Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer

Jung, So‐Youn; Kim, Hyun Yul; Nam, Byung–Ho; Min, Sun Young; Lee, Seung‐Ju; Park, Chansung; Kwon, Youngmee; Kim, Eun-A; Ko, Kyung Rae; Shin, Kyung Hwan; Lee, Keun Seok; Park, In Hae; Lee, Seeyoun; Kim, Seok Won; Kang, Hyejin; Ro, Jungsil

doi:10.1007/s10549-010-0780-8

Cited by 184 publications

(221 citation statements)

References 28 publications

Supporting

Mentioning

193

Contrasting

Unclassified

Order By: Relevance

“…Estrogen receptor positivity was ranging from 0 to 19.2%, Pr positivity was 0 to 35.7%, HEr2 expression was 0 to 15.7% and Tn was 80.4 to 100% (14, 15, 21-27). Jung et al also indicated that frequency of a Tn status was higher in MCs than invasive ductal carcinomas (28). Similarly, we found only 1 case to be positive for Er, only 2 cases to be Pr-positive and HEr2 over expression to be present in only one SCC.…”

Section: Discussionsupporting

confidence: 81%

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Çakır

Gönül²,

Uluoğlu³

2012

TJPATH

View full text Add to dashboard Cite

Objective: Metaplastic carcinoma is a rare tumor showing high histological grade and low hormone receptor expression. it has pure epithelial and mixed types. Studies have suggested that metaplastic carcinomas may have a basal-like profile. our aim was to evaluate the clinicopathological features of 11 metaplastic carcinomas and determine their resemblance to basal-like breast carcinomas regarding their morphological and immunohistochemical profile. Material and Method:Eleven metaplastic carcinoma cases were reviewed for their histopathological features. all tumors but one were evaluated for the immunohistochemical expressions of the cytokeratin 5/6, cytokeratin 14 and epidermal growth factor receptor; and hormonal status was assessed.Results: Four of eleven cases were carcinoma with chondroid metaplasia, 3 were adenosquamous carcinoma, 2 were squamous cell carcinoma and 2 were carcinosarcoma. The mean patient age was 53 years and the mean tumor size was 5,1 cm. Histological grade was 3 for all with a nuclear grade of 3. average mitotic count was 31/10 high power fields. Four cases had a central scar, 5 had central necrosis and 7 had geographic necrosis. Tumor growth pattern was pushing in 6 cases and no carcinoma in-situ was identified in 5 cases. Seven of 10 patients had axillary lymph node metastasis. Seven of 10 cases were triple-negative (estrogen receptor-, progesterone receptor-, HEr2-) and 6 of them were positive for cytokeratin 5/6 and/or epidermal growth factor receptor, consistent with basal-like immunophenotype. Cytokeratin 14 was positive in 7 cases. Conclusion:Metaplastic carcinomas are large-sized, high-grade tumors with prominent nuclear pleomorphism and frequent mitosis. They rarely overexpress hormone receptors and HEr2 and generally have basal-like immunophenotype.

show abstract

Section: Discussionsupporting

confidence: 81%

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Çakır

Gönül²,

Uluoğlu³

2012

TJPATH

View full text Add to dashboard Cite

show abstract

“…Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4)(5)(6)(7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10).…”

mentioning

confidence: 99%

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman

Miltenburg

Michalak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

View full text Add to dashboard Cite

Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4-7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter. Results Development of a GEMM-ESC Strategy for Mouse Mammary TumorModels. GEMMs have the potential to capture the cell-intrinsic and cell-extrinsic factors that drive de novo tumor formation, making them exceptionally valuable for cancer research (11). To speed up the development of novel multiallele GEMMs of human cancer, we...

show abstract

“…[1][2][3][4][5] Metaplastic carcinoma of the breast typically presents at a more-advanced stage than either invasive ductal or lobular adenocarcinoma cases and, in general, has a worse prognosis. 6,7 On routine biomarker testing for estrogen receptor (ER) and/or progesterone receptor (PR) status, most MPBCs are negative. 8 Similarly, virtually all MPBC cases are negative for HER2 overexpression and amplification by either immunohistochemistry (IHC) and/or fluorescence in situ hybridization.…”

mentioning

confidence: 99%

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Ross

Badve

Wang

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

View full text Add to dashboard Cite

Context.-Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy.Objective.-To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC.Design.-Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffinembedded specimens and sequenced to high uniform coverage.Results.-The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The mostcommon alterations were in TP53 (n ¼ 69; 75%), PIK3CA (n ¼ 37; 40%), MYC (n ¼ 28; 30%), MLL2 (n ¼ 28; 30%), PTEN (n ¼ 23; 25%), CDKN2A/B (n ¼ 19; 20%), CCND3 (n ¼ 14; 15%), CCNE1 (n ¼ 9; 10%), EGFR (n ¼ 9; 10%), and KDM6A (n ¼ 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment.Conclusions.-Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.

show abstract

Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer

Cited by 184 publications

References 28 publications

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Contact Info

Product

Resources

About