A case of advanced infantile myofibromatosis harboring a novel MYH10‐RET fusion

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137282/1/pbc26377_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137282/2/pbc26377.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137282/3/pbc26377-sup-0002-text.pd

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

Emergence of Preexisting MET Y1230C Mutation as a Resistance Mechanism to Crizotinib in NSCLC with MET Exon 14 Skipping

AbstractIntroductionMET proto-oncogene, receptor tyrosine kinase gene exon 14 skipping (METex14) alterations represent a unique subset of oncogenic drivers in NSCLC. Preliminary clinical activity of crizotinib against METex14-positive NSCLC has been reported. The full spectrum of resistance mechanisms to crizotinib in METex14-positive NSCLC remains to be identified.MethodsHybrid capture–based comprehensive genomic profiling performed on a tumor specimen obtained at diagnosis, and a hybrid capture–based assay of circulating tumor DNA (ctDNA) at the time of progression during crizotinib treatment was assessed in a pairwise fashion.ResultsA METex14 alteration (D1010H) was detected in the pretreatment tumor biopsy specimen, as was MET proto-oncogene, receptor tyrosine kinase (MET) Y1230C, retrospectively, at very low frequency (0.3%). After a confirmed response during crizotinib treatment for 13 months followed by progression, both MET proto-oncogene, receptor tyrosine kinase gene Y1230C and D1010H were detected prospectively in the ctDNA.ConclusionEmergence of the preexisting MET Y1230C likely confers resistance to crizotinib in this case of METex14-positive NSCLC. Existence of pretreatment MET Y1230C may eventually modulate the response of METex14-positive NSCLC to type I MET tyrosine kinase inhibitors. Noninvasive plasma-based ctDNA assays can provide a convenient method to detect resistance mutations in patients with previously known driver mutations

Genomic Profiling of Small Bowel Adenocarcinoma

Importance: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking. Objective: To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations. Design, Setting, and Participants: Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture–based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. Results: Of the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P &lt; .001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P &lt; .001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P &lt; .001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P &lt; .001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P &lt; .001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease–associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series. Conclusions and Relevance: This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy

FGFR2‐Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

BACKGROUND:With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2-altered GEA. We examined FGFR2 alteration frequency and frequency of co-occurring alterations in GEA. SUBJECTS, MATERIALS, AND METHODS:A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. RESULTS:We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2-amplified (amp; 193, 72% of FGFR2-altered), FGFR2-mutated (36, 13%), FGFR2-rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co-occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2-altered GEA. Co-occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild-type samples. CONCLUSION:FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2-directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. IMPLICATIONS FOR PRACTICE:Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2-altered GEA parallels the heterogeneity findings in HER2-amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas