A comprehensive overview of metaplastic breast cancer: Features and treatments

Abstract

Metaplastic breast cancer is a rare, aggressive, and chemotherapy‐resistant subtype of breast cancers, accounting for less than 1% of invasive breast cancers, characterized by adenocarcinoma with spindle cells, squamous epithelium, and/or mesenchymal tissue differentiation. The majority of metaplastic breast cancers exhibit the characteristics of triple‐negative breast cancer and have unfavorable prognoses with a lower survival rate. This subtype often displays gene alterations in the PI3K/AKT pathway, Wnt/β‐catenin pathway, and cell cycle dysregulation and demonstrates epithelial–mesenchymal transition, immune response changes, TP53 mutation, EGFR amplification, and so on. Currently, the optimal treatment of metaplastic breast cancer remains uncertain. This article provides a comprehensive review on the clinical features, molecular characteristics, invasion and metastasis patterns, and prognosis of metaplastic breast cancer, as well as recent advancements in treatment strategies.

This article provides a comprehensive review on the clinical features, molecular characteristics, invasion and metastasis patterns, and prognosis of metaplastic breast cancer, as well as recent advancements in treatment strategies.

1. INTRODUCTION

Breast cancer is the most common cancer in women globally, ¹ accounting for approximately 31% of all female cancers, ² and the most prevalent histological subtype is invasive ductal carcinoma (IDC), accounting for 55% of all breast cancer cases. ¹ Besides, there are some other subtypes such as invasive lobular carcinoma (ILC), metaplastic breast carcinoma (MpBC), apocrine breast carcinoma (ABC), adenoid cystic carcinoma (ACC), and so on. ³ As a rare histological subtype, MpBC comprises less than 1% of invasive breast cancers. ⁴ MpBC is a heterogeneous tumor characterized by adenocarcinoma with spindle cell, squamous epithelium, and/or mesenchymal differentiation. ⁵ Based on the WHO Classification 5th Edition, MpBC has been categorized into several subgroups: spindle cell carcinoma, squamous cell carcinoma, metaplastic carcinoma with heterogeneous differentiation, low‐grade adenosquamous carcinoma, low‐grade fibromatosis‐like carcinoma, and mixed metaplastic carcinoma. ⁶

Metaplastic breast carcinoma, with a median age at diagnosis of 56.2–63 years, ¹ , ⁴ , ⁵ most often presents as a rapidly growing breast mass with limited lymph node involvement, higher histological grade, increased incidence of stage III and IV diseases, and elevated risk of local recurrence compared with IDC. ⁷ , ⁸ , ⁹ , ¹⁰ Most MpBCs exhibit triple‐negative phenotype (>90%), ⁴ with metastases occurring more easily than in triple‐negative breast cancers (TNBCs). ¹⁰ , ¹¹ MpBC is typically resistant to chemotherapy, shows poor response to standard cytotoxic therapy, ⁵ , ⁷ and has a worse prognosis compared with TNBC. ⁴ , ¹² The 5‐year overall survival (OS) of MpBC is found to be lower than that of TNBC among nonmetastatic tumors, with rates of 60.5% and 65.2%, respectively ¹² (Table 2). Moreover, among several MpBC subtypes, the squamous subtype was related to better prognosis, ¹³ and mixed metaplastic carcinomas were associated with worse recurrence‐free survival and breast cancer‐specific survival (BCSS). ¹³ , ¹⁴

TABLE 2.

Differences in treatment and prognosis between MpBC and non‐MpBC.

Treatment and prognosis				MpBC	Non‐MpBC	Cases (MpBC/non‐MpBC)	Author and year
Prognosis
	OS			85.16%	94.04% (IDC)	155/16,251	Lee et al., 2023
	5‐year OS			60.5%	65.2% (IDC)	4037/4037	Polamraju et al., 2019
Treatment with radiotherapy
	Yes—out of all patients			80.00%	71.86% (IDC)	155/16,251	Lee et al., 2023
				52.5%	60.8% (IDC)	5142/50,705	Polamraju et al., 2019
Treatment with chemotherapy
Adjuvant +/− neoadjuvant	Yes—out of all patients			78.8%	87.5% (IDC)	5142/50,705	Polamraju et al., 2019
Adjuvant	Yes—out of all patients			90.32%	64.21% (IDC)	155/16,251	Lee et al., 2023
Neoadjuvant	Yes—out of all patients (pCR)			30% (17%)	—	97/−	Han et al., 2018
	pCR			2%	—	44/−	Wong et al.,2021
	pCR			23%	40%	39/172	Yam et al., 2022
	pCR			22%		255 (Total)	Liedtke et al., 2023
	pCR			37.5%		176 (Total)	Huang et al., 2023
Treatment with immunotherapy
Ipilimumab + nivolumab	ORR			18% (3/17)	—	17/−	Adams et al., 2022
Pembrolizumab + capecitabine	ORR			67% (2/3)	36% (4/11)	3/11	Page et al., 2023
Atezolizumab + nabpaclitaxel	36‐month OS(without PD)			28.1% (2.66%)		451 (Total)	Emens et al., 2021
Treatment with targeted therapy
PI3K + MEK	BYL‐719 + selumetinib	TGI	HBCx‐60 PDX	94%	—	10/−	Coussy et al., 2020
			HBCx‐165 PDX	91%	—	10/−
			HBCx‐178 PDX	All (10/10, 60% CR)	—	10/−
PARP	Talazoparib	pCR		100% (1/1)	47% (8/17)	1/17	Litton et al., 2019
PP2A	DT1154	Respond		All (5/5)	All (3/3)	5/3	Risom et al., 2020

Abbreviations: CR, complete response; IDC, invasive ductal carcinoma; MpBC, metaplastic breast cancer; ORR, objective response rate; OS, overall survival; PARP, poly‐(adenosine diphosphate [ADP]‐ribose) polymerase; pCR, pathologic complete response; PD, progressive disease; PP2A, protein phosphatase 2A; TGI, tumor growth inhibition.

The purpose of this review is to provide a comprehensive overview of MpBC, including clinical and molecular characteristics, mechanisms of invasion and metastasis, prognosis, and current treatment advancements (Figure 1).

FIGURE 1.

Metaplastic breast cancer: features, invasion, and treatments.

2. MOLECULAR CHARACTERISTICS OF MPBC

2.1. Protein molecular characteristics

Metaplastic breast carcinomas exhibit a significantly enriched epithelial‐to‐mesenchymal transition (EMT) phenotype (Table 1), accompanied by heightened inflammatory response, an active extracellular matrix (ECM), and reduced oxidative phosphorylation, which indicate deregulation of the immune system and extracellular structural organization. ¹¹

TABLE 1.

Differences in molecular characteristics among several MpBC subtypes and non‐MpBC.

Molecular characteristics		MpBC				Non‐MpBC	Cases (MpBC/non‐MpBC)	Author and year
		Squamous	Spindle cell	With heterogeneous differentiation	Others
Protein profiles	EMT	Upregulated				Reference	15/6	Djomehri et al., 2020
		—	Exhibit	Amplified	—
	Keratinization	Upregulated	—	—	—	—
	Extracellular matrix	—	—	Upregulated	—	—
	E‐cadherin expression	Aberrant				Normal/aberrant	104/453	McCart Reed et al., 2019
		Aberrant	Negative	—	—
TP53 mutations		59%				51%	39/172	Yam et al., 2022
		78%				—	60/−	da Silva et al., 2021
		86% (12/14)	63% (10/16)	83% (25/30)	—
		64%				58%	28/125	Krings et al., 2018
		60% (3/5)	0% (0/5)	90% (9/10)	75% (6/8)
PI3K family	PIK3CA mutations	23%				9%	39/172	Yam et al., 2022
		32%				13%	28/125	Krings et al., 2018
		60% (3/5)	20% (1/5)	0% (0/10)	63% (5/8)
		23%				—	60/−	Da Silva et al., 2021
		43% (6/14)	38% (6/16)	7% (2/30)	—
	Other members mutations	41%				18%	39/172	Yam C et al., 2022
Wnt pathway	Somatic mutations	51%				28%	35/69 (triple‐negative IDC)	Ng et al., 2017
	MYC amplification	26%				—	35/−	Moukarzel et al., 2021
CDKN2A	Alterations	14%				—	35/−	Moukarzel et al., 2020
	Gene loss	—	—	—	All (34/34)	‐	34 (myoepithelial‐like MpBC)/−	Bartels et al., 2018
		7% (2/28)				—	28/125	Krings et al., 2018
		0% (0/5)	—	10% (1/10)	0% (0/8)
EGFR	Amplification	17%				—	39/172	Yam C et al., 2022
TERT promoter mutations		25%				—	28/125	Krings et al., 2018
		20% (1/5)	80% (4/5)	0%(0/10)	25% (2/8)
		17%				—	60/−	DA Silva et al., 2021
		21% (3/14)	31% (5/16)	7% (2/30)	—
		0.9%					319 (Total invasive breast cancer)	Shimoi et al., 2017
BRCA‐positive		1.2%				0.2%	1114/4112	Corso et al., 2023
Angiogenesis‐related gene sets		Significant enrichment (NES = 1.81)				—	13/1051	Chouliaras et al., 2021
EMT gene sets		Significant enrichment (NES = 1.88)				—	13/1051	Chouliaras et al., 2021

Abbreviations: BRCA‐positive, carriers of a pathogenic variant in BRCA1 and/or BRCA2 genes; EMT, epithelial‐to‐mesenchymal transition; MpBC, metaplastic breast cancer; NES, normalized enrichment score.

Metaplastic breast carcinomas can be categorized into spindle, squamous, and sarcomatoid subtypes based on their histological characteristics. The high heterogeneity observed among different subtypes of MpBC is characterized by subtype‐specific proteins and pathways ¹¹ (Table 1). Spindle subtypes, which are claudin‐low subtypes, possess abundant mesenchymal stem‐like characteristics ⁴ and demonstrate high proliferation capacity with pathological evidence of EMT. They can upregulate the expression of E2F and MYC pathway proteins, ribosomal proteins, and proteins involved in ribosomal function, translation, and RNA metabolism. E2F and MYC play a significant role during carcinoma cell proliferation and EMT processes. ¹¹ The squamous subtypes of MpBC are characterized by the upregulation of inflammatory responses, keratinization, and widespread cell adhesion marker expressionand the downregulation of the oxidative phosphorylation, MYC, and E2F pathways. ¹¹ On the other hand, sarcomatoid MpBCs demonstrate an advantage in ECM signaling cascades and an amplified EMT program, with increased oxidative phosphorylation and reduced inflammatory responses compared with the other two subtypes, possibly due to their differentiation along the mesenchymal lineage. ¹¹

Furthermore, significant expression of vascular endothelial growth factor (VEGF) and programmed cell death‐ligand 1 (PD‐L1) was observed in MpBC, ⁹ accompanied by decreasing mesenchymal stem cell protein expression (CD59, CD248), macrophages (CD209), immune cells (CD8A), hematopoietic stem/endothelial progenitor/macrophages (CD34, CD36, CDH5), and the presence of endothelial‐to‐mesenchymal transition (EndMT). ¹¹

2.2. Genetic characteristics

Metaplastic breast carcinomas have a high degree of genomic instability and display intricate patterns of copy number variations. ¹¹ Compared with TNBC, MpBCs typically harbor significantly more mutations in TP53 (59% vs. 51%), PIK3CA (23% vs. 9%), and other members of the PI3K pathway (41% vs. 18%), ⁴ present genetic alterations in the Wnt pathway, ¹¹ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ and demonstrate CDKN2A loss, ¹¹ , ¹⁹ EGFR overexpression and amplification, ¹¹ MYC amplification, ²⁰ TERT promoter hotspot mutations and gene amplification, ¹⁰ , ¹⁶ , ²¹ the enrichment of angiogenic genes, ²² and changes in genes related to the cell cycle ²³ (Table 1). Furthermore, no differences between MpBCs and non‐Mp TNBCs in the domains frequently mutated in either TP53 or PIK3CA, showing they have similar genetic alterations. ⁴ TP53 mutations are relevant to the upregulation of VEGF‐A and treatment of TP53‐mutant tumors with anti‐angiogenic agents is associated with improved outcomes. ²⁴ TERT promoter hotspot mutations and TERT gene amplification are significantly correlated with PIK3CA hotspot mutations and inversely associated with TP53 mutations. ²¹ The majority of MYC amplifications is observed in relapse/progression samples compared with primary tumors. ²⁰

The expression of 115 genes has been found to be significantly different between MpBCs and non‐Mp TNBCs, with a considerable percentage of differentially expressed genes being associated with cell type identity. For instance, the expression of epithelial markers is significantly enriched in TNBCs, whereas MpBCs have a strong characteristic of mesenchymal gene expression. ⁴ Likewise, hypoxia and EMT gene signatures are upregulated in MpBCs. ⁴ , ²³

The squamous subtypes are enriched in genes associated with the RTK‐MAPK signaling pathway, exhibiting upregulation of apoptosis, immune response, cell adhesion, and modification of the microenvironment. ⁴ , ²³ Spindle MpBCs exhibit the upregulation of stem cell‐related genes and the EMT, display enrichment in claudin‐low and TGF‐β signatures, and demonstrate the downregulation of various genes involved in nucleosome organization and the cell cycle. Moreover, spindle MpBCs are associated with the enrichment of macrophage signatures and the immune inhibitory genes PD‐L2 and B3‐H3 the downregulation of the immune‐related gene TIGIT, ²³ and increased HDAC activity. ⁴ Compared with both spindle and squamous subtypes, sarcomatoid MpBCs have distinct mutations, particularly in MAPK, WNT, and protocadherin cluster genes related to calcium binding and ECM organization. ¹¹

3. INVASION AND METASTASIS

The aggressive clinical behavior of MpBC may be attributed to EMT, ¹¹ which controls tumor initiation, progression, metastasis, and resistance to anticancer therapies and plays a key role in facilitating the invasion and migration of stationary cancer cells. ²⁵ , ²⁶ , ²⁷ , ²⁸ It is reasoned that EMT is a developmental process of the loss of cell–cell adhesion among epithelial cancer cells and the acquisition of mesenchymal characteristics. ²⁶ During this process, the loss of E‐cadherin, a cell adhesion molecule presented in adherens junctions, is a pivotal molecular event necessary for EMT. ²⁹ Key transcription factors activating CDH1 (encoding E‐cadherin) expression such as EP300, FOXA1, and RUNX1 are apt to maintain the epithelial phenotype; however, Snail, Zeb, Twist, or FOXC2 repress CDH1 expression and tend to acquire a mesenchymal‐like state. ²⁹ McCart Reed et al. revealed that MpBCs were significantly enriched for aberrant or negative expression of E‐cadherin comparing the expression of E‐cadherin in MpBC and other cancers (Table 1). Those patients whose epithelial marker E‐cadherin is negative trend toward a poorer outcome, while a survival advantage was confirmed in cases with aberrant E‐cadherin in comparison with a complete loss of expression. ¹³ Both EP300 and E‐cadherin were found to have a strong downregulation in MpBCs. In cells with a permissive E‐cadherin promoter, EP300 functions as a tumor/metastasis suppressor by upregulating E‐cadherin expression, maintening the epithelial phenotype, and avoiding EMT. In cells with a hypermethylated E‐cadherin promoter, EP300 acts as an oncogene to promote traditional carcinogenesis and enhance metastasis via upregulation of aldo‐keto reductases. Notably, the combination of both markers together seems to be a better predictor of lymph node metastasis than E‐cadherin alone. ³⁰ Several potent inducers of EMT containing Snail, Twist, and Zeb1 as well as ligands including TGFβ and Wnt could induce EMT which increases the metastatic potential of cancer cells. ²⁸

In addition to EMT, the upregulation of stem cell pathways might also be implicated in the increase of drug resistance in MpBCs. ⁴ A study discovered an increase in EMT and cancer stem cell‐like cell (CSC) characteristics (ALDH⁺ and CD44^high/CD24^low) also accompanied by an increase in drug resistance. ³⁰ Moreover, CSCs could express varieties of stem cell and drug resistance markers which make them fill metastatic sites facilitating the formation of secondary cancers nonresponsive to chemotherapy. ²⁹ MicroRNAs were gradually being recognized as major regulators of drug resistance, EMT, and CSCs. Furthermore, Kumar et al. ²⁹ revealed that miR‐495‐3p regulates multidrug resistance (MDR) in metaplastic BAS cells by targeting FOXC1 and the TGF‐β mRNAs. Transforming growth factor β2 (TGFB2) also has been demonstrated to regulate MDR via downregulating FOXC1 and resensitizing BAS MDR cells, as pharmacological inhibition of this pathway leads to the downregulation of FOXC1 and restores sensitivity in BAS MDR cells. Moreover, data indicate that the upregulation of FOXC1, which is upregulated in MpBCs, could result in drug resistance, and this regulation of drug resistance is independent of E‐cadherin. ²⁹

Metaplastic breast carcinomas often harbor multinucleated cells, which are associated with increased tolerance for mutation, resistance to chemotherapy, and invasive potential. Simi et al. ³¹ have shown that matrix stiffness could regulate the degree of multinucleation in mammary epithelial cells. More specifically, the relative content of collagen is significantly related to stiffness among breast cancers, and Snail and septin‐6 have highly elevated expression levels in tumor regions characterized by high collagen. MMP3 induces the expression of the Rac1 splice variant, known as Rac1b, which on stiff substrata localizes to the plasma membrane and combines with NADPH oxidase to generate reactive oxygen species, hence resulting in the upregulation of Snail. Snail could upregulate the levels of septin‐6 in cells on stiff microenvironments. Septin‐6 overexpression increases midbody persistence, which could prevent or delay abscission and result in subsequent multinucleation. ³¹ On the contrary, a soft microenvironment safeguarded mammary epithelial cells from transforming into multinucleated cells via blocking the upregulation of septin‐6 induced by Snail. In addition, cancerous mutations in BRCA2 are associated with multinucleation by causing a failure of cytokinesis upon improper regulation of the midbody. ³¹

In addition to the above factors, SOX10 also was confirmed to be associated with poor prognosis of MpBCs. ³² Given that intratumoral heterogeneity partially arises from phenotypic plasticity and genomic instability, nuclear SOX10, a transcription factor implicated in phenotypic plasticity, was found to be able to predict poor outcome of MpBCs in a research by Saunus et al. The research demonstrated that SOX10 positivity was linked to histologic characteristics, for instance, high grade, metaplastic morphology, pushing margins, and a larger mass at diagnosis. SOX10 was also discovered to be over‐represented in brain metastatic cases rather than cross‐sectional TNBCs. Moreover, Saunus et al. ³² observed nuclear SOX10 in an independent cohort of MpBCs, where SOX10 staining was more heterogeneous compared with cross‐sectional TNBCs, and was not correlated with triple‐negative status. However, SOX10 has a prognostic effect among MpBCs with a TNBC phenotype.

4. TREATMENT PROGRESS

Currently, the optimum therapeutic regimens of patients with MpBC are still disputable. Like IDC, surgery, chemotherapy, and radiotherapy continue to be regarded as the mainstay of treatments for MpBCs based on the NCCN Clinical Practice Guidelines in Oncology for breast cancer. ⁶ Elimimian et al. ¹ have noted that surgery was performed at the primary tumor site for 93.7% of patients with MpBCs, while chemotherapy and radiotherapy accounted for 68.6% and 49.7% of patients, respectively. Compared with IDC, MpBC patients had a poor OS, ³ which indicated the inadequacy of current treatment options and an urgent need for novel therapeutic strategies to improve the prognosis of MpBC patients (Table 2).

4.1. Chemotherapy

Neoadjuvant chemotherapy (NAC) is frequently considered a treatment option for patients diagnosed with MpBC, based on the advanced stage at initial presentation and triple‐negative receptor status. ³³ Compared with the pathologic complete response (pCR) rate of 22%–48.6% in TNBCs receiving NAC, ³⁴ , ³⁵ , ³⁶ , ³⁷ the pCR rate of MpBCs is lower. However, one study by Yam et al., ⁴ the largest prospective evaluation of NAT in patients with triple‐negative MpBC, reported a pCR rate of 23%. Han et al. ¹⁴ also demonstrated a pCR rate of 17.2% in previous studies. These are substantially higher compared with historical data of less than 10% ⁴ , ³³ (Table 2). These findings suggest that sequential anthracycline‐ and taxane‐based neoadjuvant therapy should be considered for patients with MpBC. Besides these, studies have also shown that different histological subtypes responded differently to NAC. ⁴ , ¹⁴ , ³³ Therefore, given the heterogeneity in the biology of MpBC and responses to neoadjuvant therapy, biomarkers are required to ensure appropriate patient selection; also, close monitoring by serial breast imaging is necessary to assess for early disease progression during treatment.

4.2. Immunotherapy

According to research findings, frequent overexpression of PD‐L1 has been found in primary MpBCs, with PD‐L1 positivity in cancer cells. Similarly, the presence of PD‐1/PD‐L1 expressing tumor‐infiltrating lymphocytes (TILs) was demonstrated in MpBC, suggestive of an immunogenic tumor phenotype in MpBCs. ⁵ , ³⁸ , ³⁹ , ⁴⁰ Moreover, the squamous subtypes displayed higher tumoral PD‐L1 expression and presence of TILs than other subtypes. ⁴¹ , ⁴² It implied the presence of immunogenic tumor phenotype in some patients with MpBCs. Given the above findings, limited treatment options, and poor prognosis of MpBCs, studies to immunotherapies in this subtype have been taken into account rationally. ⁵

The 36th cohort of the DART trial, the first prospective trial of immunotherapy in MpBCs, demonstrated that ipilimumab (anti‐CTLA4 blockade) plus nivolumab (anti‐PD‐1 blockade) was clinically active in advanced MpBCs, accompanied by the 18% of objective response rate (Table 2). All responses observed in this cohort were durable (28+, 33+, and 34+ months). ⁵ However, in one clinical trial of pembrolizumab plus paclitaxel or flat‐dose capecitabine, two patients with MpBC observed partial response, and progression‐free survival (PFS) was only 5.3 and 5.7 months. ⁴³ Accordingly, responses to chemotherapy combined with anti‐PD‐1 therapy observed in MpBC may not be durable, and a combination with other immunotherapies was needed to obtain durable responses. ⁵ Likewise, the final analysis from IMpassion130 showed that among patients alive at 3 years, only 2.66% treated with immunotherapy plus chemotherapy did not experience disease progression. Moreover, compared with patients with PD‐L1 positivity in immune cells benefiting more significantly from anti‐PD‐L1 therapy among TNBCs, ⁵ , ⁴⁴ clinical responses have been discovered even in MpBCs with negative or low PD‐L1 expression and low TIL level, which may indicate that the anti‐CTLA therapy contributes to some extent to the clinical activity of the regimen of the DART trial. ⁵ Significantly, greater toxicity and higher mortality rates were related to the addition of anti‐CTLA‐4 to anti‐PD‐1/PD‐L1 regimens. These risks seem to be manageable by dose adjustment, as adverse events (AEs) were observed to occur more frequently at higher doses of ipilimumab. ⁵

4.3. Targeted therapies

4.3.1. Combination of PI3K and MEK inhibitors

The strong enrichment in alterations of PIK3CA and other members of the PI3K‐AKT‐mTOR pathway along with the RTK‐MAPK signaling pathway seems to indicate that these pathways are rational therapeutic targets for MpBC. ⁴ , ⁷ In fact, Coussy et al. observed that combined application of the PI3K inhibitor BYL‐719 (alpelisib) with the MEK inhibitor selumetinib showed significant efficacy among MpBC patient‐derived xenografts (PDX) models with PIK3CA variations and aberrations to the RTK‐MAPK signaling pathway (Table 2). Specifically, therapy with PI3K or MEK inhibitors alone in the treatment of two MpBC PDX models with PIK3CA mutation and FGFR4 amplification resulted in the attenuation of tumor growth with no regression. In comparison, treatment with PI3K plus MEK inhibitors resulted in some complete and persistent remissions in three MpBC PDX models, which might be connected with the high inhibition of both the PI3K and MAPK signal pathways. ⁷ Compared to chemotherapy, the combination of PI3K and MEK inhibitors has advantages with significant tumor regression in chemoresistant models and also shows similar efficacy to chemotherapy in chemosensitive models. ⁷ Furthermore, in clinical practice, the combination of PI3K and MEK inhibitors seems to be feasible, with a manageable safety and toxicity profile. ⁷

4.3.2. PARP inhibitor

MpBCs have been shown to be relevant to BCRA‐positive breast cancers. ⁴⁵ Likewise, Corso et al. ⁴⁶ demonstrated breast cancer patients who carried a germline pathogenic variant in the BRCA genes proved to have an increased risk of developing MpBC relative to other BRCA noncarriers (1.2% vs. 0.2%; Table 1). In addition to being more susceptible to platinum agents, patients carrying a germline pathogenic variant may also be more sensitive to poly‐(adenosine diphosphate [ADP]‐ribose) polymerase (PARP) inhibitors, which were approved by the FDA for a metastatic/locally advanced breast cancer indication. ⁶ , ⁴⁷ In a clinical trial of the PARP inhibitor talazoparib for patients with a known germline BRCA pathogenic variant, efficacy has been demonstrated with 53% pCR, including subtypes known for chemoresistance to neoadjuvant treatment such as metaplastic carcinoma (Table 2). The AEs associated with talazoparib were primarily anemia and nausea, and the hematologic toxicity was effectively manageable through strategies such as dosing delay, dose reduction, and blood transfusions. ⁴⁷

4.3.3. Small‐molecule activator of PP2A

Protein phosphatase 2A (PP2A) can facilitate MYC degradation through proteasome and promote the dephosphorylation of AKT, ERK, and MYC. Moreover, PP2A inactivation is observed in breast cancer, resulting in the loss of its function to dephosphorylate and downregulate the activity of kinases and oncogenes related to cell survival and proliferation. ⁴⁸ In addition, MYC;NeuNT tumors have an increased intertumoral heterogeneity, with a distinct tumor characterized by unique metaplastic histology, upregulated mesenchymal differentiation, increased expression of genes relevant to EMT, invasiveness, and relatedness to adult mammary stem cells. Risom et al. ⁴⁸ demonstrated that MYC;NeuNT tumors, including metaplastic subtypes, are sensitive to the small‐molecule activator PP2A DT1154 (Table 2), which not only reduced the phosphorylation of MYC Ser62 but also decreased the expression of p‐ERK and p‐AKT, leading to the attenuation of tumor growth. Additionally, in numerous studies with effective antineoplastic doses, DT1154 has been proven to be well tolerated in animals without obvious toxicities. ⁴⁸

4.4. Radiotherapy

Studies have shown that radiotherapy is beneficial in MpBCs. For instance, Mills et al. ³ pointed out that patients with MpBC who received lumpectomy with radiotherapy had better OS than those treated with mastectomy. Similarly, another study also found that radiotherapy was independently relevant to an improvement in OS and BCSS. ⁴⁹ Moreover, postmastectomy radiotherapy (PMRT) was associated with a better prognosis for TNBC or HER2‐negative cases but not HER2‐positive patients. ⁵⁰ , ⁵¹

5. CONCLUSION

Currently, unique treatment regimens for MpBC that are different from the recommended treatment protocol for IDC have not been provided by the NCCN Clinical Practice Guidelines in Oncology for breast cancer. Moreover, the outcomes of MpBC remain poor with conventional surgery, radiation, and chemotherapy. Considering the identification of possible target sites and the rapid advancement in immunological and targeted therapy, molecular and immunocytochemical testing as well as germline BRCA pathogenic variant testing of breast tumors should be performed for selecting the appropriate treatment strategy to improve the poor prognosis of patients with MpBC. In the future, more well‐designed clinical trials are required for exploring optimal treatment strategies in MpBC.

AUTHOR CONTRIBUTIONS

Qiaoke Yan: Writing – original draft. Yuwei Deng: Writing – review and editing. Qingyuan Zhang: Conceptualization; funding acquisition; project administration; supervision; validation; writing – review and editing.

FUNDING INFORMATION

This work was supported by the Key Program of the Natural Science Foundation of Heilongjiang Province of China (No.ZD2021H004) and the General Program of the National Natural Science Foundation of China (No.8217100680).

CONFLICT OF INTEREST STATEMENT

The authors of this manuscript have no conflict of interest. Nobody of the authors of this manuscript is a current editor or editorial board member of Cancer Science.

ETHICS STATEMENTS

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

Yan Q, Deng Y, Zhang Q. A comprehensive overview of metaplastic breast cancer: Features and treatments. Cancer Sci. 2024;115:2506‐2514. doi: 10.1111/cas.16208