Top

Journal of Hematology & Oncology

Published in:

Open Access 01-12-2016 | Case report

Case report: mismatch repair proficiency and microsatellite stability in gastric cancer may not predict programmed death-1 blockade resistance

Authors: Kuo-Hsing Chen, Chang-Tsu Yuan, Li-Hui Tseng, Chia-Tung Shun, Kun-Huei Yeh

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

Anti-programmed death-1 therapy has poor efficacy in mismatch repair-proficient (pMMR) colorectal cancers; however, its efficacy in pMMR gastric cancers remains undetermined. Here, we report the case of a patient with pMMR and microsatellite-stable gastric cancer who exhibited a partial response to salvage anti-programmed death-1 therapy with pembrolizumab.

Case presentation

Initially, the patient underwent subtotal gastrectomy 4 years ago for early-stage gastric cancer (pT1bN2M0, stage IIA). Immunohistochemical analysis of the tumor revealed strongly positive for HER2/neu. He had received trastuzumab plus pertuzumab, cisplatin, and capecitabine for recurrent tumors since September 2014 for 15 cycles. Disease progression of gastric cancer was found in August 2015. Since September 2015, the patient has received pembrolizumab monotherapy (200 mg as a fixed dose, every 3 weeks) for 3 months and the repeat computed tomography demonstrated a confirmed partial response. The plasma carcinoembryonic antigen also decreased dramatically. Both immunohistochemistry and a polymerase chain reaction-based method revealed that the patient had pMMR gastric cancer.

Conclusions

This case report provides the first report that mismatch repair-proficient and microsatellite-stable gastric cancers can respond well to anti-PD-1 monotherapy and indicates both markers may not sufficiently be predictive of anti-PD-1 therapy resistance in gastric cancer.

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.CrossRefPubMedPubMedCentral

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefPubMedPubMedCentral

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.CrossRefPubMed

Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRefPubMedPubMedCentral

Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.CrossRefPubMed

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRefPubMed

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.CrossRefPubMedPubMedCentral

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348(10):919–32.CrossRefPubMed

Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer discovery. 2015;5(1):43–51.CrossRefPubMedPubMedCentral

10.

Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145(1):148–56.PubMedPubMedCentral

11.

Hofmann M, Stoss O, Gaiser T, Kneitz H, Heinmoller P, Gutjahr T, Kaufmann M, Henkel T, Ruschoff J. Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy. Journal of clinical pathology. 2008;61(1):89–94.CrossRefPubMed

12.

Tsai JH, Lin YL, Cheng YC, Chen CC, Lin LI, Tseng LH, Cheng ML, Liau JY, Jeng YM. Aberrant expression of annexin A10 is closely related to gastric phenotype in serrated pathway to colorectal carcinoma. Modern pathology. 2015;28(2):268–78.CrossRefPubMed

13.

Shi SJ, Wang LJ, Wang GD, Guo ZY, Wei M, Meng YL, Yang AG, Wen WH. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One. 2013;8(10):e76012.CrossRefPubMedPubMedCentral

14.

Bang YJ, Shankaran V, Geva R, Yang AG, Wen WH. Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in KEYNOTE-012. J Clin Oncol. 2015;33(suppl; abstr 4001).

15.

Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRef

16.

Kim KJ, Jung HY, Oh MH, Cho H, Lee JH, Lee HJ, Jang SH, Lee MS. Loss of ARID1A expression in gastric cancer: correlation with mismatch repair deficiency and clinicopathologic features. Journal of gastric cancer. 2015;15(3):201–8.CrossRefPubMedPubMedCentral

17.

van Grieken NC, Aoyama T, Chambers PA, Bottomley D, Ward LC, Inam I, Buffart TE, Das K, Lim T, Pang B. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br J Cancer. 2013;108(7):1495–501.CrossRefPubMedPubMedCentral

18.

Wu MS, Lee CW, Shun CT, Wang HP, Lee WJ, Chang MC, Sheu JC, Lin JT. Distinct clinicopathologic and genetic profiles in sporadic gastric cancer with different mutator phenotypes. Genes Chromosomes Cancer. 2000;27(4):403–11.CrossRefPubMed

19.

Simpson AJ, Caballero OL, Pena SD. Microsatellite instability as a tool for the classification of gastric cancer. Trends Mol Med. 2001;7(2):76–80.CrossRefPubMed

20.

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.CrossRefPubMedPubMedCentral

21.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York, NY). 2015;348(6230):124–8.CrossRef

22.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45(2):136–44.CrossRefPubMedPubMedCentral

23.

Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D’Andrea AD, Wu CJ. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA oncology. 2015;1(9):1319–23.CrossRefPubMed

24.

Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clinical cancer research. 2013;19(13):3462–73.CrossRefPubMedPubMedCentral

25.

Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, Neuberg D, Shipp MA. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clinical cancer research. 2012;18(6):1611–8.CrossRefPubMedPubMedCentral

Title: Case report: mismatch repair proficiency and microsatellite stability in gastric cancer may not predict programmed death-1 blockade resistance
Authors: Kuo-Hsing Chen
Chang-Tsu Yuan
Li-Hui Tseng
Chia-Tung Shun
Kun-Huei Yeh
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0259-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Case presentation

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

H2S protects against fatal myelosuppression by promoting the generation of megakaryocytes/platelets

Hypoacetylation, hypomethylation, and dephosphorylation of H2B histones and excessive histone deacetylase activity in DU-145 prostate cancer cells

Programmed cell death-1 blockade in recurrent disseminated Ewing sarcoma

TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia

Heterogeneity of CD34 and CD38 expression in acute B lymphoblastic leukemia cells is reversible and not hierarchically organized

Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

Keynote webinar | Spotlight on antibody–drug conjugates in cancer