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.
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.
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).
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.