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Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations

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Abstract

Background

We present a comprehensive analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance.

Patients and methods

One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included. EGFR (exons 18–21), KRAS (exons 2, 3), PIK3CA (exons 9, 20), and MET (exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations, defined as “TKI non-sensitizing mutations” were used for response, time to progression (TTP), and overall survival (OS) analysis.

Results

TKI non-sensitizing mutations were associated with disease progression (p = 0.001), shorter TTP (p < 0.0001), and worse OS (p = 0.03). Cox’s multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP (p < 0.0001) and worse OS (p = 0.01).

Conclusions

When KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.

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Acknowledgments

Supported by a grant from the Italian Association for Cancer Research (AIRC) and from the Umbria Association Against Cancer (AUCC). The authors thank the patients who participated in this study.

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Authors and Affiliations

  1. Medical Oncology Division, S. Maria della Misericordia Hospital, 1, Via G. Dottori, 06132, Perugia, Italy

    V. Ludovini, L. Pistola, V. Minotti, R. Chiari, F. R. Tofanetti, A. Siggillino, E. Baldelli, A. Flacco & L. Crinò

  2. Department of Electronic and Information Engineering, University of Perugia, Perugia, Italy

    F. Bianconi

  3. Institute of Pathological Anatomy and Histology, University of Perugia, Perugia, Italy

    R. Colella, G. Bellezza & A. Sidoni

  4. Medical Oncology, Istituto Oncologico del Mediterraneo, Catania, Italy

    D. Giuffrida

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  1. V. Ludovini
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  2. F. Bianconi
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  3. L. Pistola
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  4. V. Minotti
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  14. L. Crinò
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Correspondence to V. Ludovini.

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Ludovini, V., Bianconi, F., Pistola, L. et al. Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations. Cancer Chemother Pharmacol 69, 1289–1299 (2012). https://doi.org/10.1007/s00280-012-1829-7

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  • DOI: https://doi.org/10.1007/s00280-012-1829-7

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