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Colorectal Cancer | 19-20 May 2023 | Valencia, Spain

Managing locally advanced dMMR colon cancer

with neoadjuvant immunotherapy
Dr. Ishan Mehta
Specialty Trainee in Medical Oncology - Addenbrooke’s Hospital
Clinical Research Fellow – Experimental Cancer Genetics, Wellcome Sanger Institute
Cambridge, United Kingdom

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 Disclosures

None to declare.

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 Case Details

Background:
 36-year-old lady
 Cystic Fibrosis (CF) - no hospital admissions in last 5 years.
 Very fit and active, working as a sports teacher.
 Presented in March 2019.

History of Presenting Complaint:

 Several month history of weight loss and night sweats.
 More recently severe right-sided abdominal pain.

Family History:
 Mother diagnosed with endometrial cancer (aged 42)
 Maternal uncle diagnosed with colon cancer (aged 55) + Lynch Syndrome (MSH2 mutation).

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 Initial Investigations and Management
 CT A/P - Large mass replacing the ascending colon and hepatic flexure, direct hepatic invasion,
abutting right kidney and duodenum.

 MRI Liver - No parenchymal mets. 15mm node at the liver hilum

 Lower GI Endoscopy – Large ascending colon tumour. Biopsies taken.

 Upper GI Endoscopy / EUS – tumour involves muscularis propria of duodenum.

 Completion CT Chest / CT PET - Final radiological staging T4N1M0.

 Diagnostic laparoscopy and defunctioning ileostomy. Large immobile mass adherent to inferior
edge of the liver.

Histology:
 Fragments of large bowel infiltrated by moderately differentiated adenocarcinoma.

 MMR Immunohistochemistry:
– Negative for MSH2
– Positive for MLH1 dMMR and
– Negative for MSH6 suggestive of
– Positive for PMS2 Lynch Syndrome

 KRAS p.(Gly12Asp) and PIK3CA p.(Glu345Lys) mutation detected.

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 Neoadjuvant therapy

Borderline resectable (unlikely to achieve R0 resection upfront)

Ideally neoadjuvant therapy  surgery (improve chance of an R0 resection)

Compassionate access to combination ipilimumab 1 mg/kg and nivolumab 3 mg/kg:

1. Concern of chemotherapy-related immunosuppression in context of known CF.

2. Poor response to neoadjuvant chemotherapy in dMMR (FOxTROT)

– ASCO May 2019
– 106 dMMR tumours
– 95% had no / minimal response

3. Excellent response to neoadjuvant ipi / nivo in dMMR (initial results from NICHE trial)
– ESMO Oct 2018
– 7 dMMR tumours
– 100% had major pathological response (< 10% viable tumour remaining), 57% had complete response

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 Treatment Timeline
23/05/19:
Cycle 1 Day 1 Ipilimumab / Nivolumab

6/06/19:
Cycle 1 Day 15 Nivolumab
Omitted due to grade 3 fatigue and acute albumin drop (22  14)

05/07/19:
22/03/19: Cycle 2 Day 1 Ipilimumab / Nivolumab
Emergency
defunctioning ileostomy 19/07/19:
Cycle 2 Day 15 Nivolumab

Mar Apr May Jun Jul Aug Sep

24/09/19:
Surgery

13/08/19:
Response CT and MRI: Reduction in size of
tumour (measuring 66 x 68 mm, previously 76 x
92 mm). PET shows no other sites of disease.

25/06/19:
Response CT - stable with
no evidence of metastatic disease.
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 Surgery and Histology

Findings: Tumour involving under surface of liver, gallbladder and

duodenum. Extensive porta hepatis and para-aortic nodal disease.

 Total colectomy with end ileostomy

 En-bloc pancreaticoduodenectomy
 Aortocaval lymph node dissection
 Partial right non-anatomical liver resection
 Cholecystectomy and abdominal wall resection https://www.pancreaticcancer.org.uk/

 End-to-end gastroenterostomy & end-to-side hepaticojejunostomy

Histology:
Infiltrating into adhered liver tissue
No lymphovascular or perineural invasion
ALL NODES NEGATIVE FOR MALIGNANCY (0/80)
Tumour regression grade: PARTIAL RESPONSE (> 50% viable tumour remaining)
TNM 8 Stage: ypT4b N0 V0 L0 Pn0 R0

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 Summary

Patient follow-up:
 Recovered well from surgery (Sep 2019) with no immediate or delayed complications.
 Reversal of end ileostomy (Jun 2021)
 Last CT / MRI staging shows no evidence of recurrence (Mar 2023)

 Will neoadjuvant immunotherapy become standard of care for all early

dMMR or only in borderline operable cases?

In this case, partial response (>50% viable tumour remaining)

 Is there a difference in biology between Lynch dMMR and sporadic dMMR
tumours?

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