Title:  Breast cancer and the steadily increasing maternal age: Are they colliding?
Version: 3 Date: 24 Oct 2023
Reviewer's report:
Overview:
Thank you for the opportunity to review this interesting article. Here, Londero et al. describe
pregnancy-related breast cancers in two populations – Italy and the United States – and compare
the overlap between cancers and increasing maternal age. The results of the analysis suggest
that, in a hypothetical situation where maternal age increases to an average of 35 years, breast
cancer diagnoses would overlap 16% with age at delivery in the United States and 14% in Italy,
compared to 10% and 8% when the maternal age is lower in the respective countries. While I
believe the paper has merit, my main concerns with it are related to the premise of the argument,
its presentation, particularly regarding the figures, and some of the implications raised by the
authors of the manuscript.
Comments:
- The methods are a bit confusing to me. Is it correct that all women diagnosed with breast cancer
in the United States between 2000 and 2018 were included in your analysis compared to women
from one small city in Italy? It’s not clear to me that this is an appropriate comparison to make.
- There is no information in your results on the features of these populations. This study reads to
me as more of an ecological study, so it’s possible that you do not need to include demographic
variables or even numbers of participants. However, you highlight in the methods that you
are using a variety of databases to identify socio-environmental variables, few of which are
discussed. It would be nice to know, at a minimum, the number of individuals from each
population.
- Figure 3 is very confusing, particularly 3B. Why does the American age at first birth only
start in the 2000s? Is this the only time period for which you have data? If so, this should be
in your methods. As it stands, the comparison between maternal age in the United States and
Italy is effectively meaningless. Additionally, it’s not clear to me what point is being made by
including maternal age, age at menopause, and life expectancy on the same plot. If anything,
this is a point that could be included in your introduction or discussion rather than in your results
because it adds very little to the interpretation. Finally, the y-axis does not allow for meaningful
interpretation of the maternal age plot. It's not easy to see changes in the maternal age because
the y-axis is too broad. I stand by the point that we don’t need a plot for these data (the change in
maternal age could be described in the introduction, which it currently is not) but, if you insist
on including it, I would recommend a separate plot.
- Figure 1 (both A and B) is unnecessary and could be described in the introduction.
- Figure 4C is unnecessary – it is described in the text perfectly well and is also evident in 4A
and B.
- The figures need better captions generally. For example, in Figure 4, it’s not clear just by
looking at the plots that panel A is for America and panel B is for Italy. I should be able to
understand the plots on their own without referring to the text for clarity.
- Most pertinently for this reviewer, I find the interpretation of your analysis lacking. There are
numerous benefits associated with delaying pregnancy that have been well-documented. Your
discussion does not make reference to any of these benefits. I think it’s interesting in and of
itself to discuss the potential impact of later childbirth on breast cancer rates and I think you
make a good point about the importance of screening and symptom recognition for women
who choose to become pregnant later or not at all; however, I do not believe it is wise for
the authors to suggest that later childbirth is detrimental to a woman’s health. As you know,
pregnancy can severely impact a woman’s health, can even result in death, and the likelihood
of that happening may be greater than the likelihood of a woman developing breast cancer due
to delaying pregnancy. Making policy or behavioral recommendations based on this analysis
is irresponsible and seems to willingly ignore available evidence on the benefits of delayed
childbirth.
- I think it’s also important to point out that, while the risk of breast cancer is higher in women
who delay pregnancy, the risk remains very low. Presenting only relative increase in risk is
potentially disingenuous but definitely misleading.
- If anything, I think this paper could be restructured to say that more work needs to be done on
pregnancy-associated cancers as you discuss briefly during the discussion.
- Finally, it is not clear that breast cancer risk in women under 50 years of age, especially
for women under 40 years of age, is increasing. There’s no evidence presented that delayed
pregnancy could be contributing to a greater public health concern that needs to be addressed
with behavior or policy change.
- As a structural note, there’s a lot of writing in the results that should be presented in the
discussion. For example: “From the preceding observations, it is possible to conclude that the
age distribution of women diagnosed with breast cancer is virtually identical between the two
considered settings. In contrast, the age distribution at birth is predominantly dissimilar.” This
is clearly interpretation and does not belong in the results.
- I think the results would benefit from having some headings to provide better structure and
help the reader follow this section a little easier.