119IN - Molecular Typing of Lung Cancer: More Pieces to the Puzzle

Abstract

ABSTRACT Distinct subtypes of NSCLC, so-called “oncogene addicted”, are driven by a specific genetic alteration sustaining tumor proliferation and survival – and are thus sensitive to inhibition of the corresponding activated pathway. This new paradigm has substantially impacted treatment from standard chemotherapy customized patient characteristics, expected toxicity and histological subtype to molecularly driven approaches in advanced NSCLC. Nowadays, adenocarcinoma - but also squamous carcinoma in recent reports - can be further subdivided into numerous clinically relevant molecular subsets. EGFR activating mutations or EML4-ALK translocation have been shown to be associated with better outcome when targeted by dedicated molecules. Treatment of patients with EGFR activating and sensitizing mutations-driven NSCLC with EGFR tyrosine kinase inhibitors (TKIs) results in an unprecedented response rate (RR) of 60-80%, a median progression free survival (PFS) of approximately 8-13 months, as well as an improved quality of life (QoL) compared to chemotherapy. This was the first and a strong illustration of the therapeutic relevance of molecular classification of NSCLC. In NSCLC, ALK rearrangement has at least 3 reported fusion partners: EML4, KLC1, and KIF5B. In these tumors, ALK is the sole determinant of critical growth pathways, resulting in activation of downstream canonical PI3K/AKT as well as MAPK/ERK pathways. Within the pivotal phase 1/2 clinical trial, treatment of 82 EML4-ALK positive patients with crizotinib resulted in a 57% RR and median PFS was 10 months. The kinetics of clinical response were comparable to previous experiences with EGFR TKIs in EGFR-mutated NSCLC. Other transforming genetic alterations have been identified such as MET, Her2 and FGFR1 amplification, KRAS, NRAS, BRAF, MEK1, AKT1, PIK3CA, AKT, FGFR2, DDR2, PTEN and HER2 mutations, RET, ROS1 and ALK rearrangements. While every distinct alteration remains a rare event per se in our NSCLC population, their frequency was shown to vary according to histological subtype, and defined clinical characteristics including smoking history, gender and ethnicity. All of them have to be subject of future epidemiological, fundamental, translational as well as clinical research in order to propose more active treatments to patients in the future. Disclosure The author has declared no conflicts of interest.