1. Background
Breast cancer (BC) remains one of the most prevalent malignancies among women worldwide, and neoadjuvant chemotherapy (NAC) has become an essential component of treatment for patients with locally advanced disease as well as selected cases of early-stage cancer (1, 2). Beyond its established role in tumor size reduction and facilitating surgical management, NAC offers a unique clinical opportunity to assess in vivo tumor sensitivity to systemic therapy (3).
Previous research has shown that axillary and margin clearance are associated with improved disease-free and overall survival in patients with BC, largely reflecting favorable tumor biology and effective systemic treatment (4-6). In addition, pathologic complete response (pCR) in the primary breast tumor after NAC has consistently been associated with improved patient survival, particularly among biologically aggressive subtypes such as HER2-enriched and triple-negative BC (7, 8). However, despite the favorable prognostic implications of tumor pCR, some studies have reported discrepancies between breast pCR and axillary lymph node (LN) pCR rates in patients with clinically node-positive disease, suggesting tumor heterogeneity as a key biological factor underlying differential responses between the primary tumor and metastatic LNs (9-11). As a result, response assessment following NAC has gained increasing importance not only for prognostic stratification but also for guiding subsequent surgical and adjuvant treatment decisions (12).
In this regard, understanding the relationship between treatment response in the primary tumor and in the axillary LNs is of considerable clinical relevance (13).
2. Objectives
The present study was designed to evaluate the correlation between breast tumor response and axillary LN clearance following NAC.
3. Methods
3.1. Study Design
This retrospective study included patients with histologically confirmed BC who received NAC followed by definitive breast and axillary surgery at a tertiary referral center from 1987 to 1990. Eligible patients had available pathological assessments of both the primary breast tumor and axillary LNs after completion of NAC. From a total of 390 patients, 3 male patients and 12 patients with incomplete pathological data regarding breast tumor response, axillary LN status, or immunohistochemical (IHC) profile were excluded from the analysis.
The ethics committee of Shahid Beheshti University of Medical Sciences approved the study (IR.SBMU.PHNS.REC.1404.001), and all methods were conducted in compliance with applicable guidelines and regulatory standards. Informed consent for publication was obtained from all patients.
3.2. Treatment and Pathological Assessment
All patients received standard NAC regimens in accordance with contemporary institutional protocols, based on tumor stage, receptor status, and clinical guidelines at the time of treatment. Surgical management consisted of breast-conserving surgery (BCS) or modified radical mastectomy (MRM), with axillary evaluation performed using sentinel LN biopsy and/or axillary LN dissection, as clinically indicated.
Data were extracted from pathology reports and institutional records and assessed by experienced pathologists. Breast tumor response was defined based on post-treatment histopathological findings and categorized according to the presence or absence of residual invasive disease. Axillary LN response was determined by the absence or presence of residual metastatic disease in resected LNs. Immunohistochemical analysis included standard evaluation of estrogen receptor, progesterone receptor, and HER2 status, in accordance with established guidelines.
3.3. Variables and Outcome Measures
The primary outcome was the association between breast tumor response and axillary LN response following NAC. The secondary outcome included the relationships between breast tumor response and IHC characteristics, and axillary LN response and IHC characteristics.
3.4. Statistical Analysis
The data were analyzed using IBM SPSS ver. 27. The categorical variables are expressed as proportions and frequencies. Associations between categorical variables were evaluated using the chi-square (χ2) test, and results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was defined as a P-value < 0.05.
4. Result
4.1. Patients’ Characteristics
In this study, 375 patients who received NAC were evaluated. Table 1. provides the patients’ baseline characteristics. The patients were categorized into two groups for axillary LNs and breast tumor response as follows: Pathologic complete response (pCR) without any positive LN/breast tumor remnant in the surgery report, and non-pathologic complete response (N-pCR) with one or more positive LNs/breast tumor remnants. The mean age of patients was 46.71 ± 11.52.
Table 1.Patient’s Characteristics
| Variables | No. (%) |
|---|---|
| Age group | |
| ≤ 50 | 237 (63.2) |
| > 50 | 138 (36.8) |
| Family history | |
| Negative | 257 (68.5) |
| Positive | 86 (22.9) |
| Unknown | 32 (8.5) |
| Breast tumor side | |
| Left | 148 (39.5) |
| Right | 174 (46.4) |
| Unknown | 53 (14.1) |
| Breast tumor size | |
| T1: 0 - 2 cm | 1 (0.3) |
| T2: 2 - 5 cm | 33 (8.8) |
| T3: > 5 cm | 341 (90.9) |
| Pathology | |
| IDC | 340 (90.6) |
| ILC | 19 (5.1) |
| Other | 16 (4.3) |
| LVI | |
| Positive | 68 (18.1) |
| Negative | 196 (52.3) |
| Unknown | 111 (29.6) |
| Grade | |
| 1 | 20 (5.3) |
| 2 | 180 (48.0) |
| 3 | 111 (29.6) |
| Unknown | 64 (17.1) |
| Ki67% | |
| ≤ 14 | 98 (26.1) |
| > 14 | 45 (12.0) |
| Unknown | 232 (61.9) |
| IHC | |
| Luminal A | 218 (58.1) |
| Luminal B | 74 (19.7) |
| HER2-enriched | 24 (6.4) |
| TN | 59 (15.7) |
| Breast surgery | |
| BCS | 174 (46.4) |
| MRM | 161 (30.9) |
| Unknown | 85 (22.7) |
| Breast tumor response | |
| pCR | 86 (22.9) |
| N-pCR | 289 (77.1) |
| Axillary clinical status | |
| 1 LNs | 10 (2.6) |
| > 1 LNs | 365 (97.4) |
| Axillary clearance | |
| pCR | 149 (39.7) |
| N-pCR | 226 (60.3) |
| Radiotherapy | |
| Yes | 296 (78.9) |
| No | 7 (1.9) |
| Unknown | 72 (19.2) |
| Hormone therapy | |
| Yes | 297 (79.2) |
| No | 71 (18.9) |
| Unknown | 7 (1.9) |
4.2. Correlation of Breast Tumor Response with Axillary Lymph Nodes Response
A total of 375 patients were included in the analysis, of whom 86 (22.9%) achieved breast pCR. A significant association was observed between breast tumor response and axillary LN response following NAC (Table 2). Patients demonstrating a favorable breast tumor response were significantly more likely to achieve axillary clearance, with an OR of 5.18 (95% CI: 3.07 - 8.75; P < 0.001), indicating a strong correlation between primary tumor response and nodal downstaging.
Table 2.Correlations of Breast Tumor and Axillary Lymph Nodes Responses to Neoadjuvant Chemotherapy
| Variables | ORs | Confidence Interval 95% | P-Value |
|---|---|---|---|
| Breast tumor response & axillary LNs response | 5.18 | 3.07 - 8.75 | < 0.001 |
| Breast tumor response & IHC | 1.76 | 1.02 - 3.03 | 0.03 |
| Axillary LNs response & IHC | 2.43 | 1.48 - 3.99 | < 0.001 |
Abbreviations: ORs, odds ratio; LNs, lymph nodes.
4.3. Correlation of Tumor IHC with Breast Tumor and Axillary Lymph Nodes Responses
Among IHC subtypes, non-luminal tumors were associated with increased odds of achieving pCR in both breast tumors and axillary LNs compared with luminal tumors (Table 2). Tumors with favorable response patterns showed higher odds for non-luminal types, with an OR of 1.76 (95% CI: 1.02 - 3.03; P = 0.03). Similarly, axillary LN response demonstrated a robust association with this IHC status, with an OR of 2.43 (95% CI: 1.48 - 3.99; P < 0.001).
Collectively, these findings underscore the close interrelationship between tumor biology and treatment response in both the breast and axilla.
5. Discussion
The findings of this study demonstrated a strong and clinically meaningful association between breast tumor response and axillary LN clearance following NAC. Patients who achieved a favorable response in the primary breast tumor were significantly more likely to exhibit an axillary nodal response, underscoring the coordinated biological behavior of primary and regional disease compartments under systemic treatment (14). This observation supports the concept that chemosensitivity in the breast is frequently mirrored by treatment effects in the axilla.
The magnitude of the association observed between breast tumor response and axillary LN response was substantial, suggesting that effective eradication of tumor burden in the breast often coincides with nodal downstaging. This observation is consistent with prior reports indicating higher rates of axillary pathologic complete response in patients achieving breast pCR, particularly among biologically aggressive but chemosensitive subtypes (15).
Both breast tumor response and axillary LN response showed significant associations with IHC profiles, highlighting the critical role of tumor biology in determining treatment responsiveness. The findings support the known chemosensitivity of non-luminal tumors. The observed correlations suggest that molecular characteristics not only influence primary tumor shrinkage but also govern nodal sensitivity to systemic therapy. These findings align with existing evidence demonstrating differential response patterns across BC subtypes and support the integration of biological markers into predictive models for treatment response and surgical planning (16-18).
Several limitations should be acknowledged. The retrospective design and the large proportion of missing data for some variables may introduce potential bias. Statistical analysis was limited to univariate chi-square tests and unadjusted OR; the lack of adjustment for potential confounders may have affected the observed associations. Additionally, treatment protocols and surgical practices evolved over the study period, which may have influenced response patterns; however, this historical context may offer insight into biologic concordance between breast and axillary responses. Future prospective studies are warranted to validate these findings.
5.1. Conclusions
In summary, this study demonstrates a strong correlation between breast tumor response and axillary LN clearance following NAC, highlighting the coordinated biological response of primary and regional disease to systemic treatment. Both breast and axillary responses were significantly associated with IHC characteristics, underscoring their prognostic relevance. Prospective validation is required to determine how these associations can be safely translated into management protocols without compromising oncologic outcomes.
