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Transl Lung Cancer Res
2021 Mar 01;103:1525-1535. doi: 10.21037/tlcr-21-160.
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Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib.
Li J
,
Zhang B
,
Zhang Y
,
Xu F
,
Zhang Z
,
Shao L
,
Yan C
,
Ulivi P
,
Denis MG
,
Christopoulos P
,
Thomas de Montpréville V
,
Bernicker EH
,
van der Wekken AJ
,
Wang C
,
Yue D
.
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BACKGROUND: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement characterizes a subgroup of patients who show sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, the prognoses of these patients are heterogeneous. A better understanding of the genomic alterations occurring in these tumors could explain the prognostic heterogeneity observed in these patients.
METHODS: We retrospectively analyzed 96 patients with NSCLC with ALK detected by immunohistochemical staining (VENTANA anti-ALK(D5F3) Rabbit Monoclonal Primary Antibody). Cancer tissues were subjected to next-generation sequencing using a panel of 520 cancer-related genes. The genomic landscape, distribution of ALK fusion variants, and clinicopathological characteristics of the patients were evaluated. The correlations of genomic alterations with clinical outcomes were also assessed.
RESULTS: Among the 96 patients with immunohistochemically identified ALK fusions, 80 (83%) were confirmed by next-generation sequencing. TP53 mutation was the most commonly co-occurring mutation with ALK rearrangement. Concomitant driver mutations [2 Kirsten rat sarcoma viral oncogene homolog (KRAS) G12, 1 epidermal growth factor receptor (EGFR) 19del, and 1 MET exon 14 skipping] were also observed in 4 adenocarcinomas. Echinoderm microtubule associated protein-like 4 (EML4)-ALK fusions were identified in 95% of ALK-rearranged patients, with 16.2% of them also harboring additional non-EML4-ALK fusions. Nineteen non-EML4 translocation partners were also discovered, including 10 novel ones. Survival analyses revealed that patients concurrently harboring PIK3R2 alterations showed a trend toward shorter progression-free survival (6 vs. 13 months, P=0.064) and significantly shorter overall survival (11 vs. 32 months, P=0.004) than did PIK3R2-wild-type patients. Patients with concomitant alterations in PI3K the signaling pathway also had a shorter median overall survival than those without such alterations (23 vs. 32 months, P=0.014), whereas progression-free survival did not differ significantly.
CONCLUSIONS: The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy.
Figure 1. The genomic landscape of patients with anaplastic lymphoma kinase (ALK) fusion (n=80). Top represents the number of mutations detected in each sample; bottom represents the histological type; right represents the genes; left indicates the detection rate of mutation.
Figure 2. The distribution of anaplastic lymphoma kinase (ALK) rearrangements. (A) The distribution of different ALK partners (n=80). (B) The distribution of echinoderm microtubule associated protein-like 4 (EML4)-ALK variants (n=76). (C) The list of non-EML4-ALK partners identified. * a and b indicate the partners reported in the literature and in our internal database, respectively.
Figure 3. The correlation of concomitant alterations in PIK3R2 or in the PI3K signaling pathway with progression-free survival (PFS) and overall survival (OS) (n=37). (A,B) Alteration in PIK3R2; (C,D) alterations in PI3K signaling pathway genes (MAP2K2, JAK3, PIK3R2, KIT, CDK6, MYC, FGFR4, JAK1, RPTOR, INSR, BRCA1, IRS1, STK11, EGFR, KRAS, and MET). The P value was adjusted for age, sex, smoking history, surgical history, and brain metastasis.
Figure 4. The correlation of concomitant mutations in TP53 or in the P53 signaling pathway with progression-free survival (PFS) and overall survival (OS) (n=37). (A,B) Mutations in TP53; (C,D) mutations in P53 signaling pathway genes (TP53, MDM4, and CDK6). The P value was adjusted for age, sex, smoking history, surgical history, and brain metastasis.
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