Response to crizotinib in a non-small-cell lung cancer patient harboring an &lt;em&gt;EML4-ALK&lt;/em&gt; fusion with an atypical &lt;em&gt;LTBP1&lt;/em&gt; insertion

Aguado, Cristina; Gil, M.L. Vilardell; Yeste, Zaira; Giménez‐Capitán, Ana; Teixidó, Cristina; Karachaliou, Niki; Viteri, Santiago; Rosell, R.; Molina-Vila, Miguel Ángel

doi:10.2147/ott.s148363

Cited by 4 publications

(4 citation statements)

References 6 publications

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“…In our study, a novel LTBP1 ‐ ALK fusion was detected by NGS technology at the baseline specimen of a patient with primary resistance, and his “gold standard” FISH assay result was ALK ‐positive. This fusion gene has not been reported previously, but an EML4‐ALK fusion with atypical LTBP1 insertion could responded well to crizotinib . In future research, we will explore the underlying mechanism for this result.…”

Section: Discussionmentioning

confidence: 65%

“…This fusion gene has not been reported previously, but an EML4-ALK fusion with atypical LTBP1 insertion could responded well to crizotinib. 25 In future research, we will explore the underlying mechanism for this result. Because NGS technology has displayed impressive capability for identifying the underlying molecular profile of cancers, its clinical application as a molecular screening test might favorably alter the clinical outcomes of ALK-positive NSCLC patients.…”

Section: Discussionmentioning

confidence: 93%

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Clinical features and outcomes ofALKrearranged non‐small cell lung cancer with primary resistance to crizotinib

Zhang

Xing

et al. 2019

Thoracic Cancer

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Background Crizotinib is associated with a favorable survival benefit in patients with ALK ‐positive non‐small cell lung cancer (NSCLC); however, a subset of patients harboring ALK rearrangement shows a poor response. Methods We collected the clinical features and survival outcomes of 28 primary‐resistant responders (PRR) with progression‐free survival (PFS) of < 3 months on crizotinib and compared these with 78 long‐term responders (LTR) that achieved > 24 months PFS (control). Results Primary resistance was observed in 6.5% of the patients. The median PFS of the PRR and LTR groups was 1.2 months (95% confidence interval [CI] 0.70–1.73) and 47.0 months (95% CI 34.39–59.64), respectively. A better Eastern Cooperative Oncology Group performance status score was significantly associated with longer PFS (odds ratio 0.06, 95% CI 0.01–0.33; P = 0.001). The median overall survival (OS) of the PRR group was 8.4 months (95% CI 3.47–13.42) and crizotinib as first‐line treatment was an independent predictive factor for survival outcome ( P = 0.005). Patients administered ALK‐tyrosine kinase inhibitors after crizotinib progression had significantly longer survival than the PRR group treated with best supportive care ( P = 0.007), but no significant difference was found between ALK‐tyrosine kinase inhibitor treatment and single chemotherapy ( P = 0.944). Conclusion Patients with primary resistance to crizotinib displayed unfavorable survival outcomes and the underlying mechanism cannot be identified in clinical features. Nevertheless, next‐generation ALK inhibitors and chemotherapy after crizotinib progression could confer a therapeutic and survival benefit in this population.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 93%

Clinical features and outcomes ofALKrearranged non‐small cell lung cancer with primary resistance to crizotinib

Zhang

Xing

et al. 2019

Thoracic Cancer

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“…Two reports of lung cancer LTBP1-ALK fusion mutations exist (31,32) (Table 2), and both patients received firstline treatment with crizotinib and reached PR. The kinase domain of ALK is located in exon 20 (4), and the tyrosine kinase domain (exon 20 of ALK) was present in these cases; however, in our case, the LTBP1-ALK occurred in ALK intron 19 (the retained portion was exon 1-19), leaving the kinase domain behind.…”

Section: Discussion Among Physicians From Shandong Cancer Hospital and Institutementioning

confidence: 99%

High efficacy of alectinib in a patient with advanced lung adenocarcinoma with 2 rare ALK fusion sites: a case report

Li¹,

Duan²,

Guan³

et al. 2022

Transl Lung Cancer Res

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Anaplastic lymphoma kinase (ALK) fusions have been identified in approximately 5% of nonsmall cell lung cancer (NSCLC) cases. ALK-tyrosine kinase inhibitors (TKIs) are the standard firstline treatment for patients with ALK-positive (ALK+) advanced NSCLC. Along with widespread use of next-generation sequencing (NGS) for the molecular diagnosis of lung cancer, an increasing number of ALK fusion partners are being reported, with the majority being effective for ALK-TKIs. Here, we present the case of a 42-year-old female with no smoking history who was diagnosed with stage IVB lung adenocarcinoma. Two rare ALK fusions were detected simultaneously by NGS in this patient: latent transforming growth factor beta-binding protein 1 (LTBP1)-ALK and huntingtin-interacting protein 1 (HIP1)-ALK. HIP1-ALK fusion was also detected by further RNA sequencing, but LTBP1-ALK failed to give a positive signal. The patient received alectinib as first-line therapy and consequently achieved a good response. Progression-free survival (PFS) was more than 19 months, and the treatment with alectinib is ongoing currently. During treatment, clinical symptoms disappeared and no significant adverse events occurred. This is the first case report describing a patient with an NSCLC tumor harboring 2 rare ALK fusions who responded to alectinib. Our report enriches the knowledge of ALK fusion sites and provides an effective clinical basis for the screening of sensitive fusions.

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“…Double-hop fusions can be detected by RNA-seq if their central exons are small enough. A few studies have reported sporadic cases 50 – 52 . Our discovery and PCR validation of multiple double-hop fusions that underwent canonical splicing establishes the concept of double-hop fusions and indicates that they are prevalent in cancer.…”

Section: Discussionmentioning

confidence: 99%

Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer

Namba

Ueno²,

Kojima³

et al. 2021

Commun Biol

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Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon–intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

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Response to crizotinib in a non-small-cell lung cancer patient harboring an <em>EML4-ALK</em> fusion with an atypical <em>LTBP1</em> insertion

Cited by 4 publications

References 6 publications

Clinical features and outcomes ofALKrearranged non‐small cell lung cancer with primary resistance to crizotinib

Clinical features and outcomes ofALKrearranged non‐small cell lung cancer with primary resistance to crizotinib

High efficacy of alectinib in a patient with advanced lung adenocarcinoma with 2 rare ALK fusion sites: a case report

Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer

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