Title: Molecular-Based Classification of Endometrial Carcinoma in Northern Thailand: Impact
on Prognosis and Potential for Implementation in Resource-Limited Settings
Version: 0 Date: 19 Aug 2023
Reviewer's report:
The authors studied the performance of molecular classification of endometrial carcinoma in
a Northern Thailand population and assessed the feasibility of implementing this classification
in resource-limited setting. The design of the study is reasonable; The conclusion is logical
and relevant in the setting that molecular classification is becoming standard care of gyneco-
oncologic practice while its accessibility  still varies from region to region.
Some points to be addressed:
1. I would suggest that the authors compare other methodology of POLE testing. The study
used Sanger sequencing to detect 5 hot spot "classic" POLE mutations. Additional pathogenic
POLE mutations have been reported in the literature, and other testing method have been used
or proposed in the literature.  Some techniques might be more expensive but they will lead to
detecting more mutations, and some are proposed to be less expensive alternatives for POLE
testing.  It might be of interest to compare these different methods in terms of cost-effectiveness.
PMID: 31829442
DOI: 10.1016/j.ygyno.2023.05.073
DOI: 10.1200/GO.22.00384
2. I recommend that the  authors provide details of cost-effectiveness assessment.  The authors
reported that while molecular classification resulted in 10% increase of cost, if "only POLE
testing was used", the cost would only increase by 1%.  The author did not provide details
of how the cost was reduced by " only POLE testing was used". Presumably the reduction
of cost reduction was by 1) saving money by not doing  IHCs studies for P53 or MMR
proteins; 2) consequently under-detection of  P53 mutated tumors, therefore "saving"  money for
chemotherapy.3) under-detection of MMR-deficiency, therefore "saving" money for genetics
counselling, etc.   Because of  these potential consequences, it might not be a good argument
for feasibility of molecular testing... unless the authors can provide details of cost effectiveness
assessment and provide proof that " doing POLE only" provided equal or similar patient care
results.
3. I suggest that the authors seek further follow up information. The follow up period shows a
wide range ( 1 to 95 months).  Given that the cases are from 2015 to 2017,  one would expect
longer follow up in most of the cases.  If information is not available despite efforts, the authors
probably should consider exclude cases with very short follow up period ( such as, 1 month).
4. Line 169:  Where is Table 3?  The text mentioned  Table 3.... but  there is no Table 3 found
in the manuscript.
Some minor points in the manuscripts:
Line 9:  TCGA  categories are:  POLE ultramutated, microsatellite instability hypermutated,
copy number low, and copy number high.
Line 30:   Some exclusion criteria could be better defined... Such as,  explanation on how the
study distinguish cervical cancer v.s. endometrial cancer with cervical involvement.
Line  195:  Whether to do  IHC studies  for P53 on all endometrial carcinoma is an issue of
debate.  While some authors do not recommend doing it on low grade endometrial carcinomas, it
has been reported that occasionally P53 mutation can be seen in low grade tumor. It is becoming
common practice to do IHC studies for P53 on all endometrial carcinomas,  particularly in the
setting of providing molecular classification.