Clinicopathologic characteristics and diagnostic methods of rearrangement in Chinese non-small cell lung cancer patients.

Background: Rearranged during transfection () rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses. However, the clinical characteristics, outcomes and optimal diagnostic method of -rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes.

Methods: A total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 -positive cases were screened. Non-canonical rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of rearrangement were evaluated.

Results: The prevalence of rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79% (29/330) in ///-negative cases. rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV -rearranged NSCLC patients developed brain metastases. was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including (N=5), (N=2), and (N=1). Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNA-based NGS identified 3 new partners (, , and ). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for /other- fusions. The subgroup had significantly longer progression-free survival than the subgroup, both after chemotherapy (23 9.7 months; P=0.014).

Conclusions: rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. IHC has a low sensitivity, disavowing its use in routine practice. While NGS and FISH has good performance in identifying rearrangement. Both IHC and FISH demonstrated lower sensitivity for /others- fusions. Clinical benefit with chemotherapy is different between - and fusion patients, optimal treatment should be considered when selecting therapies for patients with -rearranged lung cancers.