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.