Dear Dr. Miller,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: N/A

Reviewer #2: N/A

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

The PLOS Data policy

Reviewer #1: No

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The manuscript "Prognosis, treatment decision-making and value: a qualitative exploration of the emerging role of breast cancer prognostic assays" touches a very important and delicate topic, which has ramifications into multiple aspects of breast cancer post-diagnosis.

The manuscript is clearly written and the authors explore with incisiveness multiple aspects evolving around this novel technology.

Despite the fact that the value of reducing overtreatment (in this particular case, chemotherapy use) is extremely high, the authors give us a taste of how complex it is to practically introduce protocols to make it a reality for cancer patients. It emerges that two main approaches divide the world about the use of chemotherapy and the interview exerts in the manuscript give us a clear picture of the contrasting positions.

Costs, jurisdictional differences, acceptance of prognostic assays are also discussed to considerable details.

Despite the limitations of this study (which are frankly stated by the authors), I believe this topic is of utmost importance for the future of population health services. Precision medicine is about increasing the quality of life of people while taking care of the same diseases in a better way.

I really enjoyed reading this article and hope it contributes to facilitate discussion (and hopefully integrations) of those promising novel technologies, as they show the potential for a better living.

Reviewer #2: Thank you for the opportunity to review this manuscript, which explores clinician and researcher perspectives on the value, clinical utility, and integration of breast cancer prognostic assays into clinical care. The authors’ findings provide an interesting view of the current role of these assays in breast cancer treatment as perceived by clinicians. I believe that several key aspects of the study require clarification or expansion:

Methods

- Some participants were family physicians/general practitioners, who are not typically involved in requesting, processing, and interpreting breast cancer prognostic assays. What was the rationale for including these participants?

- Information on participants’ practice specialty should also be included in Table 1.

- The questions explored in the semi-structured interviews should be described in more detail. Ideally, the authors should provide the initial interview guide as part of the supplementary material.

Results

- Although most participants discussed prognostic assays supported by evidence for a predictive role (Oncotype Dx and DCISionRT), some mentioned assays lacking strong evidence for predicting treatment benefit in addition to their prognostic role. Did the authors observe any differences in perspectives based on the specific assay discussed? Were there any themes related to clinician preference for tools with both prognostic and predictive value, especially in settings where more than one assay is available?

Discussion

- According to the results, the primary perceived role of breast cancer prognostic assays is to reduce overtreatment. How does this relate to reimbursement decisions in some jurisdictions for patients with smaller tumors (e.g. T1b, node-negative cancers), since these patients are much less likely to receive chemotherapy in the absence of a prognostic assay? Were there any discussions about the use of these assays to escalate treatment for some patients?

- The authors’ findings could also inform the development of strategies to increase the value of prognostic/predictive assays, such as cost reduction, or by selecting patient subgroups for whom the clinical utility of avoiding overtreatment is higher. For instance, depending on baseline local chemotherapy utilization practices, this may apply for postmenopausal patients, or for those with node-positive disease.

- Could the authors clarify why conducting interviews virtually is considered a limitation in this study?

- In addition to the lack of patient perspectives, the absence of payer perspectives may also represent a limitation, given the manuscript’s strong focus on value, cost, and reimbursement decisions.

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Reviewer #1: No

Reviewer #2: No

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Prognosis, treatment decision-making and value: a qualitative exploration of the emerging role of breast cancer prognostic assays

PONE-D-24-17563R1

Dear Dr. Miller,

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.

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Kind regards,

Dongling Wu

Academic Editor

PLOS ONE