Complete pathological and serological response to immunotherapy in a patient with MMR-deficient early rectal cancer.

Randomized trials have demonstrated the importance of preoperative radiotherapy or chemoradiotherapy in reducing local recurrence rate in patients with high-risk rectal cancer.1Roeder F. Meldolesi E. Gerum S. Valentini V. Rödel C. Recent advances in (chemo-) radiation therapy for rectal cancer: a comprehensive review.Radiat Oncol. 2020; 15: 262Crossref PubMed Scopus (11) Google Scholar However, there is a paucity of data and contradictory results in rectal cancer patients presenting with mismatch repair deficiency (dMMR). In addition, organ preservation is currently a growing demand from many patient groups.2Fernandez L.M. São Julião G.P. Figueiredo N.L. et al.Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study.Lancet Oncol. 2021; 22: 43-50Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar In the NICHE trial, neoadjuvant immunotherapy with nivolumab plus ipilimumab showed remarkable efficacy in 20 patients with resectable colon cancer, particularly in those with dMMR.3Chalabi M. Fanchi L.F. Dijkstra K. et al.Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.Nat Med. 2020; 26: 566-576Crossref PubMed Scopus (290) Google Scholar A pathological complete response was found in 12 patients (60%) and a major pathological response in 19 (95%) patients. Only few cases of immunotherapy in early dMMR rectal cancer have been reported.4Demisse R. Damle N. Kim E. et al.Neoadjuvant immunotherapy-based systemic treatment in MMR-deficient or MSI-high rectal cancer: case series.J Natl Compr Canc Netw. 2020; 18: 798-804Crossref PubMed Scopus (14) Google Scholar We report a case of early dMMR rectal cancer with a remarkable response to immunotherapy. A 39-year-old man presented with a 4-cm long, non-obstructing tumour, 4 cm from the anal verge. The tumour was clinical stage T3dN1M0 with a threatened mesorectal fascia. The pathological examination identified an adenocarcinoma with normal expression of MLH1 and PMS2, but loss of MSH2 and MSH6. Standard long-course chemoradiotherapy followed by total mesorectal excision was planned and permanent colostomy was foreseen. Inspired by the NICHE trial, the patient received immunotherapy preoperatively. Four weeks after the primary biopsy, the patient received ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg), and 2 weeks later nivolumab (3 mg/kg) monotherapy.3Chalabi M. Fanchi L.F. Dijkstra K. et al.Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.Nat Med. 2020; 26: 566-576Crossref PubMed Scopus (290) Google Scholar The patient received no further therapy. Within 2 weeks, bleeding stopped and bowel habits normalized. The clinical examination and radiological investigations showed complete response, and a biopsy showed no malignancy. We still recommended resection, but based on the excellent response, the patient asked for a watch-and-wait strategy. At diagnosis, the patient was included in the ongoing Danish IMPROVE trial (NCT03637686) evaluating circulating tumor DNA (ctDNA) to optimize treatment in early-stage colorectal cancer (CRC). Blood samples collected before therapy, at 6 weeks and at 4 months after the treatment ended, were analyzed for presence of ctDNA using the validated, quantitative DNA methylation test, TriMeth.5Jensen S.Ø. Øgaard N. Nielsen H.J. Bramsen J.B. Andersen C.L. Enhanced performance of DNA methylation markers by simultaneous measurement of sense and antisense DNA strands after cytosine conversion.Clin Chem. 2020; 66: 925-933Crossref PubMed Scopus (6) Google Scholar ctDNA was bisulfite converted, and three CRC-specific methylation markers, namely, KCNQ5, C9orf50 and CLIP4, were quantified using a multiplex droplet digital PCR. Samples were defined as ctDNA positive if at least two of these markers were detected. In our patient, only the pretherapy sample was ctDNA positive (mean 1.3 copies/ml plasma). Thus the patient also showed complete molecular response. We continue a watch-and-wait strategy, which includes ctDNA analyses. Patients with early-stage dMMR CRC have a better prognosis than patients with proficient MMR and derive less benefit from adjuvant monotherapy with 5-fluorouracil. The proportion of patients with dMMR is higher among right-sided than left-sided CRC. Moreover, the proportion decreases with increasing stage; while ∼20% of stage 2 tumours are dMMR, this only applies to 5% of metastatic CRC. In patients with dMMR metastatic CRC, immune checkpoint inhibition (ICI) has become the standard of care. In early-stage dMMR CRC, early studies with ICI have shown excellent results and we believe that precision medicine must be taken into account at the individual level. In summary, we report a patient with locally advanced, nonmetastatic dMMR rectal cancer, in whom one cycle of ICI resulted in clinical, pathological and molecular complete response at 6 weeks and 4 months. The Danish CancerBiobank is acknowledged for biological material and for data regarding handling and storage. This work was supported by The Danish Cancer Society [grant numbers R231-A13845 , R257-A14700 ], The NEYE foundation and The Novo Nordisk Foundation [grant number NNF17OC0025052 ].