Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study

Cardwell, Christopher; McMenamin, Úna C.; Hughes, Carmel; Murray, Liam

doi:10.1158/1055-9965.epi-15-0052

Cited by 109 publications

(103 citation statements)

References 24 publications

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“…Importantly, TCGA data suggest that the R270H-dependent MVA pathway GOF may be shared by other DNA contact mutants in human lung tumors. Notably, while the effects of statins on cancer remain controversial (Mullen et al 2016), there are reports of improved survival among statin-treated lung cancer patients (Cardwell et al 2015;Lin et al 2016). Based on our findings, it would be important to determine whether mutant p53 status is associated with that benefit.…”

Section: Discussionmentioning

confidence: 78%

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

et al. 2017

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Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine Kras G12D -p53 null , -p53 R172H (conformational), and -p53 R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53 R270H -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant.

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Section: Discussionmentioning

confidence: 78%

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

et al. 2017

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“…Thus, treatment with aspirin would be expected to weaken the association between MI and long-term cancer [35][36][37]. Studies on statin treatment and future development of cancer are inconsistent: Some studies have observed that use of statins may reduce both the risk of developing cancer and the rates of cancer-specific mortality for several cancer types [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Myocardial infarction and future risk of cancer in the general population—the Tromsø Study

et al. 2017

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The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n=28763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariableadjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21-1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29-3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27-2.03) higher HR of future cancer more than 3 years after the event. The increased incidence rates were higher in women than men. Patients with MI had a higher short-and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.

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“…As described previously [15], we utilised record linkages between the English National Cancer Data Repository (NCDR) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) to identify lung cancer patients diagnosed between 1998 and 2009. Office of National Statistics (ONS) mortality data provided deaths up to 2012.…”

Section: Methodsmentioning

confidence: 99%

Metformin use and survival from lung cancer: A population-based cohort study

et al. 2016

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word count: 222 Manuscript word count: 1,472Number of tables and figures: 2 Abbreviations: BMI, body mass index; CIs, confidence intervals; CPRD, Clinical Practice Research Datalink; DDD, daily defined dose; GP, general practitioner; HR, hazard ratio; NCDR, National cancer Data Repository; ONS, Office of National Statistics; UK, United Kingdom; WHO, World Health Organisation. AbstractPreclinical evidence suggests that metformin, a widely prescribed anti-diabetic drug, may inhibit lung cancer progression. We investigated whether metformin use was associated with decreased risk of cancer-specific mortality in lung cancer patients. This study included newly diagnosed lung cancer patients (identified from English National Cancer Data Repository, 1998-2009) with type 2 diabetes (based on UK Clinical Practice Research Datalink prescriptions and diagnosis records). Lung cancer deaths occurring up to 2012 were identified using Office of National Statistics mortality data and the association between metformin use (before and after diagnosis) and risk of lung cancer-specific mortality was calculated using Cox regression models. In analysis of 533 patients, we found a weak non-significant reduction in lung cancer-specific mortality with metformin use after diagnosis (adjusted HR, 0.86; 95% CI, 0.68-1.09). No association was evident for metformin use before diagnosis and cancer-specific mortality in analysis of 1,350 patients (adjusted HR, 0.97; 95% CI, 0.86, 1.11). Associations were similar by duration of use. In addition, after adjustment for potential confounders, there was little evidence of an association between the use of other anti-diabetic medications (either before or after diagnosis) and lung cancer-specific mortality; including sulfonylureas, insulin or other anti-diabetic medications (such as thiazolidinediones). Overall, the results from this population-based study provide little evidence of a protective association between metformin use and cancer mortality in lung cancer patients.

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Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study

Cited by 109 publications

References 24 publications

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

Myocardial infarction and future risk of cancer in the general population—the Tromsø Study

Metformin use and survival from lung cancer: A population-based cohort study

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