Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors

Round 1

Reviewer 1 Report

Dear authors, 

thank you for this very valuable and detailed manuscript titled 'Multi-tumor case series of germline BRCA1, BRCA2 and CHEK2 mutated patients responding favorably on immune checkpoint inhibitors'. You present the outcome of seven patients with confirmed mutation compared to 13 DDR germline variant absent patients and conclude a favorable outcome.

The fundamental problem with such a case series of different primary tumors is the control group. Which is - given genetical analysis is just starting - a critical answer. Ideally the two subgroups are statistically no different. You tried to solve this by assigning a 'similar' patient group without DDR mutations but this raises the question are outcome measures in months of melanoma patients comparable with renal cell carcinoma patients. i.e. is the perspective in the clinical situation intertumor comparable? Your data demonstrates a very good radiological response to the treatment but again this might be due to different behavior of the primary tumor site or mutation or a combination of both. 

From my point of view in order to declare a 'favorable' outcome you need to provide a benchmark for each primary tumor (or at least show that the perspective for each tumor is very similar) in the clinical situation of the patient. With this you may confirm a clinical benefit for the treatment - or the opposite.

Until then your data simply adds individual cases to a possible treatment option indicating that DDR mutation may be a predictor for the treatment response for ICPIs. These cases are very detailed presented and your careful conclusion 'patients ... should be offered ICPIs...' could be supported a lot more with your data. 

Author Response

Thank you for your thorough and constructive comments. For each patient case, we have added outcome details of the corresponding phase 3 clinical trial of the respective ICPI agent and tumor type, to provide a benchmark for each clinical situation. We hope these revisions are satisfactory, please let us know should any further revision be required.

Reviewer 2 Report

In the present manuscript (case report) entitled 'Multi-tumor case series of germline BRCA1, BRCA2 and CHEK2 mutated patients responding favourably on immune checkpoint inhibitors' authors report positive response to immune checkpoint inhibitors (ICPI) in 7 patients with malignancies with germline-associated variants in DNA damage response and repair (DDR) genes BRCA1, BRCA2 and CHEK2.

This case report brings valuable new insight for patient selection and treatment with ICPIs. Before I recommend it for publication I have several points to be considered by authors:

In the beginning of the introduction it would be beneficial to write shortly about immune checkpoint inhibitors. Also maybe optionally, shortly mention what targets ipilimumab so it is clearer to the reader. Maybe also pembrolizumab in line 56? Some readers might not found it automatically in materials and methods section.

Generally, DDR abbreviation is used for DNA damage response, and not DNA damage response and repair.

Line 80-81: ..at the start of ICPI..-it might be more accurate to say at the start of ICPI treatment. This is also in line 84.

Specify which method was used to extract DNA from white blood cells.

ORR is first mentioned in line 142, however abbreviation is only in line 307.

In line 107 maybe shortly explain class 4 and class 5 variant.

Author Response

Thank you for your thorough and constructive comments. We made the following adjustments:

Point 1:

In the beginning of the introduction it would be beneficial to write shortly about immune checkpoint inhibitors. Also maybe optionally, shortly mention what targets ipilimumab so it is clearer to the reader. Maybe also pembrolizumab in line 56? Some readers might not found it automatically in materials and methods section.

Response 1:

We have added additional information on ICPIs in the introduction.

Point 2:

Generally, DDR abbreviation is used for DNA damage response, and not DNA damage response and repair.

Response 2:

We have adjusted this.

Point 3

Line 80-81: ..at the start of ICPI..-it might be more accurate to say at the start of ICPI treatment. This is also in line 84.

Response 3:

We adjusted this.

Point 4:

Specify which method was used to extract DNA from white blood cells.

Response 4.

We further specified the extraction method.

Point 5:

ORR is first mentioned in line 142, however abbreviation is only in line 307.

Response 5:

We adjusted this.

Point 6:

In line 107 maybe shortly explain class 4 and class 5 variant.

Response 6

We have provided explanation.

We hope these revisions are satisfactory, please let us know should any further revision be required.

Round 2

Reviewer 1 Report

Thank you for the alterations which now underline these excellent responses.