The prognostic value of tumor quadrant in breast cancer patients achieving pathologic complete response: a retrospective cohort study from the Sir Run Run Shaw Hospital database

Introduction

Breast cancer is the most common malignancy among women worldwide. Globally, newly diagnosed breast cancer cases account for approximately 11.6% of all cancer cases, and breast cancer-related deaths constitute about 6.9% of all cancer-related mortality (1). Neoadjuvant therapy (NAT) serves as a key treatment strategy for patients with locally advanced breast cancer or early-stage breast cancer with high-risk features. It is primarily indicated for patients who are initially inoperable (e.g., those with inflammatory breast cancer; large tumor volume or cN2; cN3; cT4) to achieve tumor downstaging and allow subsequent surgical resection. Additionally, NAT may be selectively offered to patients with cT2N0 or higher-stage disease or clinically node-positive triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as well as to those with a relatively large tumor-to-breast volume ratio who strongly desire breast-conserving surgery (2).

Currently, NAT has become a standard treatment approach for locally advanced or specific molecular subtypes of breast cancer, and the significance of pathologic complete response (pCR) has become increasingly prominent, particularly for aggressive subtypes such as HER2-positive (3) and TNBC (4). NAT is not only a means of downstaging and enabling breast conservation but also functions as an “in vivo chemosensitivity assay” for evaluating drug responsiveness and guiding comprehensive treatment planning. In these subtypes, the relatively high pCR rates (reaching 30% to 60%) (5) make it a valuable surrogate endpoint and a window for clinical investigation.

However, both clinical practice and research have revealed a critical “paradox”: although pCR is a strong predictor of improved survival, it does not equate to “cure”. Among all patients who achieve pCR, a substantial proportion (studies suggest approximately 10–20% within 10 years) still experiences disease recurrence (6). This phenomenon underscores the limitations of current understanding: the “pCR” status itself is heterogeneous, and the underlying risk of minimal residual disease varies among individuals. Therefore, simply reaching the endpoint of “achieving pCR” is no longer sufficient to meet the demands of precision medicine. The current core challenge lies in further distinguishing high-risk subgroups among this “prognostically favorable” population in real world evidence. Although domestic and international studies have suggested that factors such as higher tumor burden (cT, cN, cStage), molecular subtype (e.g., HER2 status), residual ductal carcinoma in situ, and the presence of circulating tumor DNA (ctDNA) may be associated with poor prognosis after pCR (7-14), and adverse prognostic factors may differ across molecular subtypes. Additionally, studies based on large-scale patient data from the Surveillance, Epidemiology, and End Results (SEER) database have explored poor prognostic factors (15,16).

However, a conclusive consensus on adverse prognostic factors for pCR patients remains lacking. Regarding tumor quadrant, the existing literature presents conflicting findings. Some studies suggest that tumors located in the upper outer quadrant have a favorable prognosis and medial or central tumors as having worse survival, possibly due to older age at diagnosis, higher T stage, and greater likelihood of lymph node metastasis (17,18). Most recently, Jariri et al. found that the upper outer quadrant achieved favorable 5-year relative survival (94.1%), though not the highest among quadrants (upper inner: 95.3%) (19). These discrepancies across studies likely arise from differences in study populations (e.g., all breast cancer patients vs. specific subtypes), variable definitions of tumor location, and incomplete adjustment for confounders such as treatment and response to treatment. Importantly, no study has specifically examined the prognostic role of tumor quadrant in the pCR setting, where the absence of residual disease may unmask the pure effect of anatomical location on recurrence risk, independent of treatment response.

Although key clinical indicators play a well-established role in pretreatment prognostic prediction, their value in defining risk after pCR has not been fully elucidated. Moreover, the prognostic significance of many clinical factors—such as tumor quadrant—remains controversial, and their role specifically in patients who achieve pCR has been scarcely investigated. Therefore, this retrospective study aims to explore potential prognostic factors, particularly tumor quadrant, in pCR patients, with the goal of generating hypotheses for risk stratification and advancing clinical practice beyond the binary assessment of pCR toward more refined precision medicine. We present this article in accordance with the REMARK reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0095/rc).

Methods

Study population and event definitions for pCR patients

This study included a total of 293 patients from the Sir Run Run Shaw Hospital Department of Surgical Oncology database, diagnosed between 2005 and 2024, who achieved pCR following NAT. pCR was defined as the absence of residual invasive carcinoma in both the breast and ipsilateral axillary lymph nodes (ypT0/Tis ypN0). The patient characteristics included a diagnosis of unilateral breast cancer, female sex, and no histopathological evidence of malignant cells in both the breast and axillary lymph nodes post-surgery. After surgery, patients were followed up annually. Whenever feasible, recurrence or metastasis was confirmed by pathology (core needle biopsy or surgical excision). If imaging suggested recurrence or metastasis but the patient was unable to undergo surgery or refused biopsy, the diagnosis was confirmed by imaging alone. Based on the expression status of hormone receptor (HR) and HER2, breast cancer patients were classified into three subtypes: luminal (HR-positive/HER2-negative), HER2-positive (HR-negative/HER2-positive and HR-positive/HER2-positive), and TNBC (HR-negative/HER2-negative). A Ki-67 index of ≥20% was defined as high proliferative activity, while <20% was defined as low proliferative activity. A progression event was defined as any occurrence of local recurrence, distant metastasis, or death, which can occur in the same patient.

Clinical characteristics description

Baseline clinicopathological characteristics were compared between pCR patients with and without subsequent disease progression. Categorical variables were presented as frequencies and percentages, and compared using the Chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were tested for normality using the Shapiro-Wilk test; those with normal distribution were expressed as mean ± standard deviation (SD) and compared using Student’s t-test, while non-normally distributed variables were expressed as median with interquartile range (IQR) and compared using the Wilcoxon rank-sum test. All baseline comparisons were performed using the tableone package in R.

Survival analysis and univariable Cox regression

Event-free survival (EFS) was defined as the time from pCR confirmation to the first occurrence of disease progression (recurrence, metastasis, or death). Patients without events were censored at the last follow-up.

For each variable, univariable Cox proportional hazards regression was performed using the survival package. Hazard ratios and their 95% confidence intervals (CI) were calculated. For categorical variables, the overall P value was derived from the likelihood ratio test, while P values for individual levels (compared to the reference category) were obtained from Wald tests. Variables with sparse events or zero events in certain subgroups were handled by merging clinically meaningful categories; hazard ratios that remained inestimable after merging were denoted as not estimable (NE) in the results.

Firth penalized Cox regression

To address the issue of monotone likelihood (complete separation) caused by zero events in the upper outer quadrant subgroup, a sensitivity analysis was performed using Firth’s penalized Cox regression. This method applies a penalty to the likelihood function to provide finite and stable hazard ratio estimates even in the presence of sparse data or complete separation. The analysis was conducted using the “coxphf” package in R, with profile likelihood confidence intervals and P values.

Kaplan-Meier curves and survival rate estimation

Kaplan-Meier curves were generated to visualize EFS differences across tumor quadrants, the only variable showing statistical significance in univariable analysis. The log-rank test was used to compare survival distributions among groups.

Five-year and 10-year EFS rates with 95% confidence intervals were estimated from the Kaplan-Meier survival function at 60 and 120 months, respectively. Confidence intervals for survival probabilities were calculated using the log-log transformation. The number of patients at risk (n.risk) and cumulative events (n.event) at each time point were also reported to indicate the stability of the estimates.

Statistical analysis

All statistical analyses were performed using R software (version 4.x). A two-tailed P value <0.05 was considered statistically significant.

Results

Baseline characteristics and univariable analysis of patients achieving pCR

This study included patients diagnosed between 2005 and 2024 from the Sir Run Run Shaw Hospital Department of Surgical Oncology database who received NAT. The cohort consisted of 528 HER2-positive, 557 TNBC, and 688 luminal breast cancer cases. The pCR rates were 33.5% in the HER2-positive subtype, 6.1% in the luminal subtype, and 13.3% in the TNBC subtype. As shown in Table 1, a total of 293 patients (16.5%) achieved pCR. Among them, 277 patients did not experience disease progression events (local recurrence, distant metastasis, or death), while 16 patients (5.4%) did, including 5 with recurrence, 10 with metastasis, and 8 deaths. The median follow-up time was 41 months for all three groups (the entire cohort, progression-free group, and progression group). Median progression-free survival was NE for the overall cohort due to the low event rate (only 16 of 293 patients progressed). For the 16 patients who progressed, the median progression-free time was 24 months (IQR, 11–34 months). As depicted in Figure 1, patients who experienced disease progression had significantly worse overall survival compared to those who did not (P<0.001). Treatment patterns by molecular subtype and era are summarized in Table S1.

Figure 1 Kaplan-Meier plots for OS of patients without progression events and patients with progression events. OS, overall survival.

Table 1 presents the clinical baseline characteristics of the study population stratified by the occurrence of progressive events, along with univariate analysis. Univariate analysis revealed that, aside from the Ki-67 index, no other baseline variables demonstrated statistical significance in relation to progressive events. In baseline characteristic comparisons between pCR patients with and without subsequent disease progression, Ki-67 was the only variable that differed significantly between the two groups (P<0.05). In the progression group, the ratio of high to low Ki-67 expression was markedly higher than in the progression-free group
(10-fold vs. 4.73-fold). However, in univariable Cox regression analysis for EFS, Ki-67 did not retain statistical significance (overall P=0.18; Table 2), highlighting the importance of accounting for follow-up time and censoring in prognostic assessment.

Univariable Cox analysis and survival outcomes by tumor quadrant

Univariable Cox regression analysis revealed that tumor quadrant was the only variable significantly associated with EFS (overall P=0.01 by likelihood ratio test, Table 2). Patients with tumors in the outer upper quadrant had the most favorable outcomes (log-rank P=0.06, Figure 2), with a hazard ratio that could not be estimated (NE) due to zero events occurred in this subgroup. In contrast, patients with tumors in the outer lower and inner upper quadrants showed trends toward worse prognosis, with hazard ratios of 1.21 (95% CI: 0.32–4.50) and 1.04 (95% CI: 0.12–9.30), respectively, although these did not reach statistical significance due to the limited number of events. A sensitivity analysis using Firth’s penalized Cox regression was performed to address the zero-event issue, and the results were consistent with the primary univariable analysis (outer upper quadrant hazard ratio =0.022, 95% CI: 0.00015–0.414; Table S2).

Figure 2 Kaplan-Meier plots for EFS of patients with different tumour primary quadrant. Kaplan-Meier plots for EFS of patients with different tumour primary quadrant including inner upper, inner lower, others, upper outer, upper lower, central inner/outer and central upper/lower. EFS, event-free survival.

Table 3 presents the 5-year and 10-year EFS rates for each tumor quadrant, estimated by the Kaplan-Meier method. The outer upper quadrant demonstrated the best prognosis, with 100% EFS at both 5 and 10 years. The outer lower quadrant had the lowest 5-year EFS rate (83.1%; 95% CI: 70.3–98.3%), while the inner upper quadrant showed the lowest 10-year EFS rate (70.9%; 95% CI: 44.8–100%). The corresponding Kaplan-Meier curves are shown in Figure 2, illustrating the distinct survival patterns across quadrants (log-rank P=0.06). Due to the small number of events, some subgroups had wide confidence intervals, and estimates should be interpreted with caution.

Discussion

The pCR rate among patients receiving NAT at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, was lower than that reported in published studies (8,20,21). Specifically, the pCR rates were 13.3% for TNBC, 33.5% for HER2-positive breast cancer, and 6.1% for luminal-type breast cancer. With the exception of the luminal-type pCR rate, which is comparable to the recently reported rate of 10% in Asian populations (22), the pCR rates for both TNBC and HER2-positive subtypes were lower than those reported in the literature. This discrepancy may be associated with the extensive time span of the Sir Run Run Shaw Hospital database [2005–2024]. A previously published study indicated that only 18.2% of patients receiving NAT at this institution between 1999 and 2018 achieved pCR (23), a figure consistent with the 16.5% pCR rate observed in the present study. The lower rates may be attributed to treatment protocols used in earlier years. For instance, platinum-based agents were less frequently utilized for TNBC at our center in the past, whereas most referenced studies incorporated such regimens (20). Regarding HER2-positive breast cancer, pertuzumab was not widely adopted in clinical practice in China until 2018 (23). Consequently, as research has advanced and clinical neoadjuvant treatment strategies have been continuously updated, differences exist between pCR rates from earlier periods and contemporary data. This likely explains the lower pCR rates observed among breast cancer patients at Sir Run Run Shaw Hospital compared to other reported studies.

A total of 293 patients who achieved pCR following NAT were included in this study from Sir Run Run Shaw Hospital, accounting for 16.5% of the cohort. Among these pCR patients, 277 did not experience any disease progression events (including local recurrence, distant metastasis, or death), while 16 patients (5.4%) encountered such events, comprising 5 cases of recurrence, 10 of metastasis, and 8 deaths. Due to the limited statistical power imposed by the small number of overall events (n=16), in the univariable Cox analysis, hazard ratios for certain subgroups (e.g., outer upper quadrant) could not be estimated (denoted as NE) because of zero events in those groups.

Notably, our analysis revealed that, within this pCR cohort, Ki-67 expression was significantly associated with the occurrence of disease progression. The proportion of patients exhibiting high proliferative activity among those who experienced progression events was twice that observed in the progression-free group. As a well-established biomarker of cellular proliferation, elevated Ki-67 expression is directly associated with increased tumor cell division activity (24,25) and has been linked to worse prognosis in patients receiving NAT (26). Multiple evidences have identified pre-treatment Ki-67 and the proportional change in Ki-67 levels before and after NAT as an independent prognostic marker in patients receiving NAT (27-30). However, in the present study, despite its significant association with progression status at baseline, Ki-67 did not retain prognostic significance in univariable Cox regression analysis for EFS (overall P=0.18). This discrepancy underscores the importance of time-dependent analysis in prognostic assessment: while Ki-67 differed between groups at baseline, it did not predict the timing of progression events when accounting for follow-up duration and censoring.

Consistent with previous reports (17,18), tumors originating from the upper outer quadrant accounted for the largest proportion of primary breast cancers, comprising 36.86% of this cohort. Notably, among 108 patients with primary tumors in this quadrant, none experienced disease progression. Due to zero events, the hazard ratio for this subgroup was NE. However, this long-term estimate should be interpreted with caution given the limited follow-up duration and the small number of patients remaining at risk at 10 years.

Our finding indicated that tumor quadrant may be associated with EFS in pCR patients, with the upper outer quadrant showing a particularly favorable prognosis. The complete absence of progression events in 108 patients—more than one-third of the cohort—is a clinically notable observation, even when acknowledging the limited overall event count. Several large cohort studies have demonstrated survival differences across breast quadrants. Siotos et al. analyzed 5,295 breast cancer patients and reported that although the upper outer quadrant itself did not exhibit the lowest rates of recurrence or mortality in their descriptive analysis (17). Similarly, a SEER-based study of 193,043 patients reported that central portion tumors were associated with worse overall survival and breast cancer-specific survival, possibly due to older age at diagnosis, higher T stage, and greater likelihood of lymph node metastasis (18). Most recently, Jariri et al. analyzed 36,443 invasive ductal carcinoma patients treated with breast-conserving therapy and found significant differences in 5-year relative survival across quadrants, ranging from 92.2% (lower inner) to 95.3% (upper inner), with the upper outer quadrant achieving 94.1% (P<0.001) (19).

The particularly favorable outcomes observed in the upper outer quadrant in our study are consistent with earlier reports suggesting a survival advantage for tumors in this location. Several hypotheses have been proposed in the literature to explain such differences, including variations in lymphatic drainage patterns (axillary vs. internal mammary) and molecular features (e.g., PIK3CA mutation frequency) (17,31-33). Several hypotheses may explain this phenomenon. One potential explanation for the favorable outcomes observed in the upper outer quadrant relates to lymphatic drainage patterns. Tumors in this location are more likely to metastasize to axillary lymph nodes, which are readily detected by imaging and effectively managed by axillary surgery, whereas medial quadrant tumors have a higher propensity for internal mammary node involvement—a site that is difficult to assess clinically and surgically (17,31). Thus, even in the setting of nodal metastasis, upper outer quadrant tumors may still be associated with better prognosis due to the accessibility and treatability of their draining lymphatic basin. Biologically, evidence suggested that tumor location may correlate with underlying molecular features; for instance, PIK3CA mutation status—which has prognostic implications in certain subtypes—has been shown to correlate with tumor quadrant, especially upper outer quadrant owned the highest rate of PIK3CA mutation (32). Additionally, the distribution of molecular subtypes may vary by quadrant, although this relationship requires further investigation. Comparing to inner quadrant, outer quadrant showed higher ratio of ER or PR positive and HER2 positive (33).
Another study suggested upper outer quadrants had higher proportion of TNBC patients, which may benefit more than luminal subtype, might explaining why upper outer quadrants showed best EFS among pCR patients. However, none of these mechanisms were directly examined in the present study. Therefore, we refrain from drawing firm biological conclusions and instead present these as speculative explanations that warrant further investigation.

In our pCR cohort, the complete absence of progression events in the upper outer quadrant (0/108 patients) highlights a potential prognostic signal associated with this location. Given the small number of events overall (n=16), these findings should be interpreted as hypothesis-generating rather than definitive. However, we believe they provide a meaningful signal that warrants validation in larger, independent pCR cohorts. Specifically, the median follow-up of 41 months is relatively short for capturing late recurrences, particularly in hormone receptor-positive disease where risk may extend beyond 5 years. Therefore, our findings primarily reflect early outcomes. Future studies with more events are needed to confirm whether the excellent prognosis of the upper outer quadrant is reproducible and independent of other factors such as molecular subtype and treatment era. At present, tumor quadrant may serve as a simple, readily available parameter for generating hypotheses and for inclusion in future risk stratification models, pending external validation. We also highlight the need for further research into the biological mechanisms underlying quadrant-specific differences in outcomes, such as lymphatic drainage patterns and molecular heterogeneity.

Our findings should be interpreted in light of the study’s limitations. Tumor quadrant emerged as the only factor significantly associated with EFS, consistent with prior evidence that tumor location influences breast cancer outcomes (17,18). Several limitations warrant consideration. The small number of events (n=16) limited statistical power and precluded multivariable adjustment. The single-center retrospective design may introduce bias, and the long study period [2005–2024] encompasses evolving treatment paradigms. Sparse data in certain subgroups resulted in wide confidence intervals and some inestimable hazard ratios (NE), reflecting estimate instability.

Despite these constraints, our study provides preliminary, exploratory evidence that tumor quadrant may be associated with outcomes in pCR patients. Future multicenter studies with larger cohorts are needed to validate these findings, enable multivariable analysis, and explore the biological mechanisms underlying quadrant-specific prognostic differences. If confirmed in independent cohorts, tumor quadrant could be considered as a candidate parameter for future research on post-pCR risk stratification.

Conclusions

In this retrospective cohort study of 293 breast cancer patients who achieved pCR after NAT, tumor quadrant was the only factor significantly associated with EFS in univariable analysis, with the upper outer quadrant demonstrating a 100% EFS rate at both 5 and 10 years (zero events among 108 patients). In contrast, Ki‑67 expression, although differing between progression groups at baseline, did not retain prognostic significance in time‑to‑event analysis. Due to the very small number of events (n=16) and the lack of multivariable adjustment, these results should be interpreted as exploratory and hypothesis‑generating rather than definitive. We conclude that tumor quadrant, especially the upper outer quadrant location, may represent a simple, readily available parameter for generating risk‑related hypotheses in pCR patients. However, external validation in larger, independent, and ideally multicenter cohorts with longer follow‑up is required before any clinical application.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0095/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0095/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0095/prf

Funding: This work was supported by the National Natural Science Foundation of China (grant Nos. 82272855, 81972453, and 81972597), Zhejiang Provincial Natural Science Foundation of China (grant Nos. LR22H160011, LY19H160055, LY19H160059, LY18H160005, and LY20H160026), and Zhejiang Provincial Medical and Health Science and Technology (Youth Talent Program) Project (No. 2021RC016). The work was also sponsored by Zheng Shu Medical Elite Scholarship Fund.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-1-0095/coif). All authors report that this work was supported by the National Natural Science Foundation of China (grant Nos. 82272855, 81972453, and 81972597), Zhejiang Provincial Natural Science Foundation of China (grant Nos. LR22H160011, LY19H160055, LY19H160059, LY18H160005, and LY20H160026), and Zhejiang Provincial Medical and Health Science and Technology (Youth Talent Program) Project (No. 2021RC016). The authors have no other 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.

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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