4960.\u003c/li\u003e\n\u003cli\u003eVaz-Luis I, Ottesen RA, Hughes ME, Mamet R, Burstein HJ, Edge SB, Gonzalez-Angulo AM, Moy B, Rugo HS, Theriault RL\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOutcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2014, \u003cstrong\u003e32\u003c/strong\u003e(20):2142-2150.\u003c/li\u003e\n\u003cli\u003eFisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, Wolmark N: \u003cstrong\u003ePrognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes\u003c/strong\u003e. \u003cem\u003eJ Natl Cancer Inst \u003c/em\u003e2001, \u003cstrong\u003e93\u003c/strong\u003e(2):112-120.\u003c/li\u003e\n\u003cli\u003eFehrenbacher L, Capra AM, Quesenberry CP, Jr., Fulton R, Shiraz P, Habel LA: \u003cstrong\u003eDistant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: a cohort from an integrated health care delivery system\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2014, \u003cstrong\u003e32\u003c/strong\u003e(20):2151-2158.\u003c/li\u003e\n\u003cli\u003eTolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAdjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2015, \u003cstrong\u003e372\u003c/strong\u003e(2):134-141.\u003c/li\u003e\n\u003cli\u003eGradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, Allison KH, Anderson B, Burstein HJ, Chew H\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNCCN Guidelines(R) Insights: Breast Cancer, Version 4.2023\u003c/strong\u003e. \u003cem\u003eJ Natl Compr Canc Netw \u003c/em\u003e2023, \u003cstrong\u003e21\u003c/strong\u003e(6):594-608.\u003c/li\u003e\n\u003cli\u003eCurigliano G, Burstein HJ, Gnant M, Loibl S, Cameron D, Regan MM, Denkert C, Poortmans P, Weber WP, Thurlimann B\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eUnderstanding breast cancer complexity to improve patient outcomes: The St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2023, \u003cstrong\u003e34\u003c/strong\u003e(11):970-986.\u003c/li\u003e\n\u003cli\u003eGoldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ, Panel m: \u003cstrong\u003eThresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009\u003c/strong\u003e. \u003cem\u003eAnn Oncol \u003c/em\u003e2009, \u003cstrong\u003e20\u003c/strong\u003e(8):1319-1329.\u003c/li\u003e\n\u003cli\u003eNguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, Bellon JR, Wong JS, Smith BL, Harris JR: \u003cstrong\u003eBreast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2008, \u003cstrong\u003e26\u003c/strong\u003e(14):2373-2378.\u003c/li\u003e\n\u003cli\u003eAmar S, McCullough AE, Tan W, Geiger XJ, Boughey JC, McNeil RB, Coppola KE, McLaughlin SA, Palmieri FM, Perez EA: \u003cstrong\u003ePrognosis and outcome of small (\u0026lt;=1 cm), node-negative breast cancer on the basis of hormonal and HER-2 status\u003c/strong\u003e. \u003cem\u003eOncologist \u003c/em\u003e2010, \u003cstrong\u003e15\u003c/strong\u003e(10):1043-1049.\u003c/li\u003e\n\u003cli\u003eAn X, Lei X, Huang R, Luo R, Li H, Xu F, Yuan Z, Wang S, de Nonneville A, Goncalves A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAdjuvant chemotherapy for small, lymph node-negative, triple-negative breast cancer: A single-center study and a meta-analysis of the published literature\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e2020, \u003cstrong\u003e126 Suppl 16\u003c/strong\u003e:3837-3846.\u003c/li\u003e\n\u003cli\u003eZhang Q, He Y, Luo N, Patel SJ, Han Y, Gao R, Modak M, Carotta S, Haslinger C, Kind D\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLandscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma\u003c/strong\u003e. \u003cem\u003eCell \u003c/em\u003e2019, \u003cstrong\u003e179\u003c/strong\u003e(4):829-845 e820.\u003c/li\u003e\n\u003cli\u003eParsons BM, Uprety D, Smith AL, Borgert AJ, Dietrich LL: \u003cstrong\u003eA US Registry-Based Assessment of Use and Impact of Chemotherapy in Stage I HER2-Positive Breast Cancer\u003c/strong\u003e. \u003cem\u003eJ Natl Compr Canc Netw \u003c/em\u003e2018, \u003cstrong\u003e16\u003c/strong\u003e(11):1311-1320.\u003c/li\u003e\n\u003cli\u003evon Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAdjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2017, \u003cstrong\u003e377\u003c/strong\u003e(2):122-131.\u003c/li\u003e\n\u003cli\u003eHammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAmerican Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2010, \u003cstrong\u003e28\u003c/strong\u003e(16):2784-2795.\u003c/li\u003e\n\u003cli\u003eWolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRecommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2013, \u003cstrong\u003e31\u003c/strong\u003e(31):3997-4013.\u003c/li\u003e\n\u003cli\u003eJoensuu H, Pylkkanen L, Toikkanen S: \u003cstrong\u003eLate mortality from pT1N0M0 breast carcinoma\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e1999, \u003cstrong\u003e85\u003c/strong\u003e(10):2183-2189.\u003c/li\u003e\n\u003cli\u003eIchizawa N, Fukutomi T, Iwamoto E, Akashi-Tanaka S: \u003cstrong\u003eLong-term results of T1a, T1b and T1c invasive breast carcinomas in Japanese women: validation of the UICC T1 subgroup classification\u003c/strong\u003e. \u003cem\u003eJpn J Clin Oncol \u003c/em\u003e2002, \u003cstrong\u003e32\u003c/strong\u003e(3):108-109.\u003c/li\u003e\n\u003cli\u003eKim RG, Kim EK, Kim HA, Koh JS, Kim MS, Kim KI, Lee JI, Moon NM, Ko E, Noh WC: \u003cstrong\u003ePrognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience\u003c/strong\u003e. \u003cem\u003eEur J Surg Oncol \u003c/em\u003e2011, \u003cstrong\u003e37\u003c/strong\u003e(7):629-634.\u003c/li\u003e\n\u003cli\u003eGarassino I, Gullo G, Orefice S, Tondulli L, Masci G, Salvini P, Eboli M, Di Tommaso L, Giordano L, Alloisio M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOutcome of T1N0M0 breast cancer in relation to St. Gallen risk assignment criteria for adjuvant therapy\u003c/strong\u003e. \u003cem\u003eBreast \u003c/em\u003e2009, \u003cstrong\u003e18\u003c/strong\u003e(4):263-266.\u003c/li\u003e\n\u003cli\u003eChia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA: \u003cstrong\u003eTen-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2004, \u003cstrong\u003e22\u003c/strong\u003e(9):1630-1637.\u003c/li\u003e\n\u003cli\u003eThurell J, Manouchehri N, Fredriksson I, Wilking U, Bergh J, Ryden L, Koppert LB, Karsten MM, Kiani NA, Hedayati E: \u003cstrong\u003eRisk-adjusted benchmarking of long-term overall survival in patients with HER2-positive early-stage Breast cancer: A Swedish retrospective cohort study\u003c/strong\u003e. \u003cem\u003eBreast \u003c/em\u003e2023, \u003cstrong\u003e70\u003c/strong\u003e:18-24.\u003c/li\u003e\n\u003cli\u003eJenkins EO, Deal AM, Anders CK, Prat A, Perou CM, Carey LA, Muss HB: \u003cstrong\u003eAge-specific changes in intrinsic breast cancer subtypes: a focus on older women\u003c/strong\u003e. \u003cem\u003eOncologist \u003c/em\u003e2014, \u003cstrong\u003e19\u003c/strong\u003e(10):1076-1083.\u003c/li\u003e\n\u003cli\u003eHassett MJ, O\u0026apos;Malley AJ, Pakes JR, Newhouse JP, Earle CC: \u003cstrong\u003eFrequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer\u003c/strong\u003e. \u003cem\u003eJ Natl Cancer Inst \u003c/em\u003e2006, \u003cstrong\u003e98\u003c/strong\u003e(16):1108-1117.\u003c/li\u003e\n\u003cli\u003eKim H, Hong B, Kim S, Kang SM, Park J: \u003cstrong\u003eChemotherapy-related cardiotoxicity and its symptoms in patients with breast cancer: a scoping review\u003c/strong\u003e. \u003cem\u003eSyst Rev \u003c/em\u003e2024, \u003cstrong\u003e13\u003c/strong\u003e(1):167.\u003c/li\u003e\n\u003cli\u003eQureshi Z, Altaf F, Jamil A, Siddique R, Fatima E: \u003cstrong\u003eSafety and Efficacy of Trastuzumab Deruxtecan for Metastatic HER2+ and HER2-low Breast Cancer: An Updated Systematic Review and Meta-Analysis of Clinical Trials\u003c/strong\u003e. \u003cem\u003eAm J Clin Oncol \u003c/em\u003e2024.\u003c/li\u003e\n\u003cli\u003eMilata JL, Otte JL, Carpenter JS: \u003cstrong\u003eOral Endocrine Therapy Nonadherence, Adverse Effects, Decisional Support, and Decisional Needs in Women With Breast Cancer\u003c/strong\u003e. \u003cem\u003eCancer Nurs \u003c/em\u003e2018, \u003cstrong\u003e41\u003c/strong\u003e(1):E9-E18.\u003c/li\u003e\n\u003cli\u003eSasada S, Kondo N, Hashimoto H, Takahashi Y, Terata K, Kida K, Sagara Y, Ueno T, Anan K, Suto A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePrognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer\u003c/strong\u003e. \u003cem\u003eBreast Cancer Res Treat \u003c/em\u003e2023, \u003cstrong\u003e202\u003c/strong\u003e(3):473-483.\u003c/li\u003e\n\u003cli\u003eCabel L, Peron J, Cottu PH, Rodrigues MJ: \u003cstrong\u003ePrognosis of t1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas\u003c/strong\u003e. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2015, \u003cstrong\u003e33\u003c/strong\u003e(3):291.\u003c/li\u003e\n\u003cli\u003eIgnatov T, Eggemann H, Burger E, Costa SD, Ignatov A: \u003cstrong\u003eManagement of small T1a/b breast cancer by tumor subtype\u003c/strong\u003e. \u003cem\u003eBreast Cancer Res Treat \u003c/em\u003e2017, \u003cstrong\u003e163\u003c/strong\u003e(1):111-118.\u003c/li\u003e\n\n\u003c/ol\u003e"},{"header":"Table 2 and 3","content":"\u003cp\u003eTable 2 and 3 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"T1N0M0 Breast Cancer, Adjuvant Systemic Therapy, Prognostic Heterogeneity, Molecular Subtypes, Personalized Treatment Strategies","lastPublishedDoi":"10.21203/rs.3.rs-6348915/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6348915/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eEarly-stage breast cancer (T1N0M0 BC) generally has a favorable prognosis, but relapse risks persist over time. The role of adjuvant systemic treatments (AST) for tumors\u0026thinsp;\u0026le;\u0026thinsp;10 mm remains debated. Given the limited availability of robust prospective data, retrospective studies play a crucial role in guiding clinical decision-making.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThis multicenter retrospective study included 1,733 invasive T1N0M0 breast cancer patients treated at two Chinese centers (1998\u0026ndash;2018). Patients with neoadjuvant chemotherapy or unknown estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) status were excluded. Primary endpoint was disease-free survival (DFS); secondary endpoints included distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS). Survival outcomes across four molecular subtypes (ER, PR, HER2-defined) were analyzed using Kaplan\u0026ndash;Meier and Cox models. Tumor size thresholds for AST benefit were determined via maximally selected rank statistics.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eThis study evaluated 1,733 T1N0M0 breast cancer patients, with HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;as the most common subtype (56.9%), followed by HR+/HER2+ (12.6%), HR-/HER2+ (10.8%), and triple-negative (19.7%). Molecular subtypes showed significant prognostic stratification (10-year DFS: 84.0% for HR+/HER2- vs 73.4% for HR-/HER2+, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). AST demonstrated significant overall benefit (DFS HR\u0026thinsp;=\u0026thinsp;0.33, 95% CI: 0.24\u0026ndash;0.45, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with consistent improvements in DRFS, BCSS, and OS (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Subtype-specific thresholds were identified: no AST benefit for HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;tumors\u0026thinsp;\u0026lt;\u0026thinsp;10 mm (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.33 for endocrine therapy); significant DFS improvement for HER2\u0026thinsp;+\u0026thinsp;tumors\u0026thinsp;\u0026ge;\u0026thinsp;8 mm receiving trastuzumab (HR\u0026thinsp;=\u0026thinsp;0.37, 95% CI: 0.14\u0026ndash;0.77, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018); and for triple-negative tumors\u0026thinsp;\u0026ge;\u0026thinsp;9 mm (HR\u0026thinsp;=\u0026thinsp;0.38, 95% CI: 0.21\u0026ndash;0.74, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis study highlights the prognostic heterogeneity of T1N0M0 breast cancer and identifies high-risk subgroups that benefit from AST. Integrating molecular and clinicopathologic features supports a more personalized approach to early-stage breast cancer treatment.\u003c/p\u003e","manuscriptTitle":"Novel Prognostic Stratification and Therapeutic Implications in T1N0M0 Breast Cancer: Insights from a Multi-Center Chinese Cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 01:53:05","doi":"10.21203/rs.3.rs-6348915/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-10T17:42:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-22T13:52:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227216259002536508777192008259441346331","date":"2025-11-22T07:16:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-27T23:14:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335509823846741464956262216839163696169","date":"2025-08-17T01:50:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-05T02:35:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-02T06:09:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-02T05:08:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research","date":"2025-04-01T02:56:27+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":"e477992b-d6c0-43e5-be65-4afe04d99a2b","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T03:23:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 01:53:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6348915","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6348915","identity":"rs-6348915","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}