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.
Recently, a new variant of invasive lobular breast cancer (ILBC) with solid‐papillary‐like growth pattern has been described. We present a case of ILBC with solid‐papillary‐like growth pattern in the main tumour mass and classical invasive lobular growth pattern in adjacent satellite foci. The two tumour components were subjected to comprehensive molecular analyses. Both components were ER/PR‐positive, HER2‐negative, and showed a complete loss of E‐cadherin and beta‐catenin protein expression, as determined by immunohistochemistry. Gene expression profiling classified the main tumour and a satellite focus as luminal‐B and luminal‐A subtypes, respectively. Whole‐genome copy number profiles were highly similar in both tumour components. Shared copy number alterations (CNAs) included gains of chromosome 1q21.1–q43 and losses of chromosome 16q11.2–q24.3, the locus of the CDH1/E‐cadherin tumour suppressor gene. CNAs detected only in the main tumour included a gain of chromosome 20q12–q13.33 and a loss of chromosome 1p36.33–p34.3, which has recently been associated with the solid variant of ILBC. Next generation sequencing revealed an identical, truncating CDH1 mutation (p.G169fs*5) in both tumour components confirming a common clonal ancestry. In conclusion, we confirm the recently described variant of ILBC with solid‐papillary‐like growth pattern and provide evidence that it evolves from classical ILBC by subclonal evolution.
The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.
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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