Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature

Published in?Pharmaceuticals?on February 16, 2021

ABSTRACT

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.

PRE-PUBLICATION REVIEW?審閱一:

Two carcinoma patients treated based on genomic mutations instead of FDA recommendations are presented in this manuscript. The authors also reviewed the current progress in BRAF mutation treatment in the discussion.

Major:

Treatment details. Line 101-102 : "At this point, first line 101 chemotherapy with cisplatin AUC5 and gemcitabine was administered for 6 cycles." Line 105-106:"after multidisciplinary discussion, the patient started a second line chemotherapy with 105 oxaliplatin and capecitabine, without clinical and radiological response ." The dosages of these treatments are described in case 2. It would be excellent to include the dosage of these treatments in Case 1. It would be great to include CT images for lung nodules and bone lesions in figure 1 if possible. Minor:

Terms and acronyms. There are too many unnecessary acronyms in this manuscript. Proofreading on acronyms is needed. Please avoid introducing an acronym unless it will be used more than three or four times. I can understand that doctors are generally more familiar with ALP than alkaline phosphatase; however, some of the acronyms may not be necessary., e.g. Line 26: quality of life (QoL) QoL is only used once in the whole manuscript. Line 30: "non small cell lung cancer (NSLC)" Line 58-59: "non-small cell lung cancers (NSCLCs)" Please use the same acronym for non-small cell lung cancer. Line 27: "metastatic collecting duct of Bellini (mCDC)" metastatic collecting duct carcinoma (mCDC), Collecting (Bellini) duct carcinoma, or Bellini Duct Carcinoma? Line 41: "collecting duct carcinoma of Bellini (CDC)" Please consider using the same acronym for collecting duct carcinoma. Line 65: "Pembrolizumab and nivolumab for patients with microsatellite instability high (MSI-H)...." MSI-H is only used once; please consider "Pembrolizumab and nivolumab for patients with high levels of microsatellite instability...." Line 77: "The majority of mutations occur at the V600 position, with , V600E observed in 5% of CCA [13]...." Please introduce cholangiocarcinoma (CCA) before using it. Line 250: "Biliary tract cancer reveals molecular heterogeneity, and there is a crucial need to identify a subset of patients who can benefit from targeted therapy to be used in first- or second-line progression with gemcitabine plus cisplatin as first line of therapy" Line 258: "Focusing on biliary tract cancer (BTC), preliminary data from the ROAR basket trial demonstrated promising activity of the combination with a favorable safety profile in patients with BRAF V600E (ROAR trial; NCT 02034110)." BTC is introduced when used for the second time. Please considering remove BTC as an acronym.

Authors' reply:

Point-by-point reply to review Manuscript Number: pharmaceuticals-1053813 Article Title: Tumor type agnostic therapy carrying BRAF mutation: case reports and review of literature We are grateful to the Reviewers for their feedback, which has helped us to improve the quality of the manuscript. Please find below the point-by-point reply to all the comments.

Reviewer #2: Two carcinoma patients treated based on genomic mutations instead of FDA recommendations are presented in this manuscript. The authors also reviewed the current progress in BRAF mutation treatment in the discussion. Specific points: 1) Line 101-102 : "At this point, first line chemotherapy with cisplatin AUC5 and gemcitabine was administered for 6 cycles." Line 105-106:"after multidisciplinary discussion, the patient started a second line chemotherapy with oxaliplatin and capecitabine, without clinical and radiological response ."

The dosages of these treatments are described in case 2. It would be excellent to include the dosage of these treatments in Case 1. In lines 104,105 and 107-109 we have described the dosages of these treatments of Case 1. 2) It would be great to include CT images for lung nodules and bone lesions in figure 1 if possible. Thanks for the suggestion but unfortunately we can’t recover these CT images.

3) Terms and acronyms. There are too many unnecessary acronyms in this manuscript. Proofreading on acronyms is needed. Please avoid introducing an acronym unless it will be used more than three or four times. I can understand that doctors are generally more familiar with ALP than alkaline phosphatase; however, some of the acronyms may not be necessary., e.g. We have proofread terms and acronyms (lines 26, 30, 59, 65, 77, 266). We have used the same acronym for Bellini duct carcinoma (BDC). We have erased acronyms not necessary.

Second review:

It occurs to me that the authors failed to keep necessary records of their cases, and they failed to provide CT images of case 1. A case report is an inferior type of scientific evidence, and incomplete medical cases may not worth reporting. In my opinion, this manuscript still needs moderate language editing before publication. The author failed to improve this manuscript during the first round of editing. Because of the listed reasons above, I would like to recommend the rejection of this manuscript.

POST-PUBLICATION REVIEW

Brief overview of the paper and its main findings

Two carcinoma patients treated based on genomic mutations instead of FDA recommendations are presented in this manuscript. The authors also reviewed the current progress in BRAF mutation treatment in the discussion.

Major and minor points

As a reviewer of this case report, the evidence showing that their treatment works on metastatic tumors were requested. The authors refused to provide any proof and said that they could not recover their CT images. It occurs to me that the authors failed to keep necessary records of their cases. A case report is an inferior type of scientific evidence, and incomplete medical cases may not even worth reporting. Moreover, the author decided to hide my review report from publication on MDPI. Hence, I would like to red-flag this paper and question the academic integrity showed in this case report.

Conflicts of interest

The review report is anonymous anyway, and I do not benefit from my review report's publication. The reason behind hiding my review report is intriguing. I declare no conflicts of interest.

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