Background: The detection rate of Multifocal/Multicentric Breast Cancer (MMBC) is increasing, garnering greater clinical attention. However, prognostic differences between MMBC and Unifocal Breast Cancer (UBC) remain controversial.

Methods: This retrospective cohort study analyzed 109 MMBC and 4,198 UBC patients who underwent mastectomy at the Breast Center of the Fourth Hospital of Hebei Medical University from 2010 to 2014. Propensity score matching (PSM, 1:2 ratio, caliper = 0.1) balanced baseline characteristics. Two T-staging methods were evaluated: Tmax (largest lesion diameter) and Tsum (cumulative lesion diameters). Outcomes included Locoregional Recurrence (LRR), Disease-Free Survival (DFS), and Overall Survival (OS).

Results: MMBC patients were younger (median 46 vs. 52 years, p < 0.001), more frequently premenopausal (67.0% vs. 48.5%, p < 0.001), and had higher lymph node involvement (48.6% vs. 37.1%, p < 0.001). Under Tmax staging, MMBC showed comparable OS (p = 0.127) and LRR (p = 0.118) but inferior DFS (p = 0.010) versus UBC. Tsum staging increased TNM stages in 45.0% of MMBC patients, aligning DFS (p = 0.079) and OS (p = 0.269) with UBC. Multivariate analysis identified MMBC (HR: 0.387, p = 0.015) and nodal involvement (HR: 2.446, p = 0.022) as independent DFS predictors in Tmax-staged patients.

Conclusions: Tsum staging better reflects MMBC tumor burden, mitigating prognostic disparities observed under Tmax staging. Current Tmax-based protocols may underestimate MMBC severity, advocating for revised staging criteria.

• Multifocal Breast Cancer

• Tumor Staging

• Propensity Score Matching

• Survival Analysis

Lv X, Fan Z, Li Y (2025) Using Propensity Score Matching to Compare Prognostic Differences between Multifocal/Multicentric and Unifocal Breast Cancer. Ann Breast Cancer Res 9(1): 1032.

The definitions of multifocal and multicentric breast cancer —collectively termed MMBC—vary across studies, though MMBC typically denotes ≥2 ipsilateral lesions within the same (MF) or distinct (MC) quadrants. MMBC is associated with aggressive clinicopathological features, including younger age, higher lymph node metastasis rates, and advanced histological grade [1-4]. Despite these associations, consensus on MMBC’s prognostic impact remains elusive, with studies reporting conflicting survival outcomes [5-8]. Therefore, further research is necessary to clarify the prognostic implications of MMBC. A critical knowledge concerns T-staging methodology. Current AJCC (8th Edition) guidelines stage MMBC using the largest lesion’s diameter (Tmax), neglecting cumulative tumor burden. Emerging evidence suggests that summing all lesion diameters (Tsum) may better predict outcomes, though validation in large cohorts is lacking[9-11]. This study addresses two aims: 1. Compare prognosis between MMBC and UBC using propensity score matching (PSM) to minimize confounding. 2. Evaluate the clinical utility of Tsum versus Tmax staging in MMBC.

Study Design and Population

This single-center retrospective analysis included women with stage ?-? breast cancer undergoing mastectomy (2010–2014). Exclusion criteria: prior excisional biopsy, occult/bilateral cancers, carcinoma in situ, or neoadjuvant therapy.

Data Collection

ductal Clinicopathological variables included age, menopausal status, tumor size, nodal status, TNM stage (AJCC), histology, and receptor status (ER/PR: positivity ≥1% nuclear staining; Ki-67: high ≥ 30%, based on consensus among Chinese experts.). For MMBC, immunohistochemistry was performed on the largest lesion.

Staging Methods

T stage was categorized as T1 (≤ 2 cm), T2 (> 2 cm but ≤ 5 cm), and T3 (> 5 cm) in pathology. Two approaches were used for T stage of MMBC tumors: Tmax: Based on the largest tumor lesion’s maximum diameter. Tsum: Based on the sum of all measurable tumor lesions’ maximum diameters. Pathological nodal (pN) staging: pN1: 1–3 metastases; pN2: 4–9 metastases; pN3: 10 or more metastases.

Outcomes

All patients were followed up through phone calls and outpatient visits. The follow-up period concluded on September 15, 2023, with a median duration of 144 months (range: 104–164 months). Locoregional Recurrence Free Survival (LRFS): Defined as the time from the initial diagnosis to the recurrence of cancer in the ipsilateral chest wall or regional lymph nodes (axillary, subclavian, supraclavicular, or internal mammary nodes). Disease Free Survival (DFS): Defined as the time from the initial diagnosis to disease recurrence or death from any cause. Overall survival (OS): Defined as the time from the initial diagnosis to death from any cause.

Statistical Analysis

Statistical analysis was conducted using SPSS Statistics software (version 26). Qualitative data were compared using the chi-square test, while quantitative data conforming to a normal distribution were described as means. Survival curves were generated using the Kaplan Meier method and compared between groups using the log-rank test to assess differences in LRFS, DFS, and OS before and after matching. Univariate and multivariate analyses were performed using Cox proportional hazards regression models. Statistical significance was set at p < 0.05. Propensity Score Matching (PSM) was applied to balance the characteristics of UBC patients with those of MMBC patients to minimize selection bias.

Baseline Characteristics

MMBC patients (n = 109) were younger (46 vs. 52 years, p < 0.001), more often premenopausal (67.0% vs. 48.5%, p < 0.001), and lymph node-positive (48.6% vs. 37.1%, p < 0.001) than UBC (n = 4,198)

Table 1: Clinicopathological characteristics before PSM.

(Table 1). Post-PSM cohorts (Tmax: 82 MMBC/155 UBC; Tsum: 76 MMBC/130 UBC) showed no statistically significant differences (Table 2).

Table 2: Clinicopathological characteristics after PSM.

pN: pathological N staging.

Staging Reclassification

Tsum increased T-stage in 45.0% of MMBC patients (T1→T2: 36.7%; T2→T3: 8.3%, p < 0.001), elevating TNM stage (p = 0.003) (Table 3,4).

Table 3: pT stage comparison: Tmax vs. Tsum in MMBC.

pT: pathological T staging.

Table 4: TNM stage comparison: Tmax vs. Tsum in MMBC.

Survival Analysis

In the Tmax group, MMBC had worse DFS (p = 0.010) (Figure 3),

Figure 3 Kaplan–Meier analyses of DFS between MMBC and UBC patients in Tmax group.

but comparable OS/LRR (Figure 1, 2).

Figure 1 Kaplan–Meier analyses of OS between MMBC and UBC patients in Tmax group.

Figure 2 Kaplan–Meier analyses of LRFS between MMBC and UBC patients in Tmax group.

In the Tsum group, no statistically significant differences were observed (Figure 4-6)

Figure 4 Kaplan–Meier analyses of OS between MMBC and UBC patients in Tsum group.

Figure 5 Kaplan–Meier analyses of LRFS between MMBC and UBC patients in Tsum group.

Multivariate Analysis

In Tmax-staged patients, MMBC (HR: 0.387, p = 0.015) and N1 (HR:2.446, P=0.022) independently predicted reduced DFS. In Tsum-staged patients, Pn1 predicted LRR (HR: 5.286, P = 0.008).

This study demonstrates that MMBC patients present with distinct clinicopathological profiles, including younger age and higher nodal involvement. While Tmax staging revealed inferior DFS in MMBC versus UBC, Tsum staging reconciled these differences by accounting for cumulative rumor burden, resulting in comparable survival outcomes. With advancements in imaging techniques, such as magnetic resonance imaging (MRI), the detection rate of MMBC is increasing. However, our understanding of its pathogenesis and clinicopathological characteristics remains limited. Previous studies [1–4] have highlighted that MMBC is associated with higher nodal involvement, more lymphatic and vascular invasion, negative ER/PR status, and other adverse prognostic factors. Furthermore, some researchers have suggested [9] that MMBC may originate from a primary lesion metastasizing within the ipsilateral gland to form additional lesions, potentially explaining the higher biological risk profile observed in MMBC patients. However, whether MMBC correlates with worse prognosis remains a topic of debate, with insufficient related studies in China and conflicting findings in international research [5–8]. Currently, T staging for breast cancer is determined by the maximum diameter of the largest lesion, which excludes the contribution of smaller lesions. This approach may underestimate the tumor burden in MMBC patients. To address this limitation, some studies have proposed the Tsum staging method, where the sum of the maximum diameters of all measurable lesions is used to reevaluate the T stage. For instance, a retrospective study conducted in Turkey [10] involving 323 MMBC patients demonstrated that the Tsum staging method was superior to Tmax in predicting OS, challenging the validity of the traditional T staging method. Similarly, a retrospective study in Japan [11] supported this conclusion. However, there are studies that question the prognostic utility of the Tsum staging method [12–14]. While Tsum can elevate the T stage for some MMBC patients, the lymph node metastasis rate remains similar between MMBC and UBC patients. Additionally, Tmax staging has been shown to provide prognostic information comparable to the Tsum method. Thus, whether Tsum offers improved prognostic value over Tmax requires further investigation.

Given that the majority of previous studies on MMBC were retrospective, inherent biases were unavoidable. Additionally, MMBC patients exhibit more biological risk factors, complicating direct prognostic comparisons with UBC patients. A significant challenge lies in determining the most appropriate T staging method to accurately reflect the biological characteristics of MMBC, a question that continues to perplex clinicians. To address these challenges, we applied the Propensity Score Matching (PSM) method, matching MMBC patients with UBC patients according to two different staging approaches: Tmax and Tsum. This enabled a comparison of the prognostic differences between MMBC and UBC under each T staging method. After matching, no statistically significant differences were observed in baseline characteristics between the groups, ensuring a balanced comparison. First, we compared the prognosis of MMBC patients staged by Tmax and Tsum with their respective matched UBC cohorts. In the Tmax-staged group, there was no statistically significant difference in OS between MMBC and UBC patients (P = 0.127; Figure 1). However, DFS was significantly worse for MMBC patients compared to UBC patients (P = 0.010; Figure 3). In the Tsum-staged group, neither OS (P = 0.269; Figure 4) nor DFS (P = 0.079; Figure 6) showed statistically significant differences between MMBC and UBC patients. These results suggest that, for the same T stage, the prognosis of MMBC patients is generally worse than that of UBC patients. Furthermore, the Tmax staging method may underestimate the biological behavior of MMBC. Treatment plans formulated based on Tmax staging could lead to adverse outcomes due to underestimation of the disease severity. We further examined the differences in T staging and TNM staging between the Tmax and Tsum groups. The results revealed that using the Tsum staging method resulted in a 45.0% (49/109) upstaging of the T stage for MMBC patients, accompanied by an elevation in the overall TNM stage. Traditionally, a higher T stage is associated with a poorer prognosis. However, when MMBC patients staged by Tsum were compared with matched UBC patients, no statistically significant differences were observed in OS or DFS between the two groups. This suggests that the Tsum staging method better reflects the biological behavior of MMBC by accounting for the cumulative tumor burden, thereby providing a more accurate representation of the disease.

Figure 6 Kaplan–Meier analyses of DFS between MMBC and UBC patients in Tsum group.

Current guidelines for MMBC patients typically rely on the largest lesion to determine the T stage and to formulate treatment plans based on the lesion's immunohistochemical characteristics [15]. Consistent with these guidelines, this study performed immunohistochemical tests only on the largest lesion of MMBC patients. However, differences in immunohistochemical expression among different lesions in MMBC have not been explored. Future clinical practice should incorporate immunohistochemical testing for all lesions in MMBC patients to gain a more comprehensive understanding of the disease. This approach would facilitate the development of more effective and individualized treatment strategies. Despite balancing relevant clinical factors through propensity score matching, this study has several limitations. As a single-center retrospective study, the number of included MMBC patients was relatively small. Additionally, during the study period (2010–2014), anti HER2 therapies, such as trastuzumab, were not widely used in China, and most patients with HER2 2+ status did not undergo fluorescence in situ hybridization (FISH) testing. As a result, this study did not retrospectively analyze HER2 status. Furthermore, the study did not examine subsequent treatment modalities, such as chemotherapy, radiotherapy, and endocrine therapy, making their impact on patient prognosis unknown.

In summary, MMBC patients exhibit distinct demographic and pathological features versus UBC. Tmax staging underestimates tumor burden, leading to inferior DFS in MMBC; Tsum staging aligns prognoses by incorporating cumulative disease extent. Revised staging criteria for MMBC are warranted.

Not applicable.

Ethics Approval and Consent to Participate

This retrospective cohort study was conducted in accordance with the principles of the Declaration of Helsinki.Given the retrospective nature of the study, and considering that all patient data used were de-identified (with personal identifiers such as names, hospital numbers, and contact information removed to protect patient privacy), we waived the requirement for written informed consent from individual patients. All procedures involving human participants were in compliance with relevant ethical regulations and institutional guidelines.

Availability of Data and Materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

None declared.

Founding

None received.

Author contributions

Xin Lv and Yuntao Li designed the study. Zhigang Fan acquired data. All authors involved in data interpretation. The manuscript was drafted by Xin Lv and Yuntao Li; reviewed and approved by Yuntao Li.

We thank all the patients and their families who participated in this study. We also thank all collaborators.

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