Detection of an <i>ALK</i> Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Lai, Andrea; Schrock, Alexa B.; Erlich, Rachel; Ross, Jeffrey S.; Miller, Vincent A.; Yakirevich, Evgeny; Ali, Siraj M.; Braiteh, Fadi

doi:10.1634/theoncologist.2016-0376

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…Activating alterations in RTKs, including EGFR, HER2, MET, FGFR1/2/3, ALK, ROS1, RET, and PDGFRA, were observed in 18% of cases, including HER2 amplification or point mutation in 5% of cases. RTK fusions, rare potentially targetable driver events in gastrointestinal cancers (18, 23, 24), were detected in 2% of cases, which is notably higher than in previously published frequencies in gastrointestinal tissue samples (9, 25). Examples of clinical utility were observed in a significant fraction of patients in whom potentially actionable alterations were detected in ctDNA and follow-up was available (Table 2).…”

Section: Discussioncontrasting

confidence: 58%

“…In the first case (Table 2, case 3), a STRN-ALK fusion was detected by both genomic profiling of tissue and ctDNA, despite the same tumor tissue being initially negative for ALK by local IHC testing. Details of this case have been published (18); however, since the original report, the patient relapsed on standard therapy and has enrolled on a clinical trial of a kinase inhibitor targeting ALK. In the second case (Table 2, case 4), an FGFR2 C382R activating mutation was detected and the patient subsequently initiated treatment with pazopanib, a multikinase inhibitor with anti-FGFR2 activity.…”

Section: Resultsmentioning

confidence: 99%

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Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Schrock

Pavlick

Klempner

et al. 2018

Clinical Cancer Research

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Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344of417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted.

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Section: Discussioncontrasting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Schrock

Pavlick

Klempner

et al. 2018

Clinical Cancer Research

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“…Whole‐genome sequencing or targeted hybrid capture approaches may be used for broad detection of oncogenic gene fusions across tumor entities. Indeed, single cases of ALK ‐fusion detection in liquid biopsies by DNA capture methods have already been described in the literature . Data on RNA‐based screening for gene fusions as routinely done in FFPE are still preliminary and limited but maybe equally effective.…”

Section: Future Applications Of Liquid Biopsies In Individualized Thementioning

confidence: 99%

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

Volckmar

Sültmann

Riediger

et al. 2017

Genes Chromosomes & Cancer

169

151

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Recently, many genome-wide profiling studies provided insights into the molecular make-up of major cancer types. The deeper understanding of these genetic alterations and their functional consequences led to the discovery of novel therapeutic opportunities improving clinical management of cancer patients. While tissue-based molecular patient stratification is the gold standard for precision medicine, it has certain limitations: Tissue biopsies are invasive sampling procedures carrying the risk of complications and may not represent the entire tumor due to underlying genetic heterogeneity. In this context, complementary characterization of genetic information in the blood of cancer patients can serve as minimal-invasive 'liquid biopsy'. Fragments of circulating cell-free DNA (cfDNA) are released from tissues of healthy individuals as well as cancer patients. The fraction of cfDNA that is released from primary tumors or metastases (i.e. circulating tumor DNA, ctDNA) represents genetic aberrations in cancer cells, which are a potential source for diagnostic, prognostic, and predictive biomarkers. Recent studies have demonstrated technical feasibility and clinical applications including detection of drug targets and resistance mutations as well as longitudinal monitoring of tumors under therapy. To this end, a variety of pre-analytical procedures for blood processing, isolation and quantification of cfDNA are being employed and several analytical methods and technologies ranging from PCR-based single locus assays to genome-wide approaches are available, which considerably differ in sensitivity, specificity, and throughput. However, broad implementation of ctDNA analysis in daily clinical practice requires a thorough understanding of theoretical, technical, and biological concepts and necessitates standardization and validation of pre-analytical and analytical procedures across different technologies. Here, we review the pertinent literature and discuss the advantages and limitations of available methodologies and their potential applications in molecular diagnostics.

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“…In this issue of The Oncologist , Lai et al and Wang et al describe the presence of ALK rearrangements in two distinct malignancies and highlight the use of liquid biopsies in molecular diagnostics . Wang et al report the case of an ALK ‐rearranged atypical neuroendocrine tumor with diffuse central nervous system metastases .…”

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confidence: 99%

“…Based upon this finding, the patient was treated with the next‐generation ALK inhibitor alectinib, which resulted in significant systemic and intracranial responses, both of which were ongoing at the time of reporting. Likewise, Lai et al used the same capture‐based cfDNA platform to identify an ALK rearrangement in a patient with metastatic CRC . Importantly, at the time of this patient's initial diagnosis, ALK immunohistochemistry (IHC) was negative, but parallel genomic profiling of cfDNA and available tissue using hybrid capture‐based NGS identified a STRN‐ALK fusion.…”

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confidence: 99%

ALK Fusion Detection in Circulating Free DNA: Finding an Important Needle in the Haystack

Mooradian

Gainor

2017

The Oncologist

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Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Abstract: The case of a patient with metastatic colorectal cancer is presented. This report is the first instance of an ALK fusion in colorectal cancer detected using a ctDNA assay.

Cited by 18 publications

References 37 publications

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

ALK Fusion Detection in Circulating Free DNA: Finding an Important Needle in the Haystack

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