the best - characterized mutations of egfr conferring sensitivity to egfr - tyrosine kinase inhibitors ( tki ) in non - small cell lung cancer ( nsclc ) are deletions in exon 19 ( del 19 ) and point mutations in exon 21 ( l858r ) .
conversely , the most common mutation conferring resistance to egfr - tki is the exon 20 point mutation ( t790 m ) .
this t790 m mutation is considered the major cause of acquired resistance to egfr - tki .
primary t790 m mutation can also occur at baseline ( before tki treatment ) related to a germinal mutation or somatically mutated subclones .
a recent meta - analysis of the predictive role of a pretreatment t790 m mutation in patients with activating egfr mutation receiving egfr - tki treatment shows that the pretreatment t790 m mutation has a negative impact on progression - free survival . here ,
we present the case of a young patient with a primary lung papillary adenocarcinoma and miliary pulmonary metastases , diagnosed with pretreatment complex egfr mutation combining a heterozygous somatic l858r mutation and t790 m mutation .
a 47-year - old man presented with a history of weight loss from 97 to 92 kg within 1 month , cough and fatigue . a chest x - ray ( fig .
the patient had no fever , and his oxygen saturation was 90% ( rest time without oxygen ) , improving to 94% under oxygenotherapy ( 1 liter / min ) .
2 ) confirmed miliary metastases and a nodule in the right middle lobe and revealed bilateral mediastinal lymph nodes .
bronchoscopy was macroscopically normal , but cytology of bronchoalveolar lavage ( bal ) highlighted an adenocarcinoma , which was confirmed as papillary subtype by mediastinoscopy .
molecular analysis of bal , containing 30% of tumor cells , by direct sequencing showed a somatic complex heterozygous egfr mutation ( fig .
3 ) composed of l858r mutation in exon 21 and t790 m mutation in exon 20 .
t790 m was confirmed to be somatic , as it was not detected in the paired lymphocytes of the patient .
after 15 days , the patient returned with worsened dyspnea and an oxygen saturation of 87% with 2 liters / min oxygen .
after the first cycle of chemotherapy , there was a dramatic improvement in oxygen saturation ( 96% without oxygenotherapy ) and regression of the miliary metastases .
egfr exon 20 insertions account for 4% of egfr mutations and are associated with a lack of sensitivity to egfr - tki in preclinical models and in patients [ 2 , 3 , 4 ] .
another mutation in exon 20 conferring resistance involves a substitution of methionine for threonine at position 790 ( t790 m ) .
this alteration is found as a germ - line variant in 0.5% of never - smokers with lung adenocarcinoma   and may confer genetic susceptibility to lung cancer .
in fact , egfr germinal mutations are not looked for in routine practice . in the natural history of the disease ,
t790 m mutation could be present in a small subset of tumor cells and expand selectively under egfr - tki , leading to more than 50% percent of secondary resistance .
the frequency of somatic t790 m mutation at baseline ( before tki treatment ) is controversial , and detection depends on the sensitivity of the molecular technique .
studies have suggested that pre - existing resistance may be present at a very low frequency [ 6 , 7 , 8 ] .
a study found 1 ( 0.54% ) egfr t790 m mutation among 185 nsclc patients without egfr - tki treatment , using mutant - enriched pcr analysis , but not confirmed by direct sequencing .
others have found frequencies of up to 35% with very high - sensitive molecular techniques [ 9 , 10 , 11 ] .
usually , t790 m could not be detected by direct sequencing because of lack of sensitivity .
one study reported 2 ( 0.83% ) cases harboring the egfr t790 m mutation among 240 patients with egfr - tki - nave lung adenocarcinoma detected by sequencing but , contrarily to our case , with both germ - line and somatic t790 m mutation and without any other egfr mutation .
t790 m mutation impairs the binding of egfr - tki to the egfr adenosine triphosphate - binding pocket , and emerging data suggest that t790 m change itself may potentiate oncogenic activation .
patients whose tumors harbor somatic t790 m mutations before treatment had a shorter progression - free survival [ 9 , 10 , 11 ] .
we underline the clinical importance of pretreatment t790 m mutation detection because the response to egfr - tki is less certain and could lead to a delay in the introduction of classical platinum - based chemotherapy .
diffuse , random pulmonary metastases , including miliary metastases , are quite a rare presentation in nsclc and seem to be associated with adenocarcinoma subtype and egfr mutation , suggesting that egfr - tki may be the treatment of choice for such patients especially in the asian population [ 13 , 14 , 15 ] .
a study reported 5 cases of never - smokers with lung adenocarcinoma with such a pattern of metastases . in the tumor cells of all 5 patients ,
egfr mutation gene sequencing identified a deletion in exon 19 , and all 5 patients had a dramatic response to egfr - tki .
in fact , clinical data about patients with lung adenocarcinoma harboring egfr t790 m mutations at diagnosis are not described .
this case highlights the link between an uncommon radiological presentation of adenocarcinoma ( miliary pattern ) and the clinical importance of the detection of a pretreatment ( baseline ) t790 m mutation in nsclc patients with an activating egfr mutation .
 the pretreatment detection of an activating mutation of egfr is now routinely performed in metastatic nonsquamous non - small cell lung cancer ( nsclc ) . 
 the therapeutic impact of such a detection is major , as patients with advanced nsclc exhibiting a mutation of exon 19 or 21 will benefit from egfr - tyrosine kinase inhibitors ( tki ) . 
 the presence of an egfr resistance mutation , such as t790 m in egfr - tki - nave patients , is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones . 
 it has a negative predictive impact . 
 we present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous egfr mutation , combining l858r ( exon 21 ) and a primary resistance mutation t790 m ( exon 20 ) , both detected by direct sequencing . 
Introduction
Case Description
Discussion
Conclusion