Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Abstract

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40.Ó2016 AACR.

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

“…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).…”

Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence

“…This involves the entire ALK kinase domain, which leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN (22). This rare rearrangement has been reported in thyroid cancer before (2) as well as renal cell carcinoma (23) and colorectal adenocarcinoma (24). Patients with this fusion have shown significant initial clinical response to the ALK inhibitors crizotinib and TAE864.…”

Colon cancer with micropapillary carcinoma component: a clinopathologic study of 9 cases

“…In contrast, micropapillary carcinoma does not seem to be involved in epithelial-mesenchymal transition, based on the results of this study. The alteration of BRAF or ALK gene has been identified in colon cancer [24,25,26]. However, these genes do not seem to be involved in the pathogenesis of colon micropapillary carcinoma.…”