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Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma As a Potential Therapeutic Target Evgeny Yakirevich1, Murray B

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Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma As a Potential Therapeutic Target Evgeny Yakirevich1, Murray B Published OnlineFirst March 1, 2016; DOI: 10.1158/1078-0432.CCR-15-3000 Personalized Medicine and Imaging Clinical Cancer Research Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target Evgeny Yakirevich1, Murray B. Resnick1, Shamlal Mangray1, Michael Wheeler1, Cynthia L. Jackson1, Kara A. Lombardo1, Jeeyun Lee2, Kyoung-Mee Kim3, Anthony J. Gill4, Kai Wang5, Kyle Gowen5, James Sun5, Vincent A. Miller5, Philip J. Stephens5, Siraj M. Ali5, Jeffrey S. Ross5,6, and Howard Safran7 Abstract Purpose: Chromosomal translocations in the anaplastic lym- EML4, C2orf44, CAD,andthenovelSTRN, PPP1R21, SENPF, phoma kinase (ALK) gene have been identified as oncogenic MAPRE3,andPRKAP1B partners. These advanced-stage colo- drivers in lung adenocarcinomas and other tumors, recently rectal carcinomas lacked mutations in other oncogenic drivers, including rare cases of colorectal carcinoma. We identified a predominantly involved the proximal colon, and often exhib- patient with refractory metastatic colorectal carcinoma harboring ited MSI and mucinous phenotype. The index patient was a STRN–ALK gene fusion who achieved an exceptional clinical treated with the ALK inhibitor ceritinib, resulting in a marked benefit to the ALK inhibitor ceritinib. Our goal was to further decrease in size of a skin metastasis, and resolution by com- define the clinicopathologic features of ALK-rearranged colorectal puterized tomography of all contrast enhancing tumor. After 9 carcinoma in a large cohort. months of treatment, biopsy of progressive disease demon- Experimental Design: Clinical cases of colorectal carcinoma strated a KRAS mutation, consistent with acquired resistance to evaluated by comprehensive genomic profiling (CGP) or by ALK ceritinib. immunohistochemistry (IHC) were reviewed retrospectively. Conclusions: Colorectal carcinoma harboring ALK fusions FISHandmicrosatelliteinstability(MSI) analyseswere performed. represent a rare aggressive subtype of colorectal carcinoma with Results: Nine colorectal carcinoma cases harbored ALK gene distinct clinicopathologic features. This report provides the first fusions. Six cases were identified by CGP of 3,157 colorectal clinical evidence that such patients may benefit from targeted carcinoma (0.2%) and three by IHC of 2,980 colorectal carci- monotherapy with ALK inhibitors. ClinCancerRes; 22(15); 3831–40. noma (0.1%). The ALK fusions involved known ALK partners Ó2016 AACR. Introduction 132,700 new cases in 2015 (1). Approximately 20% to 25% of patients with colorectal carcinoma present with hepatic metasta- Colorectal cancer is the third most common cancer diagnosed ses on initial diagnosis, and a further 40% to 50% of patients will in both men and women in the United States with an estimated develop hepatic metastases within 3 years of their primary surgery (2). With recent advances in chemotherapy, the median survival rate for patients with metastatic colorectal carcinoma is approx- 1 Department of Pathology, Rhode Island Hospital, and Alpert Medical imately 25 to 30 months (3, 4). Recent genome-scale molecular School at Brown University, Providence, Rhode Island. 2Department of Medicine, Division of Hematology-Oncology, Samsung Medical Cen- analyses have uncovered several potential molecular targets in this ter, Sungkyunkwan University School of Medicine, Seoul, Republic of disease, including ERBB2 amplifications and sequence mutations, 3 Korea. Department of Pathology and Translational Genomics, Sam- as well as recurrent gene fusions that lead to oncogenic tyrosine sung Medical Center, Sungkyunkwan University School of Medicine, ALK, RET, ROS1 Seoul, Republic of Korea. 4Cancer Diagnosis and Pathology Group, kinase activation, including those involving , and Kolling Institute of Medical Research, Royal North Shore Hospital, St NTRK (5–7). Given the poor prognosis of advanced colorectal Leonards and University of Sydney, Sydney NSW, Australia. 5Founda- carcinoma, investigation of the druggability of these altered tion Medicine Inc., Cambridge, Massachusetts. 6Department of Pathol- ogy and Laboratory Medicine, Albany Medical College, Albany, New kinases is important to address this unmet clinical need. York. 7Oncology Division, Department of Internal Medicine, Rhode Gene rearrangements involving ALK receptor tyrosine kinase Island Hospital, and Alpert Medical School at Brown University, Prov- were first discovered in anaplastic lymphoma, and later found in idence, Rhode Island. several tumor types from different lineages, including hemato- Note: Supplementary data for this article are available at Clinical Cancer lymphoid, mesenchymal, neural, and epithelial (8, 9). The fre- Research Online (http://clincancerres.aacrjournals.org/). quency of ALK fusions varies according to the tumor type. Among Corresponding Author: Evgeny Yakirevich, Rhode Island Hospital and Alpert the epithelial cancers they are most common in non–small cell Medical School at Brown University, Department of Pathology, APC12, 593 Eddy lung cancer (NSCLC), comprising approximately 3% to 7% of Street, Providence, RI 02903. Phone: 401-444-2780; Fax: 401-444-8514; E-mail: lung adenocarcinoma (10), while only nine cases of colorectal [email protected] carcinoma harboring ALK fusions have been described in seven doi: 10.1158/1078-0432.CCR-15-3000 previous studies (refs. 6, 7, 11–15; Supplementary Table 1). Ó2016 American Association for Cancer Research. Tumors with ALK rearrangements express activated fusion kinases www.aacrjournals.org 3831 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 1, 2016; DOI: 10.1158/1078-0432.CCR-15-3000 Yakirevich et al. biologic behavior of this rare aggressive subtype of colorectal Translational Relevance carcinoma. ALK rearrangement defines a rare molecular subtype of colorectal carcinoma with distinct clinical and pathological Patients and Methods features, including advanced stage, proximal colon location, Clinical trial often microsatellite instability, and mucinous phenotype. The index patient was enrolled in the Novartis Signature Trial Although ALK fusions occur in 0.1% to 0.2% of patients with within the arm "Ceritinib (LDK378) for Patients Who Have colorectal carcinoma, this equates to approximately 265 new Tumors with ALK or ROS1 Gene Alterations (Signature)" (Clin- cases of colorectal carcinoma per year in the United States and icalTrials.gov identifier NCT02186821). Comprehensive geno- approximately 2,800 new cases of colorectal carcinoma per mic profiling was performed after written informed consent for year worldwide. We provided the first clinical evidence that participation in the Rhode Island Hospital Institutional Review patients with ALK-rearranged colorectal carcinoma may Board (IRB) protocol "Molecular Testing of Cancer by Integrated achieve an exceptional clinical benefit from targeted mono- Genomic, Transcriptomic, and Proteomic Analysis" (Clinical- therapy with the ALK inhibitor ceritinib. These data support Trials.gov identifier NCT02213822). Response to ceritinib was further evaluation of patients with colorectal carcinoma har- classified by Response Evaluation Criteria in Solid Tumors boring ALK fusions in early-phase clinical trials and also (RECIST), version 1.1 (19). suggest that such patients today may benefit from already- approved ALK inhibitors as well as investigational agents. Study population A database of 3,117 clinical cases of colorectal carcinoma evaluated by CGP in the course of clinical care at Foundation Medicine (Cambridge, MA) was reviewed retrospectively to composed of the intact ALK tyrosine kinase domain fused with identify cases harboring ALK gene fusions, somatic mutations, different unrelated gene partners. The resulting ALK gene fusion and copy number alterations (amplifications and deletions). creates a constitutively active kinase that drives tumor cell growth All cases were clinically advanced-stage III or IV tumors at the through activation of MAP kinase, STAT3, and phosphoinositide time of sequencing. Local site permissions to use clinical 3-kinase (PI3K) pathways, among others (9). samples were obtained for this study. Four previously reported The discovery of ALK rearrangements in NSCLC has initiated a ALK-rearranged colorectal carcinoma cases (12, 14, 15) were new era of targeted therapy in lung cancer (16). The ALK inhibitors also included for the analysis. One of these cases was identified crizotinib and ceritinib have become standard of care for ALK- by the comprehensive genomic profiling of 40 colorectal driven lung cancer, with superior efficacy and improved tolera- carcinoma cases (12), another case by immunohistochemical bility, in comparison with cytotoxic drugs (17, 18). In two (IHC) screening of 1,889 colorectal carcinoma cases at the preclinical studies, the growth of colorectal carcinoma cell lines Department of Anatomical Pathology, Royal North Shore harboring EML4–ALK fusions was inhibited by the ALK inhibitors Hospital, Sydney, Australia (14), and two cases by IHC screen- crizotinib and entrectinib (7, 15). ing of 222 colorectal carcinoma cases at the Department of This article describes the first patient with advanced meta- Pathology and Translational Genomics, Samsung Medical static colorectal carcinoma harboring a STRN–ALK gene fusion Center, Sungkyunkwan University School of Medicine, Seoul, identified by comprehensive genomic profiling (CGP) after Republic of Korea (15). For this study, the database
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