Prognosis and chemotherapy efficacy in small-tumor breast cancer with different immune subtypes: a SEER-based study

Introduction

Although the survival outcomes of patients with small-tumor breast cancer show a 10-year recurrence-free survival rate exceeding 90% (1), smaller primary tumors are not always associated with a lower breast cancer-specific mortality rate. In the case of lymph node metastasis, small-tumor breast cancer patients show different survival rates. Zheng et al. found that the breast cancer-specific mortality of stage IV small-tumor breast cancer patients may be as high as that of patients with large tumors (2) and speculated that the prognosis of very small triple-negative breast cancer (TNBC) with extensive regional lymph node involvement is significantly poor, which may suggest that it is biologically invasive. Compared with the seventh edition of the American Joint Committee on Cancer (AJCC) breast cancer staging system, the eighth edition of the AJCC prognostic staging system considers the impact of immune subtypes on prognosis, and the staging of small-tumor has undergone significant changes (3). For example, T1N3M0 stage estrogen receptor positive progesterone receptor positive human epidermal growth factor receptor 2 positive (ER+PR+HER2+) subtype has been downgraded to stage IIIB, whereas T1N0M0 stage ER−PR−HER2− subtype has been upgraded to stage IIA. This indicates that for patients with small-tumor breast cancer, prognosis can be impacted by both immune subtypes and lymph node metastasis status (1,4). Current studies have not conducted in-depth analyses of small-tumor patients with different immune subtypes and different lymph node metastases.

The treatment of small-tumor breast cancer remains controversial among oncology researchers (5). They found that tumor size smaller than 0.5 cm do not require chemotherapy; In pT1b tumors, if the tumor subtype is TNBC or HER2-positive and HR-negative, adjuvant chemotherapy (AC) can be considered; In pT1c tumors, guideline-based AC is necessary. Although AC can improve the survival rate of T1cN0M0 stage triple negative breast cancer patients, the benefits of chemotherapy for patients with T1mi/a-bN0 stage triple negative breast cancer remain controversial (6-8). Therefore, some researchers and clinicians have proposed that treatment decisions for patients with small-tumor breast cancer should be based on biological subtypes rather than solely on tumor size or lymph node status (9).

In summary, not all small-tumor breast cancers have “good” biological behavior, and the efficacy of chemotherapy varies according to the different clinicopathological and biological characteristics of the patient’s tumors. Breast cancer patient with different clinicopathological and biological characteristics have significantly different responses to therapies and require individualized treatment (10). To fully understand the factors that influence prognosis in patients with small-tumor breast cancer and to guide optimal treatment, we performed a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database, a publicly available research resource based on cancer epidemiology and the TNM staging of breast and other cancers. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1349/rc).

Methods

Data collection/participants

This cohort study involved a retrospective analysis using the SEER 18 registry database, which collects basic clinical information and data on the pathological features, survival, and treatment modalities of patients with cancer in the United States. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval and informed consent were waived because all data from the SEER database are de-identified and publicly available. Follow-up lasted until 2020. According to the eighth AJCC TNM staging of breast cancer, T1 stage is generally considered small-tumor. T1mi/a stage is defined as a tumor with a maximum diameter of <5 mm (where T1mi stage is defined as small invasive cancer with a maximum diameter of <1 mm, and T1a stage is defined as small invasive with the maximum tumor diameter was >1 mm, but ≤5 mm). The T1b stage was defined when the maximum tumor diameter was >5 mm but ≤10 mm, and the T1c stage was defined when the maximum tumor diameter was >10 mm but ≤20 mm. N2+ stage is defined as patients with N2 stage and patients with N3 stage. Patients who met the following criteria were included: female, aged between 18 and 70 years, diagnosed with pathologically confirmed invasive ductal and lobular breast cancer (diagnostic level required) from 2010 to 2015, first primary cancer, unilateral, without distant metastasis, surgical treatment includes mastectomy (breast-conserving surgery) and axillary lymph node biopsy or dissection, and known HR and HER2 states, were included in the T staging. Patients who received radiotherapy and chemotherapy before surgery were excluded from the analysis. In addition, patients whose survival was <3 months or who had unknown follow-up and with unknown or unspecified variable information were excluded. The detailed exclusion criteria are presented in Figure 1.

Figure 1 Patients selection flowchart. TNM, tumour, node, and metastasis.

The variables included in this study were as follows: demographic characteristics (age at diagnosis and race), disease characteristics (tumor location, laterality, Grade, histologic type, T stage, N stage, and subtype), treatment characteristics (type of breast surgery, chemotherapy, and radiotherapy), survival status (duration of survival and cause of death), and survival time (months).

Statistical analysis

All statistical analyses were performed using R software (version 4.3.1). Categorical variables are expressed as frequencies and proportions, while continuous variables are expressed as mean ± standard deviation (SD), depending on the data distribution. Comparisons between groups were performed using the Chi-squared test or Fisher’s exact test for categorical variables and Student’s t-test or Mann-Whitney U test for continuous variables, as appropriate.

Survival outcomes, including overall survival (OS) and breast cancer-specific survival (BCSS), were assessed using Kaplan-Meier (KM) curves, and differences between the groups were evaluated using the log-rank test. Multivariate Cox proportional hazard regression models were constructed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and BCSS. Variables with a P<0.05 in univariate analysis or those of clinical relevance were included in the multivariable models.

Subgroup analyses were conducted to evaluate survival differences and the efficacy of AC according to the T stage, N stage, and molecular subtype. Interaction tests were performed to determine the heterogeneity of AC efficacy across the subgroups. The proportional hazard assumption was assessed using Schoenfeld residuals, and no significant violations were observed.

To further evaluate the robustness of chemotherapy effects across different immune subtypes in small-tumor breast cancer, we conducted a sensitivity analysis using multivariate Cox proportional hazards models. Additionally, to explore whether the effect of AC on survival was modified by tumor Grade, an interaction term between AC and Grade was introduced into the multivariate models.

The relationship between tumor size and 5-year survival was first explored using smoothing plots. Two-piecewise linear regression models were then applied to examine the threshold effect of tumor size on 5-year survival across different N stages. Based on the smoothing plots, the presence of a threshold effect was investigated. Specifically, potential inflection points were tested by moving along predefined intervals to identify the point with the maximum model likelihood.

Smoothing plots were drawn separately for different stages and subtypes of breast cancer to explore whether a threshold effect exists for tumor size at various stages. The inflection point was determined using a trial method by adjusting the interval, with the model likelihood used to identify the most likely threshold.

All tests were two-sided, and a P<0.05 was considered statistically significant. Missing data were managed using multiple imputation methods based on chained equations to ensure robustness of the results.

Results

Clinicopathological data

A total of 72,116 eligible women with small-tumor breast cancer were enrolled in this study, including 8,698 patients with T1mi/a stage, 20,984 patients with T1b stage, and 42,434 patients with T1c stage. The clinicopathological features of all the patients are shown in Table 1. Compared with patients with T1mi/a stage, patients with T1c stage tended to have poorer tumor differentiation, more lymph node metastases, and more frequent chemotherapy (all P<0.001).

Univariate and multivariate analyses affecting the survival of breast cancer patients with small-tumors

The median survival time was 92 months, and the 5-year OS rate was 96.93%. To identify the risk factors affecting survival in the patients with small-tumors, we first performed a univariate analysis of OS and BCSS for all patients (Table 2), excluding the effect of tumor growth location on survival. Multivariate Cox proportional hazard regression analyses for OS and BCSS were performed for all patients. The results showed that race, T stage, N stage, histological Grade, immune subtype, chemotherapy, and radiotherapy were independent prognostic factors affecting the survival rate of patients with small-tumor breast cancer (all P<0.05). Among them, radiotherapy was revealed as a prognostic factor beneficial for the survival of this population. Although univariate analysis showed adverse effects of AC both on OS (HR: 1.37, 95% CI: 1.29–1.46, P<0.001) and BCSS (HR:3.05, 95% CI:2.78–3.34, P<0.001), multivariate analysis showed that AC improved the OS of patients with small-tumors (HR: 0.78, 95% CI: 0.72–0.85, P<0.001), whereas no significant association between AC and tumor-related prognosis (in terms of BCSS) was observed (HR: 1.10, 95% CI: 0.98–1.23, P=0.11) (Table 3).

Relationship between continuous tumor size change on 5-year OS rate of patients with small-tumors

By mapping the relationship between continuous tumor size and 5-year OS rate, we observed that the 5-year OS rate of patients with N0 and N2+ stage small-tumors decreased with an increase in tumor size (Figure 2). The survival rate of patients with N1 stage disease first increased when the tumor size increased from small to large and then decreased after tumors reached 9 mm. Furthermore, based on relationship plots drawn according to the different immune subtypes (Figures 3-5), similar trends were found only in patients with HR−HER2+ and HR+HER2− subtypes in N1 stage (Figure 4). When the tumor size of HR−HER2+ subtype patients in N1 stage was <13 mm, the smaller the tumor, the lower the 5-year survival rate, and the 5-year survival rate was the highest when the tumor size was 13 mm; When the tumor size was greater than 13 mm, the 5-year survival rate decreased with increasing tumor size (Figure 4D). Patients with the HR+HER2− subtype in N1 stage had a cutoff point of 7 mm (Figure 4A). Other patients with different N stages and immune subtypes showed a gradual decline in the 5-year survival with an increase in tumor size; however, the downward trend varied (Figures 3,5).

Figure 2 Relationship between continuous tumor size change on 5-year overall survival rate of N0, N1, and N2+ patients with small-tumor. (A) N0 stage patients; (B) N1 stage patients; (C) N2+ stage patients. N, node.

Figure 3 Relationship between continuous tumor size change on 5-year survival rate of N0 patients with small-tumor stratified by immune subtypes. (A) HR+HER2− subtype; (B) HR+HER2+ subtype; (C) HR−HER2− subtype; (D) HR-HER2+ subtype. HER2+, human epidermal growth factor receptor 2-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor positive; HR−, hormone receptor negative.

Figure 4 Relationship between continuous tumor size change on 5-year survival rate of N1 patients with small-tumor stratified by immune subtypes. (A) HR+HER2− subtype; (B) HR+HER2+ subtype; (C) HR−HER2− subtype; (D) HR−HER2+ subtype. HER2+, human epidermal growth factor receptor 2-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor positive; HR−, hormone receptor negative.

Figure 5 Relationship between continuous tumor size change on 5-year survival rate of N2+ patients with small-tumors stratified by immune subtypes. (A) HR+HER2− subtype; (B) HR+HER2+ subtype; (C) HR−HER2− subtype; (D) HR−HER2+ subtype. HER2+, human epidermal growth factor receptor 2-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor positive; HR−, hormone receptor negative.

Interaction of tumor size, lymph node status, and immune subtypes on survival in patients with small-tumors

From the perspective of OS and BCSS, we performed a multivariate analysis of the relationship between T stage, N stage, and immune subtypes to assess their impact on the prognosis of patients with small-tumors. As shown in Table 4, using T1mi/aN0 stage HR+HER2− subtype patients as a reference, T1mi/aN0 stage HR+HER2+ subtype patients had the best OS prognosis (HR =0.58, P=0.03). Among the different immune subtypes, T1cN2+ stage patients had the highest risk of death (P<0.05). Patients with T1cN2+HR−HER2− had the highest risk of death from OS and BCSS (HR was 11.25 and 29.49 respectively, P<0.001). Compared with N stage, T1c stage had a more significant impact on the prognosis of patients with HR−HER2− subtype (all P<0.05).

Notably, in T1N1 stage cancers, compared with patients of other subtypes in T1mi/a-bN1 stage, the OS and BCSS of patients with T1mi/a-bN1HR−HER2+ were significantly worse (OS: T1mi/aN1 HR =3.22, 95% CI: 1.32–7.83; T1bN1 HR =3.22, 95% CI: 1.58–6.55; BCSS: T1mi/aN1 HR =4.48, 95% CI: 1.08–18.64; T1bN1 HR =7.7, 95% CI: 3.23–18.34; all P<0.05).The survival rate of patients with T1cN1HR−HER2+ is relatively high, even better than that of patients with T1mi/aN1HR−HER2− (OS: HR =1.98, 95% CI: 1.27–3.1 vs. HR =2.83, 95% CI: 0.9–8.86; BCSS: HR =4.32, 95% CI: 2.38–7.83 vs. HR =6.36, 95% CI: 1.53–26.45; all P<0.001).

Intriguingly, a similar phenomenon occurs within HR+HER2− subgroups. Compared with T1bN1, this subtype group had an increased risk of death in both T1mi/aN1 and T1cN1 stages (OS: HR =2.0, 95% CI: 1.28–3.15; HR =2.27, 95% CI: 1.92–2.69 vs. HR =1.55, 95% CI: 1.20–2.01; BCSS: HR =4.33, 95% CI: 2.15–8.73; HR =5.15, 95% CI: 3.63–7.29 vs. HR =2.93, 95% CI: 1.82–4.70; all P<0.05).

KM survival curves of the OS and BCSS among patients with small-tumors of different TN stages and immune subtypes were drawn (Figures 6,7). The results showed that the differences in the survival curves were inconsistent among patients with different immune subtypes at different TN stages. In addition to patients with the T1mi/a-bN0–1 and T1bN2+ stages, the survival rate of the patients with the HR−HER2− subtype of breast cancer in the other TN stages was the lowest (all P<0.05). It can be seen from the figure that the survival curve of patients with the HR−HER2+ subtype was lower than that of patients with the HR−HER2− subtype in the T1mi/a-bN1 stage (the 5-year OS rates were 89.06% and 92.13%, respectively), although the difference was not statistically significant (P>0.05).

Figure 6 Kaplan-Meier curves for BCSS of small-tumor patients with different immune subtypes in different TN stages. BCSS, breast cancer-specific survival; HER2+, human epidermal growth factor receptor 2-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor positive; HR−, hormone receptor negative; TN, tumor node.

Figure 7 Kaplan-Meier curves for OS of small-tumor patients with different immune subtypes in different TN stages. HER2+, human epidermal growth factor receptor 2-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor positive; HR−, hormone receptor negative; OS, overall survival; TN, tumor node.

Survival benefits of chemotherapy in patients with different subtypes

As shown in Table 5, the results of the multivariate analysis showed that AC can significantly improve the prognosis of T1cN2+ stage HR+HER2− subtype patients (OS: HR =0.38, 95% CI: 0.27–0.55; BCSS: HR =0.46, 95% CI: 0.30–0.70, P<0.05), and can improve the OS of T1cN1 stage HR+HER2− subtype patients (HR =0.83, 95% CI: 0.70–1.00, P=0.046). However, patients with T1mi/a-bN0–1 stage of this subtype did not benefit from AC in OS and BCSS (all P>0.05), and even in BCSS, chemotherapy had adverse effects on T1N0 stage HR+HER2− subtype patients (HR 1.67, 95% CI: 1.39–2.00, P<0.001).

AC significantly increased the OS of T1cN0 stage HR−HER2− subtype, T1bN0 stage HR+HER2+ subtype, T1cN1 stage HR+HER2+ subtype and T1cN0–1 stage HR+HER2+ subtype patients (all P<0.05); AC also increased BCSS of T1cN1 stage HR+HER2+ subtype and T1cN0 stage HR+HER2+ subtype patients (all P<0.05). However, AC did not improve the prognosis of the patients with T1mi/a-bN0 stage HR−HER2− and HR+HER2+ subtypes (both P>0.05). Although no significant benefit from AC was found in T1N2+ stage patients with HR−HER2− subtype, HR−HER2+ subtype, and HR+HER2+ subtype , AC still tended to provide survival benefits for these patients (OS: HR =0.65, 95% CI: 0.24–1.77; HR =0.51, 95% CI: 0.08–3.20 and HR =1.13, 95% CI: 0.29–4.40; BCSS: HR =0.92, 95% CI: 0.27–3.21; HR =0.28, 95% CI: 0.04–2.05, and HR =0.88, 95% CI: 0.22–3.55, P>0.05).

Sensitivity analysis

First, in a multivariable-adjusted model for age, Grade, race, surgery and radiotherapy for patients with pT1mi/a-bN0–1 HR+HER2− or pT1mi/a-bN0 HR−HER2−/HR+HER2+, It was once again verified that AC still could not bring benefits to these patients (P>0.05), and even caused harm to pT1mi/a-bN0 HR+HER2− patients (OS: HR =2.48, 95% CI: 1.34–4.60; BCSS: HR =4.67, 95% CI: 1.79–12.18; HR =1.87, 95% CI: 1.17–3.04, P<0.05) (Table 6).

Second, considering that Grade is an independent risk factor affecting the prognosis of patients with small-tumors, and that patients with higher Grade require chemotherapy, further interaction analysis revealed no significant interaction between chemotherapy and tumor grade across patients with pT1mi/a-bN0–1 HR+HER2− or pT1mi/a-bN0 HR−HER2−/HR+HER2+ for OS or BCSS (Table 7). The interaction term between chemotherapy and tumor grade was not statistically significant in these subtypes for either OS or BCSS, indicating no modifying effect of tumor Grade on chemotherapy efficacy.

Discussion

According to the traditional view, small-tumor breast cancers usually have a low Ki67 index, relatively mild biological behavior, and a good long-term prognosis for patients (11). With an increase in tumor size, the risk of lymph node metastasis increases, which is considered a sign of increased risk of locally advanced tumors and distant metastasis (12). However, clinically, some patients have obvious lymph node involvement even if the tumor is small, suggesting that the tumor may have the potential to metastasize at an early stage, thus affecting the prognosis (13). Using a large population-based cancer registry database, the prognosis and chemotherapy benefits of patients with small-tumor breast cancer were evaluated to identify the high-risk types among small-tumor patients and assess the impact of AC on the survival of patients with different subtypes. A total of 72,116 eligible women with small-tumor breast cancer were included in the study. Univariate and multivariate survival analyses showed that race, tumor Grade, immune subtype, N stage, and T stage were independent prognostic factors affecting OS and BCSS in this population.

Our analysis determined the relationship between continuous tumor size and the 5-year OS rate of patients, and the results clearly showed that the survival rate of patients with small-tumors at different N stages was affected by tumor size. In stages N0 and N2+, the larger the tumor size, the worse the 5-year survival rate. However, the survival rate of patients with small-tumors in stage N1 demonstrated a turning point in the survival rates. The 5-year survival rate was the highest when the tumor size was 9 mm, whereas the 5-year survival rate of this same group decreased with a further reduction or increase in tumor size. This result is consistent with the conclusions of Ryu et al. (14), who found that in N1 stage tumors <10 mm, the 5-year and 8-year attributable mortality of breast cancer decreased with an increase in tumor size, suggesting that very small-tumor with lymph node metastasis are highly aggressive. This indicates a biologically aggressive disease. Han et al. (15) also noted that among patients with T1N1 stage tumors, the OS rate of the small-tumor group (≤10 mm, T1mi+T1a+T1b) was significantly lower than that of the other large tumor group (T1c). Wo et al. (13) made a similar inference in their study of the survival of 50,949 patients with T1/T2 stage invasive breast cancer; however, they found that very small-tumor with four or more positive lymph nodes had aggressive biological behavior. Unlike these studies, our analysis further stratified the analysis based on immune subtypes, finding only very small-tumor with aggressive biological behavior in patients with N1 stage HR−HER2+ subtype breast cancer. Bezić et al. (16) believed that T1a-b stage HER2+ subtype breast cancer had invasive manifestations and called it a “wolf in sheep’s clothing”. Cancello et al. (5) also found that patients with HR−HER2+ subtype breast cancer had a higher recurrence risk than that of patients with HR−HER2− subtype breast cancer when the tumor was smaller than 1 cm and lymph node metastasis was not present. However, other researchers’ findings were contrary to those of Cancello et al. They thought T1a-b stage, HR−HER2+ subtype breast cancer has a good prognosis (17), particularly in patients with node-negative breast cancer with a low 5-year recurrence risk (18). To exclude the influence of T stage, N stage, and immune subtypes on the prognosis of patients with small-tumors, subgroup multivariate analysis was conducted in our study, and the results showed that clinicians should pay attention to the prognosis of the T1mi/a-bN1 stage HR−HER2+ subtype patient population. Compared with patients of other subtypes in the T1mi/a-bN1 stage, they have the highest risk of death. This further confirms that the T1mi/a-bN1 stage HR−HER2+ subtype of breast cancer has a significantly aggressive biological morphology and is a high-risk type of small-tumor breast cancer. Regarding whether T1mi/a-bN1 stage HR-HER2+ subtype is a risk factor affecting the prognosis of patients with small-tumor, using the KM survival curve, we intuitively observed that the survival curves of patients with HR−HER2+ subtype showed no statistically significant difference compared with those of patients with HR−HER2− subtype in the T1mi/a-bN1 stage. Therefore, a larger sample size is needed to confirm that minimal tumor size may be a prognostic factor for small-tumor breast cancer patients with lymph node involvement (15).

Wang et al. (19) found that T1a stage HR−HER2− subtype breast cancer had the worst prognosis. However, the KM curve and multivariate survival analysis of our study revealed that HR−HER2− subtype breast cancers are not always the most lethal cancers. T1mi/a stage HR−HER2− subtype did not have a significant impact on prognosis; however, compared with N stage, T1c stage had a more significant impact on the prognosis of HR−HER2− subtype small-tumor. These results also indicate a complex relationship between tumor size, lymph node status, and prognosis, which may be due not only to the disproportionate number of cancer cells with metastatic potential (20), but also to the influencing factors of different immune subtypes on the prognosis of small-tumor breast cancer (9). Therefore, substantially more data is needed for long-term follow-up to observe the survival outcomes of patients with small-tumor breast cancer.

The eighth edition of the AJCC prognostic staging system emphasizes that in the era of personalized breast cancer treatment, tumor burden and biological factors need comprehensive consideration, suggesting that systemic and local treatment plans for patients with the same anatomical stage but different immune types need to be reevaluated (21). Our study found that radiotherapy was a favorable prognostic factor for both OS and BCSS in small-tumor breast cancer patients. However, chemotherapy was a favorable prognostic factor for OS in patients with small-tumor but had a negative prognostic tendency for BCSS in this population. Therefore, further stratified analyses are needed to determine the prognostic effect of chemotherapy in patients with different subtypes of small-tumors. Results from the DBCG77B clinical trial (22) showed that cyclophosphamide-based AC had no benefit in high-risk premenopausal Luminal A breast cancer patients. Even for luminal A breast cancer patients with lymph node positive, additional chemotherapy did not improve the prognosis. Conversely, the side effects of additional chemotherapy may have a negative impact on the prognosis (23). Our study also found that patients with the T1mi/a-bN0-1 stage HR+HER2− subtype did not benefit from chemotherapy and that chemotherapy even had adverse effects on the BCSS in patients with the T1N0 stage HR+HER2− subtype. Patients with T1cN+ stage HR+HER2− subtype could benefit from chemotherapy.

Most researchers believe that AC is associated with better BCSS and OS in patients with pT1N0M0 stage HR−HER2− subtype breast cancer, and the effect of chemotherapy is most obvious in pT1c stage tumors (7,24). However, the benefit of chemotherapy in patients with T1mi/a-bN0 stage HR−HER2− subtype remains controversial (6,8,25). Our study confirmed that chemotherapy could improve the OS in patients with T1cN0 stage HR−HER2−/HR+HER2+ subtype, but chemotherapy had no benefit on OS and BCSS in patients with T1mi/a-bN0 stage HR−HER2−/HR+HER2+ subtype. Owing to an insufficient sample size, although chemotherapy could not be observed as an independent prognostic factor for patients with HR−HER2− subtype small-tumor with lymph node metastasis; chemotherapy showed a favorable trend for this population. Our study also found that chemotherapy can significantly improve the prognosis of T1bN0 stage and T1cN1 stage HR−HER2+ subtype breast cancer. These findings differ from those of Lin et al. (26), who suggested that chemotherapy could not confer survival benefits to patients with T1a-bN0 stage HER2+ subtype breast cancer. He et al. (27) believed that AC plus trastuzumab should be recommended for breast cancer patients with pT1N0M0 stage HER2+ subtype with a tumor diameter ≥8 mm, whereas patients with tumor diameters <8 mm may not need adjuvant therapy. Therefore, the effects of chemotherapy on patients with different subtypes of small-tumor breast cancer are different. Clinicians must distinguish whether patients with invasive subtypes of small-tumor need chemotherapy. It is important to select appropriate treatment methods for individual patients and reduce the toxic effects of chemotherapy. Patients with both pT1mi/a-bN0-1 stage HR+HER2− subtype and pT1mi/a-bN0 stage HR−HER2−/HR+HER2+ subtype can be exempted from chemotherapy.

In the sensitivity analysis, though a multivariable-adjusted model for age, Grade, race, surgery and radiotherapy for patients with pT1mi/a-bN0-1 HR+HER2− or pT1mi/a-bN0 HR−HER2−/HR+HER2+, the result did not change substantially, AC could not bring benefits to these patients (P>0.05). There was no interaction effect with Grade. This finding supports the clinical trend of gradually realizing “de-intensification” treatment.

There are some limitations in this study. First, despite the large sample size, the retrospective design and potential selection bias were unavoidable. Second, the patient information provided by the SEER database did not clearly record endocrine therapy, chemotherapy regimen, targeted therapy, disease recurrence after one treatment, or treatment history after disease recurrence. At the same time, the socioeconomic status, comorbidities, and the possible heterogeneity of HER2 detection were not described in detail. Third, the data of this study is derived from the SEER registry system in the United States. The sample size is registry-limited. This study can serve as a “starting point” for exploring individualized treatment strategies, however, prospective, multi-center studies are needed for further validation in different populations. Fourth, the number of T1mi/a-b stage breast cancer patients with lymph node metastasis was small, and a larger sample size is required to more accurately reflect the impact of chemotherapy on the survival of patients with different subtypes of lymph node metastasis. Finally, the SEER database does not include the results of relapse risk gene detection; therefore, we were unable to include the 21 gene detection results recommended by the guidelines for HR+HER2− subtype patients for further stratified analysis. However, as research has progressed, some scholars have proposed that for patients with low-grade (1 or 2) T1a-bN0 stage HR+HER2− subtype breast cancer, 21 gene test results may not be required for treatment decisions (28,29). Moreover, the high cost of this testing limits its popularity. Combined with the results of this study, we propose that with the continuous development and updating of endocrine therapy drugs, patients with breast cancers with excellent prognoses (such as breast cancers in the T1mi/a-bN0-1 stage HR+HER2− subgroup) may be directly exempt from chemotherapy without clinicians relying on the relapse score for treatment decisions. The main advantage of this study is that, through our analysis of a large-scale population-based cancer registry, the relationship between tumor size, lymph node metastasis, immune subtypes, and the prognosis of patients with small-tumors, as well as the impact of chemotherapy on the prognosis of this population is revealed, and the study provides a basis for clinical work and may be helpful to select a personalized adjuvant therapy for patients with small-tumor breast cancers.

Conclusions

In the era of precision medicine, our study aimed to screen high-risk types with invasive risks for patients with small-tumor breast cancer, and at the same time screen out types that can be exempted from chemotherapy. In addition to the T1cN2+ stage or HR−HER2− subtypes, patients with T1mi/a-bN1 stage HR−HER2+ subgroup are also highly invasive and should be monitored during follow-up for the risk of recurrence. For the pT1mi/a-bN0-1 stage HR+HER2− subgroup and pT1mi/a-bN0 stage HR−HER2−/HR+HER2+ subgroup, which, according to our results, are not recommended for AC therapy. Our research can serve as the “starting point” for exploring individualized treatment strategies and provide direction for the design of future prospective studies, especially in evaluating the true benefits of AC in different molecular subtypes.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1349/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1349/prf

Funding: This study was supported by the Natural Science Foundation of Fujian Province (Grant No. 2024J08268).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1349/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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