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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.
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Polipose Adenomatosa do Colo , Neoplasias Duodenais , Humanos , Feminino , Adulto , Cloridrato de Erlotinib/efeitos adversos , Polipose Adenomatosa do Colo/tratamento farmacológico , Neoplasias Duodenais/tratamento farmacológico , Duodeno , Endoscopia GastrointestinalRESUMO
BACKGROUND & AIMS: DNA mismatch repair deficiency drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. Individuals with LS are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not yet been demonstrated. METHODS: A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression, and mutation frequency. In silico prediction, in vivo immunogenicity testing, and epitope mapping was used to identify candidates for FSP vaccination. RESULTS: We identified 4 shared FSP neoantigens (Nacad [FSP-1], Maz [FSP-1], Senp6 [FSP-1], Xirp1 [FSP-1]) that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden, and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth, and prolonged survival even more effectively than FSP vaccination alone. CONCLUSIONS: Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
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Antígenos de Neoplasias/farmacologia , Vacinas Anticâncer/farmacologia , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Mutação da Fase de Leitura , Fenômenos Imunogenéticos , Fragmentos de Peptídeos/farmacologia , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Bases de Dados Genéticas , Modelos Animais de Doenças , Epitopos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 2 Homóloga a MutS/genética , Naproxeno/farmacologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral , Vacinação , Eficácia de VacinasRESUMO
OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.
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Anti-Inflamatórios não Esteroides/farmacologia , Quimioprevenção , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Naproxeno/farmacologia , Adulto , Idoso , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Dinoprostona/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Naproxeno/administração & dosagemRESUMO
BACKGROUND & AIMS: Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis. METHODS: This study included 44 patients with familial adenomatous polyposis (18-85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle. RESULTS: After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3-27.8) and the curcumin group (22.6; 95% CI, 12.1-33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8-2.8) and the placebo group (2.1 mm; 95% CI, 1.5-2.7; P = .76). Adverse events were few, with no significant differences between groups. CONCLUSIONS: In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147.
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Adenoma/tratamento farmacológico , Polipose Adenomatosa do Colo/tratamento farmacológico , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Curcumina/administração & dosagem , Adenoma/etiologia , Polipose Adenomatosa do Colo/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/etiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325â mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3â months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3â months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Neoplasias do Colo/prevenção & controle , Análise Espectral/métodos , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Biomarcadores Tumorais , Quimioprevenção , Dinoprostona/metabolismo , Método Duplo-Cego , Feminino , Genótipo , Glucuronosiltransferase/genética , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reto/metabolismoRESUMO
SUMMARY: Cancer prevention is central to efforts to control the burden of cancer. We propose a new terminology framework to help guide these efforts and promote a key equity principle: "equal care for equal risk."
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Neoplasias , Humanos , Neoplasias/prevenção & controleRESUMO
Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362).
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Importance: In a population with significantly increasing rates of individuals with overweight or obesity, understanding the association of obesity with long-term disease risk, such as cancer, is necessary to improve public health. Objective: To investigate the association between body mass index (BMI) and gastrointestinal (GI) cancer risk (colorectal cancer [CRC] and noncolorectal GI cancer) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants: This retrospective cohort study was a secondary analysis of data from the PLCO Cancer Screening Trial. Participants aged 55 to 74 years were enrolled and randomized to the intervention (screening group) or control group at 10 screening centers between November 8, 1993, and July 2, 2001. The initial analysis of PLCO Cancer Screening Trial data occurred after 13 years of follow-up or December 31, 2009, whichever came first. Participants were reconsented in 2011 and either continued follow-up or refused additional follow-up. For those who reconsented, follow-up for incident cancers continued until December 31, 2014, or death, whichever occurred first. Data analysis for this secondary analysis was performed from April 2022 through November 2022. Exposures: Body mass index and aspirin use, defined as the frequency of use of aspirin or aspirin-containing substances in the last 12 months. Main Outcomes and Measures: The primary outcomes were the diagnoses of CRC and noncolorectal GI cancer. The association between BMI and cancer (CRC and noncolorectal GI cancer) was assessed using Cox proportional hazards regression modeling. The association between cancer risk and change in BMI was further analyzed at different ages, and an exploratory analysis was performed to evaluate GI cancer risk among aspirin users. Results: This analysis included 135â¯161 participants (median [range] age, 62 [55-78] years; 67â¯643 [50.0%] female). Overweight BMI in early adulthood (hazard ratio [HR], 1.23; 95% CI, 1.10-1.37) and overweight BMI in middle adulthood (HR, 1.23; 95% CI, 1.13-1.34) and later adulthood (HR, 1.21; 95% CI, 1.10-1.32) as well as obese BMI in middle adulthood (HR, 1.55; 95% CI, 1.38-1.75) and later adulthood (HR, 1.39; 95% CI, 1.25-1.54) were associated with increased risk of CRC. Similar results were observed for the association with overall GI and non-CRC GI risk and BMI in middle and later adulthood. Maintaining overweight or obese BMI or increasing BMI to overweight or obese in later adulthood was also associated with increased CRC risk. Aspirin use 3 or more times per week did not significantly modify this association. Conclusions and Relevance: In this secondary analysis of the PLCO Cancer Screening Trial, overweight and obese BMI in early and middle adulthood was associated with an elevated risk of CRC and noncolorectal GI cancers. The results of the current study prompt further exploration into the mechanistic role of obese BMI in carcinogenesis.
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Neoplasias Colorretais , Neoplasias Gastrointestinais , Neoplasias Ovarianas , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/epidemiologia , Índice de Massa Corporal , Fatores de Risco , Estudos Retrospectivos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/complicações , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/diagnóstico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/etiologia , Aspirina/uso terapêuticoRESUMO
Background: Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients. Methods: Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled 'Naproxen Study' were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens. Results: Using data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen. Conclusions: Our findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.
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Antineoplásicos , Vacinas Anticâncer , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Naproxeno/farmacologia , Imunoterapia , Linfócitos , Mucosa Intestinal , QuimioprevençãoRESUMO
Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry-based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia. PREVENTION RELEVANCE: The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.
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Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Vacinas de DNA , Humanos , Vacinas de DNA/efeitos adversos , Vacinas de DNA/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Carcinoma Hepatocelular/prevenção & controle , Proteínas não Estruturais Virais/genética , Neoplasias Hepáticas/prevenção & controle , Hepatite C/prevenção & controle , Hepacivirus/genética , DNA , Interleucina-12RESUMO
PURPOSE: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. PATIENTS AND METHODS: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. RESULTS: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9-17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60-1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15-1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. CONCLUSIONS: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
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Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adenoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Imunoglobulina G , Vacinas de Subunidades AntigênicasRESUMO
The role of aspirin in cancer prevention has been well described for multiple cancers, with strong data for gastrointestinal cancers. Studies, primarily conducted in colorectal cancer, suggest that aspirin exerts its cancer-preventive effects through the inhibition of gastrointestinal inflammation. Compared with colorectal cancer, the role of aspirin in gastric cancer prevention is less well described, however it stands to reason that aspirin and/or other nonsteroidal anti-inflammatory drugs may inhibit gastric cancer progression through the inhibition of COX-2. As discussed in this issue of Cancer Prevention Research, aspirin may prevent gastric cancer, albeit it appears to exert a disparate effect in men and women, the reason for which remain unclear. These results expand upon prior studies by prospectively examining aspirin use at a wider range of doses and durations in non-Asian participants and lend support to observations from previously conducted studies in Asian populations. See related article, p. 265.
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Neoplasias Gastrointestinais , Neoplasias Gástricas , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/farmacologia , Aspirina/uso terapêutico , Ciclo-Oxigenase 2 , Feminino , Neoplasias Gastrointestinais/prevenção & controle , Humanos , Masculino , Neoplasias Gástricas/prevenção & controleRESUMO
Advances in cancer screening and early detection methodologies may lead to the detection of precancerous lesions or early-stage cancer. The development of blood-based multi-cancer early detection (MCED) tests may aid in this challenge. Furthermore, MCED tests have the potential to address early detection gaps for cancers with and without screening modalities and lessen cancer disparities, but many unknowns remain. In this issue, Clarke and colleagues describe stage- and cancer-specific incidence and survival, derived from Surveillance, Epidemiology and End Results Program Data, stratified by race/ethnicity and sex. The investigators discuss the potential to identify earlier-stage cancers (stage shift) that could improve overall patient outcomes. In a simulation model, the authors found fewer cancer-related deaths when cancers were down-staged at the time of diagnosis. In this commentary, we discuss some unanswered questions in using MCED tests for screening, as well as what stage shifting may actually mean for patient outcomes. See related article by Clarke et al., p. 521.
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Detecção Precoce de Câncer , Neoplasias , Detecção Precoce de Câncer/métodos , Humanos , Incidência , Programas de Rastreamento , Neoplasias/diagnóstico , Neoplasias/prevenção & controleRESUMO
Precision cancer prevention as it is currently envisioned is a targeted, molecular-based approach to intercept carcinogenesis before cancer develops or before it becomes untreatable. Unfortunately, due to systemic biases, current precision cancer prevention interventions might not be effective in all populations, especially in minoritized communities. In addition, not all cancer risk is attributable to genetic or even biological factors, but includes social determinants of health (SDH). Here, we propose a broader framework for precision cancer prevention, anchored in optimizing the benefits to harms for all people. We propose that precision cancer prevention considers not only what is being delivered, but also for whom, where, and how, with a goal of achieving cancer prevention health equity.
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Equidade em Saúde , Neoplasias , Promoção da Saúde , Disparidades nos Níveis de Saúde , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Determinantes Sociais da SaúdeRESUMO
Early-onset colorectal cancer (EOCRC), defined as a diagnosis under age 50, is an emerging public health burden. As many of these individuals fall outside of screening guidelines, the development of a minimally invasive, accurate screening modality for this population is warranted. We evaluated the FDA-approved blood-based biomarker methylated Septin9 (mSEPT9) test as screening tool for EOCRC. EOCRC plasma, healthy plasma, and serum-free conditioned media from cancer cell lines was collected. Cell-free DNA (cfDNA) was isolated and bisulfite converted for use in the assay. mSEPT9 and ACTB measured using Epi proColon® V2.0. EOCRC plasma was collected at Massachusetts General Hospital (2005-2019) and controls were collected at the National Institutes of Health and by ZenBio Inc. (prior to 2019). Twenty-seven EOCRC cases, 48 healthy controls <50 years old, and 39 healthy controls ≥50 years old were included in this study. mSEPT9 was detected more frequently in EOCRC cases (88.9%) compared to healthy controls age <50 (4.2%) and ≥50 (15.4%), respectively (p<0.001). The sensitivity, specificity, positive predictive value, and negative predictive values of the mSEPT9 assay to detect EOCRC was 90.8% (95% CI: 84.7-96.9%), 88.9% (95% CI: 77.0-100.0%), 96.3% (95% CI: 92.3-100.0%), and 75.0% (95% CI 60.0-90.0%), respectively, compared to all healthy controls. mSEPT9 cfDNA level was an independent predictor of survival (p=0.02). mSEPT9 is a sensitive and specific biomarker for EOCRC detection. These results suggest that mSEPT9 may be useful in the detection of EOCRC, providing a minimally invasive method for screening in this growing population of CRC patients.
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Ácidos Nucleicos Livres , Neoplasias Colorretais , Humanos , Pessoa de Meia-Idade , Neoplasias Colorretais/diagnóstico , Biomarcadores Tumorais/genética , Septinas/genética , Detecção Precoce de Câncer/métodosRESUMO
Although aspirin has been considered a promising agent for prevention of colorectal cancer, recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of colorectal cancer may benefit from aspirin remains unknown. We used a 95-variant colorectal cancer polygenic risk score (PRS) to explore the association between genetic susceptibility to colorectal cancer and aspirin use in a prospective study of 12,609 individuals of European descent ages ≥70 years, enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) double-blinded, placebo-controlled randomized trial (randomized controlled trial; RCT). Cox proportional hazards models were used to assess the association of aspirin use on colorectal cancer, as well as the interaction between the PRS and aspirin treatment on colorectal cancer. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident colorectal cancer. Aspirin assignment was not associated with incidence of colorectal cancer overall [HR = 0.94; 95% confidence interval (CI), 0.68-1.30] or within strata of PRS (P for interaction = 0.97). However, the PRS was associated with an increased risk of colorectal cancer (HR = 1.28 per SD; 95% CI, 1.09-1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR = 1.85; 95% CI, 1.08-3.15). In a prospective RCT of older individuals, a PRS is associated with incident colorectal cancer risk, but aspirin use was not associated with a reduction of incident colorectal cancer, regardless of baseline genetic risk. PREVENTION RELEVANCE: There is strong evidence to support prophylactic aspirin use for the prevention of colorectal cancer. However recent recommendations suggest the risk of bleeding in older individuals outweighs the benefit. We sought to determine whether some older individuals might still benefit from aspirin based on their genetic susceptibility.
Assuntos
Aspirina , Neoplasias Colorretais , Idoso , Aspirina/uso terapêutico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Predisposição Genética para Doença , Humanos , Estudos Prospectivos , Fatores de RiscoRESUMO
Importance: Many studies have evaluated the long-term benefits of aspirin use; however, the association of aspirin use with cancer incidence and survival in older individuals remains uncertain. Additional population-based evidence of this association is necessary to better understand any possible protective effects of aspirin in older adults. Objective: To investigate the association of aspirin use with risk of developing new cancers and site-specific cancer-associated survival in bladder, breast, esophageal, gastric, pancreatic, and uterine cancers. Design, Setting, and Participants: This cohort study used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants were aged 65 years or older at baseline (1993-2001) or reached age 65 during follow-up. Data analysis was conducted from January to June 2020. Main Outcomes and Measures: Incidence of and survival from the investigated cancer types. Univariable and multivariable hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression modeling, adjusting for covariates. Multivariable models for incidence included time-varying covariates. Results: A total of 139â¯896 individuals (mean [SD] age at baseline, 66.4 [2.4] years; 71â¯884 [51.4%] women; 123â¯824 [88.5%] non-Hispanic White individuals) were included in the analysis. During the study period, 32â¯580 incident cancers (1751 [5.4%] bladder, 4552 [14.0%] breast, 332 [1.0%] esophageal, 397 [1.2%] gastric, 878 [2.7%] pancreatic, and 716 [2.2%] uterine cancers) were reported. Aspirin use was not associated with incidence of any of the investigated cancer types among individuals aged 65 years or older. Multivariable regression analysis demonstrated that aspirin use at least 3 times/week was associated with increased survival among patients with bladder (HR, 0.67; 95% CI, 0.51-0.88) and breast (HR, 0.75; 95% CI, 0.59-0.96) cancers but not among those with esophageal, gastric, pancreatic, or uterine cancer. A similar association of any aspirin use with bladder (HR, 0.75; 95% CI, 0.58-0.98) and breast (HR, 0.79; 95% CI, 0.63-0.99) cancer survival was observed. Conclusions and Relevance: In the current study, any aspirin use and aspirin use at least 3 times/week was associated with improved bladder and breast cancer survival. Associations between aspirin use and incidence of any of the investigated cancers or between aspirin use and esophageal, gastric, pancreatic, or uterine cancer survival were not observed.
Assuntos
Aspirina/uso terapêutico , Neoplasias/epidemiologia , Idoso , Feminino , Humanos , Incidência , Masculino , Neoplasias/mortalidade , Neoplasias/prevenção & controle , Fatores de Risco , Análise de SobrevidaRESUMO
Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER-Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09-0.12; NSAIDs: 0.62; 95% CI, 0.51-0.74; statins: 0.15; 95% CI, 0.13-0.17; metformin: 0.76; 95% CI, 0.62-0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.
Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/uso terapêutico , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Medicare/estatística & dados numéricos , Metformina/uso terapêutico , Prevalência , Inibidores da Bomba de Prótons/uso terapêutico , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.
Assuntos
Focos de Criptas Aberrantes/tratamento farmacológico , Catequina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Focos de Criptas Aberrantes/diagnóstico , Focos de Criptas Aberrantes/patologia , Idoso , Catequina/administração & dosagem , Catequina/efeitos adversos , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Reto/diagnóstico por imagem , Reto/efeitos dos fármacos , Reto/patologia , Resultado do TratamentoRESUMO
BACKGROUND: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. METHODS: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. RESULTS: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). CONCLUSIONS: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.