ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date
Round 1
Reviewer 1 Report
The manuscript by Gendarme et al is a current and comprehensive overview about ROS-1 rearrangements in NSCLCs, including the mechanistic basis for oncogenicity, detection methods as well as the pharmacotherapeutic options and resistance mechanisms. The text is logically organized and the tables are useful. The review can be a valuable both as an overview about this specialized, rapidly developing field of research and also as a resource to identify specific references for original results.
Apart from minor language problems (see below), I want to raise one objection. The content and the structure of the present review is very similar to a recent paper by D'Angelo et al. [2020) Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies. Cancers (Basel). 12:3293]. It is inconceivable that the authors have not been aware of this paper, which even contains the same tables that list the main ROS1 fusion partners in non-small cell lung cancer (NSCLC) (table 1), the clinical trials (Table 2) and the resistance mutations (Table 3). Essentially, the authors have rewritten and substantially updated this review by including many new results but do not even cite the predecessor by D’Angelo et al (as well as another topical review by Guaitoliet al [2021, Deepening the Knowledge of ROS1 Rearrangements in Non-Small Cell Lung Cancer: Diagnosis, Treatment, Resistance and Concomitant Alterations. Int J Mol Sci. 22:12867). The present review is justified by the rapid progress in the field, but the authors must make clear in an introductory paragraph that their paper is an update of those previous review.
Minor point:
Overall well written and easy to read but nevertheless contains considerable number of language problems, including misleading wording and unclear formulations. Here are some examples:
Abstract:
“ROS-1 rearrangement is found in 0.9–2.6% of non-small–cell lung cancers (NSCLCs), mostly lung adenocarcinomas, in young, never-smoker women.”
This statement is misleading: There are significantly higher rates of ROS1 fusion gene in NSCLCs from female patients, non-smokers, and patients tend to be younger, but patients with ROS-1 rearrangements are not mostly (meaning at least > 50%) “young, never smoker women”.
“...resistance mechanisms appearing under crizotinib that have better brain penetration.” syntax/grammar error: relative pronouns refer to the preceding word (same error in line 39)
“ Lung cancer represents the primary cause of mortality worldwide” (line 32) I find lung cancer at 6th rank among the top ten causes of death in the WHO list (Ref. 1] but rather “Ischaemic heart disease” on the top of the list.
“In another study, Zeng et al. [43] found 154 that patients whose NSCLCs had an exclusive ROS-1 fusion lived longer without progression that those whose tumors carried a ROS-1 fusion with co-mutations” (line 156)
typo (than -> that)
“For metastatic squamous-cell tumors, ROS-1 status can be determined for never-smokers [44].” (Line 162)
strange wording, of course the status “can be determined”. What is the meaning?
“Retrospective [66,67] then prospective phase II [68–71] study results confirmed 225 crizotinib efficacy in this population (Table 2).” (line 225) I do not understand the word “then”, are there missing words?
Author Response
Please see the attachement.
Author Response File: 
Author Response.docx
Reviewer 2 Report
These authors presented a nice review about ROS-1 positive NSCLC, discussing available targeted therapies.
In my opinion, this review is well-written and logically structured. Tables recapitulating clinical trials and oncogenic co-mutations in ROS-1 positive NSCLC patients are considerable.
I have only some small suggestions:
1) Line 122, paragraph 4.2: I suggest to entitle it "Oncogenic co-mutations"
2) Line 133: the word "that" is repeated twice.
3) Line 272: the authors can evaluate to substitute "an TKI" for "a TKI", since they are using an acronym.
Author Response
Please see the attachement.
Author Response File: Author Response.docx
