Hermione Exchange Educational Program: How to Integrate Multidisciplinary Approaches to Manage HR+/HER2- Metastatic Breast Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Marina Elena Cazzaniga and colleagues have submitted a conference report entitled “Hermione Exchange Educational Program: how to integrate multidisciplinary approaches to manage HR+/HER2- metastatic breast cancer.” The manuscript addresses a clinically important topic: how multidisciplinary teams should integrate molecular testing and therapeutic sequencing in HR+/HER2- metastatic breast cancer after CDK4/6 inhibitor progression.

The manuscript is appropriately framed as a Conference Report rather than a case study or full article, and under this category, the educational value of this article is clear. The topic is timely, the multidisciplinary format is relevant, and the integration of molecular pathology, liquid biopsy, ESR1/PIK3CA testing; and post-CDK4/6 therapeutic sequencing will be useful to readers managing HR+/HER2- metastatic breast cancer.

However, the manuscript should remain firmly within the evidentiary limits of a conference report. The questionnaires should be described as structured expert/audience polling rather than as a Delphi or Delphi-like consensus process, unless authors can justify that terminology more rigorously. The reported polling results are useful for illustrating areas of agreement and uncertainty among participants, but they should not be used to imply a formal consensus, guideline-level recommendations, or demonstrated changes in physician over time.

Therefore, the main revision needed is obviously not a complete methodological redesign, but a narrowing of claims. Statements such as “genomic testing is mandatory at diagnosis and should be repeated during treatment” should be softened and aligned with the objective workshop findings and current biomarker-linked therapeutic indications. Similarly, the claim that oncologists’ opinions changed after elacestrant became available should be reframed descriptively, since the two questionnaires involved different time points and possibly (not clarified clearly) different respondent groups.

The authors should also improve transparency by reporting the number of invited participants, respondent characteristics, response times, and whether the same individuals responded to both questionnaires. The data availability statement should be revised, since aggregated questionnaire data were generated and analyzed. Finally, the authors should clarify ethics/consent considerations for the anonymized cases and disclose if the educational program, medical writing, or manuscript preparation received direct or indirect commercial support.

Overall, this reviewer finds the report suitable for publication as a conference report with moderate revision. Its value lies in documenting expert discussion and educational exchange, not in establishing formal consensus or generating clinical evidence, which is better to vividly state in the revised version of the manuscript.

Author Response

Marina Elena Cazzaniga and colleagues have submitted a conference report entitled “Hermione Exchange Educational Program: how to integrate multidisciplinary approaches to manage HR+/HER2- metastatic breast cancer.” The manuscript addresses a clinically important topic: how multidisciplinary teams should integrate molecular testing and therapeutic sequencing in HR+/HER2- metastatic breast cancer after CDK4/6 inhibitor progression.

The manuscript is appropriately framed as a Conference Report rather than a case study or full article, and under this category, the educational value of this article is clear. The topic is timely, the multidisciplinary format is relevant, and the integration of molecular pathology, liquid biopsy, ESR1/PIK3CA testing; and post-CDK4/6 therapeutic sequencing will be useful to readers managing HR+/HER2- metastatic breast cancer.

However, the manuscript should remain firmly within the evidentiary limits of a conference report. The questionnaires should be described as structured expert/audience polling rather than as a Delphi or Delphi-like consensus process, unless authors can justify that terminology more rigorously. The reported polling results are useful for illustrating areas of agreement and uncertainty among participants, but they should not be used to imply a formal consensus, guideline-level recommendations, or demonstrated changes in physician over time.

Reply: Thank you for the suggestion, the format has been modified into the main text. We have included a paragraph “Structured survey” in the Material and Methods section to better describe the survey.

Therefore, the main revision needed is obviously not a complete methodological redesign, but a narrowing of claims. Statements such as “genomic testing is mandatory at diagnosis and should be repeated during treatment” should be softened and aligned with the objective workshop findings and current biomarker-linked therapeutic indications. Similarly, the claim that oncologists’ opinions changed after elacestrant became available should be reframed descriptively, since the two questionnaires involved different time points and possibly (not clarified clearly) different respondent groups.

Reply: Thank you, claims have been narrowed in different sections of the main text. In the Abstract we have made the following changes: Genomic testing should be considered at diagnosis and repeated during treatment to monitor the disease. The claim that oncologists’ opinion changed after elacestrant became available has been removed as we have partially rewritten the entire section.

The authors should also improve transparency by reporting the number of invited participants, respondent characteristics, response times, and whether the same individuals responded to both questionnaires. The data availability statement should be revised, since aggregated questionnaire data were generated and analyzed. Finally, the authors should clarify ethics/consent considerations for the anonymized cases a more clear explanation of what we use as use-cases and the reason why the EC approval was not requested has been provided into the main text and disclose if the educational program, medical writing, or manuscript preparation received direct or indirect commercial support.

Reply: we have added the following sentence: For the purposes of the meeting, use cases were defined as descriptions of how physicians apply an intervention in clinical practice. As such, they did not meet the definition of research involving human subjects and, therefore, did not require ethical approval.

Overall, this reviewer finds the report suitable for publication as a conference report with moderate revision. Its value lies in documenting expert discussion and educational exchange, not in establishing formal consensus or generating clinical evidence, which is better to vividly state in the revised version of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Hermione Exchange Educational Program: how to integrate multidisciplinary approaches to manage HR+/HER2- metastatic breast cancer

Overview
This article summarized findings from the Hermione Exchange Educational Program (2024 to 2025), which used Delphi-like consensus surveys, lectures, and clinical case discussions to explore how oncologists and molecular pathologists manage HR+ metastatic breast cancer after progression on first-line CDK4/6 inhibitors. It emphasized the critical role of tissue and liquid biopsy for detecting ESR1 and PIK3CA mutations to guide second-line targeted therapy (e.g., elacestrant) versus chemotherapy, highlighting that treatment decisions depend on mutation status, duration of response to prior therapy, disease burden, and patient clinical condition.

Comments/Suggestions
1. Abstract does not report any numerical findings (e.g., percentages from the Delphi survey) or explicit conclusions. Adding key quantitative results would improve clarity and impact.
2. The Delphi-like process lacks details: number of rounds, anonymity rules, consensus threshold, and how statements were generated. Without these, the methodology cannot be replicated.
3. The survey responses (e.g., 65% agree on liver metastases, 80% on age not limiting chemotherapy) provide useful clinical insights. No measure of consensus (e.g., median, IQR, percent agreement threshold) or statistical treatment of disagreement is provided. This weakens the Delphi validity.
4. Appendix Tables A1 and A2 provide full questionnaires, which is valuable for transparency. The main text (e.g., pages 5 to 7) repeats many questionnaire items verbatim. This creates redundancy. Summarize in the main text and refer to the appendix for full details.
5. Real-world use cases (e.g., Figures 4 to 6) effectively illustrate treatment decisions and molecular testing. They are presented as narrative timelines without key elements: age, performance status, line of therapy, prior treatments beyond CDK4/6, and follow-up duration. Standardized case reporting would enhance educational value.
6. The manuscript does not specify whether recommendations are based on Delphi consensus, expert opinion, or published evidence. Using a grading system (e.g., ESMO-MCBS, GRADE) would improve credibility.
7. No analysis or clinical guidance is provided for double-mutant patients (e.g., sequencing of elacestrant vs alpelisib + fulvestrant).
8. No section on limitations.

Remark
The manuscript provides valuable insights from an educational program on HR+ metastatic breast cancer management, but requires major improvements including structured quantitative data, reproducible methods, visible figures, consensus metrics, standardized case reports, graded recommendations, analysis of co-mutations, and a dedicated limitations section.

Comments on the Quality of English Language

needs improvement

Author Response

This article summarized findings from the Hermione Exchange Educational Program (2024 to 2025), which used Delphi-like consensus surveys, lectures, and clinical case discussions to explore how oncologists and molecular pathologists manage HR+ metastatic breast cancer after progression on first-line CDK4/6 inhibitors. It emphasized the critical role of tissue and liquid biopsy for detecting ESR1 and PIK3CA mutations to guide second-line targeted therapy (e.g., elacestrant) versus chemotherapy, highlighting that treatment decisions depend on mutation status, duration of response to prior therapy, disease burden, and patient clinical condition.

Comments/Suggestions
1. Abstract does not report any numerical findings (e.g., percentages from the Delphi survey) or explicit conclusions. Adding key quantitative results would improve clarity and impact.

Reply: thank you for this comment. We have modified the Abstract as follows: From the surveys, it emerged that most participants (69%) considered liver metastases at CDK4/6‑inhibitor progression as a key reason to initiate chemotherapy, while lung progression influenced this choice for 50% of participants. Liver involvement guided the use of targeted therapy for 56%, and attitudes were divided on whether the duration of first‑line CDK4/6 therapy should affect decisions (44% in agreement vs 38% in disagreement). The willingness of patients to receive chemotherapy (88%) and comorbidities (81%) were significant drivers. Almost all participants agreed that both the duration of response and the molecular status were key aspects to consider when choosing a second line of therapy, along with the general clinical condition of the patient. In the lecture, tissue and liquid biopsy are considered powerful tools to describe tumor molecular features over time; such complexity should be harnessed by a close dialogue between oncologists, molecular biologists, and pathologists to optimize the therapeutic choice according to the mutational status of patients. The use cases illustrate three patients with visceral progression, non-visceral progression within 12 months and non-visceral progression after 12 months after CDK4/6 inhibitors.

2. 
   The Delphi-like process lacks details: number of rounds, anonymity rules, consensus threshold, and how statements were generated. Without these, the methodology cannot be replicated.

Reply: As another reviewer raised almost the same concern and considering that the Authors agree that the methodology is not a true Delphi process, we have modified the methodology section into the main text: we have better defined it as a survey rather than a Delphi process.

3. 
   The survey responses (e.g., 65% agree on liver metastases, 80% on age not limiting chemotherapy) provide useful clinical insights. No measure of consensus (e.g., median, IQR, percent agreement threshold) or statistical treatment of disagreement is provided. This weakens the Delphi validity.

Reply: We thank you for this observation: we have modified the methodology section, as previously stated, and reported the number along with the percentages (see the main text).

4. 
   Appendix Tables A1 and A2 provide full questionnaires, which is valuable for transparency. The main text (e.g., pages 5 to 7) repeats many questionnaire items verbatim. This creates redundancy. Summarize in the main text and refer to the appendix for full details.

Reply: We respectfully did not consider this suggestion, as it is in contrast with the comment of another Reviewer. We kindly ask to the Editor to take a decision about which of 2 suggestions we should consider.

5. 
   Real-world use cases (e.g., Figures 4 to 6) effectively illustrate treatment decisions and molecular testing. They are presented as narrative timelines without key elements: age, performance status, line of therapy, prior treatments beyond CDK4/6, and follow-up duration. Standardized case reporting would enhance educational value.

We have added further clinical details as requested: “The first use case described a 56-years old patient, PS 1, with de-novo metastatic breast cancer (left breast, multiple lymph nodes and liver), who received first-line therapy with ribociclib and fulvestrant achieving a partial response with this treatment and subsequently developed visceral progression 4 years later.” And “Another use case described a 50‑year‑old patient, PS 0, diagnosed with ductal carcinoma. After surgery, she received adjuvant chemotherapy. Fifteen years later, the patient required another surgery to remove a ductal carcinoma with cribriform features from the right breast. Radiological evaluation showed no distant metastases, and she was treated with adjuvant letrozole for five years. During this period, the patient developed a cutaneous relapse, which was surgically removed and treated with radiotherapy. In 2019, a second local relapse occurred. She then received adjuvant exemestane until 2024, when bone and lung metastases were detected. The patient (75-year old) started treatment with a cyclin inhibitor and fulvestrant; however, after four months, progressive skeletal disease was observed.” AND “ The last use case illustrated a progression after the intermediate time of 16 months of CDK4/6 inhibitor treatment. The patient was a 46-years old woman, PS ECOG 0, with no relevant comobidities and a positive familiar history of breast cancer (mother diagnosed at the age of 65 years and 1 sister diagnosed at the age of 30 years). She received adjuvant chemotherapy, radiation therapy and endocrine treatment (Tamoxifen + LHRH analogue, switched to Anastrozole after 2 years due to the appearance of endometrial poliposis. After a median Disease Free Interval of 48 months, she developed bilateral breast relapse and lymph node metastases. After the first-line therapy with palbociclib and aromatase inhibitor, she progressed at bone and lung.”

6. 
   The manuscript does not specify whether recommendations are based on Delphi consensus, expert opinion, or published evidence. Using a grading system (e.g., ESMO-MCBS, GRADE) would improve credibility.

Reply: We thank you for the suggestion, as another Reviewer raised the same topic, we have decided to modify the methodology section accordingly.

7. 
   No analysis or clinical guidance is provided for double-mutant patients (e.g., sequencing of elacestrant vs alpelisib + fulvestrant).

Reply: The topic was already addressed in the paper (lines 537-546)

8. 
   No section on limitations.

Reply: A paragraph regarding this topic has been added: This project has some limitations. The findings are based on expert opinion derived from a survey approach conducted within a limited number of workshops, which may introduce selection bias and restrict the generalizability of the results. The number of participants involved in the voting process varied across meetings, potentially affecting the consistency of the consensus. In addition, the use cases were descriptive in nature and not based on systematically collected data, thus limiting their strength as evidence. Finally, the rapidly evolving therapeutic landscape of HR+ metastatic breast cancer may impact the long‑term applicability of these findings

Remark
The manuscript provides valuable insights from an educational program on HR+ metastatic breast cancer management, but requires major improvements including structured quantitative data, reproducible methods, visible figures, consensus metrics, standardized case reports, graded recommendations, analysis of co-mutations, and a dedicated limitations section.

Reviewer 3 Report

Comments and Suggestions for Authors

The conference report entitled “Hermione Exchange Educational Program: How to Integrate Multidisciplinary Approaches to Manage HR+/HER2− Metastatic Breast Cancer” addresses a clinically important and timely topic in breast cancer management. The manuscript summarizes discussions from an educational program involving oncologists, molecular pathologists, and other specialists, highlighting the increasing importance of integrating molecular diagnostics with clinical decision-making in HR+/HER2− metastatic breast cancer.

A main strength of the manuscript is its importance on multidisciplinary collaboration and the incorporation of evolving molecular information into therapeutic strategies. The discussion regarding tissue and liquid biopsies, genomic testing, and treatment selection after progression on CDK4/6 inhibitors reflects existing challenges encountered in clinical practice. The report also specifies useful insights into evolving treatment patterns following the introduction of elacestrant and underscores the importance of continued education for healthcare professionals.

The manuscript is well-structured and provides the essential information expected from a conference report, including the educational framework, case-based discussions, the consensus-building process, and key conclusions. The inclusion of real-world clinical scenarios enhances the report's practical relevance and provides valuable perspectives on the management of HR+/HER2− metastatic breast cancer.

Overall, this conference report presents valuable perspectives on multidisciplinary management and highlights the growing role of molecular characterization in treatment selection. Subject to minor revisions, the manuscript is suitable for publication.

Comments for the Authors

1. In the Introduction section, the epidemiological statistics for breast cancer are primarily based on data from 2020. As the educational program was conducted during 2024–2025, the authors are encouraged to update these statistics with the most recent available data and references where appropriate.
2. The report primarily focuses on treatment decisions following progression on CDK4/6 inhibitors. Although several therapeutic options are briefly discussed in the introduction, the manuscript would benefit from a more comprehensive discussion of currently available treatment strategies, including PI3K, AKT, and mTOR-targeted therapies, oral SERDs, antibody-drug conjugates such as Trastuzumab deruxtecan, and chemotherapy. In particular, further discussion of treatment sequencing and mechanisms of resistance would strengthen the educational value of the report. The role of molecular testing in guiding treatment selection among these alternatives should also be emphasized.
3. The authors should consider including a brief limitations section acknowledging that the conclusions are derived from expert discussions, case-based learning, and consensus-building activities rather than prospective clinical studies. Such a statement would help readers appropriately interpret the recommendations presented.
4. The conclusion states that genomic testing is mandatory at diagnosis and should be repeated during treatment. This important recommendation would benefit from additional support through citation of current international guidelines, consensus statements, or evidence-based recommendations.

Author Response

The conference report entitled “Hermione Exchange Educational Program: How to Integrate Multidisciplinary Approaches to Manage HR+/HER2− Metastatic Breast Cancer” addresses a clinically important and timely topic in breast cancer management. The manuscript summarizes discussions from an educational program involving oncologists, molecular pathologists, and other specialists, highlighting the increasing importance of integrating molecular diagnostics with clinical decision-making in HR+/HER2− metastatic breast cancer.

A main strength of the manuscript is its importance on multidisciplinary collaboration and the incorporation of evolving molecular information into therapeutic strategies. The discussion regarding tissue and liquid biopsies, genomic testing, and treatment selection after progression on CDK4/6 inhibitors reflects existing challenges encountered in clinical practice. The report also specifies useful insights into evolving treatment patterns following the introduction of elacestrant and underscores the importance of continued education for healthcare professionals.

The manuscript is well-structured and provides the essential information expected from a conference report, including the educational framework, case-based discussions, the consensus-building process, and key conclusions. The inclusion of real-world clinical scenarios enhances the report's practical relevance and provides valuable perspectives on the management of HR+/HER2− metastatic breast cancer.

Overall, this conference report presents valuable perspectives on multidisciplinary management and highlights the growing role of molecular characterization in treatment selection. Subject to minor revisions, the manuscript is suitable for publication.

Comments for the Authors

1. In the Introduction section, the epidemiological statistics for breast cancer are primarily based on data from 2020. As the educational program was conducted during 2024–2025, the authors are encouraged to update these statistics with the most recent available data and references where appropriate.

Reply: Thank you for this comment: we have updated the statistics as follows: the estimated incidence in Italy in 2024 was just under 54,000 cases, with an estimated five-year survival rate of more than 88%, with 925,000 women living with a breast cancer diagnosis [AIRTUM I numeri del Cancro 2025].

1. The report primarily focuses on treatment decisions following progression on CDK4/6 inhibitors. Although several therapeutic options are briefly discussed in the introduction, the manuscript would benefit from a more comprehensive discussion of currently available treatment strategies, including PI3K, AKT, and mTOR-targeted therapies, oral SERDs, antibody-drug conjugates such as Trastuzumab deruxtecan, and chemotherapy. In particular, further discussion of treatment sequencing and mechanisms of resistance would strengthen the educational value of the report. The role of molecular testing in guiding treatment selection among these alternatives should also be emphasized.

Reply: thank you for this comment. We have added further discussion on these topics in the Introduction: In the metastatic setting, endocrine therapies combined with cyclin‑dependent kinase (CDK) 4/6 inhibitors continue to represent the therapeutic backbone. Endocrine agents are often administered together with additional targeted treatments, such as inhibitors of phosphatidylinositol‑3‑kinase (PI3K), Akt serine/threonine kinase (AKT), and/or the mechanistic target of rapamycin (mTOR) pathway [4].

Several new approaches are also emerging and may soon be incorporated into routine treatment algorithms. Camizestrant, a next‑generation selective estrogen receptor degrader (SERD) and full ER antagonist, has demonstrated superior progression‑free survival compared with aromatase inhibition in patients with ER‑positive, HER2‑negative advanced breast cancer harboring ESR1 mutations that developed during therapy, while maintaining CDK4/6 inhibition in the first‑line setting [5].

Upon the development of initial resistance, palliative chemotherapy is typically recommended [6]. Evidence is also growing for antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T‑DXd), which have shown improved progression‑free survival compared with chemotherapy in patients with hormone receptor‑positive, HER2‑low or HER2‑ultralow metastatic breast cancer previously treated with at least one line of endocrine‑based therapy. These agents have the potential to significantly reshape the therapeutic landscape of metastatic breast cancer, particularly for tumors classified as HER2‑low or HER2‑ultralow [7].

Genomic alterations play a key role in guiding treatment sequencing within clinical recommendations, particularly from the second line onward. The ESMO Precision Medi-cine Working Group has recently updated the classification of several biomarkers: both ESR1 and PIK3CA mutations are considered ESCAT IA. Current guidelines advise per-forming molecular testing after progression on first‑line endocrine therapy in patients with HR‑positive/HER2‑negative advanced breast cancer, in order to select the most appropri-ate endocrine options and determine whether targeted agents should be incorporated into subsequent treatment lines [4, 2].

3. The authors should consider including a brief limitations section acknowledging that the conclusions are derived from expert discussions, case-based learning, and consensus-building activities rather than prospective clinical studies. Such a statement would help readers appropriately interpret the recommendations presented.

Reply: A paragraph regarding this topic has been added: This project has some limitations. The findings are based on expert opinion derived from a survey approach conducted within a limited number of workshops, which may introduce selection bias and restrict the generalizability of the results. The number of participants involved in the voting process varied across meetings, potentially affecting the consistency of the consensus. In addition, the use cases were descriptive in nature and not based on systematically collected data, thus limiting their strength as evidence. Finally, the rapidly evolving therapeutic landscape of HR+ metastatic breast cancer may impact the long‑term applicability of these findings.

4. The conclusion states that genomic testing is mandatory at diagnosis and should be repeated during treatment. This important recommendation would benefit from additional support through citation of current international guidelines, consensus statements, or evidence-based recommendations.

Reply: Thank you, claims have been narrowed in different sections of the main text. In the Abstract we have made the following changes: Genomic testing should be considered at diagnosis and repeated during treatment to monitor the disease.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

revision is satisfactory