Outcomes of metaplastic breast cancer versus triple negative breast cancer: a propensity score matching analysis

Abstract

Purpose

This study aims to compare the survival outcomes of MBC with triple-negative breast cancer (TNBC) and identify prognostic factors that influence MBC survival.

Methods

Patients with non-metastatic MBC or TNBC were reviewed from our database from 2002 to 2021. Patient clinicopathologic features and treatment were analyzed with respect to outcomes including disease progression-free survival (DFS), and overall survival (OS). Propensity score matching (PSM) with a one-to-three matching between MBC and TNBC was performed.

Results

A total number of 857 female patients (76 MBC and 781 TNBC) were included in this study, with median age in 49 years (28–77 years). A subgroup of triple negative MBC (n = 60) was matched with TNBC (n = 180) cases based on patient characteristics and treatment. OS and DFS were significantly worse in the MBC group before (p = 0.0046 both) and after (p = 0.011 and p = 0.0046, respectively) PSM. Multivariable analysis revealed larger tumor size (T > 5cm) (HR = 3.797, 95%CI 1.118–12.902, p = 0.032) and lymph nodal status (N3 vs N0-2, HR = 6.149 95%CI 1.499–25.229, p = 0.012) were associated with worse OS after PSM. Among the 76 MBC patients, higher T stage and mesenchymal differentiation were associated with worse overall survival (pT1/2 vs pT3/4 and mesenchymal differentiation vs other type, p = 0.007 and p = 0.011, respectively). Lymph node positive and mesenchymal differentiation were associated with worse disease-free survival (Figs. 5 and 6, p = 0.005 and p < 0.001, respectively).

Conclusions

Compared with TNBC, MBC tends to have a worse OS. Mesenchymal differentiation has a worse DFS than other subtypes of MBC.

Introduction

Metaplastic breast cancer (MBC) is a rare histological subtype of breast carcinoma, with substantial heterogeneity, containing mixed epithelial and metaplastic components, composed of glandular and non-glandular tissues, accounting for only 0.25% ~ 1% of all breast carcinomas[1]. At present, it is generally recognized in clinical practice that MBC has the characteristics of older age, larger primary tumor size, lower axillary lymph node metastasis rate, and lower estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) positive rates[2–4]. Due to most MBC have triple negative phenotype, MBC were compared with triple negative breast cancer (TNBC) regularly. While, weather the prognosis of MBC is worse than TNBC is in controversial. Some studies reveled that the prognosis of MBC seems to be worse than TNBC[5–10]. Other studies showed that MBC has no significant difference in clinical outcome with TNBC[11, 12]. The controversy may come from that limited data are available in determining prognostic factors to predict outcome of patients as the rarity of the disease. Previous studies with small sample size performed propensity score matching analysis with few variables to reduce selection bias[5, 11, 13]. Therefore, a more comprehensive propensity score matching analysis needed to be performed to reduce the effect of selection bias and potential confounding.

Hence, this study aims to compare survival outcomes between non-metastases MBC and non-metastases TNBC by propensity score matching analysis, and retrospectively presents the clinicopathological characteristics, factors related to prognosis and clinical outcomes of MBC and TNBC cases. And the association of survival outcomes with neoadjuvant chemotherapy, chemotherapy, radiotherapy, surgery, histopathological and molecular characteristics among MBC patients were analyzed.

Methods

Study design

We queried the Clinical Research Center for Breast, West China Hospital, Sichuan University database, a  prospectively maintained database, for MBC and TNBC cases with stage Ⅰ to Ⅲ. Between January 2002 and August 2021，a total number of 974 non-metastasis patients were diagnosed with MBC/TNBC conforming by pathology results. Among these patients,117 patients were excluded due to failed to follow- up or no record of important information. Finally, a total of 76 metaplastic cancer patients and 781 triple negative breast cancer patients were included in the study.  

Clinical laboratory and treatment data were extracted from a prospectively maintained database. To compare the survival outcomes between patients with triple negative MBC and TNBC, we performed propensity score matching (PSM) with a one-to-three matching. Patients were matched on characteristics, which including age, T stage, lymph node status, ki67 index, Nottingham grade, type of surgery, radiotherapy, neoadjuvant chemotherapy, and chemotherapy. For patients not receiving neoadjuvant chemotherapy, tumor size and nodal status were determined by standard pathologic examination. For patients receiving neoadjuvant chemotherapy, the staging was performed by pretreatment imaging or clinical tumor size. Nodal status was considered positive if the metastatic tumor was identified on lymph node biopsy before surgical treatment or positive anterior/axillary lymph nodes were identified after the final surgery. No positive anterior/axillary nodes were identified if there was no lymph nodes metastasis at pathologic examination after the surgery. 

Ethical Statements

This retrospective study was approved by the Ethics Committee of our institution. The requirement for informed patient consent was obtained due to the retrospective nature of this study. All TNBC cases were retrieved from the BC database in the same time frame. 

Inclusion and exclusion criteria

The Inclusion criteria were: Diagnosis with metaplastic breast cancer or breast cancer with ER-/PR-/HER2-, pathologic and treatment data were available. The exclusion criteria were: No record the information of ER-/PR-/HER2; Failed to follow up or not treated in our institution; patients with metastatic disease at the time of diagnosis; patients with preexisting other malignancies.

Evaluation criterion and follow-up

Efficacy evaluation of treatment was according to the Response Evaluation Criteria in Solid Tumors objective efficacy evaluation standards (RECIST, version 1.1)[14]. Disease progression-free survival (DFS) is the time from diagnosis to the appearance of any local recurrence, distant metastasis or death. Overall survival (OS) was defined as the time from diagnosis to death from any cause. BCSS was defined as the time from diagnosis to death from breast cancer or last follow-up. Data were collected electronically from the hospital database. Follow-up was performed by clinic visit, medical record review and telephone contact. Patients were included if they were diagnosed with MBC according to pathology reports. Patients who were not treated at our center or failed to follow up were excluded from the study. 

Statistical analysis 

Propensity score matching was performed by using R 4.2.0. Each of 60 metaplastic breast cancer cases was matched with 3 controls for a total of 180 matched controls. Parameters matched were age, T stage, lymph node status, ki67 status(<30% or ≥30%),  neo-chemotherapy, chemotherapy, type of surgery and radiotherapy.

Statistical analysis was performed by using SPSS (IBM SPSS 26.0, SPSS Inc). Kaplan-Meier survival analysis was performed to estimate survival curve. Kaplan-Meier survival curves were plotted using R 4.2.0. The independent prognostic factors of risk of breast tumor mortality were determined in using univariate Cox regression and multivariate Cox regression. P-values less than 0.05 were considered to be significant.

Results

Patient characteristics

From 2002 to 2021, a total number of 857 females were included. Seventy-six patients with MBC and 781 patients with TNBC were analyzed(Figure 1). There were 60 (78.9%) of 76 MBC cases were triple negative (ER-/PR-/HER2-), 29 (38.2%) cases with SCC (squamous cell carcinoma squamous), 5 (6.6%) spindle cell carcinoma, 15 (19.7%) mesenchymal differentiation, 16 (21.1%) no special type, and 11 (14.5%) mixed type.

During PSM, each of sixty triple negative MBC cases were matched with 3 TNBC. The characteristics of patients before and after PSM were in table 1. Before matching, The median age was 48 years (range,42 to 55) for TNBC vs. 46 years (range,41 to 53.25) for MBC(P=0.229). There are significant difference in tumor size (P<0.001), ki67 index(P<0.001), neo-chemotherapy(P=0.044) between MBC and TNBC, type of radiotherapy(P=0.009), and type of surgery(P=0.04). After matching, there are no significant difference between these two groups in tumor size (P=0.172), ki67(P=0.649), neo-chemotherapy(P=1), type of radiotherapy(P=0.286), and type of surgery(P=0.763).

Eleven MBC patients (14.5%) received neoadjuvant chemotherapy (Table 2). The chemotherapy regimens included doxorubicin, cyclophosphamide, plus paclitaxel (AC-T) (n = 7), AC (n = 1), paclitaxel and epirubicin(PE)(n=2), and 5-FU, epirubicin, plus cyclophosphamide(FEC)(n=1). Upon surgical resection, pathological diagnosis, and image data, five patients (45%) got progression (AC-T n=2, FEC n=1, and PE n=2) during the follow up time, and one of the five (PE) died due to lung metastasis with an overall survival time of 10 months. Two patients (18%) (AC n=1, and AC-T n=1) achieved stable, and four patients (36%) (AC-T) achieved partial response, and no patients achieved pCR (pathologic complete response). 

Sixty-three (82.9%) patients underwent a modified radical mastectomy, five (6.6%) underwent a radical mastectomy, seven (9.2%) underwent a lumpectomy, one(1.3%) received palliative surgery. Seventy-four patients received postoperative adjuvant chemotherapy, mainly TEC (docetaxel + epirubicin + cyclophosphamide) and TC (docetaxel + cisplatin) (Table 2). Fifteen patients (19.7%) continued adjuvant radiotherapy after adjuvant chemotherapy, and two cases (2.6%) received palliative radiotherapy (Table 2). Three Her-2 positive patients (3.9%) received trastuzumab, lapatinib, and pyrrotinib, respectively. One of the three, which received lapatinib got lung metastasis at the follow-up time of 7 months and died at 11 months. While the other two patients did not get progression or died with a follow-up time of 16 months and 62 months. Seventeen patients (22.4%) received endocrine therapy (ET), three of these received tamoxifen and sequential use of toremifene, two patients received aromatase inhibitor treatment, one patient received toremifene treatment alone, and 11 patients received tamoxifen. One of the seventeen got local recurrence at nine months after the surgery, and the results of a second biopsy showed that the ER status changed from negative to positive. Another one of these died with a follow-up time of 44 months for the lung and brain metastases.

Survival Analysis

Survival results before and after matching 

Before matching, the median follow-up time ranged from 2 to 216 months, with an average follow-up time of 50 months (median follow-up time 42months). MBC tend to have worse 5-year OS (86.5% vs 94.1%) and 5-year DFS (80.9% vs 92.7%). OS and DFS were significantly worse in the MBC group, survival curves are shown for groups before propensity score matching (Figure 2, P=0.005 both). The average follow-up time of these two matching groups was 45 months (median 45 months, range,2 to 216 months). During the follow-up time, disease recurrence after surgery occurred in 11 (18.3%) patients with MBC and 9 (5%) patients with TNBC (P= 0.001). Seven (11.7%) patients died from developing of breast cancer in the MBC group, and patients died due to disease occurred in 8 of 180 (4.4%) patients with TNBC. A poorer DFS and OS was found in the MBC population (Figure 2, P=0.011 and 0.005, respectively). This result is consistent with the outcomes before matching.

Survival results for MBC subgroups

There are 76 MBC patients were included in this study. Higher T stage and mesenchymal differentiation were associated with worse overall survival (Figure 3,pT1/2 vs pT3/4 and mesenchymal differentiation vs other type, P = 0.007 and 0.011, respectively). When compared with all subtypes, mesenchymal differentiation cases tended to have a worse OS and DFS, but this difference did not reach statistical significance (Figure 3, P=0.079 and 0.052, respectively). 

Determinants of poor outcomes in 240 matching patients

In the matching groups, univariate analysis shows age, ki67 index, type of surgery, adjuvant-radiotherapy were not the risk factor of OS. Except for higher T stage (T3/4 vs T1/2, HR=6.472, 95%CI 2.251-18.606, P< 0.001), lymph nodal status (N3 vs N0-2, HR=7.85, 95%CI 2.416-25.505, P<0.001), Neo-chemotherapy (yes vs no, HR=4.775 95%CI 1.629-13.994, p=0.004) which has a worse OS (Table 3). There was a trend towards worse OS for MBC when compared with TNBC with no statistical significance (HR=2.383, 95% CI 0.851-6.673, P=0.098). For DFS, no risk factors were associated with improved recurrence-free and distant recurrence-free survival. While, on multivariable analysis, larger tumor size (T>5cm) (HR=3.797, 95%CI 1.118-12.902, P=0.032) and lymph nodal status (N3 vs N0-2, HR=6.149 95%CI 1.499-25.229, P=0.012) were associated with worse OS in the 240 matching cases (Table 4).

Discussion

Metaplastic breast cancer was widely perceived as an aggressive tumor with poor outcomes. Recent years, a large number of studies have focused on the comparison of MBC and TNBC. We identified 76 MBCs and 781 TNBCs diagnosed and treated at our institution in the past 19 years (between 2002 and 2021) to compare the outcome of MBC and TNBC. Compared with TNBC patients, a higher T stage and less advanced or similar N stage were observed in MBC patients in our study, which is concordant with the prior researches[1, 7, 9, 15]. Besides, the two groups show difference in ki67 index, WHO grade, surgery, radiotherapy, and neoadjuvant chemotherapy. These differences may cause bias in disease outcome assessment. Before matching, our results showed that MBC patients had a worse OS, that was consistent with the previous studies[2, 5, 7, 8, 10, 15, 16]. In order to investigate the difference of survival between the two groups, propensity score matching was performed. Propensity score matching was performed with one or fewer variables in previous studies[5, 11, 13]. We performed propensity matching to identify comparator triple-negative MBC and TNBC groups that were similar in age, tumor size, lymph node status, ki67 index, Nottingham grade, type of surgery, radiotherapy, neoadjuvant chemotherapy, and chemotherapy. Our matching is a more comprehensive PSM, which include more variables when comparing with the previous matched cohorts[5, 7-9]. After matching, the difference of clinical features and treatment between the propensity matched cohorts is not statistically significant. MBC still tend to have a worse DFS and OS when comparing the propensity matched cohorts. Qualitatively similar results were also found after propensity score matching, suggesting the results are consistent. These results are in line with previously studies, which comparing outcomes for patients with MBC and TNBC[8, 9, 15].

It is controversial whether the histologic subtype of MBC is associated with prognosis. Squamous cell differentiation has been shown to be associated with worse DFS than other metaplastic components in a small retrospective study [8]. Instead, another study found the opposite– patients benefited from squamous cell differentiation[13]. Besides, a small series of 97 MBC patients found that more than one metaplastic component was associated with worse recurrence-free and breast cancer-specific survival[17]. Patients with heterologous mesenchymal had the better 5-year overall and breast cancer-specific survival in previous reports[13, 18]. While in our center, the histologic subtype has no significant impact on survival, which is consistent with previous studies[9, 19]. But our research indicates that mesenchymal tend to have worse DFS than other subtype. A potential reason for this is that compared with other subtype, the mesenchymal group have a higher T stage in our study (T3/T4, 42.9% vs 14.0%). Due to the rarity of MBC, these data are likely confounded by the small, heterogeneous sample size, and larger studies with pathological subtype of MBC are required. Further research is needed to determine whether the pathological subtype of MBC is associated with better or worse prognosis. Similar to the majority of the previous studies, our research indicated that negative lymph node status was a predictor for better DFS in MBC, and smaller tumor sizes or lower T stage were good prognostic factors for OS and BCSS[17, 20-22]. 

In localized MBC, surgery remains the standard of care[3]. An analysis of Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 2006 did not suggest an association of surgery type with survival[23]. However, another SEER analysis evaluating 2010 - 2014 data showed that among those MBC patients who underwent surgery, mastectomy was associated with inferior 3-year OS (hazard ratio = 2.00, 95% CI 1.31 - 3.06), compared with breast-conserving surgery independent of the stage at presentation[24]. And lumpectomy as primary surgery was associated with improved recurrence-free and distant recurrence-free survival. While, in a prior study, type of surgery did not related to DFS [19]. That is consistent with our research.

Tseng and Martinez used the SEER database to identify MBC patients diagnosed from 1988 to 2006. 1501 MBC patients were included, and radiation therapy RT provided an OS (HR 0.64; 95% CI, 0.51-0.82; P < 0.001) and disease‐specific survival (DSS) (HR 0.74; CI, 0.56-0.96; P < 0.03) benefit. While, when patients were stratified according to the type of surgery, RT provided an OS but not a DSS benefit to lumpectomy and mastectomy patients[23]. Consistent with prior reports, C. Marc Leyrer reported that when radiation therapy was stratified by surgery type, receipt of adjuvant radiation after breast-conserving surgery (BCS) was significant for improved locoregional recurrence (LRR) (p<0.001) and OS (p = 0.009) over those who did not, and the use of radiation therapy was not significantly associated with LRR, distant- metastasis (DM), or OS for mastectomy[19]. However, in present study, five patients who received lumpectomy did not have radiation therapy. That makes statistical comparison of the two groups difficult. Postoperative adjuvant RT was given for 20 (26.3%) MBC patients in our study, and compared with those who did not receive RT, there were no statistical differences in OS, BCSS, and DFS. The difference in treatment may be due to selection bias,  more detailed and rigorous research are needed to assessment the relationship between RT and survival in MBC.

MBC is poorly responsive to neoadjuvant chemotherapy in the prior reports, with a pCR rate in the scope of 0% to 18%[2, 17, 25-28]. The previous study, including 44 MBC patients, showed 49% cases no clinical response or clinico-radiological progression to neoadjuvant chemotherapy. Only one (2%) patient had a pathologic complete response (pCR)[29]. In our study, the result of neoadjuvant chemotherapy is poor too. According to previous studies, with a large number of MBC patients, adjuvant chemotherapy was associated with better outcomes[2, 30, 31].While, the evaluation of adjuvant chemotherapy is hard due to all the MBC patients received adjuvant chemotherapy in our study. Current chemotherapy treatment protocols for the management of MBC are not very effective, but it remains an important part of the treatment regimen for MBC. And that may be changed by immunotherapy in the future cause few previous studies found that PD-L1 was over expressed in MBC and immune checkpoint inhibitors showed good efficacy in MBC[32, 33].

The previous reports showed that 13 of 55 patients were treated with tamoxifen as adjuvant treatment. In comparison, the ET has no significant impact on five-year OS (HR= 0.290, 95%CI 0.06 to 1.42, P= 0.126)[34]. Some research reports similar outcomes[8, 17]，which was consistent with our study(p=0.241). However, another analysis of 5,142 MBCs from the National Cancer Database show that ET may improve OS (HR=1.527, 95%CI 1.438 to 1.621, p<0.001). While the previous study with a large number of cases did not comment on tumor response to ET due to a lack of information about tumor response to ET[35, 36]. Because of the absence of more detailed information of ET MBCs, which may cause different research results in these studies. Further research is needed to understand if the MBC benefit from endocrine therapy.

Three HER2-positive MBC patients in our study received targeted therapy after surgery. One HER2-positive patient died due to lung metastasis, and two HER2-positive patients were alive during the follow-up period. It is difficult to assess the effect of targeted therapy in this experience due to the small sample size.

In the current study, we found that MBC is a more aggressive subtype of breast cancer when comparing with TNBC. Our current options for MBC are far from ideal. Fortunately, immunotherapy and targeted therapy may hold promise as a new therapeutic strategy for MBC, which show efficacy in previous research[33, 37, 38]. Those potential treatment approach are worth exploring and studying in detail in the future.

Limitations

A number of limitations need to be noted regarding the present study. One limitation is that this retrospective study only included 76 MBC patients, and the small sample size may cause bias. A more comprehensive PSM was performed to minimize imbalance between the arms, but there may be unmeasured factors that contribute to the outcomes. And some patients who received treatment in our institution in earlier years, which lacked information of clinical features and histopathological features.

Declarations

Acknowledgment

We would like to thank the Cancer Center，Breast Disease Center , West China Hospital, Sichuan University  for support.

Funding

This study has received funding by Post-Doctor Research Project, West China Hospital, Sichuan University (2021HXBH023) and Department of Science and Technology of Sichuan Province of China (21YYJC2782).

Conflicts

The authors declare no potential conflicts of interest in this work.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.
 

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Tables

Table 1. Baseline Patient Characteristics before and after Propensity Score Matching

p-values indicate level of significance for overall difference between subtype groups, using chi-square test for categorical variables and Kruskal-Wallis for continuous variables(non-normally distributed variables).

Abbreviations: Neo-CT, neoadjuvant chemotherapy.

Table 2. Baseline Patient Characteristics of 76 MBC Cases.

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; LN, Lymph node status; AC-T, doxorubicin and cyclophosphamide followed by taxane; FEC, fluorouracil, epirubicin and cyclophosphamide; TC, docetaxel and cyclophosphamide; X, capecitabine; CMF, cyclophosphamide, methotrexate, fluorouracil.

Table3. Univariate and Multivariate Cox regression analysis of factors predictive of overall survival for 240 matching patients

Abbreviations: MBC, metaplastic breast cancer; TNBC, triple negative breast cancer; LN, Lymph node status.

Table 4. Univariate and Multivariate Cox regression analysis of factors predictive of disease-free survival for 240 matching  patients

Abbreviations: MBC, metaplastic breast cancer; TNBC, triple negative breast cancer; LN, Lymph node status.