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Superior Overall Survival in Patients with Colorectal Cancer, Regular Aspirin Use, and Combined Wild-Type PIK3CA and KRAS-Mutated Tumors.

ABSTRACT: The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17-0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

SUBMITTER: Gebauer L

PROVIDER: S-EPMC8507980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation.

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| S-EPMC4743650 | biostudies-literature

Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited.

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Deactivation of Glutaminolysis Sensitizes PIK3CA-Mutated Colorectal Cancer Cells to Aspirin-Induced Growth Inhibition.

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| S-EPMC3623853 | biostudies-other

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| S-EPMC4775432 | biostudies-literature

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| S-EPMC7226330 | biostudies-literature

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Project description:The KRAS oncogene is present in up to 25% of solid tumors and for decades had been undruggable. Sotorasib was the first-in-class KRAS inhibitor to reach the US and European market, and its pharmacological inhibition is restricted to the KRAS p.G12C mutation. Sotorasib showed activity (tumor shrinkage) in patients with non-small cell lung cancer harboring this specific mutation, and efficacy was tested in the CodeBreaK 200, open-label, phase 3 trial (NCT04303780). The results were presented in the ESMO 2022 meeting. CodeBreaK 200 found an improvement in the primary endpoint of progression-free survival (PFS), but overall survival, a key secondary endpoint, was not improved. However, critical questions about the trial's design may limit inferences regarding the reported results. The control arm treatment was inferior to the best standard of care. A late protocol modification (which lowered the sample size and allowed a problematic crossover) prohibited the trial from making a determination regarding overall survival. Imbalance in censoring rates, with potential informative censoring, makes PFS estimates unreliable. Quality-of-life data were also limited. Ultimately, CodeBreaK 200 does not clarify how this therapy should be used in practice, and while we maintain cautious enthusiasm for this and other Ras inhibitors, we await more informative trials.

| S-EPMC9803768 | biostudies-literature

Radiation combined with KRAS-MEK inhibitors enhances anticancer immunity in KRAS-mutated tumor models

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-01 | GSE209767 | GEO

High-throughput mutation profiling of primary and metastatic endometrial cancers identifies KRAS, FGFR2 and PIK3CA to be frequently mutated.

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| S-EPMC3531332 | biostudies-literature

Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models.

Project description:Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor.

| S-EPMC4468631 | biostudies-literature

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