Objective: To explore the significance of next-generation sequencing for the screening of high-risk hereditary gastrointesti-nal cancer patients and the value of high-risk factors in screening. Methods: Twenty-five hereditary high-risk gastrointestinal cancer pa-tients from March 2016 to April 2016 in Peking University Cancer Hospital were enrolled. They received detection of 42 hereditary can-cer syndrome related genes by next-generation sequencing. Results: Out of 25 patients enrolled, 24% (6/25) patients had pathological germline mutations. The expression of mismatch repair protein was absent in 50% (3/6) patients. There were 83% (5/6) patients with family history of malignant tumors and were diagnosed when younger than 50 years. Six patients had hereditary cancer syndrome re-lated gene mutation, 1 patient had MYH gene missense mutation, 1 patient had APC gene deletion mutation, 4 patients had heredi-tary colorectal cancer related gene mutation, including MLH1, MLH3, and TGFBR2 germline missense mutations as well as MSH6 non-sense mutation. Conclusions: Out of 25 patients with high-risk factors of hereditary gastrointestinal cancer, 6 (24%) had pathological germline mutations. Given the high frequency and wide spectrum of mutations, the application of next-generation sequencing for screening of hereditary high-risk gastrointestinal cancer patients has the clinical value for improving the positive rate of diagnosis.

OBJECTIVETo evaluate the efficacy and safety of trastuzumab combined with chemotherapy in the treatment for HER-2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma.

METHODSTwenty consecutive cases of chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma treated in Peking University Cancer Hospital between 2009 June and 2013 August were included in this study. The patients with adenocarcinoma were previously confirmed and were eligible if their tumor showed overexpression of HER-2+++ by immunohistochemistry or HER-2 gene amplification-positive by FISH, and if they failed to at least one previous chemotherapy. Response and toxicities were evaluated with RECIST 1.0 and CTC AE 3.0 criteria.

RESULTSThe twenty patients received trastuzumab plus second- or later-line chemotherapy, consisting of nine platinum with fluoropyrimidines, five paclitaxel with fluoropyrimidines, three fluoropyrimidines monotherapy, two irinotecan monotherapy, and one docetaxel monotherapy. In these 20 cases, 3 PR (15.0%) and 10 SD (50.0%) were achieved, with a disease control rate of 65.0%. The median PFS was 6.1 months (95%CI 3.0-9.2) and median OS was 11.1 months (95%CI 8.4-13.7). The median cycle number of Trastuzumab administration was 6.5. The patients treated with Trastuzumab ≥ 6 times had a median OS of 13.8 months, significantly longer than that of 9.5 months in the patients treated <6 times (P < 0.001). The patients treated with Trastuzumab ≥ 6 times had a median PFS of 7.8 months, significantly longer than that of 3.7 months in patients treated <6 times (P = 0.029). Among the 20 cases, loss of appetite (13 cases of grade 1-2), neutropenia (12 cases of grade 1-2 and 3 cases of grade 3-4) and fatigue (9 cases of grade 1-2 and 3 cases of grade 3-4) were the most frequent adverse events. No cardiac events including asymptomatic decreases in LVEF ≥ 10% and no treatment-related death were recorded.

CONCLUSIONSCombination of trastuzumab with chemotherapy is effective and safe in patients with HER2-positive advanced chemo-refractory gastric or gastro-esophageal junction adenocarninoma. However, prospective studies are warranted to further confirm its efficacy and safety.

Adenocarcinoma ; drug therapy ; metabolism ; secondary ; surgery ; Adult ; Aged ; Anorexia ; chemically induced ; Antibodies, Monoclonal, Humanized ; administration & dosage ; adverse effects ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Camptothecin ; administration & dosage ; adverse effects ; analogs & derivatives ; Cisplatin ; administration & dosage ; adverse effects ; Disease Progression ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Esophagogastric Junction ; Fatigue ; chemically induced ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; drug therapy ; secondary ; Male ; Middle Aged ; Neutropenia ; chemically induced ; Paclitaxel ; administration & dosage ; adverse effects ; Pyrimidines ; administration & dosage ; adverse effects ; Receptor, ErbB-2 ; metabolism ; Remission Induction ; Retrospective Studies ; Stomach Neoplasms ; drug therapy ; metabolism ; secondary ; surgery ; Survival Rate ; Trastuzumab