Clinicopathologic characteristics, genetic variability and therapeutic options of RET rearrangements patients in lung adenocarcinoma

Abstract

Background: RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients.

Patients and methods: For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test.

Results: Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET rearrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangements was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B-RET and two CCDC6-RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases. And the level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10^-4 vs. 394±457×10^-4, P=0.019).

Conclusion: The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET rearrangements are characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

Keywords: Non-small cell lung cancer; RET; Survival; Thymidylate synthetase.