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

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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.

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Acknowledgments

The authors appreciate the excellent technical support of Gabriele Rieck, Silvia Schnöger, Sascha Eghtessadi, Jana Hagemann, and Sina Dietrich.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Tobias J. Grob, Alexander Quaas, Waldemar Wilczak, Matthias Choschzick, Guido Sauter & Annette Lebeau

  2. Department of Gynecology, Hospital Itzehoe, Itzehoe, Germany

    Uwe Heilenkötter

  3. Department of Gynecology, Hospital Pinneberg, Pinneberg, Germany

    Stefan Geist & Peter Paluchowski

  4. Department of Gynecology, Hospital Elmshorn, Elmshorn, Germany

    Christian Wilke

  5. Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Fritz Jaenicke

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  1. Tobias J. Grob
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Correspondence to Tobias J. Grob.

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Grob, T.J., Heilenkötter, U., Geist, S. et al. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Cancer Res Treat 134, 561–567 (2012). https://doi.org/10.1007/s10549-012-2092-7

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