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Front Oncol
2020 Apr 02;10:596937. doi: 10.3389/fonc.2020.596937.
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Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer.
Kang J
,
Zhang XC
,
Chen HJ
,
Zhong WZ
,
Xu Y
,
Su J
,
Zhou Q
,
Tu HY
,
Wang Z
,
Xu CR
,
Yang XN
,
Chen ZH
,
Wu X
,
Zhang X
,
Shao Y
,
Wu YL
,
Yang JJ
.
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BACKGROUND: Echinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.
METHODS: Ninety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.
RESULTS: 54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.
CONCLUSION: Our results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.
Figure 1. The clinical response of crizotinib in different ALK fusion groups. Kaplan-Meier curve of PFS (A) or OS (B) of crizotinib treatment in 43 patients with baseline CGP in strata of different ALK fusion patterns. Kaplan-Meier curve of PFS (C) or OS (D) of crizotinib treatment in all 98 ALK-positive patients in strata of different ALK fusion patterns. Log-rank test was used to analyze the OS or PFS for all 3 groups (The p value was shown within the Kaplan-Meier curve). Benjamini and Hochberg (BH)-adjusted p values of the log-rank test were reported for all pairwise comparisons (Individual pairwise comparison p values were shown below the Kaplan-Meier curve).
Figure 2. The correlation between the crizotinib response and the clinical/mutational characteristics. (A) Forest plot of multivariate Cox regression analysis demonstrating the association between different clinical characteristics and OS in 98 ALK-positive NSCLC patients after crizotinib treatment. (B) Top changed genomic features in 98 NSCLC patients. Patient clinicopathologic characteristics (upper panel), co-mutation plot of genetic alterations (middle panel), and gene-level copy-number variation (lower panel) were illustrated. Genes were ranked based on the number of alterations. CNV, copy-number variation; PS score, performance status score; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. (C) Forest plot of multivariate Cox regression analysis demonstrating the association between clinical/mutational characteristics and OS in 98 ALK-positive NSCLC patients after crizotinib treatment.
Figure 3. Therapeutic response to next-generation ALK TKIs in post-crizotinib patients. (A) Swimmer plot demonstrating the post-crizotinib treatment history in 63 NSCLC patients. The asterisk represents ongoing treatment with the last follow-up on November 30, 2019. Kaplan-Meier curve of PFS (B) or OS (C) in 63 next-generation ALK TKI-treated NSCLC patients in strata of different ALK fusions. When multiple next-generation ALK TKIs were used after crizotinib, the ALK TKI that immediately followed crizotinib treatment was included for the analysis. The OS was calculated from the date of initiation of crizotinib treatment to death resulting from any causes or was censored at the last follow-up. BH-adjusted p values of the log-rank test were reported for pairwise comparisons.
Figure 4. Non-canonical ALK fusions detected by CGP in an NSCLC patient (P64) resulted in a canonical EML4-ALK fusion mRNA. (A)
ALK intron1-ALK intron19 fusion was detected at DNA levels by DNA-sequencing (DNA-Seq). (B) Mature EML4-ALK v3b fusion was detected at RNA levels by mRNA-seq. (C) Validation of EML4-ALK intron1 fusion and ALK intron1-ALK intron19 fusion at DNA levels, respectively, by PCR amplification of the fusion region followed by Sanger Sequencing. (D) RT-PCR validation of EML4-ALK v3b fusion at mRNA levels. (E) The relative expression level of ALK and EML4 detected by RNA-seq. FPKM: Fragments per kilobase of transcript per Million mapped reads. (F) Model for stepwise EML4-ALK fusion formation during gene transcription.
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