title: 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.
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. t.grob@uke.de
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Grob
authors.forename: Uwe
authors.initials: U
authors.lastname: Heilenkötter
authors.forename: Stefan
authors.initials: S
authors.lastname: Geist
authors.forename: Peter
authors.initials: P
authors.lastname: Paluchowski
authors.forename: Christian
authors.initials: C
authors.lastname: Wilke
authors.forename: Fritz
authors.initials: F
authors.lastname: Jaenicke
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
authors.forename: Matthias
authors.initials: M
authors.lastname: Choschzick
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Annette
authors.initials: A
authors.lastname: Lebeau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009154:Mutation; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C117307:KRAS protein, human; C495901:TP53 protein, human; C000626173:ALK protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human