Review Reports

Round 1

Reviewer 1 Report

This is an interesting well documented case study with a topic of interest on the use of CDK4/6 inhibitors even in cases of crisis. While there was no visceral crisis, the patient did present with local crisis.

Comments :

- could the authors share whether there was any local therapy (e.g RT) administered that may have contributed to the dramatic local response seen?

- line 88-89 : the statement suggests that the improvement of patient symptoms are due to CD4/6 inhibtiors. However, this could also be due to transfusion and other symptomatic treatment. Could the authors quantify the contribution if they feel that the rapid improvement is CDK 4/6 related or due to other symptomatic treatment? What was the period over which the improvement was observed?

- why was abemaciclib picked over palbociclib or ribociclib?

- was there any marrow involvement that also contirbuted to the low hemaglobin in view of high bone disease burden that the authors stated?

- the authors may consider a graph indicating the trend of hemaglobin and tumor markers to help show pace of response

- MONARCH3 data has been updated at ESMO this year and authors may want to consider updating the discussion to include this data

Author Response

Response to Reviewer 1:

Point 1: could the authors share whether there was any local therapy (e.g RT) administered that may have contributed to the dramatic local response seen?

Response 1: no local therapy was administered (no RT and no electrochemotherapy): the dramatic local response was related only to the rapid response to oncological treatment with letrozole and Abemaciclib. We added a statement in the case report to clarify this point.

Point 2: line 88-89: the statement suggests that the improvement of patient symptoms are due to CD4/6 inhibtiors. However, this could also be due to transfusion and other symptomatic treatment. Could the authors quantify the contribution if they feel that the rapid improvement is CDK 4/6 related or due to other symptomatic treatment? What was the period over which the improvement was observed?

Response 2: The symptoms improvement was due both to symptomatic treatment (transfusions, low flow oxygen and local management of the ulcerative lesion) and the prompt CDK4/6 inhibitors plus ET treatment start. The initial symptomatic treatment with blood transfusions was fundamental to rescue hemoglobin levels and reach hemoglobin security levels to start CDK4/6 inhibitors. After Abemaciclib and letrozole begin, an important improvement was seen in two weeks since the patient did no longer needed oxygen therapy and hemoglobin levels stabilized. We clarified this point in the case report.

Point 3: why was abemaciclib picked over palbociclib or ribociclib?                                       

Response 3: We chose Abemaciclib over Palbociclib and Ribociclib since in our experience the every-day schedule is associated with better patients’ compliance and a lower risk of dosage mistakes. We added a statement in the case report to clarify this point.

Point 4: was there any marrow involvement that also contributed to the low hemoglobin in view of high bone disease burden that the authors stated?

Response 4: No. Despite the high bone disease burden, the patient did not present with marrow failure since the platelets and the white blood cells levels were normal. The dramatic hemoglobin levels were due to the chronic bleeding of the ulcerative breast lesion, lasting for at least 12 months. We clarified this point in the case report.

Point 5: the authors may consider a graph indicating the trend of hemoglobin and tumor markers to help show pace of response

Response 5: Of course. We added them in the manuscript (Hb, CEA and CA15.3).

Point 6: MONARCH3 data has been updated at ESMO this year and authors may want to consider updating the discussion to include this data

Response 6: We decided not to discuss further the results of the MONARCH 3 trial presented at ESMO 2022 Congress since the PFS results were confirmed, while the OS data did not reach the statistical significance in this update (although it was clinically relevant). In lines 201-220 we discussed only the results of the MONALEESA and MONARCH trials in which the OS benefit was statistically confirmed in the endocrine sensitive and resistant population. We added the reference of the MONARCH 3 trial in the references to completion.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors present a prevalent case and discuss a very clinically relevant dilemma. The authors cite the appropriate literature and wrote a comprehensive discussion. Yet, to make this case presentation better please address 2 issues:

1. Please revise the English- words such as "suddenly" (line 72), "mammalian" (line 131), and "At the state of the art" (line 134) should be changed.

2. There is an important missing part to the discussion- why did the authors insisted not to give chemotherapy...? Please add to complete the picture.

Author Response

Response to Reviewer 2:

Point 1: Please revise the English- words such as "suddenly" (line 72), "mammalian" (line 131), and "At the state of the art" (line 134) should be changed.

Response 1: English words modified as indicated and English review in progress.

Point 2: There is an important missing part to the discussion- why did the authors insisted not to give chemotherapy...? Please add to complete the picture.

Response 2: We chose fist-line CDK4/6 inhibitors therapy instead of chemotherapy in consideration of the non-substantial difference in terms of ORR and PFS between the two strategies highlighted in the literature data mentioned in the case discussion. In addition, rapidity of responses described in the MONARCH 3 and MONALEESA 2 trials were encouraging and the safety profile was in favor of the CDK4/6 inhibitors plus ET treatment. Furthermore, the patient did not present with severe organ compromise as in the proper visceral crisis since bone marrow function was adequate and hemoglobin value stabilized after multiple blood transfusions and appropriate local management of the breast ulcerated lesion. These considerations are mostly reported in the discussion and conclusions of the manuscript, but we can add an explanation paragraph at the end of the discussion or in the conclusion one.

Author Response File: Author Response.docx