domingo, 19 de noviembre de 2017

Clinical and translational implications of RET rearrangements in non-small cell lung cancer. - PubMed - NCBI

2017 Nov 8. pii: S1556-0864(17)32866-6. doi: 10.1016/j.jtho.2017.10.021. [Epub ahead of print]

Clinical and translational implications of RET rearrangements in non-small cell lung cancer.

Ferrara R1, Auger N2, Auclin E3, Besse B4.

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Abstract

Since the discovery in 2012 of RET rearrangements in non-small cell lung cancer (NSCLC), at least 12 different fusion variants have been identified, with KIF5B-RET being the most frequent and the best characterized. Unlike ALK and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization and reverse transcriptase PCR are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histology, never-smoking status, younger age, more advanced stage disease, potentially higher chemo-sensitivity (in particular to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multi-target inhibitors with anti-RET activity in RET-rearranged lung cancer patients. In the clinical setting, the benefit in terms of response (16% to 47%) and progression-free survival (2 to 7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multi-kinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn, due to discordant data, coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET-oncogene-addicted NSCLC underscores the clear need for the development of more selective and potent RET inhibitors and for a better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in lung cancer patients.