Review for 10.1186/s12876-025-03843-w (2025)

Title: The Impact of KRAS Mutations on Risk of Venous Thromboembolism Recurrence in
Patients with Metastatic Colorectal Cancer
Version: 3 Date: 13 Mar 2025
Reviewer's report:
This manuscript presents a retrospective study evaluating the association between KRAS
mutations and the risk of recurrent venous thromboembolism (VTE) in patients with metastatic
colorectal cancer (mCRC) receiving anticoagulation therapy. The study leverages a large
dataset from The Sixth Affiliated Hospital of Sun Yat-sen University and assesses VTE risk
stratification models incorporating KRAS mutation subtypes. The findings indicate a significant
correlation between KRAS mutations and an increased risk of recurrent proximal deep vein
thrombosis (DVT), with varying hazard ratios observed for specific KRAS subtypes. The
study aims to refine existing VTE risk models by integrating molecular data to enhance
predictive accuracy. This research addresses a clinically relevant issue, as VTE represents a
major complication in oncology, particularly in patients receiving targeted therapies, such as
anti-angiogenic agents. The inclusion of over 2,000 patients strengthens the statistical power of
the study and enhances the generalizability of the findings.
Major limitations are:
The study does not account for crucial VTE risk factors such as age, performance status (PS), and
body mass index (BMI) in its multivariate analysis or descriptive tables. Are there imbalances
in these factors across different KRAS variants? Given their established role in VTE risk, these
parameters should be included to ensure a comprehensive assessment of potential confounders.
Currently, the multivariate regression model only adjusts for bevacizumab, regorafenib, and
fruquintinib, neglecting other clinically relevant variables. A more robust statistical approach
should incorporate these factors into both the descriptive analysis and multivariate models to
accurately assess their influence on VTE risk.
The manuscript does not include any discussion—even at a descriptive level—regarding patient
comorbidities. Given the potential impact of comorbid conditions on VTE risk, at least a baseline
description should be provided.
This study holds particular scientific and cultural value, as it reinforces the notion that not all
KRAS variants have the same biological significance. This point could be further elaborated
by citing PMID: 37509241 and PMID: 32708575, which demonstrate that in mCRC, different
KRAS pathogenic variants exert distinct prognostic effects.
While the study explores various KRAS mutation subtypes, some subgroups (e.g., KRAS G12R,
KRAS G12A) have limited sample sizes, leading to wide confidence intervals. This limitation
should be explicitly discussed in the manuscript.
The study primarily focuses on tissue factor (TF) upregulation as the mechanistic link between
KRAS mutations and hypercoagulability. However, other potential pathways—including
inflammatory cytokine signaling and platelet activation—are not explored. Expanding the
Discussion section to acknowledge alternative mechanisms would strengthen the scientific rigor
of the study. Consider referencing PMID: 30441823, PMID: 35159208, and PMID: 27297136
to support this expanded discussion.