TP53 mutations predict for poor survival in ALK rearrangement lung adenocarcinoma patients treated with crizotinib

Wang, Wenxian; Xu, C.; Chen, Yanping; Liu, Wei; Zhong, Lintao; Chen, Fang‐Fang; Zhuang, W.; Huang, Yun-jian; Huang, Zhongyang; Chen, Rongrong; Guan, Yanfang; Yi, Xin; Lv, T.; Zhu, Weixing; Lu, Jianping; Wang, Xiaojiang; Shi, Yi; Lin, Xiaoxiao; Chen, Gang; Song, Yong

doi:10.21037/jtd.2018.04.98

Cited by 35 publications

(34 citation statements)

References 26 publications

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“…In this study, we were able to obtain only one postbiopsy from a patient with acquired resistance and an ALK-G1220R mutation was detected which is known to induce crizotinib resistance. Recent studies showed a clear association between TP53 mutation and worse PFS (23,27), and we were able to observe a similar effect in our cohort with 3 of 3 intrinsically Cou€ etoux du Tertre et al…”

Section: Discussionsupporting

confidence: 86%

“…In contrast to previously published work (29,30), specific EML4-ALK variants were not sufficient to explain patient response to crizotinib in our cohort. In addition, the article highlights novel concurrent genomic events (loss of ALK and gain of EGFR) only present in intrinsically resistant patients and confirmed unfavorable association between ALK rearrangement and TP53 mutation for patient outcome (23,27). Because of the small sample size in our study, further validation will be essential to confirm our observations in crizotinib or other ALK-TKI-treated patients with ALKþ NSCLC.…”

Section: Discussionsupporting

confidence: 60%

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Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Tertre

Marques

Tremblay

et al. 2019

Molecular Cancer Therapeutics

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Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALKþ NSCLC and investigate its relationship with response to crizotinib. Using wholeexome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALKþ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALKþ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALKþ NSCLC.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 60%

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Tertre

Marques

Tremblay

et al. 2019

Molecular Cancer Therapeutics

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“…14 A recent study revealed that TP53 mutations reduced responsiveness to crizotinib and worsened prognosis in patients with ALK-rearranged NSCLC. 15 We found that 41.7% CSF samples harbored TP53 compared with 27.3% of plasma samples. The higher rate of TP53 in CSF might be related to resistance and the emergence of LM.…”

Section: Discussionmentioning

confidence: 64%

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Zheng

Jiang

et al. 2019

Journal of Thoracic Oncology

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Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene-mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce. Methods: Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing. Results: LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p ¼ 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p ¼ 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response. Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.

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“…The present data provide a novel insight into the differences in prognosis between EML4-ALK variant V1 and variant V3 patients. A number of studies have demonstrated that TP53 mutations predict a poor outcome following systemic therapy for ALK fusion NSCLC, and coalterations between EML4-ALK variant V3 and TP53 mutations define a patient subset with worse prognosis [55][56][57]. The present study demonstrated that the frequency of concurrent TP53 mutations and EML4-ALK variant V3 was markedly higher compared with that of concurrent TP53 mutations and EML4-ALK variant V1, which indicates that TP53 mutation may be one of the critical reasons for the differences in prognosis between patients with EML4-ALK variant V1 and variant V3 NSCLC.…”

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confidence: 99%

Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer

et al. 2019

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Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non‐small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK‐rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next‐generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4‐ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2 = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle‐aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK‐rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non‐EML4‐ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4‐ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular‐clinical profiles of patients with ALK‐rearranged NSCLC that may improve the treatment strategy of this population.

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TP53 mutations predict for poor survival in ALK rearrangement lung adenocarcinoma patients treated with crizotinib

Abstract: mutations reduce responsiveness to crizotinib and worsen prognosis in rearrangement NSCLC patients.

Cited by 35 publications

References 26 publications

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer

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