Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer

Abstract

Women with triple-negative breast cancer (TNBC) do not benefit from endocrine therapy or trastuzumab. Chemotherapy is the only systemic therapy currently available. To reduce the elevated risk of disease progression in these patients, better treatment options are needed, which are less toxic and more targeted to this patient population. We performed a comprehensive analysis of potential targetable genetic aberrations affecting the receptor tyrosine kinase/RAS/MAPK pathway, which are observed at higher frequencies in adenocarcinomas of other organs. Sixty-five individual TNBCs were studied by sequence analysis for HER2 (exon 18-23), EGFR (exon 18-21), KRAS (exon 2), and BRAF (exon 15) mutations. In addition, a tissue microarray was constructed to screen for EGFR gene copy gain and EML4-ALK fusion by FISH. Triple-negative status was confirmed by immunohistochemistry and FISH on tissue microarray sections. EGFR and CK5/6 immunohistochemical analyses were performed for identification of the basal-like phenotype. In addition, mutation analysis of TP53 (exon 5-8) was included. Sequence analysis revealed HER2 gene mutation in only one patient (heterozygous missense mutation in exon 19: p.L755S). No mutations were found in EGFR, KRAS, and BRAF. High polysomy of EGFR was detected in 5 of the 62 informative cases by FISH. True EGFR gene amplification accompanied by strong membranous EGFR protein expression was observed in only one case. No rearrangement of the ALK gene was detected. Basal-like phenotype was identified in 38 of the 65 TNBCs (58.5 %). TP53 gene mutation was found in 36/63 (57.1 %) tumors. We conclude that targetable genetic aberrations in the receptor tyrosine kinase/RAS/MAPK pathway occur rarely in TNBC.

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

“…30,31 We also assessed EGFR amplification by the University of Colorado Cancer Center criteria and found that EGFR amplification was quite rare, being present in only 2% of cases, which is consistent with some previous studies. 10,19,25 However, EGFR high polysomy was found in 31% of cases, which is relatively higher than in previous studies. This result may be related to the heterogeneity of high polysomy in some cases, which will be discussed later.…”

“…EGFR gene amplification and high polysomy were reported in up to 24% and 27% of triple-negative breast cancer, respectively (Table 8). 10,11,13,14,19,25 However, the frequency of EGFR gene amplification is quite variable, even though most studies used the same, University of Colorado Cancer Center criteria. 30,31 We also assessed EGFR amplification by the University of Colorado Cancer Center criteria and found that EGFR amplification was quite rare, being present in only 2% of cases, which is consistent with some previous studies.…”

“…in triple-negative breast cancer (Table 8). 11,17,19,25,26 However, Teng et al reported the presence of EGFR mutation, specifically exon 19 deletions and exon 21 missense (L858R) mutations, in 11% (8/70) of triple-negative breast cancer samples from predominantly Chinese patients. 16 In this study, EGFR mutation was found in 3% (4/151) of triplenegative breast cancer samples from Korean patients.…”

“…24 EGFR gene amplification, one of the mechanisms of EGFR overexpression, is highly variable and found in up to 24% of triple-negative breast cancer. 10,11,13,14,19,25 EGFR gene mutation, another mechanism of EGFR overexpression, has been reported to be rare, 11,17,19,25,26 although a recent study reported that it was present in 11% of triplenegative breast cancers. 16 EGFR immunoreactivity has been presented as an independent indicator of poor prognosis in patients with triple-negative breast cancer.…”

Correlation between p53 and epidermal growth factor receptor expression in breast cancer classification

“…p53 mutations play an important role in tumorigenesis. It was reported that p53 is not highly expressed in breast cancer (Sjögren et al, 1996), but it has been found to be highly expressed in TNBC (Grob et al, 2012). Epidermal growth factor receptor (EGFR) can promote tumor cell migration and increase the invasiveness of tumor cells.…”