The Use of Breath Analysis in the Management of Lung Cancer: Is It Ready for Primetime?

Round 1

Reviewer 1 Report

This manuscript provides a comprehensive review of the current status of the analysis of volatile organic compounds in breath for detection of lung cancer. It was concluded that the use of breath analysis has largely been limited to translational research due to methodological issues.   There is a lack of standardization or validation and the paucity of large multi-center studies.   However,  breath analysis offers a potentially non-invasive  alternative to investigations such as tumor biopsy and blood sampling. The manuscript covers almost all aspects of breath analysis and progress. However, there is no description of literature search methods and selection criteria of references. Many important references in the field were not included.  There is a need for major revision.   

1.      Introduction:  please provide a literature search methods for the review, including data bases, key words for literature search, inclusion and exclusion criteria, covering period and number of papers found for the searches. A flow diagram will be very helpful.

2.      There were many review papers of breath analysis of VOCs for detection of lung cancer in recent years. These review papers should be included.  Please include a brief summary of the main differences of this manuscript in comparison with other published reviews.     For example:

a.       MA. Floss et al.  Exhaled Aldehydes as Biomarkers for Lung Diseases:

A Narrative Review,  Molecules 2022, 27, 5258. https://doi.org/10.3390/molecules27165258.

b.      SX. Antoniou et al. The potential of breath analysis to improve outcome for patients with lung cancer, J. Breath Res. 13 (2019) 034002.

c.       E. Janssens, Volatile organic compounds in human matrices as lung cancer biomarkers: a  systematic review, Critical Reviews in Oncology / Hematology 153 (2020) 103037.

d.      D. Marzorati,  A review of exhaled breath: a key role in lung cancer diagnosis, J. Breath Res. 13 (2019) 034001

e.       Z. Jia,  Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer. Metabolites 2019, 9, 52; doi:10.3390/metabo9030052.

f.        Dent A., Sutedja T.G., Zimmerman P.V. Exhaled breath analysis for lung cancer. J Thorac Dis. 2013,5(S5), pp.S540-S550.

 

3.      There were many important references, progress and biomarkers that were not included. What was the criteria for excluded these references.  For example:

a.       Fu X. Noninvasive Detection of Lung Cancer Using Exhaled Breath.  Cancer Medicine 2014, 3, pp.174-181.

b.      Bousamra M.   Quantitative analysis of exhaled carbonyl compounds distinguishes benign from malignant pulmonary disease.  J Thora Cardio Surgery 2014, 148, pp.1074-1081.

c.       Schumer E., Normalization of exhaled carbonyl compounds after lung cancer resection”  Ann Thorac Surg 102,1095-1100, 2016.

4.      Table 1 of the summary of  VOCs identified in clinic lung cancer studies can be combined with Table 2 to make it clear for detected compounds by different analytical and sampling methods.

5.      Section 6.2:  Smoking does affect VOCs of exhaled breath.  Please see references

a.       Z. Jia,  Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer. Metabolites 2019, 9, 52; doi:10.3390/metabo9030052.

b.      Kischkel et al. Breath biomarkers for lung cancer detection and assessment of smoking related effects — confounding variables, influence of normalization and statistical algorithms, Clinica Chimica Acta 411 (2010) 1637–1644.

c.       Wang, Y.; Hu, Y.; Wang, D.; Yu, K.; Wang, L.; Zou, Y.; Zhao, C.; Zhang, X.; Wang, P.; Ying, K. The analysis of

volatile organic compounds biomarkers for lung cancer in exhaled breath, tissues and cell lines. CBM 2012,11, 129–137.

d.      Euler, D.E.; Davé, S.J.; Guo, H. Effect of cigarette smoking on pentane excretion in alveolar breath. Clin. Chem.

1996, 42, 303–308

Author Response

Reviewer 1:

This manuscript provides a comprehensive review of the current status of the analysis of volatile organic compounds in breath for detection of lung cancer. It was concluded that the use of breath analysis has largely been limited to translational research due to methodological issues.   There is a lack of standardization or validation and the paucity of large multi-center studies.   However,  breath analysis offers a potentially non-invasive  alternative to investigations such as tumor biopsy and blood sampling. The manuscript covers almost all aspects of breath analysis and progress. However, there is no description of literature search methods and selection criteria of references. Many important references in the field were not included.  There is a need for major revision.   

Response: We thank the reviewer for their comments and the opportunity to address their comments.

 

Introduction:  please provide a literature search methods for the review, including data bases, key words for literature search, inclusion and exclusion criteria, covering period and number of papers found for the searches. A flow diagram will be very helpful.

Response: We have amended our manuscript to include a detailed description of the methods used in addition to a flow diagram illustrating the process (see page 2,3, line 74-101).

 

There were many review papers of breath analysis of VOCs for detection of lung cancer in recent years. These review papers should be included.  Please include a brief summary of the main differences of this manuscript in comparison with other published reviews.     For example:

• MA. Floss et al.  Exhaled Aldehydes as Biomarkers for Lung Diseases: A Narrative Review,  Molecules 2022, 27, 5258. https://doi.org/10.3390/molecules27165258.

• SX. Antoniou et al. The potential of breath analysis to improve outcome for patients with lung cancer, J. Breath Res. 13 (2019) 034002.
• E. Janssens, Volatile organic compounds in human matrices as lung cancer biomarkers: a  systematic review, Critical Reviews in Oncology / Hematology 153 (2020) 103037.
• D. Marzorati,  A review of exhaled breath: a key role in lung cancer diagnosis, J. Breath Res. 13 (2019) 034001
• Z. Jia,  Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer. Metabolites 2019, 9, 52; doi:10.3390/metabo9030052.
• Dent A., Sutedja T.G., Zimmerman P.V. Exhaled breath analysis for lung cancer. J Thorac Dis. 2013,5(S5), pp.S540-S550.

Response: We thank the reviewer for highlighting this point. We largely focused on prospective studies however on review, we have made amendments of our manuscript and include several review articles in our discussion. We did not include the review article by M.A. Floss et al. as this was published after our literature review which included studies up to the 1^st June 2022. On reflection, we agree this is a limitation of our manuscript and so have included them in our review (references 15, 17, 18, 22, 24).

 

There were many important references, progress and biomarkers that were not included. What was the criteria for excluded these references.  For example:

• Fu X. Noninvasive Detection of Lung Cancer Using Exhaled Breath.  Cancer Medicine2014, 3, pp.174-181.
• Bousamra M.   Quantitative analysis of exhaled carbonyl compounds distinguishes benign from malignant pulmonary disease.  J Thora Cardio Surgery2014, 148, pp.1074-1081.
• Schumer E., Normalization of exhaled carbonyl compounds after lung cancer resection”  Ann Thorac Surg 102,1095-1100, 2016.

Response: We thank the reviewer for highlighting this allowing us the opportunity to improve the content of our manuscript. We have included these references in our manuscript and updated our tables to reflect this (references 64, 65, 66).

 

Table 1 of the summary of  VOCs identified in clinic lung cancer studies can be combined with Table 2 to make it clear for detected compounds by different analytical and sampling methods.

Response: We agree with the reviewer with regards to this and have merged the two tables to include detected compounds by different analytical methods used (see page 8-10, table 1).

 

Section 6.2:  Smoking does affect VOCs of exhaled breath.  Please see references

• Z. Jia,  Critical Review of Volatile Organic Compound Analysis in Breath and In Vitro Cell Culture for Detection of Lung Cancer. Metabolites 2019, 9, 52; doi:10.3390/metabo9030052.
• Kischkel et al. Breath biomarkers for lung cancer detection and assessment of smoking related effects — confounding variables, influence of normalization and statistical algorithms, Clinica Chimica Acta 411 (2010) 1637–1644.
• Wang, Y.; Hu, Y.; Wang, D.; Yu, K.; Wang, L.; Zou, Y.; Zhao, C.; Zhang, X.; Wang, P.; Ying, K. The analysis of volatile organic compounds biomarkers for lung cancer in exhaled breath, tissues and cell lines. CBM 2012,11, 129–137.
• Euler, D.E.; Davé, S.J.; Guo, H. Effect of cigarette smoking on pentane excretion in alveolar breath. Clin. Chem. 1996, 42, 303–308

Response: We appreciate the reviewer highlighting this additional research into the association between smoking and specific VOCs in exhaled breath. We have amended our review article to take this into account and highlight the impact smoking has on exhaled breath (see page 14, line 354-362, reference 17, 52, 103, 107).

Reviewer 2 Report

Journal of Current Oncology

Review Article;

The article entitled “The use of breath analysis in the management of lung cancer: is it ready for primetime?’’. The authors tried their best to review the Breath analysis in lung cancer, as breathing is a complex mixture of organic compounds that are produced as end-products of metabolism. As many studies have explored the designs of these compounds and have postulated that a unique breath signature is emitted in the setting of lung cancer. Machine learning gaseous chemical sensing and identification devices are the key methods for the detection of breathing in modern research. These devices offer hope for a point-of-care test in the future. This study summarizes the history of breath analysis and provides a wonderful analysis of current methodologies used for breathing analysis and explores the potential applications and limitations of breath biopsy, which will help the treatment of patients with lung cancer.

I carefully read the manuscript and found it suitable for publication in the journal. I accept this article for possible publication. There are some common mistakes in the article which should be corrected by the authors. After the correction of all the mistakes, the article could be considered for publication in the prestigious Current Oncology Journal.

 

 

Comments for Authors

Ø  In abstract (line 16) what is VOCs. Write complete name

Ø  (line 81, 99, 457) Volatile organic compounds are repeatedly used, why not change to VOCs as abbreviation which already used in manuscript.

Ø  (Line 150) EBC abbreviation stand for? Revised all the abbreviation.

Ø  Images of breath collection devices will give more brief to the article.

Ø  Section; Factors affecting Breath Analysis. If can include the hypoxia effect on breathing and pollution effect on breathing, it will be more explanatory.

Ø  Section Introduction; Revise it and include the data on worldwide Lung cancer mortality and morbidity [Line 28,29].

Ø  The author should make the (Figures-1) more self-explanatory.

Ø  Include some more

Ø  Nardi-Agmon et al. (line 541) are mentioned, and the same reference number 18 (line 543, 548) was included in the same paragraph. Revised the reference 

Ø  Makes bar and border bold for Figure-1.

Ø  Mentioned the original dimension clearly in Figure 1.

Ø  The authors want to put more latest related citations in the introduction part.

Ø  Why does the author cite one reference again in the same paragraph? Remove this error.

Ø  Use EndNote or Mendeley software for reference sequences.

Ø  Check grammatically and spelling throughout the manuscript. There are some mistakes.

Cite the following references;

v  https://doi.org/10.1038/s41419-021-03771-z

v  DOI: 10.1080/14737159.2019.1559052.

Author Response

Reviewer 2: The article entitled “The use of breath analysis in the management of lung cancer: is it ready for primetime?’’. The authors tried their best to review the Breath analysis in lung cancer, as breathing is a complex mixture of organic compounds that are produced as end-products of metabolism. As many studies have explored the designs of these compounds and have postulated that a unique breath signature is emitted in the setting of lung cancer. Machine learning gaseous chemical sensing and identification devices are the key methods for the detection of breathing in modern research. These devices offer hope for a point-of-care test in the future. This study summarizes the history of breath analysis and provides a wonderful analysis of current methodologies used for breathing analysis and explores the potential applications and limitations of breath biopsy, which will help the treatment of patients with lung cancer.

I carefully read the manuscript and found it suitable for publication in the journal. I accept this article for possible publication. There are some common mistakes in the article which should be corrected by the authors. After the correction of all the mistakes, the article could be considered for publication in the prestigious Current Oncology Journal.

 

1. In abstract (line 16) what is VOCs. Write complete name

Response: We have amended our manuscript to include this (see page 1, line 16).

 

2. (line 81, 99, 457) Volatile organic compounds are repeatedly used, why not change to VOCs as abbreviation which already used in manuscript.

 Response: We have made these suggested modifications (see page 3, line 111).

 

3. (Line 150) EBC abbreviation stand for? Revised all the abbreviation.

Response: We have changed this in our manuscript (see page 5, line 171)

 

4. Images of breath collection devices will give more brief to the article.

Response: We have included this in our manuscript (see page 5,6, line 186-194)

 

5. Section; Factors affecting Breath Analysis. If can include the hypoxia effect on breathing and pollution effect on breathing, it will be more explanatory.

Response: We agree with the reviewer that this adds valuable information to our review. We have included a section on hypoxia and the impact of air pollution on breath analysis and lung cancer. The association of air pollution is of significant clinical interest given the recent link between increased ambient particulate matter and the development of lung cancer (see page 14 and 15, 16, line 365-377 and 426-438).

 

6. Section Introduction; Revise it and include the data on worldwide Lung cancer mortality and morbidity [Line 28,29].

Response: We have updated our introduction with up-to-date data (see page 1, line 28)

 

7. The author should make the (Figures-1) more self-explanatory. Include some more

Response: We thank the reviewer for this comment and believe our figure illustrates the various sources that content of breath well. We have included more figures such as an flow diagram of how we selected articles and pictures of the various breath sampling devices available (see page 3 and 5,6, line 99-101 and 186-194).

 

8. Nardi-Agmon et al. (line 541) are mentioned, and the same reference number 18 (line 543, 548) was included in the same paragraph. Revised the reference

Response: We have made the suggested modification (line 587)

 

9. Makes bar and border bold for Figure-1. Mentioned the original dimension clearly in Figure 1.

Response: We have included a bold border for Figure 1 (see page 4, line 147-148).

 

10. The authors want to put more latest related citations in the introduction part.

Response: We thank the reviewer for highlighting this and have added additional citations throughout our review article including the introduction (see page 1, line 28, 29, see references 17, 52, 64, 65, 66, 103, 107)

 

11. Why does the author cite one reference again in the same paragraph? Remove this error.

Response: We have removed this error (page 19).

 

12. Use EndNote or Mendeley software for reference sequences.

We have used endnote for our references.

 

13. Check grammatically and spelling throughout the manuscript. There are some mistakes.

Cite the following references;

v  https://doi.org/10.1038/s41419-021-03771-z

v  DOI: 10.1080/14737159.2019.1559052.

We have checked our manuscript and corrected and grammatical and spelling mistakes. We have Included the references in our manuscript (page 4 and 16, line 140 and 436, reference 16, 124)

Round 2

Reviewer 1 Report

The authors addressed the reviewer 1's comments.