Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival

Abstract

BACKGROUND Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers. METHODS We obtained data on 964 patients with rectal or colon cancer from the Nurses’ Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1. RESULTS Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer–specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P = 0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer–specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P = 0.76 by the log-rank test; P = 0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P = 0.96 by the log-rank test; P = 0.07 for interaction). CONCLUSIONS Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.)

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…[40][41][42] This disease-specific focus has identified novel oncogenic drivers, and the genes contributing to functional change, 43 importantly, revealed that different molecular features contribute to individual differences that occurred in clinicopathological characteristics, disease behavior, prognosis, and response to treatments, which thus helped to establish definitions of molecular subtypes and identified new biomarkers on the basis of omic alterations. [44][45][46] It is now well known that some CRC cases are linked to some factors, such as environment, 47 inflammation, 48,49 immunity, 50 and epigenetic alterations 51,52 rather than heritable genetic changes. An interesting thing is that these factors can influence each other, for instance, epigenetic aberrations induced by environmental factors contribute to cancer processes; 53 interaction of drug and molecular characteristics can influence lncRNAs and clinical outcome; 46,54,55 and epigenetic factors such as lncRNAs can also coordinate cellular responses to environment in turn.…”

“…[44][45][46] It is now well known that some CRC cases are linked to some factors, such as environment, 47 inflammation, 48,49 immunity, 50 and epigenetic alterations 51,52 rather than heritable genetic changes. An interesting thing is that these factors can influence each other, for instance, epigenetic aberrations induced by environmental factors contribute to cancer processes; 53 interaction of drug and molecular characteristics can influence lncRNAs and clinical outcome; 46,54,55 and epigenetic factors such as lncRNAs can also coordinate cellular responses to environment in turn. 56 The significance of lncRNAs in human CRC was realized in 2001 when Tanaka et al 57 determined that a loss of imprinting of long QT intronic transcript 1 (LIT1/KCNQ1OT1) was frequently observed in CRC patients, suggesting a link between lncRNAs and CRC.…”

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

“…Rather, it appears that an increase in intracellular cAMP levels with subsequent PKA activation (28) is involved in this effect, because pharmacological manipulations designed to lower cAMP or to suppress PKA reduced the killing of tetraploid cells by resveratrol. At least in the context of colon cancer, aspirin is generally thought to act via inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, better known as cyclooxygenase-2, COX2) (44,45). Nonetheless, we did not observe that more selective COX2 inhibitors than aspirin would selectively kill tetraploid cells (Fig.…”

Distinguishing Grade I Meningioma From Higher Grade Meningiomas Without Biopsy

“…If the lower overall incidence of meningiomas in men than women included a greater decrease in the incidence of WHO Grade I than Grade II-III tumors, then the proportion of Grade II-III meningiomas would be higher in men than women. Because of the known carcinogenic properties of smoking, and the suspected anti-carcinogenic properties of statins [16] and cox-2 inhibitors [17], we decided to investigate these medications as well as hormonal therapy. For completion, we also investigated patient co-morbidities and presenting symptoms.…”