Reviewer’s report
Title: 
Prediction of distant metastatic recurrence by tumor-infiltrating lymphocytes in hormone receptor-
positive breast cancer
Version: 
0 
Date: 
03 Jan 2021
Reviewer's report:
This paper from Takada et al is an interesting paper which needs some revisions, starting with the language
that needs to be improved.
Then there are some inconsistencies 
Background: 
line 65: what does it mean "local"? 
line 67: the sentence is not clear.
In this Reviewer's opinion, it is not clear which is the endpoint of the study: more exactly, which is the site
of metastases the Authors are referring to. Lymph node metastases or distant metastases? And amongst
distant metastases, would they predict the sites?
Then, in this session, the Authors should argument why they think that TILs density could be correlated to
site of recurrences.
Methods: the Authors state that diagnosis was made on bioptic material (CNB/VAB) as well as the
histological subtyping of the disease. Does it mean that even the biological characteristics
(ER/PgR/Ki67/HER2) were assessed only on the biopsies? Authors should explain this issue in detail, as
well was, they should explain if there was complete correspondence in all bioptic cases matched with their
surgical specimens.
Why the Authors have used the 14 ref to divide the patients into high and low Ki67 rate, when Cheang et
al referred to luminal B breast cancer? 
Moreover, the Authors are encouraged to indicate which edition of TNM has been used. In table 1
micrometastatic diseases are staged as "pT1mic", which is not currently the correct way to stage those
diseases.
Finally, there are no piece of information about the way the Authors have collected the data. This reviewer
means if the histological slides have been diagnosed by one of more pathologists or if the Authors have
simply extracted the data from the reports.
Results: it is declared that the cohort of patients enrolled int the study excluded patients treated with
chemotherapy; nevertheless, there were some patients who had axillary clearance because of metastatic
disease in the sentinel lymph node. It is not clear why these pattens with axillary dissection and further
metastases were not treated with chemotherapy. It could depend on the age, but the Authors should clarify.
How did the Authors differentiate the venous from lymphatic tumoral invasion? How the Authors explain
this high percentage (50%) of vascular invasion with the low rate of metastatic disease?
lines 146-149: it is not clear the distribution of the recurrences. Please, the Authors should rephrase the
sentence.
It is not understandable for this Reviewer why the Authors have used a nuclear grade. Please, Authors
explain this issue. 
Discussion: the Authors claim that operative procedures are predictive or recurrences, but do not explain
the reasons (lines 195-6).
In this Reviewer's opinion, the item regarding the molecular characterization of tumor cells is not
pertinently introduced at this point without any hints in the previous sections.
Finally, Authors claimed and claim that "…TILs may also be involved in lymph node metastasis…" in
Luminal cancer. Nevertheless, the results indicate that they correlate with venous invasion (p=0.007)
which is already related to metastatic diseases.
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Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
2
Are the methods sufficiently described to allow the study to be repeated?
1
Is the use of statistics and treatment of uncertainties appropriate?
1
Is the presentation of the work clear?
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Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
1