Reviewer’s report
Title: Impact of Primary Colorectal Cancer Location on the KRAS Status and its Prognostic Value
Version: 1 Date: 07 Nov 2018
Reviewer: Matthew Burge
Reviewer's report:
This paper analyses the prognostic impact of KRAS status by tumour location.
Unfortunately, I find that there are flaws in this paper which need to be addressed.
Specifically:
- Introduction: Authors should detail what is defined by a right and left sided colon cancer. How were  
transverse colon cancers classified? It's not clear why they also divided the left colon and rectum and  
compared these 2 entities
                      A discussion/reference to RAS mutations outside codons 12 and 13 should take place.  
Why were these patients excluded? What might their impact on the results be?
Methods:   A more detailed description of this study is needed. Was it prospective? Why was there no  
survival data?
                More detail is needed regarding the types of studies included in the meta-analysis. Were they  
prospective or retrospective? randomised? An important paper on this topic comes from the QUASAR  
study:11)Hutchins et al DOI: 10.1200/JCO.2010.30.1366 Journal of Clinical Oncology 29, no. 10  
(April 1 2011) 1261-1270. Not cited but it should be.
                The statistical section is inadequate. Was a multivariate analysis performed to take into  
account confounding prognostic factors? How many patients were included in the meta-analysis of the  
prognostic impact of KRAS? The study population includes all stages of colorectal cancer hence is  
very heterogeneous and I can't see how any definitive conclusions can be drawn based on the data  
presented. The effect size of KRAS appears modest. What were the endpoints? "Survival time' is  
inadequate. Overall survival; disease free survival?
               There needs to be justification for the inclusion/exclusion criteria. Why were patients  
receiving pre-operative chemotherapy/radiotherapy excluded? The target population for this study is  
not well described
  Results:  The figures are somewhat confusing and need better explanation. In addition figures 3 and 4  
appear to be the wrong way around.
Discussion: I do not agree with the concluding statement that this studies data indicate the crucial  
importance of categorising CRC by primary side and KRAS status. This is important in metastatic  
colorectal cancer, but this is already well established. The utility of these same factors in early stage  
CRC is less.
                
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional  
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further  
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation  that  may  in  any  way  gain  or  lose  financially  from  the  publication  of  this  
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose financially  
from the publication of this manuscript, either now or in the future?
3. Do  you  hold  or are  you  currently applying  for  any patents  relating  to  the  content  of  the  
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds or  
has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If  
your reply is yes to any, please give details below.
I declare that I have no competing interets
I agree to the open peer review policy of the journal. I understand that my name will be included on my  
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not  
be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: Impact of Primary Colorectal Cancer Location on the KRAS Status and its Prognostic Value
Version: 1 Date: 07 Nov 2018
Reviewer: Matthew Burge
Reviewer's report:
This paper analyses the prognostic impact of KRAS status by tumour location.
Unfortunately, I find that there are flaws in this paper which need to be addressed.
Specifically:
- Introduction: Authors should detail what is defined by a right and left sided colon cancer. How were  
transverse colon cancers classified? It's not clear why they also divided the left colon and rectum and  
compared these 2 entities
                      A discussion/reference to RAS mutations outside codons 12 and 13 should take place.  
Why were these patients excluded? What might their impact on the results be?
Methods:   A more detailed description of this study is needed. Was it prospective? Why was there no  
survival data?
                More detail is needed regarding the types of studies included in the meta-analysis. Were they  
prospective or retrospective? randomised? An important paper on this topic comes from the QUASAR  
study:11)Hutchins et al DOI: 10.1200/JCO.2010.30.1366 Journal of Clinical Oncology 29, no. 10  
(April 1 2011) 1261-1270. Not cited but it should be.
                The statistical section is inadequate. Was a multivariate analysis performed to take into  
account confounding prognostic factors? How many patients were included in the meta-analysis of the  
prognostic impact of KRAS? The study population includes all stages of colorectal cancer hence is  
very heterogeneous and I can't see how any definitive conclusions can be drawn based on the data  
presented. The effect size of KRAS appears modest. What were the endpoints? "Survival time' is  
inadequate. Overall survival; disease free survival?
               There needs to be justification for the inclusion/exclusion criteria. Why were patients  
receiving pre-operative chemotherapy/radiotherapy excluded? The target population for this study is  
not well described
  Results:  The figures are somewhat confusing and need better explanation. In addition figures 3 and 4  
appear to be the wrong way around.
Discussion: I do not agree with the concluding statement that this studies data indicate the crucial  
importance of categorising CRC by primary side and KRAS status. This is important in metastatic  
colorectal cancer, but this is already well established. The utility of these same factors in early stage  
CRC is less.
                
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional  
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further  
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation  that  may  in  any  way  gain  or  lose  financially  from  the  publication  of  this  
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose financially  
from the publication of this manuscript, either now or in the future?
3. Do  you  hold  or are  you  currently applying  for  any patents  relating  to  the  content  of  the  
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds or  
has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If  
your reply is yes to any, please give details below.
I declare that I have no competing interets
I agree to the open peer review policy of the journal. I understand that my name will be included on my  
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not  
be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: Impact of Primary Colorectal Cancer Location on the KRAS Status and its Prognostic Value
Version: 1 Date: 07 Nov 2018
Reviewer: Matthew Burge
Reviewer's report:
This paper analyses the prognostic impact of KRAS status by tumour location.
Unfortunately, I find that there are flaws in this paper which need to be addressed.
Specifically:
- Introduction: Authors should detail what is defined by a right and left sided colon cancer. How were  
transverse colon cancers classified? It's not clear why they also divided the left colon and rectum and  
compared these 2 entities
                      A discussion/reference to RAS mutations outside codons 12 and 13 should take place.  
Why were these patients excluded? What might their impact on the results be?
Methods:   A more detailed description of this study is needed. Was it prospective? Why was there no  
survival data?
                More detail is needed regarding the types of studies included in the meta-analysis. Were they  
prospective or retrospective? randomised? An important paper on this topic comes from the QUASAR  
study:11)Hutchins et al DOI: 10.1200/JCO.2010.30.1366 Journal of Clinical Oncology 29, no. 10  
(April 1 2011) 1261-1270. Not cited but it should be.
                The statistical section is inadequate. Was a multivariate analysis performed to take into  
account confounding prognostic factors? How many patients were included in the meta-analysis of the  
prognostic impact of KRAS? The study population includes all stages of colorectal cancer hence is  
very heterogeneous and I can't see how any definitive conclusions can be drawn based on the data  
presented. The effect size of KRAS appears modest. What were the endpoints? "Survival time' is  
inadequate. Overall survival; disease free survival?
               There needs to be justification for the inclusion/exclusion criteria. Why were patients  
receiving pre-operative chemotherapy/radiotherapy excluded? The target population for this study is  
not well described
  Results:  The figures are somewhat confusing and need better explanation. In addition figures 3 and 4  
appear to be the wrong way around.
Discussion: I do not agree with the concluding statement that this studies data indicate the crucial  
importance of categorising CRC by primary side and KRAS status. This is important in metastatic  
colorectal cancer, but this is already well established. The utility of these same factors in early stage  
CRC is less.
                
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Unable to assess
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional  
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further  
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation  that  may  in  any  way  gain  or  lose  financially  from  the  publication  of  this  
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose financially  
from the publication of this manuscript, either now or in the future?
3. Do  you  hold  or are  you  currently applying  for  any patents  relating  to  the  content  of  the  
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds or  
has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If  
your reply is yes to any, please give details below.
I declare that I have no competing interets
I agree to the open peer review policy of the journal. I understand that my name will be included on my  
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not  
be published.
I agree to the open peer review policy of the journal
assistant