1458 - Uncommon EGFR mutations in lung adenocarcinomas: clinical features and response to tyrosine kinase inhibitors

Background

The detection of pro-oncogenic mutations such as mutations in the epidermal growth factor receptor (EGFR) allowed the development of targeted therapies as inhibitor of tyrosine kinase (ITK)(1-3). Rare mutations need to be further investigated and their clinical and therapeutic significance is still unknown (4). We conducted a retrospective study to estimate the incidence and to describe the pathological characteristics of rare EGFR mutations as well as the clinical features detected among cases of lung adenocarcinomas analysed in a single molecular platform in Lyon, France.

Methods

A total of 7539 molecular analyses were performed at the regional genomics facility of the Lyon University Hospital; techniques included Sanger sequencing and next generation sequencing (from 2009 to 2017) covering exons 18 to 21 of the EGFR. EGFR-mutant tumors excluding L858R, exon 19 deletions, T790M and exon 20 insertions. Mutations were reviewed by two pathologists. The clinical data were collected from the medical records of the patients.

Results

A total of 857 EGFR somatic mutations were identified, including 95 (11%) considered as uncommon EGFR-mutations: there were 47 (50%) exon 18 mutations, including E709X (15%) and G719X (35%), 26 (27%) exon 20 mutations, including S768I (9%) and A767_V769dup (18%), and 22 (23%) L861Q in exon 21 mutations. Interestingly, 27(28%) presented another mutation of which 9 with L858R. Patients treated with first-line chemotherapy had a longer median OS than patients treated with TKI; 27.7 months 95% CI [21.6-35] vs 16.9 months 95% CI [13.6-25.9] p=0.075 all mutations included. Overall survival was correlated with the type of mutation. The mutations of exon 18 and exon 20 were correlated with a better prognosis. On the other hand, the mutation L861Q was linked with a bad prognosis. The presence of a second rare EGFR mutation was correlated with better overall survival (p = 0.002).

Conclusions

In this study, we observed a tendency for chemotherapy to improve survival compared to TKI among rare-EGFR mutation cases. Noteworthy, some mutations showed a better prognosis than others as well as the association with a double mutation in patients treated by ITK. A deeper analysis within a larger cohort would help to stratify the answer to the different treatment for each rare mutation.

Clinical trial identification

Editorial Acknowledgement