Double Duty: Complete Pathologic Response of Two Colonic Primaries with Mosaicism of a Novel MLH1 Mutation to Neoadjuvant Pembrolizumab

Round 1

Reviewer 1 Report

This is an interesting case report. Overall, well-written. Please note the following-

1. The tumor marker is CA 19-9. Please add serial CEA values, if available.

2. Case description- ‘The patient underwent colonoscopy, which revealed an obvious, nearly obstructing sigmoid mass at the 25 cm mark, which substantiated the presence of dual primaries, ..’ This is inconsistent since the scope could not be advanced past the obstructive sigmoid lesion.

3. Discussion- Reference 3 is irrelevant as this study was on pMMR patients.

4. Reference 4- not a Chinese study- it was from the Netherlands.

5. References 5 and 7- please add the published manuscripts- both manuscripts have been published. Please update the data.

6. Reference 7- Please mention that this study was on localized dMMR rectal cancer patients.

7. Conclusion- a lot of repetitions- should be shortened. The conclusion should include ‘neoadjuvant immunotherapy should be investigated for organ-preservation in patients with dMMR localized CRC’.

8. Please clarify if the patient achieved radiologic CR on pembrolizumab. Based on the fig1, it seems the patient had radiologic CR.

9. Figure 1- please use arrows to show the relevant findings.

10. In the discussion, the authors should add NICHE-2 data.

 

11. Line 161 in discussion- please delete ‘all 20 had pathological responses’.

English is fine.

Author Response

• CEA values for this patient remained low throughout disease course and were not recorded or followed.
• We have omitted the phrasing regarding dual primaries.
• We have adjusted the references as indicated.
• I apologise that I am unsure what is meant by "add the published manuscript". Is this a DOI?
• We have tried to adjust the manuscript and word count in accordance with all of the reviewers' comments.
• Phrasing of radiographic findings adjusted
• Deletions/phrasing altered in accordance with reviewer request
• I apologise that I am unable to find final published data for the NICHE-2 trial.

Reviewer 2 Report

This is an interesting report showing that ICB therapy in a neoadjuvant setting could contribute to the cure of CRC harboring a novel MLH1 mutations. The case is well written and discussion is appropriate. There is only one minor comment:

1 Since the authors have performed NGS of tumor tissues, please report the mutation load (e.g. TMB) to show that it is consistent with a MSI-H/MMR phenotype, and compare it to the literature.  

Only minor revision is required. 

Author Response

We do not record TMB routinely outside of trials for patients at our centre with colorectal cancer. 

Reviewer 3 Report

The authors present a case of a 57-year-old male colon cancer patient with dual, synchronous novel mutations in MLH1 (including MLH1:c.1288G>T, p.(Glu430*)), where a complete pathological response was obtained at the time of surgery by neoadjuvant pembrolizumab treatment. Initially, the tumor was deemed unresectable due to abdominal wall invasion. Notwithstanding, the patient experienced a substantial tumor response on pembrolizumab, which allowed for consideration of surgery. Pathology demonstrated a complete pathological response at both tumor sites. Extensive genetic testing revealed a likely post-zygotic mosaicism event associated with a Lynch/HNPCC-like cancer phenotype in this patient.

Strengths:

While case reports lack statistical comparison, this study provides important individual clinical insights that are missed in clinical trials.

Limitations:

Perhaps pre-treatment and pre-surgery CT Scans in Figure 1 would be more educational for the average reader with arrows (or circles) pinpointing the changes.

 

 

Author Response

Figures have been adjusted

Round 2

Reviewer 1 Report

I agree with the revisions.

Reviewer 2 Report

Can be accepted in present form.