Metaplastic Breast Cancer: Current Understanding and Future Directions

Abstract

Metaplastic breast cancers (MBC) encompass a group of highly heterogeneous tumors which share the ability to differentiate into squamous, mesenchymal or neuroectodermal components. While often termed rare breast tumors, given the relatively high prevalence of breast cancer, they are seen with some frequency. Depending upon the definition applied, MBC represents 0.2% to 1% of breast cancers diagnosed in the United States. Less is known about the epidemiology of MBC globally, though a growing number of reports are providing information on this. These tumors are often more advanced at presentation relative to breast cancer broadly. While more indolent subtypes exist, the majority of MBC subtypes are associated with inferior survival. MBC is most commonly of triple-negative phenotype. In less common hormone receptor positive MBCs, hormone receptor status appears not to be prognostic. In contrast, relatively rare HER2-positive MBCs are associated with superior outcomes. Multiple potentially targetable molecular features are overrepresented in MBC including DNA repair deficiency signatures and PIK3/AKT/mTOR and WNT pathways alterations. Data on the prevalence of targets for novel antibody-drug conjugates is also emerging. While chemotherapy appears to be less active in MBC than in other breast cancer subtypes, efficacy is seen in some MBCs. Disease-specific trials, as well as reports of exceptional responses, may provide clues for novel approaches to this often hard-to-treat breast cancer. Strategies which harness newer research tools, such as large data and artificial intelligence hold the promise of overcoming historic barriers to the study of uncommon tumors and could markedly advance disease-specific understanding in MBC.

Keywords: Breast cancer; Digital pathology; Metaplastic; Rare; Spindle cell.

Figure 1

Lower Risk Metaplastic Breast Cancer Histologies (a) Low-grade adenosquamous carcinoma (b) Fibromatosis-like metaplastic carcinoma

Figure 2

Aggressive Metaplastic Histologies (a) Spindle cell carcinoma (b) Squamous cell carcinoma (c) metaplastic carcinoma matrix producing type

Figure 2

Aggressive Metaplastic Histologies (a) Spindle cell carcinoma (b) Squamous cell carcinoma (c) metaplastic carcinoma matrix producing type

Figure 3

Pathologic complete response rates to neoadjuvant therapy in single institution and database series. Abbreviations: MDACC, MD Anderson Cancer Center; MSKCC, NCDB, National Cancer Database.

Figure 4

Proposed schema for prospective identification of participants with metaplastic breast cancer entering onto clinical trials.

Figure 5

Proposed schema for utilizing artificial-intelligence and digital pathology in the electronic health record to prospectively identify and group patients with uncommon breast tumors. Abbreviations: EHR, electronic health record