RESUMEN
IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. OBJECTIVE: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. DESIGN, SETTING AND PARTICIPANTS: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. EXPOSURES: Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. MAIN OUTCOMES AND MEASURES: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). RESULTS: Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. CONCLUSION: In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. TRIAL REGISTRATION NUMBER: NCT02961374.
Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Duodenales , Humanos , Femenino , Adulto , Clorhidrato de Erlotinib/efectos adversos , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Neoplasias Duodenales/tratamiento farmacológico , Duodeno , Endoscopía GastrointestinalRESUMEN
INTRODUCTION: Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database. METHODS: Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives. RESULTS: Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk. DISCUSSION: Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population.
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Adenocarcinoma/diagnóstico , Poliposis Adenomatosa del Colon/diagnóstico , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Predisposición Genética a la Enfermedad , Sistema de Registros , Medición de Riesgo/métodos , Adenocarcinoma/epidemiología , Poliposis Adenomatosa del Colon/etiología , Poliposis Adenomatosa del Colon/genética , Anciano , Colonoscopía/métodos , Neoplasias Colorrectales/epidemiología , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Linaje , Estudios Retrospectivos , Factores de Riesgo , Síndrome , Utah/epidemiologíaRESUMEN
Sessile serrated adenoma/polyps (SSA/Ps) of the colon account for 20-30% of all colon cancers. Small non-coding RNAs, including microRNAs (miRNAs), may function as oncogenes or tumor suppressor genes involved in cancer development. Small RNA sequencing (RNA-seq) was used to characterize miRNA profiles in SSA/Ps, hyperplastic polyps (HPs), adenomatous polyps and paired uninvolved colon. Our 108 small RNA-seq samples' results were compared to small RNA-seq data from 212 colon cancers from the Cancer Genome Atlas. Twenty-three and six miRNAs were differentially expressed in SSA/Ps compared to paired uninvolved colon and HPs, respectively. Differential expression of MIR31-5p, MIR135B-5p and MIR378A-5p was confirmed by RT-qPCR. SSA/P-specific miRNAs are similarly expressed in colon cancers containing genomic aberrations described in serrated cancers. Correlation of miRNA expression with consensus molecular subtypes suggests more than one subtype is associated with the serrated neoplasia pathway. Canonical pathway analysis suggests many of these miRNAs target growth factor signaling pathways.
Asunto(s)
Adenoma/genética , Neoplasias del Colon/genética , Pólipos del Colon/genética , MicroARNs/genética , Adenoma/patología , Anciano , Animales , Biomarcadores de Tumor/genética , Neoplasias del Colon/patología , Pólipos del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Thoracica/genéticaRESUMEN
BACKGROUND: Patients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance. METHODS: Individuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number. RESULTS: The distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype. CONCLUSIONS: Most FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location. TRIAL REGISTRATION: NCT 01187901 registered August 24, 2010, prospective to enrollment.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias Duodenales/genética , Pólipos Intestinales/genética , Penetrancia , Neoplasias Gástricas/genética , Poliposis Adenomatosa del Colon/patología , Poliposis Adenomatosa del Colon/cirugía , Adolescente , Adulto , Factores de Edad , Anciano , Colectomía , Neoplasias Duodenales/patología , Endoscopía Gastrointestinal , Femenino , Genes APC , Humanos , Pólipos Intestinales/patología , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estudios Prospectivos , Factores Sexuales , Neoplasias Gástricas/patología , Adulto JovenRESUMEN
Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. Objective: To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Design, Setting, and Participants: Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Interventions: Patients 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 Measurements: The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Results: Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). Conclusion and Relevance: In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. Trial Registration: clinicaltrials.gov Identifier: NCT01187901.