MpBC is a heterogeneous subtype of breast cancer that they are highly invasive and more prone to distant metastases except for fibromatosis-like metaplastic carcinoma and low-grade adenosquamous carcinoma [11].

There are controversies about prognoses of other histological subtypes. MpBCs are classified as monophasic (only one metaplastic component) or biphasic (both metaplastic and non-metaplastic components) tumors. The former includes pure SpCC and SqCC, and the latter includes mixed MpBC and MpBC with heterologous mesenchymal differentiation. In monophasic MpBC, Rakha et al. [9] and McCart et al. [12] also indicated that squamous cell carcinoma had more prolonged survival while Tadros et al. [8] reported a worse outcome for it. In biphasic MpBC, we found that patients with mesenchymal differentiation had better RFS and BCSS. Tadros et al. [8], Rakha et al. [9] and Takala et al. [13] also demonstrated this finding. The lack of PI-3 kinase and Ras-Map kinase aberrations and TERT promoter mutations may account for their less aggressive feature [14]. For mixed MpBC, previously, scholars generally agreed that it contains two or more metaplastic components. It revealed that conventional mixed MpBC had a worse outcome [13, 15, 16], and the prognosis was worse with the number of components increasing [12]. After publishing the 5th edition of the WHO classification, metaplastic carcinoma with adenocarcinoma component was also classified as a mixed subtype. In this study, most mixed MpBCs were the mixture of one metaplastic component with invasive ductal carcinoma. The mixed subtypes with either squamous or spindle differentiation had shorter survival outcomes than the pure subtypes. Consistent with our findings, recent research of 39 squamous cell carcinomas showed that invasive carcinoma with squamous differentiation had a worse prognosis and was more aggressive than pure squamous subtype [17]. A similar phenomenon was seen in uterine carcinosarcoma, where Renske et al. found that most metastases (72%) and vascular invasion (70%) were caused by epithelial components rather than mesenchymal components [18]. These phenomena suggest the need for further research into the origin of MpBC. The conversion theory is generally accepted, which asserts that the mesenchymal component is derived from the epithelial component through metaplastic progress. Some studies confirmed that when MpBC with the invasive ductal component, the genetic progression and evolution of its metaplastic component was from its paired invasive ductal carcinoma [14, 19]. The poorer prognosis of mixed MpBC with invasive carcinoma may imply that the epithelial component drives the high proliferation of MpBC. For example, vascular endothelial growth factor [20] and matrix metalloproteinase-7 (MMP-7) [21] were higher expressed in the epithelial component compared to the mesenchymal component, all of which contribute to its invasion and metastasis. In contrast, a study of mixed histological subtypes of invasive breast carcinoma showed no prognostic difference between pure and mixed MpBC [22], possibly due to the small sample sizes and subtype discrepancies included in their cohort. The different conclusions may reflect the different classification criteria and sample sizes of each study, furthermore, it is recommended that pathologists should record the morphology and proportion of each component at diagnosis in order to make subsequent therapeutic options.

The prognostic significance of clinicopathological features has been reported a lot, but there is no consensus on the most useful. Multiple reports, including our study, have found the mixed subtype to be an unfavorable factor [12, 13, 15, 16]. Many authors regarded tumor size was correlated with survival [12, 13, 15, 23, 24]. However, one multi-center research indicated that only lymph node status and lymphovascular invasion influenced prognosis, not tumor size and histological grade [9]. A series of studies with the SEER database proved that age and TNM stage were all independent prognostic factors [25,26,27,28]. Chemotherapy was effective for survival, but there remains controversy in radiotherapy. Multiple research confirmed that radiotherapy could improve OS or BCSS[6, 29, 30], but some considered it of limited benefit. For example, Leyrer et al. showed it decreased the local–regional but not distant recurrence [31]. Haque et al. suggested that mastectomy with radiotherapy was associated with improved OS only in the high-risk (T3–4 or node-positive) but lumpectomy with it both in high or low-risk (T1–2N0) cohorts[32]. Similar to us, a multi-center study showed no association between radiotherapy and outcomes[9]. These biases may be caused by objective differences between Asian and Western cohorts, with only 5.6–28.1% receiving radiotherapy in our and other Asian studies[3] but 37.9–92.9% in Western studies[33]. Besides, it showed that surgery type [34, 35] and race [5, 25] might affect clinical outcomes.

MpBCs are often triple-negative breast cancers, but up to 23 and 5.2% acquired HR and HER2 according to an analysis for SEER [36], which was broadly similar to our results (25.3 and 6.5%). HR-positive breast cancer is usually considered to have a better outcome. However, recent findings, including ours, found that HR-positive status and endocrine therapy might not provide a survival benefit for MpBC patients [25, 27]. Wu et al. [37] observed that HR-positive increased the death risk compared to HR-negative subtypes. In contrast, one research based on NCDB held the opposite view suggesting that endocrine therapy can improve OS [7]. In addition, our study showed HER2 status was not associated with prognosis. Interestingly, one revealed that HER2-positive MpBC might derive more benefits for survival [36], but Lei et al. [38] reported that HER2-positive squamous carcinoma was associated with an inferior prognosis. Rare reports mentioned targeted therapy for MpBC. In our research, none of the eight patients receiving targeted therapy had recurred, while two of the remaining six patients occurred recurrence and death. Anti-HER2 therapy appears to improve the prognoses of HER2-positive patients. But it is not convincing due to the limited sample size. It requires us to expand the sample to prove this conclusion.

MpBC has little response to NAC, with previous studies showing the pCR rate in the range of 0–17% [7, 15, 16, 23, 24, 39]. A recent prospective trial (NCT02276443) showed the pCR rate reaching 23% [40]. In this study, only 6.3% of MpBC patients achieved pCR, which contrasts with high pCR rates in TNBC, 30–40% with T+A regimens and over 50% with platinum-containing regimens [41, 42]. It has been certified that the enrichment of the EMT pathway and the widespread expression of tumor stem cells in MpBC make them resistant to anthracycline and paclitaxel drugs [43, 44]. Besides, the up-regulation of FOXC1 plays an important part in this process [45]. For the adjuvant treatment, the T+A regimen substantially improved the RFS and BCSS of MpBC. Unlike it is reported to be effective for TNBC, the platinum-containing regimen did not have a better outcome than the T+A regimen in our analysis, possibly due to less use and clinician selection bias, with a preference for platinum when large tumors or lymph node metastases. However, it seems to be improved when using the dense dose. A retrospective review reported that weekly paclitaxel and platinum chemotherapy could prolong survival significantly [46].

Because of deriving less benefit from chemoradiotherapy and endocrine therapy, exploring efficient treatments becomes an urgent need. With more researchers finding the prevalence of PI3K mutations in MpBC [12, 47,48,49], inhibitors of the PI3K/AKT/mTOR pathway combined with chemotherapy or targeted therapy have provided effective therapeutic methods [50, 51]. Furthermore, MpBC has been reported that frequent expression of programmed death-ligand 1 (PD-L1) which is similar to TN-IDC [44, 47, 48, 52, 53]. Several clinical trials (NCT02834013, NCT02752685) using anti-PD-1/PD-L1 antibodies in advanced MpBC patients have achieved explicit survival benefits [54, 55]. Other studies have proved that TERT promoter hotspot mutations [56] and the RPL39 A14V mutations [57] occur at high frequency in MpBC, and MYC amplification is highly enriched after metastasis [58]. These may become potential targets for treating MpBC in the future.

This study presented the clinicopathological characteristics, treatment strategies and prognoses of 217 patients with MpBC from our institution over eight years and compared them with IDC-NST. This study has some limitations: Firstly, it may have some selection bias because of its retrospective analysis and limited sample size. Secondly, this research is single-center, and the cases included may have local characteristics and limitations. Finally, some indicators such as Ki-67, P53 and menopausal status can't be matched, so there may still be an imbalance between the two cohorts. However, our study is one of the largest single institutions by far to include relatively comprehensive clinicopathological features of this rare tumor, and it’s representative and credible due to the long follow-up period and wide sample variety.