Metaplastic breast cancer (MPBC) is a rare and highly aggressive subtype of breast cancer, characterized histologically by the transformation of neoplastic epithelium into cells with squamous or mesenchymal features (1). This process, known as metaplasia, results in the formation of abnormal tissue types within the breast that can behave aggressively and metastasize distant sites. Although MPBC accounts for only a small percentage of all breast cancers, it is disproportionately associated with a poorer prognosis compared to other breast cancer subtypes (2).

Clinically, MPBC is often managed similarly to triple-negative breast cancer (TNBC), given the lack of expression of hormone receptors and HER2 amplification (3). However, MPBC is generally more aggressive than TNBC, with higher rates of distant metastasis and worse overall prognosis. Due to its low incidence and significant heterogeneity, there are currently no specific treatment guidelines tailored to MPBC. Instead, treatment strategies are largely extrapolated from those used for TNBC and typically include surgery (4), chemotherapy (5), and radiotherapy (6).

The role of surgery in the treatment of MPBC has been increasingly recognized and validated (7). However, there remains a significant gap in research regarding treatment options for patients who did not undergo surgery due to factors such as refusal, tumor progression, comorbidities, or delayed diagnosis.

In this study, we aim to investigate the prognostic impact on MPBC patients who did not undergo surgical treatment. The data were obtained from the SEER database and from patients at The Third People’s Hospital of Chengdu, The First Affiliated Hospital of Chongqing Medical University, and the Chongqing University Cancer Hospital. We expect that this study will provide valuable insights into the management of MPBC patients who did not undergo surgical treatment.

MPBC is a rare and highly aggressive subtype of breast cancer, characterized by its heterogeneous histology and poor prognosis (8). While surgery remains the cornerstone of treatment for MPBC, a portion of patients are not undergoing surgical intervention due to advanced disease, comorbidities, or patient refusal. This study aimed to evaluate the prognostic impact of chemotherapy and radiotherapy in non-surgical MPBC patients using both data from the SEER database and clinical cohort. Our findings demonstrate that chemotherapy significantly improves overall survival (OS) and breast cancer-specific survival (BCSS) in this patient population, while radiotherapy did not show a significant survival benefit. These results underscore the critical role of chemotherapy as a systemic treatment option for non-surgical MPBC patients.

The significant survival benefit observed with chemotherapy in non-surgical MPBC patients has highlighted the aggressive nature of this cancer subtype. MPBC is often compared to triple-negative breast cancer (TNBC) due to its lack of hormone receptor and HER2 expression, which limits the effectiveness of endocrine and targeted therapies (9). In our clinical cohort, the rates of estrogen receptor (ER) and progesterone receptor (PR) negativity were significantly higher than those reported in the SEER database (86.7% and 100%, respectively). Chemotherapy, therefore, remains one of the few systemic treatment options available for MPBC patients. Previous research has indicated that chemotherapy may exert its therapeutic effects in MPBC patients by inhibiting epithelial-mesenchymal transition (EMT) processes (10). However, the SEER database lacks detailed information on specific chemotherapy regimens, limiting our ability to assess the efficacy of different drug combinations or dosing strategies. Future studies should aim to identify optimal chemotherapy protocols for MPBC, particularly in the non-surgical setting.

In our clinical cohort, the proportion of patients with M1 disease was higher than that in the SEER database cohort (53.3% vs. 26.28%). Although radiotherapy did not significantly impact survival in our study, its role in palliative care for advanced MPBC patients should not be overlooked. Radiotherapy is often used to manage local symptoms, such as pain from bone metastases or neurological symptoms from brain metastases. While it may not extend survival, radiotherapy can improve quality of life by alleviating debilitating symptoms. This is particularly relevant for non-surgical patients, who may benefit from symptom control. Future research should explore the impact of radiotherapy on patient-reported outcomes, such as pain relief and functional status, to better understand its role in the management of MPBC.

Current studies on MPBC predominantly concentrate on evaluating the efficacy of chemotherapy and radiotherapy, while lacking comprehensive stratification based on surgical intervention status. For example, Chen et al. demonstrated that chemotherapy might improve survival outcomes in patients with T1c tumors but not in those with T1a or T1b tumors (11). Li et al. observed that radiotherapy may be advantageous for elderly patients or those with larger tumors (12). Wang et al. showed that radiotherapy could enhance breast cancer-specific survival in high-risk patients (13). Hu et al. proposed that postoperative radiotherapy for metaplastic breast cancer could improve breast cancer-specific survival in high-risk groups and overall survival in medium- to high-risk groups (14). Although previous studies have demonstrated the benefits of radiotherapy in reducing local recurrence and improving survival in surgical patients, our results suggest that these benefits may not apply to non-surgical patients, as they often present with more advanced diseases. This discrepancy calls for a more nuanced approach to MPBC treatment, particularly in non-surgical settings, where systemic therapies such as chemotherapy may play a more critical role.

MPBC is characterized by a high degree of molecular heterogeneity, with frequent mutations in genes. These molecular alterations may contribute to the aggressive behavior of MPBC and its resistance to conventional therapies (15). One study reported a case of MPBC with a BRAF V600E mutation that showed a positive response to targeted therapy with dabrafenib and trametinib, highlighting the potential for personalized treatment methods in MPBC (16). Another study demonstrated that MPBC patients had an excellent response to combination therapy including PD-L1 inhibitors and paclitaxel (17, 18). Common genetic mutations in MPBC, such as TP53, PIK3CA, and PTEN, suggest that new targeted strategies could improve survival outcomes for patients (15). A recent study showed that mTOR inhibitors can extend survival in patients with advanced breast cancer or metaplastic triple-negative breast cancer, indicating that drugs targeting the PI3K/AKT/mTOR pathway may benefit MPBC patients (19). Additionally, methylation of the BRCA1 gene promoter has been identified as a potentially relevant factor in metaplastic cancers (20). Research also indicates that activation of the WNT signaling pathway and amplification, and overexpression of the EGFR gene frequently occur in MPBC, pointing to potential therapeutic targets (21, 22). While the treatments show promises for MPBC, all require further validation through large-scale clinical trials.

Our study has several limitations that should be acknowledged. First, the SEER database lacks detailed information on chemotherapy regimens, radiotherapy doses, and patient comorbidities, which may influence treatment outcomes. Second, the small sample size of non-surgical MPBC patients limits the generalizability of our findings. Larger, prospective studies are needed to validate these results and explore the impact of different treatment modalities in this patient population. Additionally, the retrospective nature of our study introduces potential selection bias, as patients who received chemotherapy may have had better performance status or fewer comorbidities. Future studies should aim to control these confounding factors through propensity score matching.

In conclusion, our study demonstrates that chemotherapy significantly improves survival in non-surgical MPBC patients, highlighting its importance as a systemic treatment option. While radiotherapy did not show a survival benefit, it remains a valuable tool for symptom control local symptoms. Future research should focus on identifying optimal chemotherapy regimens, exploring the role of targeted therapies and immunotherapy, and improving palliative care for non-surgical MPBC patients. By addressing these gaps, we can aim to improve outcomes for this challenging and understudied non-surgery patient population.