Breast Cancer Survivors Undergoing Endocrine Therapy Have a Worrying Risk Factor Profile for Cardiovascular Diseases

Round 1

Reviewer 1 Report

Major

Comment 1. In Table 1, the total number or factors listed appears to be 24.

Comment 2. Exclusion of women using cholesterol-lowering medications may lead to some selection bias. In addition, background information on detailed medications of background risk factors and history of CVD are lacking.

Comment 3. Figure 3 appears to be rough and less impact.

Comment 4. During the observation period, what cardiovascular adverse effects do authors think occurred due to the baseline treatment for breast cancer in your cohort?

Comment 5. This reviewer cannot understand the precise meaning of sentences of P18L525-527.

Comment 6. Data from very small sample size, one institute, and one country. The Brazilian Healthy Eating index is universal design?

 

Minor

Comment 1. In Table 1, please correct ‘NFR’.

Comment 2. Please correct ‘analyzes’ (P6L213).

Comment 3. In Table 2, please correct ‘ou’. (‘or’?)

Comment 4. Please correct ‘Table 2’ (P8L261) (‘Table 3’?)

Comment 5. There may be excess space between ‘Protein’ ad ‘General’ (P11L346).

Comment 6. There may be excess space between ‘(data not shown).’ and ‘The’ (P12L357).

Comment 7. In Table 7, please correct ‘Reactive Protein C’.

Comment 8. Authors should more explain ‘^a’ and ‘^b’ in some tables.

 

 

Author Response

Dear Editor and Reviewers,

We would like to thank for the important comments and valuable suggestions regarding our manuscript nutrients-1152219 entitled “Breast Cancer Survivors Undergoing Endocrine Therapy Have a Worrying Risk Factor Profile for Cardiovascular Diseases”. Please find attached the revised manuscript. We carefully considered the suggestions and modified our manuscript accordingly. We believe the manuscript has been substantially improved. We have also highlighted (emboldened in red) the changes made in our manuscript and enumerated all points raised by the reviewers with a response for each one of them. We have included new references, so the citations have been re-enumerated.

 

Yours sincerely,

 

Yara Cristina de Paiva Maia, PhD.

Molecular Biology and Nutrition Research Group

School of Medicine

Federal University of Uberlandia,

Uberlandia, Minas Gerais, Brazil

E-mail: [email protected]

 

 

ANSWERS TO THE REVIEWER’S COMMENTS

 

(The responses are presented immediately below the reviewer’s comments. The author’s responses are in red).

 

Reviewer#1

Major Revisions

 

1. In Table 1, the total number or factors listed appears to be 24.

Response to reviewer#1: Thanks for the correction. We had not listed Trans Fat in Table 1. In this new version of our manuscript, we included this nutrient in Table 1, totaling 25 risk factors for analysis 2, as described in the first paragraph of section 2.7 (P6L229-239).

2. Exclusion of women using cholesterol-lowering medications may lead to some selection bias. In addition, background information on detailed medications of background risk factors and history of CVD are lacking.

Response to reviewer#1: Thanks for your interesting point of view. We decided to include in the analysis 2 women using cholesterol-lowering medications, considering that the risk factor (dyslipidemia) remains despite being controlled by medication. In the material and methods section, we removed the sentence regarding exclusion of patients using cholesterol medication and insert the new sample number (P6L236-238). Regarding the new results, the percentages of inadequate lipid profile (Table 6) (P14L388) and the average number of risk factors in analysis 2 were modified (P14L393-394). The 25 risk factors (Analysis 2) continued not impacting the CRP and PhA values (P15L402-404).  

Regarding to medications, we included the drug classes used for diabetes mellitus, systemic arterial hypertension and dyslipidemia in the materials and methods section (P4L116-122 and P5L159-160). In addition, we described the percentage of women in use of each medication class in the results section (P7L274-279). About cardiovascular diseases (CVDs), we found that 13,5% of the women had history of these diseases. We included this information in the material and methods (P4L122-123) and results section (descriptive analysis) (P7L270-274).

 

3. Figure 3 appears to be rough and less impact.

Response to reviewer#1: Thanks for this comment. We removed the figure and kept only its description in the text (P14L392-394).

 

4. During the observation period, what cardiovascular adverse effects do authors think occurred due to the baseline treatment for breast cancer in your cohort?

Response to reviewer#1: We appreciate your interesting question. In our study we found that women had a high percentage of inadequacy of several modifiable risk factors for cardiovascular diseases. Considering that endocrine therapy with aromatase inhibitors [1] and previous treatments, such as chemotherapy and radiotherapy lead to cardiotoxicity [2], we assume that an increase in the incidence and mortality of CVDs may occur. To assess these outcomes, a longer follow-up study would be necessary. This objective was not part of our study, and we leave this for future work.

 

5. This reviewer cannot understand the precise meaning of sentences of P18L525-527.

Response to reviewer#1: We thank for pointing out this issue. We removed those sentences that had been incorrectly included.

 

6. Data from very small sample size, one institute, and one country. The Brazilian Healthy Eating index is universal design?

Response to reviewer#1: Thanks for your comment. Despite the small sample of our study, we evaluated several cardiovascular risk factors. In addition, to the best of our knowledge, our study is the first one with this objective in this specific population. Future studies could evaluate a larger sample, to confirm our results, and we included this point in the discussion section (P19L564-565). Regarding dietary index, the Health Eating Index (HEI) [3] was developed for the North American population, and was adapted by Fisberg and collaborators [4] for a Brazilian population in 2004, defining the Brazilian Healthy Eating Index (BHEI). As a new food guide was published in 2006 in Brazil, there was a need for revision, and Previdelli and collaborators [5] in 2011 authored the Brazilian Healthy Eating Index Revised (BHEI-R), used in our study. Although BHEI-R is specific to the Brazilian population, its focused on assessing the quality of the diet and other countries can use the original instrument (HEI) to reproduce this study. To clarify that BHEI-R was derived from HEI, we added this information in the methods and material section (P5L194-197).

 

References

1. Matthews, A.; Stanway, S.; Farmer, R.E.; Strongman, H.; Thomas, S.; Lyon, A.R.; Smeeth, L.; Bhaskaran, K. Long Term Adjuvant Endocrine Therapy and Risk of Cardiovascular Disease in Female Breast Cancer Survivors: Systematic Review. BMJ 2018, 363, doi:10.1136/bmj.k3845.
2. Lee Chuy, K.; Yu, A.F. Cardiotoxicity of Contemporary Breast Cancer Treatments. Curr. Treat. Options in Oncol. 2019, 20, 51, doi:10.1007/s11864-019-0646-1.
3. Kennedy, E.T.; Ohls, J.; Carlson, S.; Fleming, K. The Healthy Eating Index: Design and Applications. J Am Diet Assoc 1995, 95, 1103–1108, doi:10.1016/S0002-8223(95)00300-2.
4. Fisberg, R.M.; Slater, B.; Barros, R.R.; Lima, F.D. de; Cesar, C.L.G.; Carandina, L.; Barros, M.B. de A.; Goldbaum, M. Índice de Qualidade da Dieta: avaliação da adaptação e aplicabilidade. Revista de Nutrição 2004, 17, 301–318, doi:10.1590/S1415-52732004000300003.
5. Previdelli, Á.N.; Andrade, S.C. de; Pires, M.M.; Ferreira, S.R.G.; Fisberg, R.M.; Marchioni, D.M. Índice de Qualidade da Dieta Revisado para população brasileira. Revista de Saúde Pública 2011, 45, 794–798, doi:10.1590/S0034-89102011005000035.

 

 

 

Minor Revisions

 

1. In Table 1, please correct ‘NFR’.

Response to reviewer#1: We made the requested adjustment.

2. Please correct ‘analyzes’ (P6L213).

Response to reviewer#1: We made the requested adjustment.

3. In Table 2, please correct ‘ou’. (‘or’?)

Response to reviewer#1: We made the requested adjustment.

4. Please correct ‘Table 2’ (P8L261) (‘Table 3’?)

Response to reviewer#1: We made the requested adjustment.

5. There may be excess space between ‘Protein’ ad ‘General’ (P11L346).

Response to reviewer#1: We made the requested adjustment.

6. There may be excess space between ‘(data not shown).’ and ‘The’ (P12L357).

Response to reviewer#1: We made the requested adjustment.

7. In Table 7, please correct ‘Reactive Protein C’.

Response to reviewer#1: We made the requested adjustment.

8. Authors should more explain ‘^a’ and ‘^b’ in some tables.

Response to reviewer#1: Thanks for your comment. In the legend of the tables, we write the following sentence “The different letters represent the statistically significant differences between the times detected by the post-hoc comparisons”. In this sense, results represented by the letter A differ from those represented by the letter B and C. Results represented by the same letter do not present a statistically significant difference.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Summary: The current manuscript investigated the number of risk factors (NRF) for CVDs in breast cancer survivors.

The authors show a higher presence of some risk factors such as excess abdominal fat and overweight, hypertension, and physical inactivity.

Here some suggestions.

Introduction: Overall, the introduction provides a broad background and rationale for the research. However, specific interest in breast cancer is needed to explain the rationale better.  Moreover, some hypotheses are required.

Methods and Analysis: The method is comprehensive, and the analyses are well conducted. I suggest replying the power analysis.

Results: The summary of the study provided is well-defined and fits according to the analysis plan provided. 

Discussion: the discussion appears to be a summary of the results. I suggest reporting some inferences and better explaining this study's novelty (I think it is one of the first on this topic).

Also, some aspects could be improved, such as different perspectives and clinical relevance. Finally, some aspects regarding psychological effect are needed

(Guarino, A., Polini, C., Forte, G., Favieri, F., Boncompagni, I., & Casagrande, M. (2020). The effectiveness of psychological treatments in women with breast cancer: A systematic review and meta-analysis. Journal of clinical medicine, 9(1), 209.)

General comment: I would also encourage the authors to check all references in line with the journal request.

 

Author Response

Dear Editor and Reviewers,

We would like to thank for the important comments and valuable suggestions regarding our manuscript nutrients-1152219 entitled “Breast Cancer Survivors Undergoing Endocrine Therapy Have a Worrying Risk Factor Profile for Cardiovascular Diseases”. Please, find enclosed the revised manuscript. We carefully considered the suggestions and modified our manuscript accordingly. We believe the manuscript has been substantially improved. We have also highlighted (emboldened in red) the changes made in our manuscript and enumerated all points raised by the reviewers with a response for each one of them. We have included new references, so it was necessary to adjust the number of all of them.

 

Yours sincerely,

Yara Cristina de Paiva Maia, PhD.

Molecular Biology and Nutrition Research Group

School of Medicine

Federal University of Uberlandia,

Uberlandia, Minas Gerais, Brazil

E-mail: [email protected]

 

ANSWERS TO THE REVIEWER’S COMMENTS

 

(The responses are presented immediately below the reviewer’s comments. The author’s responses are in red).

 

Reviewer#2

 

Summary: The current manuscript investigated the number of risk factors (NRF) for CVDs in breast cancer survivors.

The authors show a higher presence of some risk factors such as excess abdominal fat and overweight, hypertension, and physical inactivity.

 

Here some suggestions.

 

1. Introduction: Overall, the introduction provides a broad background and rationale for the research. However, specific interest in breast cancer is needed to explain the rationale better. Moreover, some hypotheses are required.

Response to reviewer#2: We appreciate your comment and suggestions. To improve the reasoning, we include the breast cancer (BC) incidence and reported that the improvement of the treatments increased the women survival with this disease (P1L41-43) [1]. In addition, we described that, despite longer survival, worse cardiovascular outcomes are observed among these women (P1L43-45) [2]. In the first paragraph of the introduction section, we addressed the possible factors related to the increased risk of mortality from cardiovascular disease (CVDs) in breast cancer (BC) survivors. Among them, we described the modifiable risk factors [3]  and cardiotoxic anticancer treatments [4] (P1L45-47 and P2L48-49). Following the rationale, details on the relationship of endocrine therapy, especially with aromatase inhibitors, and CVDs were addressed in the following paragraph (P2L50-57). We also added the hypotheses (P2L83-86) in our manuscript.

 

2. Methods and Analysis: The method is comprehensive, and the analyses are well conducted. I suggest replying the power analysis.

Response to reviewer#2: Power analysis has been described in Section 2.2 as follows: “To calculate the sample size of a group of individuals and three measurements, the software G * Power version 3.1 [5] was used. A total of 28 women were required at each time, based on an F test ANOVA repeated measures with an intermediate effect size of 0.25, an alpha level of 0.05 and at 80% power.”

3. Results: The summary of the study provided is well-defined and fits according to the analysis plan provided.

Response to reviewer#2: Thanks for your comment and your appreciation.

4. Discussion: the discussion appears to be a summary of the results. I suggest reporting some inferences and better explaining this study's novelty (I think it is one of the first on this topic).

Response to reviewer#2: Thanks for your important comment and suggestion. We summarized the fourth paragraph, which contained more description of the results, and included a text about the importance of diet qualitative guidance (P17L482-487). Regarding the novelty of our study, we have included in P17L436-437 some details about this topic. To explain the importance of this novelty, we included a new text in P17L436-437 and P17L447-448. Besides that, we inserted a sentence reinforcing that our study is the first one to assess risk factors in BC survivors in Brazil (P19L563-564).

5. Also, some aspects could be improved, such as different perspectives and clinical relevance. Finally, some aspects regarding psychological effect are needed.

(Guarino, A., Polini, C., Forte, G., Favieri, F., Boncompagni, I., & Casagrande, M. (2020). The effectiveness of psychological treatments in women with breast cancer: A systematic review and meta-analysis. Journal of clinical medicine, 9(1), 209.)

Response to reviewer#2: We included the importance of implementing nutritional protocols (P17L482-483), encouraging physical activity (P18L493-494), advice on weight control (P18L502-503), monitoring waist circumference measurements (P18L511-513) and adopt a healthy lifestyle for prevention and treatment of chronic diseases (P18L527-529). We suggest more studies to verify the importance of the phase angle (PhA) in cardiovascular disease (P18L520-521) and the prevalence of risk factors as well as smoking and alcoholism (P18L533-536). We also add about practical applications and psychological aspects in P19L569-573.

 

6. General comment: I would also encourage the authors to check all references in line with the journal request.

Response to reviewer#2: Thanks for your comment and suggestion. We reviewed all references of our manuscript and made our best effort to solve all the journal requirements.

References

1. Harbeck, N.; Penault-Llorca, F.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast Cancer. Nat Rev Dis Primers 2019, 5, 66, doi:10.1038/s41572-019-0111-2.
2. Bradshaw, P.T.; Stevens, J.; Khankari, N.; Teitelbaum, S.L.; Neugut, A.I.; Gammon, M.D. Cardiovascular Disease Mortality Among Breast Cancer Survivors. Epidemiology 2016, 27, 6–13, doi:10.1097/EDE.0000000000000394.
3. Buttros, D. de A.; Branco, M.; Orsatti, C.; Almeida-Filho, B. de; Nahas-Neto, J.; Nahas, E. High Risk for Cardiovascular Disease in Postmenopausal Breast Cancer Survivors. Menopause 2019, 26, 1024–1030, doi:10.1097/GME.0000000000001348.
4. Lee Chuy, K.; Yu, A.F. Cardiotoxicity of Contemporary Breast Cancer Treatments. Curr. Treat. Options in Oncol. 2019, 20, 51, doi:10.1007/s11864-019-0646-1.
5. Faul, F.; Erdfelder, E.; Lang, A.-G.; Buchner, A. G*Power 3: A Flexible Statistical Power Analysis Program for the Social, Behavioral, and Biomedical Sciences. Behavior Research Methods 2007, 39, 175–191, doi:10.3758/BF03193146.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Thank you for your hard work and adequate response to my comments.

This reviewer has no further comment.