Reviewer’s report
Title: 
Cardiometabolic Risk Factors, Physical Activity, and Postmenopausal
Breast Cancer Mortality: Results from the Women’s Health Initiative
Version: 
0 
Date: 
23 Jun 2021
Reviewer's report:
The authors Dieli-Conwright et al. have contributed a short, but meaningful
report on the presence of metabolic syndrome components and their associations
with higher physical activity on overall and cancer specific mortality in breast
cancer patients. 
Major revisions:
The authors state that the physical activity tool they used has been validated, but
it's barely mentioned in the methods section. For a more clear understanding of
the procedures employed, I urge the authors to extend their methods section, not
only with details on the before mentioned tool, but also, how was the information
on metabolic syndrome components collected and measured. Furthermore, the
authors gave no concrete explanation in the text that they decided to use quartiles
for the physical activity, to define the relationship between metabolic
components and physical activity. The variables for which the Cox multivariable
model was adjusted for should be clearly stated in the statistical methods
sections, so readers could evaluate if an appropriate number of confounders were
included in the model, to indicate how (un)biased is the reported effect estimate.
This should not be hidden as a footnote only under Table 2.
Looking at Table 1, considering the big sample size even a small difference
would be significant, focusing only on the p-value is less meaningful and
exploring the actual numbers provides a more insightful interpretation. There are
no clinically meaningful differences between history of diabetes (first vs last
quartile, 93% vs 97%), and blood pressure levels seems to be equally distributed
between normal and high, across quartile of physical activity. The more
meaningful differences are seen in waist circumference measurements and the
increase of proportion of patients with less metabolic syndrome components in
higher quartiles of physical activity.
The results of the Table 2 Cox model are hardly surprising. Higher physical
activity was associated with lower all-cause mortality which is logical
considering that from Table 1 we observe that people with higher physical
activity levels are healthier, by not having the same number of metabolic
disturbances as people with less physical activity. It has been shown in multiple
studies that being metabolically healthy is associated with better survival. But
what is clear from the present study and the breast cancer-specific Cox model is
that the number of metabolic components don't have the same influence on breast
cancer-specific survival. 
While using the number of components as a variable in the model makes the
statistical analysis easier, however not every components would have the same
weight in the contribution to cancer-specific mortality. I believe the authors can
have a more meaningful report if they redo the analysis reporting exactly the
combinations of metabolic factors. For example, having higher waist
circumference, as a proxy to visceral obesity probably is a bigger contributor to
mortality, as it is the place for subclinical chronic inflammation. A recent study
has concluded that "Research has shown that chronic inflammation is associated
with an increased cancer risk. Moreover, different markers of inflammation, such
as cytokines, C-reactive protein, and NLR, are often elevated in patients with
cancer and are associated with poor survival." (DOI:
https://doi.org/10.1186/s13058-018-1062-3). Because of this, knowing the
number of components without knowing the exact combination of components is
not clinically meaningful. Looking at the components separately or at specific
combinations could provide more detailed information on the potential
implications.
As we can see from Table 1, high cholesterol did not differ between quartiles of
physical activity, so if that is the one and only component a certain patient had,
the results in Table 2, where there is a possibility that cholesterol was the only
present component for some, and waist circumference or diabetes for others,
there can be confounding introduced in the analysis due to the potential different
effect of the metabolic components on the mortality outcome. This makes the
interpretation of the "number of metabolic risk factors" variable impossible.
Minor revision:
The WHI abbreviation should be first explained in the first sentence of the
Methods section, not in the second sentence.
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