Amongst others, three genes have been frequently reèprted for showing mutations of diagnostic and predictive significance in lung cancer: EGFR, ALK and BRAF.
EGFR
EGFR (7p21) has 28 exons. The two most common mutations are in-frame deletions (15bp) in exon 19 and L858R in exon 21 (these represent about 90% of all EGFR mutations in lung adenocarcinoma). EGFR mutations are typical of lepidic growth pattern with acinar/papillar growth. EGFR exon 19 and exon 21 mutations are associated with EGFR gene amplification. In the past EGFR amplification was also tested, but exon 19/exon 21 testing now shows better predictability.
Response to Gefitinib is seen in 85% of patients with exon 19/exon 21 mutations, although resistance mutations may then arise in exon 18 and exon 20. Somehow paradoxical: patients with exon 18 and exon 20 mutations (resistance mutations) may show better survival than patients without this mutations.
ALK
ALK mutations show first of all a diagnostic value: they are mostly found in adenocarcinomas. A minority is also found in squamous cells cancers. Adenocarcinomas with ALK mutations are poorly differentiated, often with solid or acinar growth, often express mucin and sometimes signet ring differentiation.
The therapeutic value of ALK mutations is in that they may confer sensitivity to crizotinib. Overall, a response rate of 57% in high-stage lung adenocarcinoma after 6 months of therapy has been found. Over 70% of patients showed an estimated 6 months PFS (progression free survival), in contrast with a normal expectation of 10-30%. The gold-standard approach to ALK mutations detection is FISH (Fluorecence In Situ Hybridization).
BRAF
BRAF gene mutations are exclusive of EGFR, ALK and KRAS mutations and are often seen in smokers (in contrast to EGFR and ALK mutations). BRAF mutations are mostly V600E, G469A and G594G. BRAF mutations are more typical of the elderly and show same sex distribution.
The diagnostic value of BRAF mutations is in that they are typical of higher stage adenocarcinoma, poorly differentiated, with acinar and solid, papillary and micropapillary growth, and mucin production.
As for what concerns the therapeutic value of BRAF mutations: PLX4032 is drug in early stage trails (phase I) for the treatment of high stage lung adenocarcinoma.
In summary. Molecular testing is useful for less than 50% patients with lung cancer, even if currently ongoing trials are promising. Lung carcinomas seem to be “genetically simple”, as they are tend to be dominated by a single molecular alteration.
