Metaplastic Breast Cancer: Current Insights and Therapies

Metaplastic breast cancer (MpBC) is a rare and aggressive subtype of breast cancer, accounting for less than 5% of cases. It is distinguished by its resistance to standard treatments, making management particularly challenging. Due to its rarity, research remains limited compared to other breast cancer types, necessitating ongoing efforts to improve understanding and therapeutic options.

Given its unique characteristics and poor response to conventional therapies, MpBC requires specialized diagnostic and treatment strategies. Understanding its histology, molecular features, clinical behavior, and management approaches can help guide more effective interventions.

Histological Variations

MpBC exhibits diverse histological patterns that set it apart from more common breast malignancies. Unlike invasive ductal carcinoma, which maintains a uniform epithelial morphology, MpBC features both epithelial and mesenchymal components. This biphasic nature contributes to its heterogeneity, with tumors often displaying squamous, spindle cell, chondroid, or osseous differentiation. These variations influence tumor behavior, making histopathological classification essential for understanding disease progression.

Among the recognized subtypes, spindle cell carcinoma consists of elongated, fibroblast-like cells that can resemble sarcomas, complicating diagnosis. Squamous cell carcinoma features keratinizing or non-keratinizing epithelial cells forming nests or sheets. Less frequently, MpBC may exhibit cartilaginous or osseous metaplasia, where tumor cells differentiate into chondrocytes or osteoblast-like cells, respectively. These mesenchymal components contribute to the tumor’s aggressive nature, often correlating with increased proliferation and treatment resistance.

Most MpBC cases are triple-negative, lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. This aligns with the basal-like phenotype, known for its poor prognosis and limited treatment options. Additionally, MpBC tumors are typically high-grade, with marked nuclear pleomorphism, abundant mitotic figures, and areas of necrosis, all contributing to their aggressive clinical course.

Genetic and Molecular Traits

MpBC exhibits a distinct genetic landscape. Unlike hormone receptor-positive or HER2-amplified subtypes, MpBC lacks targetable molecular drivers, complicating treatment. Genomic studies reveal frequent mutations in TP53, PIK3CA, and PTEN, genes associated with basal-like breast cancer. TP53 mutations, present in over 60% of MpBC cases, lead to defective DNA damage response and uncontrolled proliferation, contributing to the disease’s aggressive behavior.

Alterations in the PI3K/AKT/mTOR pathway, particularly through PIK3CA mutations and PTEN loss, promote sustained oncogenic signaling. Approximately 30–40% of MpBC tumors harbor PIK3CA mutations, a rate comparable to other triple-negative breast cancers (TNBC). While PI3K inhibitors show promise in hormone receptor-positive breast cancer, their efficacy in MpBC remains uncertain.

Epigenetic modifications also play a role, with aberrant promoter methylation and histone modifications contributing to gene silencing. Hypermethylation of tumor suppressor genes such as RASSF1A and CDH1 may facilitate epithelial-to-mesenchymal transition (EMT), enhancing tumor invasiveness and metastatic potential. EMT-related transcription factors like ZEB1, SNAI1, and TWIST1 are frequently upregulated, reinforcing MpBC’s mesenchymal phenotype and resistance to conventional therapies.

Genomic instability, characterized by high tumor mutational burden (TMB) and chromosomal rearrangements, adds to MpBC’s heterogeneity. Whole-exome sequencing studies identify recurrent copy number alterations, including MYC gains and RB1 losses, complicating therapeutic targeting. These genomic aberrations suggest MpBC may respond differently to emerging treatments, including immune checkpoint inhibitors, though clinical evidence remains limited.

Clinical Presentation

Patients with MpBC often present with rapidly growing breast masses. Unlike the small, irregular lumps seen in invasive ductal carcinoma, MpBC tumors are typically larger at diagnosis, frequently exceeding 3–5 cm. Rapid expansion can cause skin changes such as erythema, ulceration, or dimpling, sometimes resembling inflammatory breast cancer.

On palpation, MpBC tumors feel firm and well-circumscribed, sometimes lobulated. Their mesenchymal components can give them a deceptively benign appearance. Unlike classic ductal carcinomas, which frequently spread through the lymphatic system, MpBC has a lower rate of axillary lymph node involvement (10–30%) but a higher propensity for hematogenous dissemination, often affecting the lungs, bones, and liver. This pattern underscores the need for thorough systemic evaluation at diagnosis.

Imaging findings can complicate early identification. Mammography may show round or oval masses with circumscribed margins, resembling benign fibroadenomas. Ultrasound often reveals mixed echogenicity, while MRI highlights irregular enhancement patterns suggesting high vascularity. Despite these tools, histopathological confirmation is essential for diagnosis.

Diagnostic Methods

Diagnosing MpBC requires imaging, histopathological evaluation, and molecular testing. While mammography is the first-line imaging modality, MpBC often appears as a well-circumscribed, non-calcified mass, sometimes mistaken for a benign lesion. Ultrasound and MRI provide further characterization, revealing heterogeneous internal structures and irregular enhancement patterns. Given MpBC’s low rate of axillary lymph node involvement, a large primary tumor with minimal nodal disease should raise suspicion.

Core needle biopsy is preferred over fine-needle aspiration, as it provides sufficient tissue for analysis. Histological examination reveals a mixture of epithelial and mesenchymal components, requiring differentiation from sarcomas and other rare breast tumors. Immunohistochemical staining typically confirms triple-negative status, with additional markers such as cytokeratins, vimentin, and p63 highlighting epithelial and mesenchymal differentiation. Given MpBC’s frequent EMT features, identifying spindle cell, squamous, or cartilaginous elements is key to distinguishing it from other TNBCs.

Common Treatment Approaches

Managing MpBC is challenging due to its resistance to conventional therapies. Standard treatment includes surgery, chemotherapy, and radiation, though response rates are lower than in other breast cancer subtypes. Given its triple-negative status, hormone therapy and HER2-targeted treatments are generally ineffective, necessitating alternative strategies.

Surgical resection, via mastectomy or lumpectomy with clear margins, is the cornerstone of local management. MpBC has a higher risk of local recurrence than invasive ductal carcinoma, emphasizing the need for negative surgical margins. Sentinel lymph node biopsy or axillary dissection may be performed, though nodal involvement is less common.

Chemotherapy, typically with anthracycline- and taxane-based regimens, remains the mainstay of systemic treatment, but MpBC often exhibits limited chemosensitivity. Platinum-based drugs show variable effectiveness in small studies. Radiation therapy is recommended post-surgery, particularly in cases with large tumors or positive margins, though its impact on survival remains uncertain due to MpBC’s tendency for distant recurrence.

Emerging therapies aim to improve outcomes. Given frequent PI3K/AKT/mTOR pathway activation, targeted inhibitors are under investigation, though clinical efficacy remains unproven. Immunotherapy, particularly immune checkpoint inhibitors targeting PD-1/PD-L1, shows promise in early studies. Research into EMT inhibitors continues, as MpBC’s mesenchymal phenotype contributes to its aggressive behavior and treatment resistance. These novel strategies highlight the evolving landscape of MpBC management and the need for tailored approaches.

Prognostic Factors

MpBC generally has a poorer prognosis than other breast cancer subtypes due to its aggressive biology and limited treatment options. Prognosis is influenced by tumor size, histological subtype, molecular characteristics, and treatment response. Larger tumors at diagnosis correlate with worse outcomes, as they often indicate advanced disease and higher metastatic potential.

Histological composition also impacts prognosis, with tumors exhibiting chondroid or osseous differentiation sometimes showing slightly better outcomes than those with purely spindle cell or squamous features. Molecular markers further refine prognostic predictions, with frequent TP53 mutations and PI3K/AKT pathway activation driving rapid progression and treatment resistance.

Despite MpBC’s lower rate of axillary lymph node involvement, distant hematogenous spread is common. Five-year survival rates range from 40% to 60%, depending on disease stage and treatment response. Given its aggressive nature, continued research into novel therapies remains critical to improving outcomes.