Breast cancers with EGFR and HER2 co‑amplification favor distant metastasis and poor clinical outcome

Abstract

ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25.2%), 44 (36.9%), 0 (0.0%) and 1 (0.8%) patients, respectively. EGFR amplification was associated with estrogen receptor status (P=0.028) and higher possibilities of recurrence (P=0.015) and distant metastasis (following initial surgery) (P=0.011). In survival analysis, EGFR amplification was also associated with disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.003). HER2 amplification was associated with larger tumor size (P=0.006), later clinical stage (P=0.003) and distant metastasis (following initial surgery) (P=0.006). In survival analysis, HER2 amplification was also associated with DFS (P=0.011). Notably, the present study identified a group of patients in whom EGFR and HER2 were co-amplified. This group of patients appeared to have a higher possibility of metastasis (when diagnosed) (P=0.014) and distant metastasis (following initial surgery) (P<0.001). In survival analysis, these patients were noticed to be associated with DFS (P<0.001) and OS (P=0.002). With respect to treatment regimen, this was also true for the DFS association with chemotherapy (P<0.001), radiotherapy (P<0.001) and hormonal therapy (P=0.001). The present results suggest that EGFR and HER2 amplification favor distant metastasis following initial surgery and are significantly associated with poor clinical outcome in breast cancer patients.

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

“…In line with previous reports that showed co-amplification of c-MET and ERBB pathways and their role in metastatic BC [ 24 , 56 , 57 ], we observed the higher expression of c-MET and ERBB1 receptors in ERBB2 + brain-seeking SKBrM3 cells as compared to its parental cell line, and in organoids derived from ERBB2-Tg mouse. As both the brain metastatic cell lines SKBrM3 and JIMT-1-BR3 showed altered molecular expression as compared to their parental cell line, our results support the existing notion that molecular expression is influenced during the gain of metastatic traits and in response to the microenvironment at metastatic sites [ 5 , 7 , 58 ].…”

“…Interestingly, there was differential genomic profiles in case of BrM as compared to their respective primary tumors and more than 20% patients showed subtype switching, including ERBB2+ patients [ 59 ]. In the case of BC, the amplification of ERBB receptors correlates with disease aggressiveness and distant metastasis [ 56 , 57 ]. Particularly, ERBB1 overexpression or its co-amplification with other ERBB receptors has been reported to favor distant metastasis [ 57 ].…”

“…In the case of BC, the amplification of ERBB receptors correlates with disease aggressiveness and distant metastasis [ 56 , 57 ]. Particularly, ERBB1 overexpression or its co-amplification with other ERBB receptors has been reported to favor distant metastasis [ 57 ]. Similarly, c-MET overexpression has been reported to contribute to BC metastasis, particularly to the brain.…”

Inhibition Capacity of the n-Hexane Fraction of Myrmecodia pendens as a Potential Anti-Cancer in Breast and Cervical Cancer: In Vitro Study

“…Importantly, regarding BC cells this data indicates that the n-hexane fraction of M. pendens is more active in HCC-1954 cells, which is HER2+ BC subtype than to the MCF-7, Luminal A BC subtype. Previous study has shown that the HER2+ BCs are more aggressive BC subtype, responsible for poor prognosis and correlated with tumor metastasis (Guo, et al, 2017). Importantly, HCC-1954 cells are intrinsically resistant to trastuzumab, a primer targeted therapy for HER2+ BC patients (Brien, et al, 2010).…”

Signaling pathways downstream to receptor tyrosine kinases: targets for cancer treatment

“…Overexpression of HER2 can lead to the overactivation of the MAPK/ERK and PI3K/AKT/mTOR pathways, leading to uncontrolled cell growth and evasion of apoptosis. HER: human epidermal growth factor receptor; EGFR: epidermal growth factor receptor; RTK: receptor tyrosine kinase; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin with higher rates of recurrence and shorter rates of survival in patients with breast cancer [38,39] . Once activated, HER2 is shown to recruit proto-oncogene Src.…”