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PONE-D-22-06443Patterns of Metastases Progression- The Linear Parallel RatioPLOS ONE

Dear Dr. Gofrit,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Specifically, I find your manuscript very interesting, as it provides some novel insights into metastasis and the interpretation of CT scans. In accordance with the expert reviewers, there are however, a few concerns that need to be addressed. Rather than repeat those points here, I refer you to the specific remarks (below) for details.

Please submit your revised manuscript by Aug 04 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Nikolas K. Haass, MD/PhD

Academic Editor

PLOS ONE

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Additional Editor Comments:

I find your manuscript very interesting, as it provides some novel insights into metastasis and the interpretation of CT scans. In accordance with the expert reviewers, there are however, a few concerns that need to be addressed. Rather than repeat those points here, I refer you to the specific remarks (below) for details.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors present a study examining CT features to trace the lineage of lung metastases. By measuring and comparing the size of lung mets in each patient, they draw conclusions regarding the metastatic progression of each of the 9 diseases included in the study. Some cancer types had a high linear/parallel ratio (LPR) that indicated similarity between the different metastases, while other cancers had low LPR indicating greater variation.

Overall, I find their observations interesting. These results could have clinical relevance as CT scans are routine in the diagnosis and treatment of cancer patients.

I have a few points that I’d like the authors to comment on:

1. For some of the cancers presented here, melanoma and breast cancer for example, there are multiple histological subtypes that are related to different treatments and varied patient outcomes. Perhaps the data is over simplified by combining the subtypes. Can you be more specific about the clinical data presented. Is some of the variation in LPR in theses cancers due to histological subtype?

2. Is there any relationship between LPR and treatment using targeted or immunotherapy?

3. Have you looked for a relationship between LPR and overall patient survival?

4. Does the LPR ratio for each cancer type align with published tumour mutation burden rates for each cancer?

Reviewer #2: Review

This is an interesting study that reports on data obtained from lung CT scans.

Overall, I think it is worth publication in this journal. However, I there are a few issues that I believe the authors should address. Allow me to expand

as follows:

1. It is not clear the authors have a hypothesis even though they state they are performing the study to test their hypothesis. What is the hypothesis?

If there is one, it needs to be stated clearly, and it needs to be stated how these data obtained can address the likelihood of the hypothesis being true.

If this is not possible, then I think the study is best framed as an investigation that provides evidence that supports the hypothesis that

alternative metastatic disease morphologic patterns in lung (and by extension, possibly elsewhere) may reflect alternate pathogenic routes.

And the evidence is the correlation between known genomic data and CT morphologic patterns. Because there is a possible mechanism that may

account for this correlation, it may represent causation, thus a valid hypothesis may exist.

2. The authors provide evidence for such a correlation, but I think this should be the main finding of the investigation, and should be part of the

abstract and conclusion. The review of the literature with respect to genomic studies in primary and secondary tumours is welcome. However,

any evidence that doesn’t support the idea that

(i) uniformly size metastatic lesions are associated with genomic similarity

(ii) variably sized metastatic lesions are associated with genomic dissimilarity (with respect to each tumour type) should also be reported.

The readers can then weigh the evidence with respect to the hypothesis noted in #1.

3. However, the most important question remains: how do metastases arise? It is an extraordinarily complex issue, and as the authors rightly point out, there

are many potential confounders that prevent definitive conclusions to be drawn from morphologic data obtained from CT scans with respect to pathogenesis.

Although the study provides evidence associating morphologic patterns to genomic data, the derivation of the pathogenic route of metastatic disease

from genomic data alone, may not, in principle, be possible. For example, inter-tumour metastatic pleomorphism does not necessarily imply early and

pre-clinical seeding events, given the presence of significant genomic instability in many advanced tumours. The authors, I believe, should discuss

these issues in a little more detail.

4. Although the ratio measured by the authors (DPR) seems reasonable, it is interesting that the lowest mean values are ~ 0.5. This is clearly

much larger than the potential lowest value of -1. Does this imply that the linear pathogenic route is ubiquitous? If there is an an element of a parallel

pathogenic route in most tumours, how do we explain - from a biological perspective - both routes arising from the same tumour?

5. While the LPR has the advantage of being simple, are there more complicated measures that could be applied to the patient cohort that may

have added utility? For example, could the longest and shortest axis length of the metastatic tumours be

pooled (with respect to the tissue of origin) and an unsupervised clustering algorithm applied to these data? Investigators could then

simultaneously investigate tumour size and similarity of size. Perhaps different tumour types cluster into specific regions of axis-size space, with varying

sizes of the resultant clusters - we might hypothesise that, for example, metastatic pancreatic tumours cluster into very few clusters, in a particular

region of the space, with negligible intracluster variation. Perhaps the authors, in the discussion, could expand a little on the potential of

analysing metastatic patterning in human cancer.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-22-06443R1

Patterns of Metastases Progression- The Linear Parallel Ratio

PLOS ONE

Dear Dr. Gofrit,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

This very interesting manuscript provides insights into the metastatic process and can potentially change the way we interpret CT scans. It will certainly be of interest for the community. There are a few minor comments by the expert reviewer, that should be addressed prior to acceptance for publication.

Please submit your revised manuscript by Sep 19 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Nikolas K. Haass, MD/PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

This very interesting manuscript provides insights into the metastatic process and can potentially change the way we interpret CT scans. It will certainly be of interest for the community. There are a few minor comments by the expert reviewer, that should be addressed prior to acceptance for publication.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

********** 

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

********** 

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

********** 

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

********** 

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I still have an issue with the ideas regarding the hypothesis of this paper.

The authors state that the hypothesis is that the two leading models of metastatic progression can be identified by measuring the diameters of metastases (with the assumption that the leading models of tumour progression are, in fact, true - this latter point needs to made clear). But then how do these data support this hypothesis?

What would the expected distribution of metastatic sizes look like (between and within tumour types) if the leading models of metastatic spread were true? Or false? What if all tumours spread via a mixture of both mechanisms with differences in the variances (with respect to tumour type) of the tumour sizes? And how would that differ if the leading models of metastatic spread were mutually exclusive?

Could the results be simply due to stochastic variation where the two leading models of metastatic progression are irrelevant, or could the results be due to a mixture of both mechanisms of metastatic spread in all tumour types with the main differences between tumour types inherent and history-independent differences in the variances of the tumour sizes?

The problem is somewhat Bayesian. The authors are (sort of) asking Pr(A/B) where A is these data and B is the leading model of tumour spread, but the important quantity is Pr(B/A); that is, the probability of the theory of tumour spread being true given these data. Can the authors provide more rigour in the analysis of their data?

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Patterns of Metastases Progression- The Linear Parallel Ratio

PONE-D-22-06443R2

Dear Dr. Gofrit,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Nikolas K. Haass, MD/PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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