Neoadjuvant immunotherapy in a locally advanced colon cancer patient with MSI-H and suspected Lynch syndrome: A case report

Abstract

Carrilizumab, a PD-1 inhibitor, has shown therapeutic effectiveness in patients with late-stage or metastatic solid tumors exhibiting DNA mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). dMMR/MSI-H cancer patients are known to be responsive to PD-1 inhibitors. However, the use of carrilizumab for preoperative immunotherapy in early, unresectable MSI-H/dMMR primary colon cancer lesions is relatively underexplored. We present the case of a 46-year-old male who sought medical attention at our institution due to a history of hematochezia for two weeks, right-sided abdominal pain for one week, and loose stools. Imaging indicated duodenal involvement, and a biopsy confirmed ascending colon adenocarcinoma with MSI-H status. Given that the patient’s family exhibited a history of more than three confirmed cases of colorectal cancer spanning two generations, Lynch syndrome was considered. After four cycles of PD-1 antagonist immunotherapy with carrilizumab, the patient’s symptoms resolved, and physical examination revealed no abdominal tenderness or palpable masses. Following radical colectomy, the primary tumor exhibited a pathological complete response. This case highlights the potential of preoperative neoadjuvant immunotherapy to improve staging accuracy and increase surgical resection rates in T4b MSI-H colon cancer patients without distant metastasis, suggesting a need for reconsideration of the treatment approach.

Zusammenfassung

Carrilizumab, ein PD-1-Inhibitor, hat sich bei Patienten mit soliden Tumoren im Spätstadium oder mit Metastasen, die einen Mangel an DNA-Mismatch-Reparatur (dMMR) oder eine hohe Mikrosatelliteninstabilität (MSI-H) aufweisen, als therapeutisch wirksam erwiesen. dMMR/MSI-H-Krebspatienten sprechen bekanntermaßen gut auf PD-1-Inhibitoren an. Der Einsatz von Carrilizumab zur präoperativen Immuntherapie bei frühen, inoperablen MSI-H/dMMR-Kolonkarzinom-Primärläsionen ist jedoch noch relativ wenig erforscht. Wir stellen den Fall eines 46-jährigen Mannes vor, der sich wegen einer zweiwöchigen Hämatochezie, einwöchigen rechtsseitigen Bauchschmerzen und eines lockeren Stuhlgangs in unserer Einrichtung vorstellte. Die Bildgebung wies auf eine Beteiligung des Zwölffingerdarms hin, und eine Biopsie bestätigte ein Adenokarzinom des aufsteigenden Dickdarms mit MSI-H-Status. Da in der Familie des Patienten über zwei Generationen hinweg mehr als drei bestätigte Fälle von Darmkrebs aufgetreten waren, wurde das Lynch-Syndrom in Betracht gezogen. Nach vier Zyklen einer PD-1-Antagonisten-Immuntherapie mit Carrilizumab klangen die Symptome des Patienten ab, und bei der körperlichen Untersuchung wurden keine abdominalen Schmerzen oder tastbare Massen festgestellt. Nach der radikalen Kolektomie zeigte der Primärtumor ein pathologisch vollständiges Ansprechen. Dieser Fall unterstreicht das Potenzial der präoperativen neoadjuvanten Immuntherapie zur Verbesserung der Staging-Genauigkeit und zur Erhöhung der chirurgischen Resektionsraten bei T4b MSI-H-Darmkrebspatienten ohne Fernmetastasen, was auf die Notwendigkeit eines Überdenkens des Behandlungsansatzes hinweist.

Keywords

Colon cancer - Neoadjuvant therapy - Immunotherapy - Microsatellite Instability-High - Deficient mismatch repair - case report

Schlüsselwörter

Darmkrebs - Neoadjuvante Therapie - Immuntherapie - Mikrosatelliteninstabilität - mangelhafte Fehlanpassungsreparatur - Fallbericht

Publication History

Received: 05 December 2023

Article published online:
11 April 2024

• References

• 1 Siegel RL, Miller KD, Fuchs HE. et al. Cancer Statistics, 2021. CA Cancer J Clin 2021; 71 (01) 7-33 DOI: 10.3322/caac.21654. (PMID: 33433946)
• 2 Feng RM, Zong YN, Cao SM. et al. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics?. Cancer Commun (Lond) 2019; 39 (01) 22 DOI: 10.1186/s40880-019-0368-6. (PMID: 31030667)
• 3 Zlobec I, Kovac M, Erzberger P. et al. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 2010; 127 (11) 2569-2575 DOI: 10.1002/ijc.25265. (PMID: 20162668)
• 4 Yoshino T, Arnold D, Taniguchi H. et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Annals of Oncology 2018; 29 (01) 44-70
• 5 Latham A, Srinivasan P, Kemel Y. et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol 2019; 37 (04) 286
• 6 Arnold CN, Goel A, Compton C. et al. Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer. Cancer Biol Ther 2004; 3 (01) 73-78 DOI: 10.4161/cbt.3.1.590. (PMID: 14726676)
• 7 Goel A, Boland CR. Epigenetics of colorectal cancer. Gastroenterology 2012; 143 (06) 1442-1460 e1 DOI: 10.1053/j.gastro.2012.09.032. (PMID: 23000599)
• 8 Tan E, Sahin IH. Defining the current role of immune checkpoint inhibitors in the treatment of mismatch repair-deficient/microsatellite stability-high colorectal cancer and shedding light on future approaches. Expert Rev Gastroenterol Hepatol 2021; 15 (07) 735-742 DOI: 10.1080/17474124.2021.1886077. (PMID: 33539189)
• 9 Yi M, Zheng X, Niu M. et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer 2022; 21 (01) 28
• 10 Chen J, Quan M, Chen Z. et al. Camrelizumab in advanced or metastatic solid tumour patients with DNA mismatch repair deficient or microsatellite instability high: an open-label prospective pivotal trial. J Cancer Res Clin Oncol 2020; 146 (10) 2651-2657 DOI: 10.1200/JCO.19.02105. (PMID: 31682550)
• 11 Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. The Lancet 2012; 13 (11) 1152-1160 DOI: 10.1016/S1470-2045(12)70348-0. (PMID: 23017669)
• 12 André T, Shiu KK, Kim TW. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020; 383 (23) 2207-2218 DOI: 10.1056/NEJMoa2017699. (PMID: 33264544)
• 13 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18 (09) 1182-1191 DOI: 10.1016/S1470-2045(17)30422-9. (PMID: 28734759)
• 14 Marabelle A, Le DT, Ascierto PA. et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 2020; 38 (01) 1
• 15 Le DT, Uram JN, Wang H. et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372 (26) 2509-2520
• 16 Le DT, Durham JN, Smith KN. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357: 409-413 DOI: 10.1126/science.aan6733. (PMID: 28596308)
• 17 Powles T, Kockx M, Rodriguez-Vida A. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25 (11) 1706-1714 DOI: 10.1038/s41591-019-0628-7. (PMID: 31686036)
• 18 Huang AC, Orlowski RJ, Xu X. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med 2019; 25 (03) 454-461 DOI: 10.1038/s41591-019-0357-y. (PMID: 30804515)
• 19 Forde PM, Chaft JE, Smith KN. et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018; 378 (21) 1976-1986 DOI: 10.1056/NEJMoa1716078. (PMID: 29658848)
• 20 Blank CU, Rozeman EA, Fanchi LF. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018; 24 (11) 1655-1661 DOI: 10.1038/s41591-018-0198-0. (PMID: 30297911)
• 21 Amaria RN, Reddy SM, Tawbi HA. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018; 24 (11) 1649-1654 DOI: 10.1038/s41591-018-0197-1. (PMID: 30297909)
• 22 Trojan J, Stintzing S, Haase O. et al. Complete Pathological Response After Neoadjuvant Short-Course Immunotherapy with Ipilimumab and Nivolumab in Locally Advanced MSI-H/dMMR Rectal Cancer. Oncologist 2021; 26 (12) e2110-e2114
• 23 Gim G, Kim Y, Park Y. et al. Response to Nivolumab and Ipilimumab in Microsatellite Instability-High (MSI-H) Cervical Carcinoma with Acquired Resistance to Pembrolizumab: A Case Report and Literature Review. Oncologist 2022; 27 (07) 525-531
• 24 Yang J, Bi F, Gou H. Complete Pathologic Response After Concurrent Treatment with Pembrolizumab and Radiotherapy in Metastatic Colorectal Cancer: A Case Report. Onco Targets Ther 2021; 14: 2555-2561
• 25 Robert C. Is earlier better for melanoma checkpoint blockade?. Nat Med 2018; 24 (11) 1645-1648 DOI: 10.1038/s41591-018-0250-0. (PMID: 30401867)