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: 2 Date: 02 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-The study is conducted at a single institution (The Sixth Affiliated Hospital of Sun Yat-sen
University), which may limit the external validity of the findings. While the use of a large
database increases sample size, multicenter studies would strengthen the generalizability of the
results.
-The absence of certain patient-specific factors, such as comorbidities or other medications,
could be a limitation. These factors may contribute to VTE recurrence but are not accounted
for in the study.
-While the study mentions standard anticoagulation treatment (rivaroxaban and apixaban), the
lack of detailed data on how anticoagulation therapy was managed throughout the study period
could introduce variability in the results. For instance, the duration and dosage of anticoagulation
therapy could significantly impact the recurrence rate.
-The role of baseline anticoagulation use is acknowledged as a limitation, but it would be helpful
to assess the degree to which this factor could have influenced the findings.
-While the authors account for bevacizumab and regorafenib/fruquintinib use as confounders,
other treatments and clinical variables (e.g., tumor burden, and organ dysfunction) might
contribute to VTE recurrence. It would be beneficial to conduct sensitivity analyses adjusting
for these potential confounders.
-The study also does not address the potential influence of other genetic mutations or
alterations (e.g., TP53 mutations) on VTE recurrence. While KRAS is a primary focus, a more
comprehensive genetic analysis might offer additional insights.
-The manuscript mentions that the study includes a large cohort, but it would be useful to provide
more details about the sample size calculation and the statistical power for detecting significant
differences, particularly for subgroup analyses (e.g., by KRAS mutation subtype).
-The criteria for confirming recurrent VTE are detailed, but there is a slight risk that imaging
results could be subject to interpretation biases, especially for asymptomatic patients. While this
is a common challenge in retrospective studies, further clarification on the standardization of
diagnostic criteria would improve confidence in the results.
-While the authors mention the single-center nature of the study, this limitation could be
emphasized more in the context of the findings. Given the potential variability in treatment
practices and patient populations across centers, the generalizability of these results to other
institutions, particularly outside of China, may be limited. It would be beneficial to highlight
how this could affect the broader applicability of the study’s findings.
-While the authors compare their results to previous studies, particularly those that evaluated
the Khorana and Ottawa scores, it would be helpful to further elaborate on the study designs
and patient populations of these studies. This would better contextualize why their study’s
findings differ from those of others and provide a more thorough understanding of the observed
discrepancies.
-The authors acknowledge the potential for confounding variables such as treatment choices, but
there is no detailed discussion of how these might specifically influence the study’s findings.
The discussion could be strengthened by considering how these factors might have confounded
the results and whether there are any known strategies to mitigate this risk in future studies.
-The authors briefly mention the need for future research to explore the biological mechanisms
underlying the link between KRAS mutations and VTE recurrence, such as through heparanase
production or elevated tissue factor expression. However, a more in-depth exploration of these
potential mechanisms in the Discussion would help readers understand the pathophysiological
processes involved. Furthermore, connecting the genetic mutations to specific biological
pathways would strengthen the manuscript’s impact and suggest more focused directions for
future research.
-The study notes that surveillance for asymptomatic VTE was not routinely performed, which
may have led to an underestimation of VTE prevalence. While the authors state that all patients
underwent imaging during hospitalization, it would be beneficial to further explore the potential
implications of this limitation. For example, how might the lack of routine screening for
asymptomatic VTE have influenced the overall findings, and could this impact the predictive
validity of the VTE scores discussed?