Total neoadjuvant therapy involving checkpoint inhibitors in locally advanced MSI/dMMR rectal cancer – a case report

Czech version

Authors: S. Křivonosková ¹; A. Opluštilová ¹; M. Levý ²; M. Komár ³; B. Rosová ⁴; R. Lohynská ¹; L. Boublíková ¹
Authors‘ workplace: Onkologická klinika 1. LF UK a FTN Praha ¹; Chirurgická klinika 1. LF UK a FTN Praha ²; Radiodia gnostické oddělení, FTN Praha ³; Ústav patologie a molekulární medicíny 3. LF UK a FTN Praha ⁴
Published in: Klin Onkol 2024; 38(5): 370-374
Category: Case Reports
doi: https://doi.org/10.48095/ccko2024370

Overview

Background: Typically, the management of locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy, followed by surgery and adjuvant chemotherapy. In addition to neoadjuvant chemoradiotherapy, total neoadjuvant therapy (TNT) involving radiotherapy and combined chemotherapy has been increasingly used and shown to reduce the risk of distant metastasis and improve local control. Patients with microsatellite instability and deficient mismatch repair (MSI/dMMR) tumors represent a specific group that benefits from different approaches if TNT is considered. Case: Our case report describes the diagnosis and treatment of a patient with locally advanced rectal cancer indicated for clinical characteristics to predictive molecular testing. Microsatellite instability was confirmed. Based on this finding, after short-course radiotherapy, she was offered neoadjuvant immunotherapy with checkpoint inhibitors. She subsequently underwent surgery with a confirmed pathologic complete response. The treatment was well-tolerated and she stays in complete remission, with a follow-up according to the standard recommendations. Conclusion: This case highlights the importance of molecular testing in rectal cancer, which should be performed in all advanced cases requiring more intensive oncologic therapy than surgery alone. MSI/dMMR status indicates the need for a specific approach that may significantly improve the outcomes of these patients.

Keywords:

rectal cancer – immunotherapy – checkpoint inhibitors – total neoadjuvant therapy – microsatellite instability (MSI) – deficient mismatch repair (dMMR)

Sources

1. Liu S, Jiang T, Xiao L et al. Total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. Oncologist 2021; 26 (9): e1555–e1566. doi: 10.1002/onco.13824

2. Glynne-Jones R, Wyrwicz L, Tiret E et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl_4): iv22–iv40. doi: 10.1093/annonc/mdx224. (Published correction appears in Ann Oncol 2018; 29 (Suppl 4): iv263).

3. Bahadoer RR, Dijkstra EA, van Etten B et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (2): e42. doi: 10.1016/S1470-2045 (20) 30781-6.

4. Conroy T, Bosset JF, Etienne PL et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (5): 702–715. doi: 10.1016/S1470-2045 (21) 00079-6.

5. Eikenboom EL, van der Werf-’t Lam AS, Rodriguez--Girondo M et al. Universal immunohistochemistry for Lynch syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas. Clin Gastroenterol Hepatol 2021; 20 (3): e496-e507. doi: 10.1016/j.cgh.2021. 04.021.

6. Cohen R, Taieb J, Fiskum J et al. Microsatellite instability in patients with stage III colon cancer receiving fluoropyrimidine with or without oxaliplatin: an ACCENT pooled analysis of 12 adjuvant trials. J Clin Oncol 2021; 39 (6): 642–651. doi: 10.1200/JCO.20.01600.

7. Sinicrope FA, Mahoney MR, Smyrk TC et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013; 31 (29): 3664–3672. doi: 10.1200/JCO.2013.48.9591.

8. André T, de Gramont A, Vernerey D et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol 2015; 33 (35): 4176–4187. doi: 10.1200/JCO.2015.63.4238.

9. Chun P, Wainberg ZA. adjuvant chemotherapy for stage II colon cancer: the role of molecular markers in choosing therapy. Gastrointest Cancer Res 2009; 3 (5): 191–196.

10. Zhoubný novotvar kolorekta (C18-20). Modrá kniha České onkologické společnosti. Brno: Masarykův onkologický ústav 2023.

11. National Comprehensive Cancer Network (NCCN). NCCN Guidelines: rectal cancer. Version 6.2023. [online]. Available from: https: //www.nccn.org/guidelines/guidelines-detail?category=1&id=1461.

12. Chalabi M, Verschoor YL, van den Berg J et al. LBA7 neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study. Ann Oncol 2022; 33 (Suppl 7): S808–S869. doi: 10.1016/j.annonc.2022.08.016.

13. Cercek A, Lumish M, Sinopoli J et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022; 386 (25): 2363–2376. doi: 10.1056/ NEJMoa2201445.

14. Lohynská R, Pechačová Z, Mazaná E et al. Radioterapie a radiosenzitivní syndromy u mutací genů reparace DNA. Klin Onkol 2022; 35 (2): 119–127. doi: 10.48095/ccko 2022119.

15. Verschoor, Y. Neoadjuvant nivolumab/relatlimab demonstrates 100% pathological response in MMRd colon cancer. [online]. Available from: https: //conferences.medicom-publishers.com/specialisation/oncology/esmo-2023/neoadjuvant-nivolumab-relatlimab-demonstrates-100-pathological-response-in-mmrd-colon- cancer/.

16. Veen T, Kanani A, Lea D et al. Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer. Cancer Immunol Immunother 2023; 72 (10): 3135–3147. doi: 10.1007/s00262-023-03480-w.

17. Sokop T, Obermannová R. Efekt imunoterapie u mladého pacienta s mismatch repair deficientním karcinomem rekta – kazuistika. Klin Onkol 2023; 36 (3): 241–245. doi: 10.48095/ccko2023241.