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Conflict of interest
Introduction Gastric cancer is a major cause of cancer deaths worldwide, particularly in East Asia. Metastatic gastric cancer is associated with poor outcomes. The median overall survival of metastatic gastric cancer ranges from 9 to 13 months despite treated with systemic chemotherapy, anti-human epidermal growth factor receptor (HER) 2 therapy (trastuzumab) for HER2-positive disease, and anti-vascular endothelial growth factor receptor (VEGFR) 2 monoclonal antibody (ramucirumab) in second-line treatments. Since 2011, a novel class of anticancer therapy, immune checkpoint blockade, has been introduced, leading to a paradigm shift in oncology. Patients with metastatic gastric cancer are among those with fatal diseases who may benefit from these agents. Cancer cells can evade the human immune system by regulating immune checkpoint molecules. The programmed death 1 (PD-1) protein, an inhibitory immune checkpoint molecule that has been extensively studied, downregulates immune responses by binding to its ligands, PD-L1 and -L2. Monoclonal procollagen c proteinase against PD-1, including pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration for treating melanoma, lung cancer, and lymphoma. PD-1 blockade is effective in a fraction of patients with metastatic gastric cancer. Until now, an ideal biomarker for predicting the response to PD-1 blockade remains elusive in metastatic gastric cancer. Mismatch repair-deficient cancers are rich in lymphocyte infiltration, which indicates an immune response. This finding led to the hypothesis that such tumors more favorably respond to immune checkpoint blockade. Le et al reported an association between mismatch repair deficiency (dMMR) and the response to PD-1 blockade in metastatic colorectal cancer (CRC). Patients with mismatch repair-deficient CRC showed a substantially higher response rate to PD-1 blockade than did those with proficient mismatch repair (pMMR) function. Several other dMRR cancers have shown high response rates to anti-PD-1 therapy. Herein, we report a chemotherapy-refractory metastatic gastric cancer patient with dMMR and microsatellite instability (MSI) who showed a satisfactory response to pembrolizumab (formerly MK-3475), a humanized monoclonal IgG4 antibody against PD-1, for more than 24 months.
Case report A 66-year-old man visited the outpatient clinic at National Taiwan University Hospital in September 2009 after experiencing difficulty in swallowing, particularly when consuming solid food, for 3 weeks. The patient did not report marked weight loss, vomiting, or pain in the chest and abdomen. He did not smoke cigarettes or consume alcohol. The patient mentioned no history of cancer in first and second-degree relatives. No remarkable findings were observed on initial examinations at the clinic. Esophagogastroduodenoscopy showed an ulcerative mass with irregular borders at the gastric cardia, with lower esophageal involvement. The epicenter of the tumor was greater than 5 cm away from the esophagogastric junction. Biopsy of the mass showed adenocarcinoma, diffusely positive for cytokeratine but negative for CK7, CK20, and CDX2. Serial imaging studies for staging did not reveal distant metastasis. The patient underwent thoracoscopic esophagectomy and gastric tube reconstruction (Ivor Lewis procedure) in October 2009. The pathological stage was pT4aN1M0, stage IIIA. Adjuvant chemotherapy with cisplatin (60 mg/m2 on day 1 every 2 weeks) plus infusional 5-fluorouracil (5-FU) and leucovorin (2200 mg/m2 and 300 mg/m, respectively, on day 1 every 2 weeks) was administered from December 2009 to March 2010. In February 2011, computed tomography (CT) of the abdomen revealed multiple nodular lesions at the peritoneum and mesentery, which were later histologically proven as metastatic adenocarcinoma. The patient received salvage chemotherapy with oxaliplatin (85 mg/m2 on day 1) and capecitabine (1250 mg/m2 BID on days 1–14 every 2 weeks) from June 2011 to March 2012. Treatment assessment in April 2011 revealed progressive disease, and second-line chemotherapy with paclitaxel (80 mg/m2 on day 1) and infusional 5-FU plus leucovorin (2600 and 300 mg/m, respectively, on day 1) every 2 weeks was administered from May 2012. A new metastatic tumor in the spleen was observed in July 2012, and the patient underwent debulking surgery of the peritoneal tumors and splenectomy in August 2012, as the tumor was limited in the abdomen. Metastasis at S6 of the liver was reported in August 2013; therefore, the patient underwent radiofrequency ablation in August and November 2013. In February 2014, CT revealed a new lymphadenopathy at the right perivertebral space next to the aortic hiatus. The patient started receiving 10 mg/kg pembrolizumab every 2 weeks in April 2014. Eight weeks after therapy initiation, the lymphadenopathy, which was considered the target lesion, shrunk from 4.8 cm (Fig. 1) to 3.2 cm, representing a 33% reduction of relative to the pretreatment size. In April 2016, the highest reduction (59%) of the target lesion was achieved (Fig. 2). The response to pembrolizumab was durable, lasting for more than 24 months, and is still ongoing. The treatment was well tolerated by the patient, and no adverse effects other than grade 1 fatigue, elevation of alkaline phosphatase, and hypothyroidism were observed during the treatment period. The patient completed 2 years of pembrolizumab treatment in April 2016. He is currently alive and is not receiving any active anticancer treatment.