Abstract 2718: Molecular Tumor Board treatment predictions on rare EGFR exon 20 mutations
Authors: Wekken Anthonie J. van der , Groves Matthew R. , Elst Arja ter , Hart Nils A. 't , Hijmering-Kappelle Lucie B. , Hiltermann Thijo J. , Berg Anke van den , Timens Wim , Schuuring Ed , Groen Harry J. 
Published: July 2017

Abstract
Purpose:
To evaluate treatment response following the Multidisciplinary Molecular Tumor Board (MTB) decisions which focused on EGFR exon 20 mutations in lung adenocarcinoma.
Methods:
Molecular studies were routinely performed using the Ion Torrent sequencing platform for histologically or cytologically diagnosed lung adenocarcinoma. Since October 2014 patients with rare (prevalence &lt;1%) or combinations of rare mutations were discussed at the MTB of the University Medical Center Groningen. More common, known sensitive EGFR, BRAF V600E, as well as KRAS, and PIK3CA mutations were excluded. To predict the best therapy for a subset of patients with EGFR exon 20 insertion mutations the literature is reviewed and molecular models were built using SWISS-MODEL, is used to predict protein tertiary structure (https://swissmodel.expasy.org/interactive/wcurbt/models/).
Summary of data:
Over a period of 2 years 1389 samples were tested. A total of 170 (12.2%) rare mutations were detected in lung cancer. Among these rare mutations we observed 16 EGFR exon 20 insertions and other mutations like e.g: p.T790M, p.D761N, p.D770delinsGY, p.S768_D770dup, p.V769_D770insSFL, p.N771_H773dup, p.T790S. Using an in silico modeling of protein responses with TKI were predicted to be likely in EGFR T790M mutations and p.S768_V769delinsIL, but not in p. D770delinsGY, p.S768_D770dup, p.V769_D770insSFL, and p.N771_H773dup mutations. Eight patients with an exon 20 mutation were treated with an EGFR TKI. One patient (p.D761N) had a partial response on erlotinib 300mg daily. On afatinib monotherapy 2 out of 3 pts had stable disease (PFS 3-11 months). On afatinib/cetuximab treatment 1 out of 2 pts (p.D770delinsGY) had a partial response and the other patient had stable disease (p.S768_D770dup) (PFS 11 and 4 months, resp.). Two evaluable patients were treated with osimertinib: the first patient initially progressed on afatinib (p.V769_D770insSFL). The protein model predicted no response, since we predicted hindrance of osimertinib. The model predicted no response on osimertinib in the second patient as well, and during treatment a stable disease for 4 months was observed (p.N771_H773dup).
This molecular information from the weekly MTB meeting was delivered within 2 weeks to the treating physician. Feedback on treatment outcome helped to further improve treatment predictions.
Conclusion:
The Molecular Tumor Board is an effective multidisciplinary team to discuss rare mutations. Our pilot data show that the evaluation of the use and effectiveness of a theoretical model concerning protein structures is not possible yet, however, did provide a clear insight in protein structures in a mutated EGFR receptor supporting decision making of treatment options.
Citation Format: Anthonie J. van der Wekken, Matthew R. Groves, Arja ter Elst, Nils A. 't Hart, Lucie B. Hijmering-Kappelle, Thijo J. Hiltermann, Anke van den Berg, Wim Timens, Ed Schuuring, Harry J. Groen. Molecular Tumor Board treatment predictions on rare EGFR exon 20 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2718. doi:10.1158/1538-7445.AM2017-2718