Title: Relationship between HER2 overexpression and long-term outcomes of early gastric
cancer: A prospective observational study with a 6-year follow-up
Version: 1 Date: 01 Mar 2022
Reviewer:  William Chapin
Reviewer's report:
The present study aims to identify the prognostic impact of Her2 overexpression in patients with
early gastric cancer who underwent endoscopic resection. It uses a prospective cohort design to
identify patients with and without Her2 overexpression and follow them prospectively for patient
important outcomes including overall survival, disease specific survival, and disease recurrence.
The study is novel and adjusts for clinically important covariables, but has several weaknesses.
The main issue that needs to be addressed prior to publication is a full accounting of how patients
were determined to be “lost to follow up” and how many from each group of interest (Her 2
overexpressing and not Her2 overexpressing) were lost to follow up. This is an important point,
as being lost to follow up could be significantly associated with outcomes, such as death. Given
the small number of outcomes in the study, this could have a large impact on the results and
could represent a significant selection bias, especially if differential between groups. Specific
suggestions for exploring this possibility are outlined below.
If this issue and other methodologic issues are addressed adequately, I believe that the paper
could merit publication and would represent a unique contribution to the literature. My specific
comments follow.
Page 2, Results paragraph, last line: HR is reported as 30.66.59 and is presumably a typo.
Page 2, line 24: I think this conclusion is too strong, as the study did not assess how more- or less-
strict follow up impacted clinical outcomes. In fact, with both exposure groups (with or without
Her2 overexpression) who presumably received the same follow up, there is no survival or
disease-specific survival difference despite the increased risk of recurrence identified in the Her2
overexpression group. Would favor a statement such as, “Her2 testing at diagnosis is important
and differential treatment and/or follow up strategies for patients with Her2 overexpression may
merit future study.”
Page 3, Line 8: The phrase “,the early stage of gastric cancer,” is redundant and can be removed.
Page 3, Line 17: This paragraph seems to imply that outcomes for endoscopic resection are
comparable to surgical outcomes, even for patients with clinical evidence of lymph node
metastases (based on the definition for early gastric cancer in lines 8 – 9). I would clarify this
section to state that for patients with early gastric cancer without clinical evidence of lymph
node metastasis the cited studies have found similar long-term outcomes.
Page 4, line 7: Exclusion criteria note that patients were excluded if they were “lost to follow
up”. This needs to be clarified. What qualified as lost to follow up? Did this just mean that
patients with clinical and pathologic data for the study that could not be contacted by phone
were excluded from the study? This has the potential to include significant selection bias as
experiencing the outcome (death) is a likely mechanism for being “lost to follow up”.
At a minimum, additional information needs to be provided on how patients were declared to
be “lost to follow up”. We also need more information on these patients. If baseline clinical and
pathologic information is available, how many of the patients that were lost to follow up are
Her2 overexpressing vs not Her2 overexpressing? If the loss to follow up is differential between
the Her2 overexpressing vs not Her2 overexpressing patients, this could significantly bias the
results. Do patients have information on clinical follow up after endoscopic resection? If this
is the case, patients can be included and censored at the time of their last clinical follow up if
they have not experienced the outcome.
I would consider a CONSORT diagram or patient flow diagram with more specific details of
how many patients were excluded and for what reasons.
If more detailed information is not available on excluded patients, sensitivity analysis should
explore what impact these patients being lost to follow up could have on the results of the study.
Page 5, line 22: For OS outcome, what led to patient censoring? Were patients censored at last
clinical contract verifying vital status? Was there administrative censoring at the end of the
study?
Page 5, line 23: For disease specific survival outcome, how were patients censored? Were they
censored if they died from another cause and were no longer at risk for dying from gastric cancer?
Were they censored at date of last clinic follow up? Were they censored administratively at the
end of the study?
Page 5, line 23: How was “death from recurrent gastric cancer” determined? Would death from
neutropenic fever during treatment for metastatic gastric cancer qualify? There needs to be
a definition for how patients would qualify for this outcome and how it was adjudicated for
uncertain cases.
Page 5, line 5: Please cite the scoring system used for classifying lesion morphology as elevated,
flat, or depressed.
Page 5, line 14: I would favor splitting up the discussion of H. pylori infection into three separate
sentences.
Page 5, line 25: Since this was a prospective study, were patients followed on a regular schedule
with endoscopy and CT scans? Was the assessment the same for both patients with Her2
overexpression and those without Her2 overexpression?
Page 6, line 4: Please include additional information regarding the backward selection procedure.
Which baseline covariables were considered? What was the criteria used in the backward
selection procedure (p > 0.05 for exclusion)? I see this information is provided in the results,
but I recommend that it be moved to the methods.
Page 7, line 11: I believe that your criteria stating “factors that showed no or limited statistically
significant association (P < 0.1)” should read “(p > 0.1)” to correctly indicate that variables with
p-values higher than 0.1 were excluded from the model.
Page 7, line 13: Since the stated goal of the paper is to identify the association of Her2 status
with prognostic outcomes (OS, DSS, recurrence), the backward stepwise selection procedure
should be prespecified to always include Her2 status in the model so that its association with
the outcome can be assessed and reported, even if not statistically significant.
Figures 1 -3: Recommend including a “number at-risk table” below survival curves and
cumulative hazard curves to ensure appropriate interpretation of these figures.
Title: Relationship between HER2 overexpression and long-term outcomes of early gastric
cancer: A prospective observational study with a 6-year follow-up
Version: 1 Date: 01 Mar 2022
Reviewer:  William Chapin
Reviewer's report:
The present study aims to identify the prognostic impact of Her2 overexpression in patients with
early gastric cancer who underwent endoscopic resection. It uses a prospective cohort design to
identify patients with and without Her2 overexpression and follow them prospectively for patient
important outcomes including overall survival, disease specific survival, and disease recurrence.
The study is novel and adjusts for clinically important covariables, but has several weaknesses.
The main issue that needs to be addressed prior to publication is a full accounting of how patients
were determined to be “lost to follow up” and how many from each group of interest (Her 2
overexpressing and not Her2 overexpressing) were lost to follow up. This is an important point,
as being lost to follow up could be significantly associated with outcomes, such as death. Given
the small number of outcomes in the study, this could have a large impact on the results and
could represent a significant selection bias, especially if differential between groups. Specific
suggestions for exploring this possibility are outlined below.
If this issue and other methodologic issues are addressed adequately, I believe that the paper
could merit publication and would represent a unique contribution to the literature. My specific
comments follow.
Page 2, Results paragraph, last line: HR is reported as 30.66.59 and is presumably a typo.
Page 2, line 24: I think this conclusion is too strong, as the study did not assess how more- or less-
strict follow up impacted clinical outcomes. In fact, with both exposure groups (with or without
Her2 overexpression) who presumably received the same follow up, there is no survival or
disease-specific survival difference despite the increased risk of recurrence identified in the Her2
overexpression group. Would favor a statement such as, “Her2 testing at diagnosis is important
and differential treatment and/or follow up strategies for patients with Her2 overexpression may
merit future study.”
Page 3, Line 8: The phrase “,the early stage of gastric cancer,” is redundant and can be removed.
Page 3, Line 17: This paragraph seems to imply that outcomes for endoscopic resection are
comparable to surgical outcomes, even for patients with clinical evidence of lymph node
metastases (based on the definition for early gastric cancer in lines 8 – 9). I would clarify this
section to state that for patients with early gastric cancer without clinical evidence of lymph
node metastasis the cited studies have found similar long-term outcomes.
Page 4, line 7: Exclusion criteria note that patients were excluded if they were “lost to follow
up”. This needs to be clarified. What qualified as lost to follow up? Did this just mean that
patients with clinical and pathologic data for the study that could not be contacted by phone
were excluded from the study? This has the potential to include significant selection bias as
experiencing the outcome (death) is a likely mechanism for being “lost to follow up”.
At a minimum, additional information needs to be provided on how patients were declared to
be “lost to follow up”. We also need more information on these patients. If baseline clinical and
pathologic information is available, how many of the patients that were lost to follow up are
Her2 overexpressing vs not Her2 overexpressing? If the loss to follow up is differential between
the Her2 overexpressing vs not Her2 overexpressing patients, this could significantly bias the
results. Do patients have information on clinical follow up after endoscopic resection? If this
is the case, patients can be included and censored at the time of their last clinical follow up if
they have not experienced the outcome.
I would consider a CONSORT diagram or patient flow diagram with more specific details of
how many patients were excluded and for what reasons.
If more detailed information is not available on excluded patients, sensitivity analysis should
explore what impact these patients being lost to follow up could have on the results of the study.
Page 5, line 22: For OS outcome, what led to patient censoring? Were patients censored at last
clinical contract verifying vital status? Was there administrative censoring at the end of the
study?
Page 5, line 23: For disease specific survival outcome, how were patients censored? Were they
censored if they died from another cause and were no longer at risk for dying from gastric cancer?
Were they censored at date of last clinic follow up? Were they censored administratively at the
end of the study?
Page 5, line 23: How was “death from recurrent gastric cancer” determined? Would death from
neutropenic fever during treatment for metastatic gastric cancer qualify? There needs to be
a definition for how patients would qualify for this outcome and how it was adjudicated for
uncertain cases.
Page 5, line 5: Please cite the scoring system used for classifying lesion morphology as elevated,
flat, or depressed.
Page 5, line 14: I would favor splitting up the discussion of H. pylori infection into three separate
sentences.
Page 5, line 25: Since this was a prospective study, were patients followed on a regular schedule
with endoscopy and CT scans? Was the assessment the same for both patients with Her2
overexpression and those without Her2 overexpression?
Page 6, line 4: Please include additional information regarding the backward selection procedure.
Which baseline covariables were considered? What was the criteria used in the backward
selection procedure (p > 0.05 for exclusion)? I see this information is provided in the results,
but I recommend that it be moved to the methods.
Page 7, line 11: I believe that your criteria stating “factors that showed no or limited statistically
significant association (P < 0.1)” should read “(p > 0.1)” to correctly indicate that variables with
p-values higher than 0.1 were excluded from the model.
Page 7, line 13: Since the stated goal of the paper is to identify the association of Her2 status
with prognostic outcomes (OS, DSS, recurrence), the backward stepwise selection procedure
should be prespecified to always include Her2 status in the model so that its association with
the outcome can be assessed and reported, even if not statistically significant.
Figures 1 -3: Recommend including a “number at-risk table” below survival curves and
cumulative hazard curves to ensure appropriate interpretation of these figures.
Please review this paper.
user
Title: Relationship between HER2 overexpression and long-term outcomes of early gastric
cancer: A prospective observational study with a 6-year follow-up
Version: 1 Date: 01 Mar 2022
Reviewer:  William Chapin
Reviewer's report:
The present study aims to identify the prognostic impact of Her2 overexpression in patients with
early gastric cancer who underwent endoscopic resection. It uses a prospective cohort design to
identify patients with and without Her2 overexpression and follow them prospectively for patient
important outcomes including overall survival, disease specific survival, and disease recurrence.
The study is novel and adjusts for clinically important covariables, but has several weaknesses.
The main issue that needs to be addressed prior to publication is a full accounting of how patients
were determined to be “lost to follow up” and how many from each group of interest (Her 2
overexpressing and not Her2 overexpressing) were lost to follow up. This is an important point,
as being lost to follow up could be significantly associated with outcomes, such as death. Given
the small number of outcomes in the study, this could have a large impact on the results and
could represent a significant selection bias, especially if differential between groups. Specific
suggestions for exploring this possibility are outlined below.
If this issue and other methodologic issues are addressed adequately, I believe that the paper
could merit publication and would represent a unique contribution to the literature. My specific
comments follow.
Page 2, Results paragraph, last line: HR is reported as 30.66.59 and is presumably a typo.
Page 2, line 24: I think this conclusion is too strong, as the study did not assess how more- or less-
strict follow up impacted clinical outcomes. In fact, with both exposure groups (with or without
Her2 overexpression) who presumably received the same follow up, there is no survival or
disease-specific survival difference despite the increased risk of recurrence identified in the Her2
overexpression group. Would favor a statement such as, “Her2 testing at diagnosis is important
and differential treatment and/or follow up strategies for patients with Her2 overexpression may
merit future study.”
Page 3, Line 8: The phrase “,the early stage of gastric cancer,” is redundant and can be removed.
Page 3, Line 17: This paragraph seems to imply that outcomes for endoscopic resection are
comparable to surgical outcomes, even for patients with clinical evidence of lymph node
metastases (based on the definition for early gastric cancer in lines 8 – 9). I would clarify this
section to state that for patients with early gastric cancer without clinical evidence of lymph
node metastasis the cited studies have found similar long-term outcomes.
Page 4, line 7: Exclusion criteria note that patients were excluded if they were “lost to follow
up”. This needs to be clarified. What qualified as lost to follow up? Did this just mean that
patients with clinical and pathologic data for the study that could not be contacted by phone
were excluded from the study? This has the potential to include significant selection bias as
experiencing the outcome (death) is a likely mechanism for being “lost to follow up”.
At a minimum, additional information needs to be provided on how patients were declared to
be “lost to follow up”. We also need more information on these patients. If baseline clinical and
pathologic information is available, how many of the patients that were lost to follow up are
Her2 overexpressing vs not Her2 overexpressing? If the loss to follow up is differential between
the Her2 overexpressing vs not Her2 overexpressing patients, this could significantly bias the
results. Do patients have information on clinical follow up after endoscopic resection? If this
is the case, patients can be included and censored at the time of their last clinical follow up if
they have not experienced the outcome.
I would consider a CONSORT diagram or patient flow diagram with more specific details of
how many patients were excluded and for what reasons.
If more detailed information is not available on excluded patients, sensitivity analysis should
explore what impact these patients being lost to follow up could have on the results of the study.
Page 5, line 22: For OS outcome, what led to patient censoring? Were patients censored at last
clinical contract verifying vital status? Was there administrative censoring at the end of the
study?
Page 5, line 23: For disease specific survival outcome, how were patients censored? Were they
censored if they died from another cause and were no longer at risk for dying from gastric cancer?
Were they censored at date of last clinic follow up? Were they censored administratively at the
end of the study?
Page 5, line 23: How was “death from recurrent gastric cancer” determined? Would death from
neutropenic fever during treatment for metastatic gastric cancer qualify? There needs to be
a definition for how patients would qualify for this outcome and how it was adjudicated for
uncertain cases.
Page 5, line 5: Please cite the scoring system used for classifying lesion morphology as elevated,
flat, or depressed.
Page 5, line 14: I would favor splitting up the discussion of H. pylori infection into three separate
sentences.
Page 5, line 25: Since this was a prospective study, were patients followed on a regular schedule
with endoscopy and CT scans? Was the assessment the same for both patients with Her2
overexpression and those without Her2 overexpression?
Page 6, line 4: Please include additional information regarding the backward selection procedure.
Which baseline covariables were considered? What was the criteria used in the backward
selection procedure (p > 0.05 for exclusion)? I see this information is provided in the results,
but I recommend that it be moved to the methods.
Page 7, line 11: I believe that your criteria stating “factors that showed no or limited statistically
significant association (P < 0.1)” should read “(p > 0.1)” to correctly indicate that variables with
p-values higher than 0.1 were excluded from the model.
Page 7, line 13: Since the stated goal of the paper is to identify the association of Her2 status
with prognostic outcomes (OS, DSS, recurrence), the backward stepwise selection procedure
should be prespecified to always include Her2 status in the model so that its association with
the outcome can be assessed and reported, even if not statistically significant.
Figures 1 -3: Recommend including a “number at-risk table” below survival curves and
cumulative hazard curves to ensure appropriate interpretation of these figures.
assistant