Response to Combination of Pembrolizumab and Axitinib in Hereditary Leyomiomatosis and Renal Cell Cancer (HLRCC)

Round 1

Reviewer 1 Report

The authors reported a case with HLRCC who showed a good partial response to combination of pembrolizumab and axitinib.

1) In the Introduction section, only the genomic alteration in HLRCC is described. Thus, the significance of this case is unclear in the Introduction section. Why do the authors report this case?

2) Pathological data of the surgical specimen should be added. HE stain image should be added. I think that immunohistochemistry data for loss of FH are necessary.

3) I think the following paper should be cited and discussed. 

Yonese I, Ito M, Takemura K, Kamai T, Koga F. A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy. J Kidney Cancer VHL. 2020 Jul 20;7(2):6-10. doi: 10.15586/jkcvhl.2020.148. PMID: 32953419; PMCID: PMC7479808

Author Response

Dear Reviewer, 

Those are the points that has been reviewed.

1. In the Introduction section, only the genomic alteration in HLRCC is described. Thus, the significance of this case is unclear in the Introduction section. Why do the authors report this case?

• A short explanation of the importance of this case has been made as introduction to the case report. 

2. Pathological data of the surgical specimen should be added. HE stain image should be added. I think that immunohistochemistry data for loss of FH are necessary.

• We have contacted with the Pathology Department of the hospital the patient was intervened to obtain the histological sections with the HE stain and the confirmation of FH loss. 

3. I think the following paper should be cited and discussed: A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy

• It has been cited at the end of the discussion as recommended 

We also have made some changes in the language and style

Thank you for your corrections and considerations,

Sincerely,

Reviewer 2 Report

This case report is interesting, given two facts: the rarity of the disease and the novelty of the treatment strategy used, which turned out to be successful, even if the follow up is not long. I think these two points should be stressed in the title, which  could be something like: A CASE OF HEREDITARY LEYOMIOMATOSIS AND RENAL CELL CANCER (HLRCC) IN A 18-YEAR OLD BOY,  SUCCESSFULLY TREATED WITH SURGERY AND A NOVEL COMBINATION OF PEMBROLIZUMAB AND AXITINIB.

Moreover, the paper needs extensive language revision by an expert mother-tongue English speaker.

Some changes are needed to be more accurate in the terminology, and conceptualisation, especially related to genetic information.

SIMPLE SUMMARY

Mutations of the gene coding for fumarate hydratase in which both alleles are affected lead to premature deaths; however if the mutation is present on one allele only... (THIS CONDITION CAN BE CALLED HETEROZIGOSITY)

Treatment possibilities for this rare tumour are scarce at the moment, with high mortality in metastatic cases.

ABSTRACT

In current clinical guidelines, such as the National Comprehensive Cancer Network guidelines, evidence based on a small clinical trial including patients with HLRCC, supports the use of a combination of erlotinib and bevacizumab as first therapeutic option in this rare condition. In the present study we report a rare case of this condition in a 18 year old boy with family history for kidney cancer, successfully treated with surgery and a novel drug treatment modality  based on the combination of a check-point inhibitor and a tyrosine-kinase inhibitor, with excellent results. 

INTRODUCTION

...associated with a mutation of the gene encoding for fumarate hydratase at the level of the 1q chromosome.... This gene codes for an enzyme which catalyzes  the....

Patients who are affected by the biallelic mutations (can be called also homozigous patients for the mutation).....

Nevertheless, patients who present a mutation in only one allele (can be called heterozigous patients for the mutation)...

To date, three large series of cases have been reported, analysing their mutation patterns.

CASE REPORT

...a grand father and an uncle dead for renal cancer....

...a radical right nephrectomy with extended retroperitonel, retrocaval and periaortic lymphadenectomy was performed.

After recovery, a PET-CT scan was performed, showing disease persistence at lateroconal fascia...The patient was also submitted to genetic mapping,  and then genetic counselling, identifying a deletion...

At the first 2-month follow up visit, the patient...and a new node at the anterior surface of the right psoas...

After 2 months the patient showed resolution of the abdominal pain, and a CT scan revealed important partial response to therapy with reduction of the retroperitoneal node and disappearance of the other lesions. Currently the patient is undergoing his 11th cycle of treatment with persistent good response, and with grade 1-2 diarrhea ...(HOW MANY MONTHS HAVE PASSED SINCE THE SURGERY AND START OF TREATMENT?)

DISCUSSION

HLRCC is a rare hereditary condition with no more that 300 families reported worldwide; it is considered an orphan condition with no high-level evidence available or controlled dedicated clinical trials undertaken so far. The options available at the moment for medical treatment of this condition in its metastatic stage are supported by results of small subgroups of cases gathered from larger trials on kidney cancer. 

It would be finally advisable for the authors to re-write the conclusions, for example as shown below, to make the paper more interesting and to highlight which are the new points that this paper makes. It would also be very appropriate, and it would make the paper really up to date, to mention in the conclusions (and also probably in the discussion section) the ERN e UROGEN, recently established as a international European platform were cases like the one presented by the authors can be in the next future discussed and uploaded. A paper presenting the eUROGEN Network is currently in press in European Urology, and should be included in the references list. See below:

CONCLUSIONS

This study reports the case of a young patient with a rare disease, HLRCC. It underlines the need to look for genetic alterations in young patients with kidney tumours (especially if, as in this case, they present a family history for kidney cancer in young relatives). Moreover, it highlights that adequate genetic profiling should be available in these cases in order to identify specific mutations and syndromes. Genetic counselling should be also recommended, especially in young patients of reproductive age. Finally, this case report proposes a novel treatment strategy based on a combination of surgery, pembrolizumab and axitinib, which showed promising results. The newly establish European Reference Network ERN eUROGEN, is currently working on building online platforms to discuss rare urological diseases, as the one here reported, update and adapt current guidelines and offer physicians and patients a unique opportunity to afford complex and rare conditions, such as HLRCC (reference: Oomen L., et al.: Rare and Complex Urology: Clinical Overview of ERN eUROGEN, European Urology, 2021, in press; http://doi.org/10.1016/j.eururo.2021.02.043). 

Author Response

Dear Reviewer, 

1. We have corrected all the suggested points in the different parts of the article 
2. It also has been revised the writing style and corrected by a fluent English speaker
3. It has been mentioned the ERN eUROGEN paper as recommended. 

Thank you for your corrections and considerations,

Sincerely,

Round 2

Reviewer 2 Report

The paper has significantly improved with the changes made by the authors, which are satisfactory.  Only a minor change has to be made to the last paragraph of the conclusions, which could sound as follows:

"The newly established European Reference Network (ERN) eUROGEN is currently working on building online platforms to discuss rare urological diseases as the one here presented, update and adapt to rare diseases current guidelines, and offer physicians and patients a unique opportunity to manage in an dedicated environment complex and rare conditions, including rare urological tumors, such as HLRCC (13). It is highly desirable that in the next future rare cases as the one presented in this work will find a place for shared management in the dedicated platform of the ERN eUROGEN.