Reviewer’ s report
Title: Association between levels of tumor-infiltrating lymphocytes in different subtypes of
primary breast tumors and prognostic outcomes: A meta-analysis
Version: 0Date: 01 Feb 2020
Reviewer: Roberto Salgado
Reviewer's report:
The authors have performed a meta-analysis assembling TILs-studies that have been
prognostically assessed in different breast cancer subtypes. Methodologically the paper is welldesigned and the interpretation of the data is correct. They do provide new information of interestto the community, notably in the HER+/ER+ vs HER2-/ER+ space. Therefore, this reviewersupports publication of these results, but only if the following items are taken into consideration:1. A thorough review of grammatical English by preferably a native English speaker is advised.For example, page 2 bottom line "...tumor subtype was inert to improve…" or page 3, 2ndparagraph "These benefits in Luminal tumor subtype need to be warranted." I know what theauthors mean but this is not appropriate English.2. The term lymphocyte-predominant breast cancer is not used anymore. I would suggest to do ananalysis, and assess which cut-off predicts the best benefit to patients in the adjuvant setting.Based on a pooled analysis of 9 phase 3 trials (Loi et al., JCO 2019), the appropriate cut-offidentified in TNBC was 30% in the adjuvant setting. Can the authors confirm this in their meta-analysis? Are the cut-offs different in the different subtypes?4. It is not clear form their article whether the association between high TILs and pCR translatedinto a global survival gain based on their meta-analysis. It would be good to describe in separate
tables the TIL-pCR-OS analysis, and in a separate table the TILs-OS analysis in the adjuvant
setting, and this for the different subtypes.5. The authors need to avoid systematically using just the word "luminal" while is not always clearwhich luminal-subtype they mean, ER+/HER2+ or always ER+/HER2-.6. It would be interesting, if the authors have the data, to analyse the prognostic impact in Asian vsnon-Asian patients. There's emerging evidence that there are differences between both.7. Page 11: the reasoning on why ER+ behave prognostically inversely with TILs is debated. Theinterpretation of the authors is largely speculative and sometimes wrong and is best removed. Forexample: the sentence "line 239...with a low mutation burden of TILs, which can worsen thetumor response to AI" is wrong and the reference associated with is doesn't make that claim either.Figure 6 should therefore also be removed as this doesn't add anything to the overall conclusion ofthe paper.8. Can the authors focus on evaluating whether features of clinicall high-risk ER+ patients, forexample those with grade 3, BRCA+, high proliferation-index, etc... do have higher TILstranslating this into a higher survival? According to emerging evidence this is probbaly the case,and the authors may have the data to suppor this emerging evidence.
Minor items:
1. In the title I would suggest to replace the word "the elevation" by "levels".
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
YesDoes the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
NoAre the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
YesAre you able to assess any statistics in the manuscript or would you recommend an
additional statistical review?If an additional statistical review is recommended, please specify what aspects require furtherassessment in your comments to the editors.
I am able to assess the statisticsQuality of written English
Please indicate the quality of language in the manuscript:
Not suitable for publication unless extensively edited
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