Association of Single-Nucleotide Polymorphisms in Capecitabine Bioactivation Pathway with Adjuvant Therapy Safety in Colorectal Cancer Patients
, Almudena Sánchez-MartÃn 1, Noelia Márquez-Pete 1, Encarnación González-Flores 2,3, Fernando MartÃnez-MartÃnez 4, Cristina Pérez-RamÃrez 5,†and Alberto Jiménez-Morales 1,†
Round 1
Reviewer 1 Report
This manuscript describes relationship of genetic variants of selected bioactivation enzymes (CES1/2, CDA, TP) in 161 Spanish CRC patients.
The study is essentially valuable in adding knowledge in relationship between polymorphisms and capecitabine safety.
Strong point of the paper is clear presentation of relationship between CES1 allele rs71647871 and hand-foot syndrome. Although the hypothesis that CES1 allele can relate to increased exposure, thus read to adverse effect, is rational, clear relationship with safety endpoint is seldom seen.
On the other side, relationship between CDA allele rs1048977 and safety is already known.
Weakness of the study is small number of alleles studied. This inevitably limit the interpretation of research outcomes.
Writing and reporting are in good shape.
Minor points:
Line 66: “thymidine phosphorylase (TYMP) gene” should be “thymidine phosphorylase gene (TYMP)”, as TP is used to describe “thymidine phosphorylase” enzyme.
Figure 1: Preferably bio-activation and catabolism can be illustrated in one figure for readers’ understanding.
Author Response
"Please see the attachment."
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The aim of this study was to evaluate the association of these SNPs with severe toxicity and treatment suspension in CRC patients treated with capecitabine-based therapy. The study found that CES1 rs71647871-A was associated with severe hand-foot syndrome (p = 0.030; OR = 11.92; 95%CI = 1.46 - 73.47; GG vs A). CDA s1048977-CC (p = 0.030; OR = 2.30; 95%CI 1.09 - 5.00; T vs CC) and capecitabine monotherapy (p = 0.003; OR = 3.13; 95%CI 1.49 - 6.81) were associated with treatment suspension due to toxicity. Overall, the study provides useful information and the manuscript is well-written. Thus, I just have one minor suggestion.
1. Please add some discussion about the clinical implication of the findings of the present work.
Author Response
"Please see the attachment."
Author Response File: Author Response.pdf
Reviewer 3 Report
In this study, the authors tried to determine the role of SNPs in the capecitabine metabolic pathway that might contribute to treatment toxicity and treatment suspension, and identified CES1 and CES1P1 variants as potential biomarkers. The study is well designed and presented. The following are suggested for improvements:
1. The main limitation is the small number of patients, and the lack of a validation cohort.
2. Although the authors focused on the use of single SNPs for predicting toxicity, have they considered the use of different combinations of SNPs to further improve the predictive value?
3. Please provide more discussion on CES1P1 as a potential predictor of capecitabine toxicity.
Only minor editing is required.
Author Response
"Please see the attachment."
Author Response File: Author Response.pdf
