MLH1 expression predicts the response to preoperative therapy and is associated with PD‑L1 expression in esophageal cancer

Momose,Kota; Yamasaki,Makoto; Tanaka,Koji; Miyazaki,Yasuhiro; Makino,Tomoki; Takahashi,Tsuyoshi; Kurokawa,Yukinori; Nakajima,Kiyokazu; Takiguchi,Shuji; Mori,Masaki; Doki,Yuichiro

doi:10.3892/ol.2017.6215

MLH1 expression predicts the response to preoperative therapy and is associated with PD‑L1 expression in esophageal cancer

Authors:
- Kota Momose
- Makoto Yamasaki
- Koji Tanaka
- Yasuhiro Miyazaki
- Tomoki Makino
- Tsuyoshi Takahashi
- Yukinori Kurokawa
- Kiyokazu Nakajima
- Shuji Takiguchi
- Masaki Mori
- Yuichiro Doki
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565‑0871, Japan
Published online on: May 19, 2017 https://doi.org/10.3892/ol.2017.6215
Pages: 958-964

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Abstract

Programmed death‑ligand 1 (PD‑1/PD‑L1) inhibition therapy demonstrates potential as a future treatment for esophageal cancer. Mismatch repair status and tumor PD‑L1 expression are the candidate predictive biomarkers for response to this therapy. In colorectal cancer, mismatch repair‑deficient tumors are associated with improved survival, although they are not sensitive to 5‑fluorouracil‑based chemotherapy. The purpose of the present study was to investigate the association between MutL homolog 1 (MLH1) expression and prognosis, response to therapy and PD‑L1 expression in esophageal cancer. Immunohistochemistry was used to evaluate MLH1 and PD‑L1 expression in 251 resected specimens. Of the specimens, 30.3% exhibited low MLH1 expression and 15.5% exhibited high PD‑L1 expression. The 5‑year overall survival rates for the high MLH1 expression group and the low MLH1 expression group were 51.3 and 55.6%, respectively (P=0.5260). The responder ratio was 45.7% in the high MLH1 expression group and 15.4% in the low MLH1 expression group (P<0.0001). The frequency of high PD‑L1 expression was 11.4% in the high MLH1 expression group (P=0.0064) and 25.0% in the low MLH1 expression group. MLH1 expression may be a predictive factor for the response to preoperative therapy in esophageal cancer, and esophageal cancer with low MLH1 expression may have a mechanism that assists in promoting tumor PD‑L1 expression.

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1	Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, et al: A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 19:68–74. 2012. View Article : Google Scholar : PubMed/NCBI
2	Cunningham D, Allum WH, Stenning SP, Thompson JN, van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006. View Article : Google Scholar : PubMed/NCBI
3	van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 366:2074–2084. 2012. View Article : Google Scholar : PubMed/NCBI
4	Fujita H: History of lymphadenectomy for esophageal cancer and the future prospects for esophageal cancer surgery. Surg Today. 45:140–149. 2015. View Article : Google Scholar : PubMed/NCBI
5	Nakajima M and Kato H: Treatment options for esophageal squamous cell carcinoma. Expert Opin Pharmacother. 14:1345–1354. 2013. View Article : Google Scholar : PubMed/NCBI
6	Akutsu Y and Matsubara H: Chemoradiotherapy and surgery for T4 esophageal cancer in Japan. Surg Today. 45:1360–1365. 2015. View Article : Google Scholar : PubMed/NCBI
7	Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI
8	Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366:2455–2465. 2012. View Article : Google Scholar : PubMed/NCBI
9	Kojima T, Hara H, Yamaguchi K, Hironaka S, Iwasa S, Kato K, Tsushima T, Yasui H, Ura T, Muro K, et al: Phase II study of nivolumab (ONO-4538/BMS-936558) in patients with esophageal cancer: Preliminary report of overall survival. J Clin Oncol. 34 Suppl 4S:abstr TPS1752016. View Article : Google Scholar
10	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
11	Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, Giannarelli D, Chilosi M, et al: Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One. 10:e01301422015. View Article : Google Scholar : PubMed/NCBI
12	Hewish M, Lord CJ, Martin SA, Cunningham D and Ashworth A: Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nat Rev Clin Oncol. 7:197–208. 2010. View Article : Google Scholar : PubMed/NCBI
13	Tzao C, Hsu HS, Sun GH, Lai HL, Wang YC, Tung HJ, Yu CP, Cheng YL and Lee SC: Promoter methylation of the hMLH1 gene and protein expression of human mutL homolog 1 and human mutS homolog 2 in resected esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 130:13712005. View Article : Google Scholar : PubMed/NCBI
14	Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M and Gallinger S: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 342:69–77. 2000. View Article : Google Scholar : PubMed/NCBI
15	Ward R, Meagher A, Tomlinson I, O'Connor T, Norrie M, Wu R and Hawkins N: Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 48:821–829. 2001. View Article : Google Scholar : PubMed/NCBI
16	Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 28:3219–3226. 2010. View Article : Google Scholar : PubMed/NCBI
17	Popat S, Hubner R and Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 23:609–618. 2005. View Article : Google Scholar : PubMed/NCBI
18	Sobin LH, Gospodarowicz MK and Wittekind C: TNM classification of malignant tumours. Wiley; 2009
19	Makino T, Yamasaki M, Miyata H, Yoshioka S, Takiguchi S, Fujiwara Y, Nakajima K, Nishida T, Mori M and Doki Y: p53 mutation status predicts pathological response to chemoradiotherapy in locally advanced esophageal cancer. Ann Surg Oncol. 17:804–811. 2010. View Article : Google Scholar : PubMed/NCBI
20	Japan Esophageal Society, . Japanese Classification of Esophageal Cancer, tenth edition: part I. Esophagus. 6:1–25. 2009. View Article : Google Scholar
21	Japan Esophageal Society, . Japanese classification of esophageal cancer, tenth edition: parts II and III. Esophagus. 6:71–94. 2009. View Article : Google Scholar
22	Kishi K, Doki Y, Yano M, Yasuda T, Fujiwara Y, Takiguchi S, Kim S, Higuchi I and Monden M: Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers. Clin Cancer Res. 9:4368–4375. 2003.PubMed/NCBI
23	Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 515:563–567. 2014. View Article : Google Scholar : PubMed/NCBI
24	Lanza G, Gafa R, Maestri I, Santini A, Matteuzzi M and Cavazzini L: Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol. 15:741–749. 2002. View Article : Google Scholar : PubMed/NCBI