Subclonal analysis in a lobular breast cancer with classical and solid growth pattern mimicking a solid‐papillary carcinoma

Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/ 13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triplenegative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.

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“…Genomic DNA was extracted as described previously [ 25 ]. In brief, tumor tissue was marked on HE-stained sections of FFPE tissue blocks.…”

Section: Methodsmentioning

confidence: 99%

E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements

et al. 2020

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“…In a subset of cases ( n = 41), namely in all ILBCs with high risk characteristics by molecular expression profiling and/or pleomorphic histology and in all cases with an ERBB2 mutation detected by pyrosequencing, the ERBB2 mutation status was additionally determined by next generation sequencing (NGS). NGS was performed with genomic DNA on an Ion PGM System (LifeTechnologies, Carlsbad, CA) as described previously . In brief, a commercially available NGS panel covering the ERBB2 mutation hotspots in the tyrosine kinase domain (amino acid residues 752‐769 in exon 19, amino acid residues 770‐797 in exon 20, and amino acid residues 839‐882 in exon 21) and mutation hotspot regions of 21 additional cancer‐related genes ( PIK3CA , TP53 , MET , AKT , PTEN , EGFR , MAP2K1 , FGFR1 , FGFR2 , FGFR3 , KRAS , NRAS , BRAF , STK11 , ALK , DDR2 , CTNNB1 , SMAD4 , FBXW7 , NOTCH1 , ERBB4 ) with 92 amplicons was used (Ion AmpliSeq, LifeTechnologies, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

“…In brief, a commercially available NGS panel covering the ERBB2 mutation hotspots in the tyrosine kinase domain (amino acid residues 752‐769 in exon 19, amino acid residues 770‐797 in exon 20, and amino acid residues 839‐882 in exon 21) and mutation hotspot regions of 21 additional cancer‐related genes ( PIK3CA , TP53 , MET , AKT , PTEN , EGFR , MAP2K1 , FGFR1 , FGFR2 , FGFR3 , KRAS , NRAS , BRAF , STK11 , ALK , DDR2 , CTNNB1 , SMAD4 , FBXW7 , NOTCH1 , ERBB4 ) with 92 amplicons was used (Ion AmpliSeq, LifeTechnologies, Carlsbad, CA). In these cases, NGS analysis was also carried out for the CDH1 /E‐cadherin tumor suppressor gene using a separate, customized NGS panel covering the complete protein‐coding sequence of the CDH1 gene with 26 amplicons …”

Section: Methodsmentioning

confidence: 99%

ERBB2 mutation frequency in lobular breast cancer with pleomorphic histology or high‐risk characteristics by molecular expression profiling

Christgen

Bartels

Radner

et al. 2019

Genes Chromosomes & Cancer

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HER2-positive breast cancer is defined by amplification or overexpression of the HER2/ERBB2 oncogene and accounts for about 15% of breast cancer cases. Somatic mutation of ERBB2 is an alternative mechanism, by which activation of HER2 signaling can occur. ERBB2 mutation has been associated with invasive lobular breast cancer (ILBC). This study investigates the frequency and phenotype of ILBC harboring mutated ERBB2. The ERBB2 mutation status was determined by next generation sequencing and/or pyrosequencing in n = 106 ILBCs, including n = 86 primary or locally recurrent tumors and n = 20 metastases from visceral organs, soft tissue, or skin.Immunohistochemical characteristics were determined using tissue microarrays. This series was enriched for ILBCs with pleomorphic histology and/or high-risk expression profiles (Oncotype DX, recurrence score RS > 25). Nearly all specimens were E-cadherin-negative (99%), estrogen receptor (ER)-positive (92%), and lacked ERBB2 overexpression (96%). ERBB2 mutations (p.V777L, p.L755S, p.S310F) were identified in 5/106 (5%) cases. ERBB2-mutated cases included 2/86 (2%) primary tumors and 3/20 (15%) metastases (P = 0.045). ERBB2-mutated cases were associated with loss of ER (2/7, 29%, P = 0.035) and histological grade 3 (4/34, 12%, P = 0.023), but not with solid growth (3/31, 10%, P = 0.148) or pleomorphic histology (2/27, 7%, P = 0.599). No ERBB2 mutation was detected in ILBCs with RS > 25 (0/22, 0%). In 10 patients with multiple matched specimens (n = 25), the ERBB2 mutational status was always concordant. In summary, a small subset of ILBCs harbors potentially actionable ERBB2 mutations. In ERBB2-mutated ILBCs, no association with pleomorphic histology was found. K E Y W O R D SHER2/ERBB2 mutation, lobular breast cancer, Oncotype DX, recurrence score 1 | INTRODUCTION HER2-positive breast cancer is defined by amplification or overexpression of the HER2/ERBB2 oncogene and accounts for approximately 15% of breast cancer (BC) cases. 1-3 Somatic mutation of ERBB2 gene is a rare alternative mechanism, by which activation of HER2 signaling can occur. 4,5 Most ERBB2 mutations in BC affect the tyrosine kinase domain (amino acid residues 755-781) or the extracellular domain (amino acid residues 309-310). 4,5 These two different ERBB2 mutation types have different gain-of-function characteristics and enhance tyrosine kinase activity or dimerization, respectively. 4BCs harboring an ERBB2 mutations do not show overexpression of the mutant ERBB2 protein. 4 Except for rare instances, the mutated ERBB2 gene is not amplified. 4 Accordingly, conventional clinical HER2/ERBB2 assessment by immunohistochemistry and/or in situ hybridization fails to detect these cases. 4 Importantly, ERBB2 mutations are therapeutically relevant. In fact, recent clinical studies have shown that HER2/EGFR kinase inhibitors (lapatinib, neratinib) are highly effective in metastatic BCs harboring activating ERBB2 mutations. 6-8

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“…Genome‐wide detection of copy number changes and copy neutral losses of heterozygosity (LOHs) was performed with OncoScan arrays, as described previously (Affymetrix, Santa Clara, CA, USA) . All samples meeting the quality control (QC) criteria (median of absolute pairwise difference of ≤0.3 and a normal diploid single‐nucleotide polymorphism QC of ≥26) were analysed with Chromosome Analysis Suite software (v.3.1.1.27; Affymetrix).…”

Section: Methodsmentioning

confidence: 99%

CDKN2A loss and PIK3CA mutation in myoepithelial‐like metaplastic breast cancer

Bartels

Luttikhuizen

Christgen

et al. 2018

The Journal of Pathology

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Metaplastic breast carcinoma comprises a heterogeneous group of tumours with poorly understood pathogenesis. A subset of metaplastic breast cancers show myoepithelial differentiation and constitute a morphological spectrum with ill-defined borders from fibromatosis-like spindle cell carcinoma to myoepithelial carcinoma. In a series of 34 metaplastic breast cancers with spindle cell and myoepithelial differentiation, we found recurrent genetic aberrations, which set them apart from other metaplastic breast cancers and suggest a unique pathogenesis. The majority of cases (28 of 34 patients; 82.4%) showed distinct chromosomal loss in the 9p21.3 region, including CDKN2A and CDKN2B. Biallelic loss of the CDKN2A/B region was found in 50% of deleted cases. Expression of the cyclin-dependent kinase inhibitor CDKN2A (p16) was missing in all samples affected by 9p21.3 loss. Other genomic alterations frequently occurring in triple-negative and metaplastic breast cancer were absent or found in only a minority of cases. Gains of whole chromosome 5 and chromosomal region 5p were observed in nine cases, and were associated with recurrences (p < 0.001). In 64.3% of cases, 9p21.3 loss was accompanied by concurrent PIK3CA mutation. Both genomic abnormalities were also detectable in adenomyoepitheliomas (4/12), which are considered to represent the precursor lesion of myoepithelial metaplastic breast cancer. In adenomyoepithelioma, PIK3CA mutation was present in both luminal epithelial and myoepithelial cells, whereas p16 loss was found only in the latter. We conclude that 9p21.3 (CDKN2A) loss and PIK3CA mutation characterize a subgroup of metaplastic breast cancers with myoepithelial and spindle cell differentiation. Myoepithelial cells in adenomyoepithelioma may show identical aberrations. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Subclonal analysis in a lobular breast cancer with classical and solid growth pattern mimicking a solid‐papillary carcinoma

Cited by 28 publications

References 40 publications

E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements

E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements

ERBB2 mutation frequency in lobular breast cancer with pleomorphic histology or high‐risk characteristics by molecular expression profiling

CDKN2A loss and PIK3CA mutation in myoepithelial‐like metaplastic breast cancer

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