Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Seung Ah Lee; Ki Jo Kim; Do Youn Woen; Su Min Lee; Kawon Oh; Cho Eun Lee; Woong Ki Park; Ji Won Yoo; Dong Seung Shin; Jai Min Ryu; Se Kyung Lee; Byung Joo Chae; Jonghan Yu; Seok Won Kim; Seok Jin Nam; Ji-Yeon Kim; Yeon Hee Park; Eun Young Ko; Eun Sook Ko; Jeong Eon Lee

doi:10.4143/crt.2025.219

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Original Article Breast cancer Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer: Seung Ah Lee¹, Ki Jo Kim¹, Do Youn Woen¹, Su Min Lee¹, Kawon Oh¹, Cho Eun Lee¹, Woong Ki Park¹, Ji Won Yoo¹, Dong Seung Shin¹, Jai Min Ryu¹, Se Kyung Lee¹, Byung Joo Chae¹, Jonghan Yu¹, Seok Won Kim¹, Seok Jin Nam¹, Ji-Yeon Kim², Yeon Hee Park², Eun Young Ko³, Eun Sook Ko³, Jeong Eon Lee¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2026;58(3):780-789.
DOI: https://doi.org/10.4143/crt.2025.219
Published online: July 8, 2025

¹Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

³Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: Jeong Eon Lee, Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: 82-2-3410-3479 E-mail: jeongeon.lee@samsung.com

• Received: February 24, 2025 • Accepted: July 6, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
This study aims to investigate the clinical characteristics, outcomes, and predictors of brain metastases in human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer patients who achieved pathological complete response (pCR) following neoadjuvant chemotherapy (NAC). This research seeks to inform surveillance strategies and optimize management for high-risk subgroups.
Materials and Methods
A retrospective analysis of 1,757 patients (2008-2022) classified them into pCR (n=914) and non-pCR (n=843) groups post-NAC. Collected data included demographics, clinical features, and metastasis parameters. Survival outcomes and brain metastasis predictors were assessed using Kaplan-Meier curves, Cox models, and logistic regression.
Results
Among pCR patients, brain metastases accounted for 54.2% of distant metastases, significantly affecting overall survival (p < 0.001). Median distant metastasis-free survival was shorter for brain metastases (13.4 months) compared to extracranial metastases (31.1 months) in the pCR group (p=0.005). Positive supraclavicular node (SCN) fine needle aspiration (FNA) and clinical N3 (cN3) category were the strongest predictors of brain metastases (SCN FNA: odds ratio [OR], 12.9; p < 0.001; cN3: OR, 12.1; p < 0.001). Multivariable Cox regression analysis revealed that positive SCN FNA and cN3 category were strong predictors of reduced distant metastasis-free survival (SCN FNA: hazard ratio, 2.5; 95% confidence interval [CI], 1.3 to 3.6; p < 0.001; cN3: hazard ratio, 11.3; 95% CI, 4.9 to 33.0; p < 0.001).
Conclusion
This study highlights the challenges of brain metastases in HER2-positive pCR patients, emphasizing the need for tailored therapeutic strategies and enhanced surveillance. High lymph node burden prior to NAC is a significant factor in risk assessment. Therefore, it may be advisable to recommend post-surgery surveillance for high-risk patients.
Key words: HER2-positive breast cancer, Neoadjuvant therapy, Complete response, Brain metastasis

Introduction

Breast cancer is the most common cancer in women around the world [1]. Human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer is well known for its aggressive behavior and high potential for distant metastases, which presents significant treatment challenges [2]. Recent advances in neoadjuvant chemotherapy (NAC), particularly with the introduction of trastuzumab and pertuzumab, have led to significantly improved pathological complete response (pCR) rates [3,4]. Achieving pCR is strongly associated with improved survival, especially in HER2-positive patients [5,6].

However, despite these improvements, a notable subset of patients still develops distant metastases, with the brain being a common and clinically significant site [7]. This highlights the need to understand the mechanisms underlying brain metastases in patients who achieve pCR. Standard HER2-targeted therapies, such as trastuzumab and pertuzumab, have limited ability to penetrate the blood-brain barrier (BBB), leaving residual tumor cells in the central nervous system (CNS) unchecked [8,9]. Studies show that brain metastases are disproportionately more frequent in HER2-positive pCR patients compared to extracranial metastases, underscoring the need for targeted surveillance strategies and therapies for this unmet clinical challenge [7]. Despite increased awareness, surveillance for asymptomatic brain metastases in these patients remains undefined.

This study investigated the clinical characteristics and outcomes of brain metastases in HER2-positive advanced breast cancer patients who achieve pCR after NAC. By analyzing predictors of brain metastases and comparing distant metastasis-free survival (DMFS) and overall survival (OS) between pCR and non-pCR groups, it sought to identify key clinical and pathological factors associated with high-risk patients. Ultimately, we aimed to propose tailored surveillance strategies and provide insights into improving outcomes for this patient population.

Materials and Methods

This retrospective cohort study was conducted at Samsung Medical Center in Seoul, South Korea, and included HER2-positive advanced breast cancer patients who were treated with NAC between 2008 and 2022. A total of 1,804 patients were included in the initial dataset. HER2-positivity was defined according to the American Society of Clinical Oncology/College of American Pathologists guidelines as immunohistochemistry (IHC) 3+, or IHC 2+ with HER2 gene amplification confirmed by fluorescence in situ hybridization or silver in situ hybridization [10]. Eligible patients met the following criteria: (1) diagnosis of HER2-positive breast cancer, including mostly locally advanced disease (clinical stage ≥ T2N1 or T3N0 according to the American Joint Committee on Cancer 8th edition [11]) although a small subset with lower clinical stages (e.g., cT1 or cN0) was also included based on multidisciplinary treatment decisions; (2) completion of NAC; and (3) subsequent curative surgery with pathological assessment of treatment response. Pathologic complete response (pCR) was defined as no residual invasive cancer or ductal carcinoma in situ in both the breast and axillary lymph nodes (ypT0/is ypN0), based on the pathological evaluation of surgical specimens. Patients were excluded if they had received palliative treatment or had incomplete clinical, pathological, or follow-up data.

Patients were stratified into two groups based on their pathological response to NAC: the pCR group (n=914), which included those who achieved complete pathological response in both the breast and axillary lymph nodes, and the non-pCR group (n=843), which included patients with incomplete pathological response in the breast, axillary lymph nodes, or both. The NAC regimens varied across the study period (2008-2022), reflecting changes in clinical practice and drug accessibility. The chemotherapy backbones most commonly included anthracycline plus taxane combinations, anthracycline monotherapy, or 5-fluorouracil, epirubicin, and cyclophosphamide. In terms of HER2-targeted therapy, trastuzumab was administered as a single agent or in combination with pertuzumab (dual blockade), with an increasing trend toward dual therapy use in recent years.

Clinical, survival, demographic, pathological, and metastasis-related data were collected from electronic medical records. Clinical data included age, supraclavicular node (SCN) fine needle aspiration (FNA) results, clinical tumor category (cT), clinical nodal category (cN), hormone receptor (HR) status, and the NAC regimen used. Pathological data included pathological tumor stage, histological subtype, and pCR/non-pCR status, while metastasis data comprised site of metastasis (brain vs. extracranial), time to recurrence, and metastasis-related symptoms. Distant metastasis was defined based on the first documented site of recurrence following curative surgery. In patients with multiple metastatic sites, the location of the initial recurrence—whether brain or extracranial—was used to categorize metastasis type. Survival outcomes were evaluated by DMFS and OS. Clinical N3 category was defined based on imaging studies (e.g., computed tomography [CT], positron emission tomography [PET], magnetic resonance imaging [MRI], or ultrasound) that reported SCN involvement, level 3 axillary lymph node (infraclavicular lymph nodes) involvement, or concurrent involvement of internal mammary lymph nodes and axillary lymph nodes.

Data were analyzed using IBM SPSS Statistics ver. 26 (IBM Corp.) and R Studio ver. 4.1.1 (R Foundation for Statistical Computing). Descriptive statistics were used to summarize demographic and clinical characteristics, with t-tests and chi-square tests used to compare continuous and categorical variables between the pCR and non-pCR groups. Kaplan-Meier survival curves were constructed to evaluate DMFS and OS, stratified by metastasis type, and median DMFS values were presented using boxplots. Cox proportional hazards models were used to identify risk factors for brain metastasis and survival outcomes, while logistic regression was used to identify independent predictors of brain metastasis. Statistical significance was set at p < 0.05, and multivariable analyses were conducted to account for potential confounders, with models built separately for variables like SCN FNA and cN3 to address multicollinearity concerns. In addition, the type of HER2-targeted therapy (dual vs. single) was included as an independent variable in both the logistic regression and Cox models to evaluate its association with brain metastasis.

Results

A total of 1,804 patients were initially evaluated, with 47 patients excluded from the analysis due to treatment with palliative intent or lack of surgical data. The final analysis included 1,757 patients. Among these, 914 patients (52.0%) achieved pCR in both breast and axillary lesions (Fig. 1). Additionally, 42 patients (2.4%) achieved breast pCR but had residual disease in the axillary nodes, while 309 patients (17.6%) did not achieve pCR in either the breast or axillary nodes. A total of 492 patients (28.0%) achieved pCR in the axillary nodes despite residual disease in the breast (Table 1).

The demographic and clinical characteristics of patients are summarized in Table 1. Patients in the pCR group were significantly older (50.6±9.6 years) compared to those in the non-pCR group (49.2±10.2 years, p=0.003). Menopause status also differed significantly between the two groups, with a higher proportion of postmenopausal women in the pCR group (54.1%) compared to the non-pCR group (44.0%, p < 0.001). Clinical tumor (T) and nodal (N) categories showed notable differences between groups. More advanced clinical N3 category was observed in non-pCR patients (19.6%) compared to pCR patients (11.8%, p < 0.001). Dual HER2-targeted therapy was administered more frequently in the pCR group compared to the non-pCR group, with 79.3% of pCR patients receiving dual therapy versus 59.7% of non-pCR patients (p < 0.001). This reflects a higher utilization of dual HER2-targeted therapy, including trastuzumab and pertuzumab, among patients achieving pCR. In contrast, single-agent HER2-targeted therapy, predominantly trastuzumab monotherapy, was less commonly associated with achieving pCR. Among pCR patients receiving single-agent therapy, trastuzumab monotherapy was used in 138 out of 142 cases, with pertuzumab monotherapy observed in only four cases. Similarly, in the non-pCR group, 194 of 199 patients receiving single therapy were treated with trastuzumab monotherapy, while pertuzumab monotherapy was used in only five cases.

Distant metastases were observed in 2.6% (24/914) of the pCR group, with brain metastases comprising 54.2% (13/24) of these cases. In the non-pCR group, distant metastases occurred more frequently at 9.7% (82/843), but brain metastases accounted for only 13.4% (11/82) of these cases (Fig. 2A). In the pCR group, OS was significantly worse in patients with brain metastases compared to those with extracranial metastases or no metastases (p < 0.001) (Fig. 2B).

In the pCR group, brain metastases were associated with significantly shorter DMFS compared to extracranial metastases, with a median of 13.4 months versus 31.1 months (p=0.005) (Fig. 3). Kaplan-Meier curves demonstrated distinct separation between these groups, emphasizing the impact of brain metastases on DMFS. In contrast, the non-pCR group showed no significant difference in DMFS between brain and extracranial metastases, with both having a median of 15.8 months (p=0.88). The Kaplan-Meier survival curves overlapped, indicating no meaningful distinction between these metastasis sites.

Multivariable logistic regression analysis identified positive SCN FNA as the strongest predictor of brain metastases, with an odds ratio (OR) of 12.9 (95% confidence interval [CI], 3.7 to 45.0; p < 0.001) (Table 2). Clinical N3 (cN3) category was also a significant predictor, with an OR of 12.1 (95% CI, 4.1 to 36.2; p < 0.001). Neither patient age nor HR status showed a significant association with brain metastasis in this analysis. Similarly, the type of HER2-targeted therapy (dual vs. single) was not significantly associated with brain metastasis in either the logistic regression (OR, 0.9; p=0.909) or Cox model (HR, 1.0; p=0.981), indicating no independent effect.

Cox regression analysis revealed that positive SCN FNA was associated with significantly shortened DMFS, with a multivariable hazard ratio of 2.5 (95% CI, 1.3 to 3.6; p < 0.001). cN3 category also emerged as a significant factor, with a multivariable hazard ratio of 11.3 (95% CI, 4.9 to 33.0; p < 0.001) (Table 3).

Discussion

This study highlights a paradoxical finding in HER2-positive breast cancer patients who achieved pCR after NAC: while their overall risk of distant metastasis was lower than in non-pCR patients, the proportion of brain metastases was disproportionately high. This pattern suggests that the CNS may remain a sanctuary site for micrometastatic disease, even in the context of excellent systemic response. The association between pCR and favorable outcomes is well established [12], yet the present findings underscore that pCR does not equate to uniform protection across all metastatic sites. In particular, brain metastases in the pCR group were associated with markedly poor survival outcomes, consistent with the known challenges of treating CNS disease in HER2-positive breast cancer. These results highlight the need for CNS-directed surveillance and treatment strategies tailored to this unique high-risk subgroup.

Notably, among pCR patients, those with brain metastases had markedly worse outcomes (median DMFS, 13.4 months) compared to those with extracranial metastases (31.1 months), suggesting a substantial survival disadvantage of approximately 17.7 months. This contrast was not observed in the non-pCR group, where DMFS was similarly poor for both brain and extracranial metastases (15.8 months each; p=0.88), indicating an overall aggressive disease course. This pattern may reflect the predominance of early systemic progression to visceral organs—such as the lung, liver, and bone—rather than intrinsic metastatic preference for the CNS. Accordingly, the proportion of brain metastases may appear elevated in the pCR group due to the effective suppression of extracranial metastases by NAC and HER2-targeted therapy. In contrast, the non-pCR group exhibited a broader metastatic profile, with a higher frequency of visceral organ involvement. Although some patients had concurrent brain and extracranial metastases, classification of metastasis in this study was based on the initial site of recurrence to reflect early metastatic behavior. These findings suggest distinct metastatic pathways depending on treatment response and underscore the need to evaluate the full metastatic spectrum when interpreting patient prognosis.

Additionally, SCN FNA positivity and cN3 status emerged as significant predictors of brain metastases. SCN FNA positivity, in particular, showed the strongest association with reduced OS, highlighting its prognostic utility in identifying high-risk patients. These observations highlight the need to incorporate SCN FNA and cN3 category into surveillance planning and to optimize care for patients at high risk of CNS metastases [13]. In line with this, current clinical guidelines such as those from European Society for Medical Oncology and National Comprehensive Cancer Network suggest considering CNS surveillance in high-risk patients, although routine brain imaging in asymptomatic individuals remains controversial. Incorporating such risk-stratified approaches may help identify CNS involvement at an earlier stage in select subgroups [14,15].

In our cohort, dual HER2-targeted therapy was more commonly used in patients who achieved pCR with 79.3% receiving dual blockade compared to 59.6% in the non-pCR group (p < 0.001). While this finding is consistent with prior studies reporting higher pCR rates with dual blockade [16], our study did not include a separate multivariable analysis to evaluate this association. Compared to the superior ability of dual HER2-targeted therapy to block HER2 signaling and achieve comprehensive systemic tumor control, single-agent HER2-targeted therapy was significantly less effective, with nearly all patients in this group receiving trastuzumab monotherapy—specifically, 138 of 142 pCR cases and 194 of 199 non-pCR cases. These findings support the continued use of dual HER2 blockade as a more effective standard of care for achieving systemic tumor control [17].

However, dual blockade was not independently associated with a reduced risk of brain metastases in our multivariable analysis. This indicates that while dual therapy enhances systemic and locoregional tumor control, additional strategies are needed to address the risk of CNS involvement, particularly in high-risk patients. While HR positivity (i.e., triple-positive subtype) was not a significant independent predictor of brain metastases in our analysis, this may reflect the biological and therapeutic heterogeneity observed within triple-positive breast cancer, which can influence metastatic patterns and treatment responses. Additionally, a subset of patients did not receive any HER2-targeted therapy. Due to substantial heterogeneity in treatment regimens and limited sample size, this group was excluded from multivariable models. Nonetheless, descriptive analyses showed that these patients had lower pCR rates and a higher frequency of distant metastases.

Emerging therapies capable of crossing the BBB, such as trastuzumab deruxtecan (T-Dxd) and tucatinib, may offer promising solutions for addressing residual CNS disease [18]. By targeting micrometastases in the brain, these agents have the potential to significantly reduce the risk of brain metastases and improve OS outcomes for HER2-positive patients [19-21]. There is also a strong rationale for evolving surveillance strategies to incorporate routine brain imaging and symptom monitoring for high-risk patients, particularly those with high lymph node burden or other advanced nodal features, such as SCN FNA positivity or cN3 category. These characteristics are strongly associated with a higher risk of distant metastases, including CNS involvement. Among the patients with brain metastases in this study, symptoms such as headache (9 patients, 37.5%), dizziness (6 patients, 25%), and nausea/vomiting (5 patients, 20.8%) were commonly reported. A full list of neurologic symptoms from all 24 patients with brain metastases is presented in S1 Table. Recognizing these symptom patterns in clinical practice could facilitate earlier detection and intervention, as similar symptom profiles have been reported in previous studies of brain metastasis in HER2-positive breast cancer [8,22,23]. Furthermore, integrating regular brain MRI with advanced diagnostics like PET-CT, alongside BBB-penetrant therapies, could significantly improve early detection and contribute to better survival outcomes [24,25].

Based on the median DMFS of 13.4 months observed in this study, proactive MRI screening during the first 1-2 years after surgery is recommended to identify brain metastases early and improve patient management. By addressing these gaps in treatment and surveillance, this study underscores the critical importance of personalized approaches to managing HER2-positive breast cancer, particularly for high-risk or pCR patient populations.

While this study provides valuable insights into HER2-positive breast cancer management, certain limitations should be considered when interpreting the findings. As a retrospective study, the analysis is subject to inherent biases, such as potential patient selection bias and incomplete data collection. These factors could influence the generalizability of the results, and future prospective studies are necessary to confirm and expand upon the observed trends. Another consideration is the feasibility of implementing routine brain MRI for high-risk patients. While early detection offers clear clinical benefits, the adoption of such strategies may vary due to differences in healthcare systems, insurance, and resource availability. By acknowledging these challenges, this study lays the groundwork for refining surveillance strategies and developing tailored therapeutic approaches that can better address the needs of HER2-positive breast cancer patients, particularly those at high risk of CNS involvement.

This study investigates the clinical characteristics and outcomes of brain metastases in HER2-positive advanced breast cancer patients who achieve pCR after NAC. The findings highlight that brain metastases account for over 50% of all distant metastases in pCR patients, underscoring a significant challenge in managing this population. Despite achieving pCR, the risk of brain metastases remains high, emphasizing the need for tailored surveillance strategies and CNS-specific therapies. The study also suggested key clinical and pathological factors, such as positive SCN FNA and cN3 category, which are strongly associated with worse outcomes in both DMFS and OS.

These results directly address the study’s aim to identify high-risk patients and improve surveillance strategies. The survival difference observed in pCR patients with brain metastases, compared to those with extracranial metastases or no metastases, highlights the need for targeted strategies to improve outcomes. Incorporating routine brain MRI, symptom monitoring, and emerging CNS-targeted therapies could help mitigate the risks of brain metastases and improve survival outcomes.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2025-219_S1_Table.pdf

NOTES

Ethical Statements

Ethical approval for the study was granted by the Institutional Review Board (IRB) of Samsung Medical Center (IRB number: 2025-02-124), and the need for informed consent was waived due to the retrospective nature of the study. All patient data were anonymized and de-identified to protect patient privacy, in compliance with ethical standards outlined in the Declaration of Helsinki.

Author Contributions

Conceived and designed the analysis: Lee SA, Lee JE.

Collected the data: Lee SA, Kim KJ, Woen DY, Lee SM, Oh K, Lee CE, Park WK, Yoo JW, Shin DS, Lee JE.

Contributed data or analysis tools: Ryu JM, Lee SK, Chae BJ, Yu J, Kim SW, Nam SJ, Kim JY, Park YH, Ko EY, Ko ES, Lee JE.

Performed the analysis: Lee SA.

Wrote the paper: Lee SA, Lee JE.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Fig. 1.

Flowchart of patient selection and group classification. The pathological complete response (pCR) group has a lower overall rate of distant metastases (2.6%) compared to the non-pCR group (9.7%), which aligns with the general understanding that pCR is associated with better outcomes. However, the proportion of brain metastases within distant metastases is higher in the pCR group (54.2%, 13/24) compared to the non-pCR group (13.4%, 11/82), highlighting the unique challenge of brain metastases in pCR patients. NAC, neoadjuvant chemotherapy.

Fig. 2.

(A) Comparison of brain and extracranial metastasis distributions in pathological complete response (pCR) and non-pCR groups (B) Overall survival stratified by metastasis location in pCR patients. Metastasis sites are classified based on the initial location of distant metastasis. The histogram compares the frequencies of brain metastases and extracranial metastases as the first sites of distant metastasis in human epidermal growth factor receptor 2 (HER2)–positive breast cancer patients with or without pCR. The classification is based on the initial location where metastases were observed, highlighting the distinct patterns of metastatic spread in pCR and non-pCR groups. The Kaplan-Meier survival curve highlights the variation in overall survival among patients with pCR, stratified by the location of first metastasis. The comparison underscores the significant survival disadvantage associated with brain metastases relative to extracranial metastases and the absence of metastasis. The corresponding number at risk table provides further detail on patient distribution over time.

Fig. 3.

Kaplan-Meier survival curve for distant metastasis–free survival stratified by metastasis location in pathological complete response (pCR) (A) and in non-pCR (B) groups. Boxplots showing distant metastasis–free survival distributions by metastasis location in (pCR) (C) and in non-pCR (D) groups. Panel A shows that in the pCR group, patients with brain metastases had significantly shorter distant metastasis–free survival compared to those with extracranial metastases (p=0.005), indicating worse outcomes for brain metastases. Panel B demonstrates no significant difference in distant metastasis–free survival between brain and extracranial metastases in the non-pCR group (p=0.88), with survival curves closely aligned. Panel C shows that in the pCR group, brain metastases had a shorter median distant metastasis–free survival (13.4 months; range, 5.3 to 29.2) compared to extracranial metastases (31.1 months; range, 6.0 to 48.4). Panel D demonstrates that in the non-pCR group, distant metastasis–free survival was similar between brain metastases (15.8 months; range, 1.9 to 74.3) and extracranial metastases (15.8 months; range, 0.1 to 88.9).

Table 1.

Patients’ demographics comparison between pCR status

Variable	pCR in breast and axillary (n=914)	Non-pCR in breast or axillary (n=843)	p-value
Age (yr)	50.6±9.6	49.2±10.2	0.003
Menopause status
Premenopause	420 (46.0)	471 (55.9)	< 0.001
Postmenopause	494 (54.1)	371 (44.0)
Unknown	-	1 (0.1)
Clinical T category
cT0	3 (0.3)	-	0.004
cT1	49 (5.4)	35 (4.2)
cT2	608 (66.5)	526 (62.4)
cT3	211 (23.1)	225 (26.7)
cT4	43 (4.7)	55 (6.5)
Unknown	-	2 (0.2)
Clinical N category
cN0	242 (26.5)	176 (20.9)	< 0.001
cN1	368 (40.3)	296 (35.1)
cN2	196 (21.4)	206 (24.4)
cN3^a)	108 (11.8)	165 (19.6)
SCN FNA
Negative	880 (96.3)	780 (92.5)	< 0.001
Positive	34 (3.7)	63 (7.5)
Target therapy type
Dual^b)	725 (79.3)	502 (59.6)	< 0.001
Single^c)	142 (15.5)	199 (23.6)
No target therapy^d)	47 (5.1)	142 (16.8)
Pathologic T category
ypT0	328 (35.9)	26 (3.1)	< 0.001
ypTis	586 (64.1)	16 (2.0)
ypT1	-	592 (70.2)
ypT2	-	152 (18.0)
ypT3	-	53 (6.3)
ypT4	-	4 (0.5)
Pathologic N category
ypN0	914 (100)	492 (58.4)	< 0.001
ypN1	-	243 (28.8)
ypN2	-	65 (7.7)
ypN3	-	43 (5.1)
HR status
Positive	318 (34.8)	475 (56.4)	< 0.001
Negative	595 (65.1)	367 (43.5)
Unknown	1 (0.1)	1 (0.1)

Values are presented as mean±standard deviation or number (%). Percentages may not total 100% due to rounding. For age, both groups followed a normal distribution. A t-test was performed. For categorical variables, Pearson’s chi-square test, Fisher’s exact test, or Wilcoxon-Mann-Whitney test were conducted. “Unknown” values were included as a separate category to maintain data completeness. “-” indicates no observed cases for the corresponding category. FNA, fine needle aspiration; HR, hormone receptor; pCR, pathological complete response.

^a) cN3 is defined as suspicious findings on imaging involving supraclavicular lymph node (SCN), infraclavicular lymph node, or concurrent internal mammary lymph node and axillary lymph nodes,

^b) Dual therapy refers to the combined use of trastuzumab and pertuzumab as part of the treatment regimen,

^c) Single therapy includes trastuzumab or pertuzumab used alone,

^d) No targeted therapy indicates patients who received cytotoxic chemotherapy alone without human epidermal growth factor receptor 2 (HER2)–targeted agents (e.g., anthracycline-based or taxane-based regimens).

Table 2.

Univariable and multivariable logistic regression analysis for predicting brain metastasis in pCR group

Variable	Univariable (95% CI)	p-value	Multivariable OR (95% CI)	p-value
Age (per 1-year increase)	1.0 (0.9-1.0)	0.567	1.0 (0.9-1.0)	0.636
SCN FNA
Negative	1	-	1	-
Positive	11.6 (3.4-39.1)	< 0.001	12.9 (3.7-45.0)	< 0.001
cN3
Non-cN3	1	-	1	-
cN3	10.7 (3.6-31.3)	< 0.001	12.1 (4.1-36.2)	< 0.001
Target therapy
Single	1	-	1	-
Dual	0.7 (0.2-2.6)	0.608	0.9 (0.2-3.6)	0.909
HR
Negative	1	-	1	-
Positive	2.4 (0.8-7.0)	0.109	2.5 (0.8-7.7)	0.110

Reference groups are indicated as ‘1’ for odds ratio (OR). All other groups are compared against the reference group. Variables such as cN1, cN2, cT categories (cT1-cT4) were included in the analysis but did not show statistical significance (p > 0.05) or presented wide confidence intervals (CIs) indicating insufficient precision. These variables were excluded from the final table for clarity but are available upon request or in the supplementary materials. OR values for supraclavicular lymph node (SCN) fine needle aspiration (FNA) and clinical N3 (cN3) were obtained from separate models due to multicollinearity concerns. SCN FNA was analyzed excluding cN3 to assess its independent effect, and vice versa. This approach ensures that the odds ratios reflect the unique contribution of each variable. Patients who did not receive human epidermal growth factor receptor 2 (HER2)–targeted therapy (“No targeted therapy”) were excluded from multivariable models due to heterogeneity in treatment regimens and limited sample size. HR, hormone receptor; pCR, pathological complete response.

Table 3.

Univariable and multivariable Cox proportional hazards regression analysis for predicting DMFS in pCR group

Variable	Univariable hazard ratio (95% CI)	p-value	Multivariable hazard ratio (95% CI)	p-value
Age (per 1-year increase)	1.0 (0.9-1.0)	0.617	1.0 (0.9-1.0)	0.722
SCN FNA
Negative	1	-	1	-
Positive	2.4 (1.2-3.5)	< 0.001	2.5 (1.3-3.6)	< 0.001
cN3
Non-cN3	1	-	1	-
cN3	2.3 (1.2-3.4)	< 0.001	11.3 (4.9-33.0)	< 0.001
Target therapy
Single	1	-	1	-
Dual	0.8 (0.2-2.8)	0.704	1.0 (0.3-3.7)	0.981
HR
Negative	1	-	1	-
Positive	2.3 (0.8-6.7)	0.118	2.4 (0.8-6.9)	0.112

Reference groups are indicated as ‘1’ for hazard ratio. All other groups are compared against the reference group. Variables such as cN1, cN2, cT categories (cT1-cT4) were included in the analysis but did not show statistical significance (p > 0.05) or presented wide confidence intervals (CIs) indicating insufficient precision. These variables were excluded from the final table for clarity but are available upon request or in the supplementary materials. Hazard ratio values for supraclavicular lymph node (SCN) fine needle aspiration (FNA) and clinical N3 (cN3) were obtained from separate models due to multicollinearity concerns. SCN FNA was analyzed excluding cN3 to assess its independent effect, and vice versa. This approach ensures that the hazard ratios reflect the unique contribution of each variable. Patients who did not receive human epidermal growth factor receptor 2 (HER2)–targeted therapy (“No targeted therapy”) were excluded from multivariable models due to heterogeneity in treatment regimens and limited sample size. DMFS, distant metastasis–free survival; HR, hormone receptor; pCR, pathological complete response.

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Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Cancer Res Treat. 2026;58(3):780-789. Published online July 8, 2025

DOI: https://doi.org/10.4143/crt.2025.219

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
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Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Fig. 1. Flowchart of patient selection and group classification. The pathological complete response (pCR) group has a lower overall rate of distant metastases (2.6%) compared to the non-pCR group (9.7%), which aligns with the general understanding that pCR is associated with better outcomes. However, the proportion of brain metastases within distant metastases is higher in the pCR group (54.2%, 13/24) compared to the non-pCR group (13.4%, 11/82), highlighting the unique challenge of brain metastases in pCR patients. NAC, neoadjuvant chemotherapy.

Fig. 2. (A) Comparison of brain and extracranial metastasis distributions in pathological complete response (pCR) and non-pCR groups (B) Overall survival stratified by metastasis location in pCR patients. Metastasis sites are classified based on the initial location of distant metastasis. The histogram compares the frequencies of brain metastases and extracranial metastases as the first sites of distant metastasis in human epidermal growth factor receptor 2 (HER2)–positive breast cancer patients with or without pCR. The classification is based on the initial location where metastases were observed, highlighting the distinct patterns of metastatic spread in pCR and non-pCR groups. The Kaplan-Meier survival curve highlights the variation in overall survival among patients with pCR, stratified by the location of first metastasis. The comparison underscores the significant survival disadvantage associated with brain metastases relative to extracranial metastases and the absence of metastasis. The corresponding number at risk table provides further detail on patient distribution over time.

Fig. 3. Kaplan-Meier survival curve for distant metastasis–free survival stratified by metastasis location in pathological complete response (pCR) (A) and in non-pCR (B) groups. Boxplots showing distant metastasis–free survival distributions by metastasis location in (pCR) (C) and in non-pCR (D) groups. Panel A shows that in the pCR group, patients with brain metastases had significantly shorter distant metastasis–free survival compared to those with extracranial metastases (p=0.005), indicating worse outcomes for brain metastases. Panel B demonstrates no significant difference in distant metastasis–free survival between brain and extracranial metastases in the non-pCR group (p=0.88), with survival curves closely aligned. Panel C shows that in the pCR group, brain metastases had a shorter median distant metastasis–free survival (13.4 months; range, 5.3 to 29.2) compared to extracranial metastases (31.1 months; range, 6.0 to 48.4). Panel D demonstrates that in the non-pCR group, distant metastasis–free survival was similar between brain metastases (15.8 months; range, 1.9 to 74.3) and extracranial metastases (15.8 months; range, 0.1 to 88.9).

Fig. 1.

Fig. 2.

Fig. 3.

Impact of High Lymph Node Burden on Brain Metastases in Patients Who Achieved Pathological Complete Response after Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Variable	pCR in breast and axillary (n=914)	Non-pCR in breast or axillary (n=843)	p-value
Age (yr)	50.6±9.6	49.2±10.2	0.003
Menopause status
Premenopause	420 (46.0)	471 (55.9)	< 0.001
Postmenopause	494 (54.1)	371 (44.0)
Unknown	-	1 (0.1)
Clinical T category
cT0	3 (0.3)	-	0.004
cT1	49 (5.4)	35 (4.2)
cT2	608 (66.5)	526 (62.4)
cT3	211 (23.1)	225 (26.7)
cT4	43 (4.7)	55 (6.5)
Unknown	-	2 (0.2)
Clinical N category
cN0	242 (26.5)	176 (20.9)	< 0.001
cN1	368 (40.3)	296 (35.1)
cN2	196 (21.4)	206 (24.4)
cN3^a)	108 (11.8)	165 (19.6)
SCN FNA
Negative	880 (96.3)	780 (92.5)	< 0.001
Positive	34 (3.7)	63 (7.5)
Target therapy type
Dual^b)	725 (79.3)	502 (59.6)	< 0.001
Single^c)	142 (15.5)	199 (23.6)
No target therapy^d)	47 (5.1)	142 (16.8)
Pathologic T category
ypT0	328 (35.9)	26 (3.1)	< 0.001
ypTis	586 (64.1)	16 (2.0)
ypT1	-	592 (70.2)
ypT2	-	152 (18.0)
ypT3	-	53 (6.3)
ypT4	-	4 (0.5)
Pathologic N category
ypN0	914 (100)	492 (58.4)	< 0.001
ypN1	-	243 (28.8)
ypN2	-	65 (7.7)
ypN3	-	43 (5.1)
HR status
Positive	318 (34.8)	475 (56.4)	< 0.001
Negative	595 (65.1)	367 (43.5)
Unknown	1 (0.1)	1 (0.1)

Variable	Univariable (95% CI)	p-value	Multivariable OR (95% CI)	p-value
Age (per 1-year increase)	1.0 (0.9-1.0)	0.567	1.0 (0.9-1.0)	0.636
SCN FNA
Negative	1	-	1	-
Positive	11.6 (3.4-39.1)	< 0.001	12.9 (3.7-45.0)	< 0.001
cN3
Non-cN3	1	-	1	-
cN3	10.7 (3.6-31.3)	< 0.001	12.1 (4.1-36.2)	< 0.001
Target therapy
Single	1	-	1	-
Dual	0.7 (0.2-2.6)	0.608	0.9 (0.2-3.6)	0.909
HR
Negative	1	-	1	-
Positive	2.4 (0.8-7.0)	0.109	2.5 (0.8-7.7)	0.110

Variable	Univariable hazard ratio (95% CI)	p-value	Multivariable hazard ratio (95% CI)	p-value
Age (per 1-year increase)	1.0 (0.9-1.0)	0.617	1.0 (0.9-1.0)	0.722
SCN FNA
Negative	1	-	1	-
Positive	2.4 (1.2-3.5)	< 0.001	2.5 (1.3-3.6)	< 0.001
cN3
Non-cN3	1	-	1	-
cN3	2.3 (1.2-3.4)	< 0.001	11.3 (4.9-33.0)	< 0.001
Target therapy
Single	1	-	1	-
Dual	0.8 (0.2-2.8)	0.704	1.0 (0.3-3.7)	0.981
HR
Negative	1	-	1	-
Positive	2.3 (0.8-6.7)	0.118	2.4 (0.8-6.9)	0.112

Table 1. Patients’ demographics comparison between pCR status

cN3 is defined as suspicious findings on imaging involving supraclavicular lymph node (SCN), infraclavicular lymph node, or concurrent internal mammary lymph node and axillary lymph nodes,

Dual therapy refers to the combined use of trastuzumab and pertuzumab as part of the treatment regimen,

Single therapy includes trastuzumab or pertuzumab used alone,

No targeted therapy indicates patients who received cytotoxic chemotherapy alone without human epidermal growth factor receptor 2 (HER2)–targeted agents (e.g., anthracycline-based or taxane-based regimens).

Table 2. Univariable and multivariable logistic regression analysis for predicting brain metastasis in pCR group

Table 3. Univariable and multivariable Cox proportional hazards regression analysis for predicting DMFS in pCR group