Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.

Standard treatment for unresectable esophageal squamous cell carcinoma (ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT), in which the incidence of esophageal fistula (EF) is reported to be 10–12%. An ad hoc analysis of JCOG0303, a phase II/III trial of dCRT for patients with unresectable ESCC (including non-T4b), suggested that esophageal stenosis is a risk factor for EF. However, risk factors for EF in patients limited to T4b ESCC treated with dCRT have yet to be clarified. The aim of this study was to investigate risk factors for EF in T4b thoracic ESCC treated with dCRT. We retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015. Excluding 8 patients with esophageal fistula clearly attributable to other iatrogenic interventions, the data of 116 patients who met the inclusion criteria were analyzed. Esophageal fistula was observed in 28 patients (24%). Although the fistula was closed in 5 patients, overall survival was significantly shorter in patients who experienced esophageal fistula (8.0 vs. 26.8 months; p < 0.0001). Among four potential variables extracted in univariate analysis, namely, total circumferential lesion, elevated CRP level, elevated white blood cell count, and anemia, the first two were revealed as risk factors for esophageal fistula in multivariate analysis. This study demonstrated that total circumferential lesion and CRP ≥1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT. This study was retrospectively registered.

Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer. Moreover, there are few reports about nomograms in inoperable locally advanced or metastatic gastric cancer (AGC), although several studies have been reported regarding other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors to predict the survival outcomes of AGC patients starting first-line treatment. Methods: In this study, 838 consecutive AGC patients starting first-line chemotherapy at the Aichi Cancer Center Hospital (ACC) were included to establish the nomograms that calculated the predicted probability of survival at different time points, 6 months and 1 and 2 years for overall survival (OS) and 3 and 6 months, and 1 year for progression free survival (PFS). Nomograms were independently validated with 269 consecutive AGC patients at the Cancer Center Hospital (SCC) who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2 positive. Results: At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, the median OS was 12.5 and 12.4 months (P=1.00), and the median PFS was 4.8 and 5.8 months (P=0.03), respectively. The nomograms showed good C-index values: OS was respectively 0.688 and 0.576 and PFS was respectively for 0.643 and 0.544. Conclusions: The nomograms including HER2 status as covariate are crucial determinants of clinical care.