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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial
The Lancet, Volume 390, No. 10105, Year 2017
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Description
Background Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence. Methods We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017). Findings Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31). Interpretation Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required. Funding Novartis Pharmaceuticals. © 2017 Elsevier Ltd
Authors & Co-Authors
Ridker, Paul M.
United States, Boston
Brigham and Women's Hospital
MacFadyen, Jean G.
United States, Boston
Brigham and Women's Hospital
Thurén, Tom Y.
Switzerland, Basel
Novartis International ag
Everett, Brendan M.
United States, Boston
Brigham and Women's Hospital
Libby, Peter A.
United States, Boston
Brigham and Women's Hospital
Glynn, Robert James
United States, Boston
Brigham and Women's Hospital
Lorenzatti, Alberto J.
Unknown Affiliation
Krum, Henry
Unknown Affiliation
Varigos, John D.
Unknown Affiliation
Siostrzonek, Peter
Unknown Affiliation
Sinnaeve, Peter R.
Unknown Affiliation
Fonseca, Francisco Antônio Helfenstein
Unknown Affiliation
Nicolau, José Carlos
Unknown Affiliation
Gotcheva, Nina N.
Unknown Affiliation
Genest, Jacques J.G.
Unknown Affiliation
Yong, Huo
Unknown Affiliation
Urina-Triana, Miguel
Unknown Affiliation
Miličić, Davor
Unknown Affiliation
Cífkova, Renata
Unknown Affiliation
Vettus, Riina
Unknown Affiliation
Koenig, Wolfgang F.
Unknown Affiliation
Anker, Stefan D.
Unknown Affiliation
Manolis, Athanasios John
Unknown Affiliation
Forster, Tamás
Unknown Affiliation
Pais, Prem S.
Unknown Affiliation
Fucili, Alessandro
Unknown Affiliation
Shimokawa, Hiroaki
Unknown Affiliation
Kastelein, Johannes Jacob Pieter
Unknown Affiliation
Cornel, Jan Hein
Unknown Affiliation
Medina, Félix A.
Unknown Affiliation
Budaj, Andrzej J.
Unknown Affiliation
Kobalava, Zhanna D.
Unknown Affiliation
Pella, Daniel
Unknown Affiliation
Lainščak, Mitja
Unknown Affiliation
Seung, Ki-bae
Unknown Affiliation
Commerford, Patrick Joseph
Unknown Affiliation
Dellborg, Mikael
Unknown Affiliation
Donath, Marc Yves
Unknown Affiliation
Hwang, Juey-Jen
Unknown Affiliation
Flather, Marcus D.
Unknown Affiliation
Ballantyne, Christie Mitchell
Unknown Affiliation
Bohula, Erin A.
Unknown Affiliation
Chou, Sherry H.Y.
Unknown Affiliation
Maron, Bradley A.
Unknown Affiliation
Rost, Natalia Sana
Unknown Affiliation
Singhal, Aneesh Bhim
Unknown Affiliation
Ghosh, Nilanjan S.
Unknown Affiliation
Gralow, Julie R.
Unknown Affiliation
Rugo, Hope S.
Unknown Affiliation
Lópes, Renato Deláscio
Unknown Affiliation
Manning, Brian
Unknown Affiliation
Manfreda, Sheryl
Unknown Affiliation
Collins, Rory
Unknown Affiliation
Bailey, Kent R.
Unknown Affiliation
Blumenthal, Roger S.
Unknown Affiliation
Colhoun, Helen M.
Unknown Affiliation
Gersh, Bernard John
Unknown Affiliation
Statistics
Citations: 847
Authors: 57
Affiliations: 2
Identifiers
Doi:
10.1016/S0140-6736(17)32247-X
ISSN:
01406736
Research Areas
Cancer
Disability
Environmental
Health System And Policy
Study Design
Cross Sectional Study
Cohort Study
Exploratory Study