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Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles.

ABSTRACT: INTRODUCTION: Triple-negative breast cancers (TNBCs) are characterised by lack of expression of hormone receptors and epidermal growth factor receptor 2 (HER-2). As they frequently express epidermal growth factor receptors (EGFRs), anti-EGFR therapies are currently assessed for this breast cancer subtype as an alternative to treatments that target HER-2 or hormone receptors. Recently, EGFR-activating mutations have been reported in TNBC specimens in an East Asian population. Because variations in the frequency of EGFR-activating mutations in East Asians and other patients with lung cancer have been described, we evaluated the EGFR mutational profile in tumour samples from European patients with TNBC. METHODS: We selected from a DNA tumour bank 229 DNA samples isolated from frozen, histologically proven and macrodissected invasive TNBC specimens from European patients. PCR and high-resolution melting (HRM) analyses were used to detect mutations in exons 19 and 21 of EGFR. The results were then confirmed by bidirectional sequencing of all samples. RESULTS: HRM analysis allowed the detection of three EGFR exon 21 mutations, but no exon 19 mutations. There was 100% concordance between the HRM and sequencing results. The three patients with EGFR exon 21 abnormal HRM profiles harboured the rare R836R SNP, but no EGFR-activating mutation was identified. CONCLUSIONS: This study highlights variations in the prevalence of EGFR mutations in TNBC. These variations have crucial implications for the design of clinical trials involving anti-EGFR treatments in TNBC and for identifying the potential target population.

SUBMITTER: Jacot W

PROVIDER: S-EPMC3326575 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles.

Jacot William W Lopez-Crapez Evelyne E Thezenas Simon S Senal Romain R Fina Frédéric F Bibeau Frédéric F Romieu Gilles G Lamy Pierre-Jean PJ

Breast cancer research : BCR 20111222 6

<h4>Introduction</h4>Triple-negative breast cancers (TNBCs) are characterised by lack of expression of hormone receptors and epidermal growth factor receptor 2 (HER-2). As they frequently express epidermal growth factor receptors (EGFRs), anti-EGFR therapies are currently assessed for this breast cancer subtype as an alternative to treatments that target HER-2 or hormone receptors. Recently, EGFR-activating mutations have been reported in TNBC specimens in an East Asian population. Because varia ...[more]

PMID: 22192147

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Project description:Lung cancer is a leading cause of cancer-related mortality in many countries. Although recent advances in targeted therapy against driver oncogenes have significantly improved patient outcome, cure of this disease is still exceptional. Although tobacco is a known cause of lung cancer, not all smokers develop lung cancer, and conversely many patients, especially Asian female patients with lung cancer, are lifetime never-smokers. Therefore, efforts to understand the basis for different susceptibilities to lung cancer among individuals with different genetic, biologic, ethnic, and social backgrounds are important to help develop effective preventive measures. Lung cancer in never-smokers has many different characteristics to lung cancer in smokers, such as adenocarcinoma predominance and high frequency of epidermal growth factor receptor (EGFR) mutation yet low number of genetic changes. Epidemiologic studies suggest that East Asians are more susceptible to smoking-unrelated lung cancer but less susceptible to smoking-related lung cancer compared with Caucasians. Mutations in the EGFR gene are more common in Asian females and never-smokers. Our case-control study suggests that EGFR mutation occurs independent of smoking, and that the apparent low frequency of EGFR mutations in smokers may be the result of dilution by smoking-related lung cancer. The frequencies of three EGFR gene polymorphisms associated with increased protein expression are significantly different between East Asians and Caucasians, favoring lower protein expression in East Asians. Although these may be associated with preferred expression of the EGFR mutant allele, it is difficult to explain the frequent EGFR mutation in Asian patients. Genome wide association studies (GWAS) revealed several loci related to lung cancer susceptibility. In the future, GWAS may identify loci that are specifically related to EGFR-targeted carcinogenesis, leading to identification of carcinogens that induce EGFR mutations and effective prevention measures.

Project description:Investigating geographic variations in mammography screening participation and breast cancer incidence help improve prevention strategies to reduce the burden of breast cancer. This study examined the suitability of health insurance claims data for assessing and explaining geographic variations in mammography screening participation and breast cancer incidence at the district level. Based on screening unit data (1,181,212 mammography screening events), cancer registry data (13,241 incident breast cancer cases) and claims data (147,325 mammography screening events; 1,778 incident breast cancer cases), screening unit and claims-based standardized participation ratios (SPR) of mammography screening as well as cancer registry and claims-based standardized incidence ratios (SIR) of breast cancer between 2011 and 2014 were estimated for the 46 districts of the German federal state of Lower Saxony. Bland-Altman analyses were performed to benchmark claims-based SPR and SIR against screening unit and cancer registry data. Determinants of district-level variations were investigated at the individual and contextual level using claims-based multilevel logistic regression analysis. In claims and benchmark data, SPR showed considerable variations and SIR hardly any. Claims-based estimates were between 0.13 below and 0.14 above (SPR), and between 0.36 below and 0.36 above (SIR) the benchmark. Given the limited suitability of health insurance claims data for assessing geographic variations in breast cancer incidence, only mammography screening participation was investigated in the multilevel analysis. At the individual level, 10 of 31 Elixhauser comorbidities were negatively and 11 positively associated with mammography screening participation. Age and comorbidities did not contribute to the explanation of geographic variations. At the contextual level, unemployment rate was negatively and the proportion of employees with an academic degree positively associated with mammography screening participation. Unemployment, income, education, foreign population and type of district explained 58.5% of geographic variations. Future studies should combine health insurance claims data with individual data on socioeconomic characteristics, lifestyle factors, psychological factors, quality of life and health literacy as well as contextual data on socioeconomic characteristics and accessibility of mammography screening. This would allow a comprehensive investigation of geographic variations in mammography screening participation and help to further improve prevention strategies for reducing the burden of breast cancer.

Project description:PurposeWhile chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.Experimental designWe performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.ResultsWe reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing.ConclusionsThese findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.

Dataset Information

Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles.

Publications

Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles.

Similar Datasets

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