Metaplastic breast cancer (MBC) was rare and the World Health Organization identified it as a unique pathological type in 2000 (1). MBC is a rare histologic subtype, accounting for about 2-5% of breast cancer (2). It was classified into 5 subtypes: squamous cell carcinoma, spindle cell carcinoma, matrix-producing carcinoma, carcinosarcoma, and metaplastic carcinoma with osteoclastic giant cells (3–7). With the improvement of pathologists’ awareness of MBC, the incidence also increases (8). However, due to its rarity, the role of human epidermal growth factor receptor 2 (HER2) status in the treatments and prognoses of MBC is unclear.

Of note, although treatments of MBC are parallel to that of infiltrating ductal carcinoma (IDC) (9), the prognosis of MBC patients was worse than that of IDC even after receiving comprehensive treatment (10, 11). However, there is no consensus on post-mastectomy radiotherapy (PMRT) in the management of MBC. On the one hand, some researchers reported that PMRT of patients showed a better prognosis than that non-PMRT (9, 12–17). On the other hand, others debated that no connection was presented between PMTR and outcomes (18–21). The management strategy and sample sizes of the study populations may result in this conflict.

HER2-positive (HER2 +) status in traditional breast cancers is an aggressive disease related to drugs resistance, regional recurrence, metastases, and outcomes (22). It had been proved that HER2+ patients that underwent radiotherapy and anti-HER2 therapy had better survival outcomes (23). However, our published report showed that HER2 + patients diagnosed with MBC receiving RT had not a superior breast cancer-specific survival (BCSS) than that not RT (24). This discrepancy may be due to several reasons. Firstly, the characteristics of MBC are different from traditional breast cancer. Secondly, there is no study to explore the role of HER2 status in MBC patients underwent PMRT.

Therefore, to improve the comprehensive treatment of MBC, it is urgent to explore PMRT. Based on the above factors, the information of MBC patients was extracted from the Surveillance, Epidemiology, and End Results (SEER) registry to explore the effect of PMRT on MBC patients under different HER2 statuses.

Our study explored the role of PMRT in the prognosis of MBC patients and verified the effectivity of HER2 status in prognosis. After propensity score matching, our results showed that PMRT and HER2-positive status were associated with a better prognosis. However, only HER2-negative patients could benefit from PMRT.

The effectiveness of radiotherapy (RT) on MBC is still controversial. Jung et al. (28) reported that RT was not associated with a better prognosis. Those patients’ information was extracted from the Center for Breast Cancer Database and they diagnosed from 2001 to 2008. However, only 35 patients were diagnosed with MBC in those studies. Cecilia et al. (15) included stage I–III MBC patients diagnosed from 2010 to 2014. They illustrated that RT was associated with improved survival. The reasons for this effect could be the fact that, firstly, the sample size of the study varies greatly. Secondly, different eras might exist different results. As pathologists’ understanding and surgeons’ recognition of MBC has been improved, the prognosis might have also been improved.

As we all know, to minimize local recurrence after patients undergoing lumpectomy, post-surgery radiotherapy is considered as a standard component of lumpectomy to treat patients with IDC. Dave et al. (29) and Yu et al. (10) found that patients receiving lumpectomy but not total mastectomy can benefit from radiotherapy. The National Comprehensive Cancer Network breast cancer guidelines recommended that the T1-2N1 stage patients should receive PMRT, while those with stage N2 might undergo PMRT (30). In addition, 5-year survival rates of the MBC patients ranged from 49 to 83%, which suggested that the effect of PMRT in those tumors is not clear. In the present study, PMRT was associated with a better prognosis for MBC patients.

According to previously published studies, the rate of MBC underwent CT ranged from 33 to 86% (31–33). The reasons might be that, firstly, the widely gapped rates might suggested that the effectivity of patients underwent CT remained unclear, but some studies with small sample size showed that patients receiving CT had a superior prognosis (34–36). Secondly, the high rate may be that the triple-negative phenotype was the common molecular subtype of MBC, which is characterized by more aggressive cancer (37). The next but not the last reason is that in the NCCN guideline, its treatment was paralleled to that of IDC (38). Nevertheless, CT can not affect the prognosis of MBC patients, which is supported by most researchers (28, 39–41). 64.2% of patients received CT but they had no better outcomes than that not receiving CT, in the present study, which was consistent with the previous study (15, 42). The presence of more than one metaplastic component may be one of reasons for chemotherapy-resistant.

Although the triple-negative phenotype was the common molecular subtype in MBC, HR-positive and HER2 over-expression tumors do exist (43).

A published study reported that HER2 status was associated with a better prognosis for MBC patients (37). This is in contrast to invasive ductal and lobular carcinoma of the breast (22). Interestingly, some small sample reports suggest that anti-estrogen therapy does not improve the disease-free and overall survival of HR-positive MBC (8, 32, 44). In our study, HER2-positive status was associated with better outcomes, this conclusion is consistent with a recent study by Schroeder et al. that was published. Additionally, little is known about the presentations and prognoses of HER2 positive MBC, due to lack of reports of tumor HER2 receptor status. There was a particularly significant gap when consider the availability and use of HER2-directed therapy. In addition, by investigating the response of MBC to HER2 targeted therapy, we can understand the vulnerability to antibodies (37).

Owing to the rarity of HER2 over-expression tumors, clinicopathologic features need to be fully determined. The incidence of MBC is unknown, so the association of these therapeutic factors with MBC is unknown. Her2-positive breast cancer is an invasive disease, and until recently the overall survival rate for this subtype of breast cancer had been the worst (45, 46). Overall survival in this subtype had been greatly improved due to the use of HER2-targeted therapies by antibody-based approaches (e.g., trastuzumab, pertuzumab) and small-molecule inhibitors (lapatinib, neratinib) (47, 48). However, the involvement of HER2 over-expression in MBC prognoses is unknown. Previous studies have found the rate of HER2 over-expression ranging from 0% to 25% (49, 50). In our study, 7.3% of MBC patients had HER2 over-expression, which is consistent with previous studies. According to the current consensus guidelines, the degree of HER2 overexpression or amplification was thought to be intermediate between typical breast cancer and MBC, as reported in previous studies (51).

Our study has several key strengths. The role of HER2 status and PMRT in the prognosis of MBC is unclear. From our results, the prognosis was improved in MBC patients receiving PMRT. In addition, HER2 status can redefine the role of PMRT in the prognosis of MBC.

Our study has several limitations. First, due to its retrospective study, it is characterized by the nature of observation and the possibility of selection bias. Second, the SEER database lacks information on hormone therapy, anti-Her-2 therapy, and baseline characteristics including working status, comorbidity, and socio-economic environmental parameters. Third, the SEER database can not provide detailed chemotherapy and radiotherapy information, so it is impossible to conduct further case-control studies. However, our results will help researchers understand the role of HER2 in the prognosis of MBC.

Our findings supported that, after PSM, PMRT and HER2-positive status were associated with a better prognosis. However, only HER2-negative patients could benefit from PMRT.

The datasets presented in this study can be found online at https://doi.org/10.6084/m9.figshare.19800526.

We sincerely appreciate our department members for providing great support. Thanks are due to TH, LL, and HC for their conception and design of this study and to YZ for her help with the methodology. During the period of writing and revising our manuscript, FD and JS had given us many good suggestions, thanks sincerely. All authors contributed to the article and approved the submitted version.

This study was supported from the National Science Foundation Committee (NSFC) of China (Grant number: No. 81702397 to LL). This project is supported by Hainan Province Clinical Medical Center.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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