Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial.

IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. OBJECTIVE: To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. INTERVENTIONS: Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. MAIN OUTCOMES AND MEASURES: The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. RESULTS: Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]. CONCLUSIONS AND RELEVANCE: Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 01187901.

Activating mutation in MET oncogene in familial colorectal cancer.

BACKGROUND: In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. METHODS: MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. RESULTS: Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC. CONCLUSIONS: Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP.

Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, an approximately 99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with a locus on chromosome 6q22.1. This mutation is inherited by family members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon 13-exon 15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.