Different responses to anti‑programmed cell death protein 1 (PD‑1) immunotherapy in a patient with Lynch syndrome and metachronous urothelial and colon cancer: A case report

Feng,Yu; Cao,Yufeng; Yuan,Mingming; Chen,Rongrong; Ji,Xue; Hu,Xingsheng

doi:10.3892/ol.2019.10909

Different responses to anti‑programmed cell death protein 1 (PD‑1) immunotherapy in a patient with Lynch syndrome and metachronous urothelial and colon cancer: A case report

Authors:
- Yu Feng
- Yufeng Cao
- Mingming Yuan
- Rongrong Chen
- Xue Ji
- Xingsheng Hu
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Affiliations: Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China, Department of Oncology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, P.R. China, Department of R&D, Geneplus‑Beijing Institute, Beijing 102206, P.R. China
Published online on: September 23, 2019 https://doi.org/10.3892/ol.2019.10909
Pages: 5085-5090
Copyright: © Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lynch syndrome (LS), as a result of the germline mutations in DNA mismatch repair genes, is characterized by the increased risk of endometrium, colon, and urinary tract cancer. Individuals with this disorder may occasionally have multiple primary carcinomas. Regardless of tumor type, pembrolizumab was approved for the treatment of patients with unresectable or metastatic mismatch repair deficient tumors, which may be an optional therapeutic method for patients with LS with multiple primary carcinomas. This case study is of a MSH2‑deficient patient with LS with metachronous urothelial and colon cancer, who received pembrolizumab treatment for 8 months. The responses of the two primary sites to immunotherapy differed. Based on the changes of tumor markers and tumor size illustrated by imageological examinations, no response was observed in the sigmoid colon lesion, whereas an immune‑associated phenomenon known as pseudoprogression was detected in the ureteral lesion. Immunotherapy was innovatively applied to the patient with multiple primary carcinomas. This case proposes a novel concept in which immunotherapy may potentially control the cancer growth in patients with LS and multiple primary carcinomas. However, further large‑scale investigations are required. Furthermore, it raises a challenge to monitor the effectiveness of immunotherapy.

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1	Lynch HT, Snyder CL, Shaw TG, Heinen CD and Hitchins MP: Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. 15:181–194. 2015. View Article : Google Scholar : PubMed/NCBI
2	Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357:409–413. 2017. View Article : Google Scholar : PubMed/NCBI
3	Marcus L, Lemery SJ, Keegan P and Pazdur R: FDA approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 25:3753–3758. 2019. View Article : Google Scholar : PubMed/NCBI
4	Food and Drug Administration (FDA), . FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indicationFDA; Silver Spring, MD: 2018, https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htmJuly. 30, 2018
5	Win AK, Parry S, Parry B, Kalady MF, Macrae FA, Ahnen DJ, Young GP, Lipton L, Winship I, Boussioutas A, et al: Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol. 20:1829–1836. 2013. View Article : Google Scholar : PubMed/NCBI
6	Obermair A, Youlden DR, Young JP, Lindor NM, Baron JA, Newcomb P, Parry S, Hopper JL, Haile R, Jenkins MA, et al: Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer. 127:2678–2684. 2010. View Article : Google Scholar : PubMed/NCBI
7	Eble JL, Sauter G and Epstein JI: Pathology and genetics of tumours of the urinary system and male genital organs: WHO classification of tumours. World Health Organ. 2004.
8	Bianchi F, Rosati S, Belvederesi L, Loretelli C, Catalani R, Mandolesi A, Bracci R, Bearzi I, Porfiri E and Cellerino R: MSH2 splice site mutation and endometrial cancer. Int J Gynecol Cancer. 16:1419–1423. 2006. View Article : Google Scholar : PubMed/NCBI
9	Rakobradović J, Krivokuća A, Jovandić S, Kesić V and Branković-Magić M: Confirmation of damaging effect of MSH2 c. 2634+ 1G>C mutation on splicing, its classification and implications for counseling. Cancer Genet. 239:1–7. 2019. View Article : Google Scholar : PubMed/NCBI
10	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
11	Liu Q, Wang LA, Su J, Tong D, Lan W, Wang L, Liu G, Zhang J, Zhang VW, Zhang D, et al: Giant bilateral adrenal myelolipomas in two Chinese families with congenital adrenal hyperplasia. Endocr Connect. Sep 1–2018.(Epub ahead of print). View Article : Google Scholar
12	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
13	Bonadona V, Bonaiti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, et al: Cancer risks associated with germline mutations in MLH1, MSH2 and MSH6 genes in Lynch syndrome. JAMA. 305:2304–2310. 2011. View Article : Google Scholar : PubMed/NCBI
14	Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons R, et al: Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: First report from the prospective Lynch syndrome database. Gut. 66:464–472. 2017. View Article : Google Scholar : PubMed/NCBI
15	Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, Lindblom A, Macrae F, Blanco I, Sijmons RH, et al: Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: A report from the Prospective Lynch Syndrome Database. Gut. 67:1306–1316. 2018. View Article : Google Scholar : PubMed/NCBI
16	Casper M, Weber SN, Kloor M, Müllenbach R, Grobholz R, Lammert F and Zimmer V: Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis. Scand J Gastroenterol. 48:344–351. 2013. View Article : Google Scholar : PubMed/NCBI
17	Vernez M, Hutter P, Monnerat C, Halkic N, Gugerli O and Bouzourene H: A case of Muir-Torre syndrome associated with mucinous hepatic cholangiocarcinoma and a novel germline mutation of the MSH2 gene. Fam Cancer. 6:141–145. 2007. View Article : Google Scholar : PubMed/NCBI
18	Yan H, Jin H, Xue G, Mei Q, Ding F, Hao L and Sun SH: Germline hMSH2 promoter mutation in a Chinese HNPCC kindred: Evidence for dual role of LOH. Clin Genet. 72:556–561. 2007. View Article : Google Scholar : PubMed/NCBI
19	Hemminki A, Peltomäki P, Mecklin JP, Järvinen H, Salovaara R, Nyström-Lahti M, de la Chapelle A and Aaltonen LA: Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 8:405–410. 1994. View Article : Google Scholar : PubMed/NCBI
20	Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wang Q, Gao J and Wu X: Pseudoprogression and hyperprogression after checkpoint blockade. Int Immunopharmacol. 58:125–135. 2018. View Article : Google Scholar : PubMed/NCBI
22	Agarwala SS: Practical approaches to immunotherapy in the clinic. Semin Oncol. 42 (Suppl 3):S20–S27. 2015. View Article : Google Scholar : PubMed/NCBI
23	Guibert N, Mazieres J, Delaunay M, Casanova A, Farella M, Keller L, Favre G and Pradines A: Monitoring of KRAS-mutated ctDNA to discriminate pseudo-progression from true progression during anti-PD-1 treatment of lung adenocarcinoma. Oncotarget. 8:38056–38060. 2017. View Article : Google Scholar : PubMed/NCBI
24	Lee JH, Long GV, Menzies AM, Lo S, Guminski A, Whitbourne K, Peranec M, Scolyer R, Kefford RF, Rizos H and Carlino MS: Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with anti-programmed cell death 1 antibodies. JAMA Oncol. 4:717–721. 2018. View Article : Google Scholar : PubMed/NCBI
25	Yarchoan M, Hopkins A and Jaffee EM: Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 377:2500–2501. 2017. View Article : Google Scholar : PubMed/NCBI
26	Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, et al: Pembrolizumab as second-line therapy for advanced Urothelial Carcinoma. N Engl J Med. 376:1015–1026. 2017. View Article : Google Scholar : PubMed/NCBI
27	Vanderwalde A, Spetzler D, Xiao N, Gatalica Z and Marshall J: Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 7:746–756. 2018. View Article : Google Scholar : PubMed/NCBI