title: Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy.
abstract: BACKGROUND
  The microsatellite-instable gastric cancer subtype, because of its supposed high antigenic potential, is a promising candidate for immunotherapy. We analyzed if the presence of a defective mismatch repair (MMR) system is associated with other markers of immune response and their relationship with outcome in advanced gastric cancer patients.
  
  
  METHODS
  We analyzed the relationship between clinical outcome and MMR status, the presence of tumor-infiltrating lymphocytes (TIL), lymphocytosis, and neutrophil-to-lymphocyte ratio (NLR) in metastatic gastric cancer patients treated with a chemotherapy doublet in the first-line setting. Other stratification factors were sex, age, Eastern Cooperative Oncology Group performance status, adjuvant/neoadjuvant chemotherapy, metastatic sites, and histotype.
  
  
  RESULTS
  One hundred three patients were eligible for analysis. Defective MMR was found in 15 patients (14 %), TILs were found in 18 patients (17 %), lymphocytosis was found in 24 patients (23 %), and high NLR was found in 75 patients (72 %). Significant correlations were found between defective MMR and TIL positivity (p = 0.0004), between defective MMR and lymphocytosis (p = 0.0062), between defective MMR and low NLR (p = 0.000069), and between TIL positivity and lymphocytosis (p = 0.000147). All factors had a statistically significant impact on overall survival, although on multivariate analysis only defective MMR (p = 0.0001) and TIL positivity (p = 0.0192) maintained their independent prognostic role. Similar results were observed for progression-free survival, with defective MMR (p = 0.0001) and TIL positivity (p = 0.0195) maintaining their prognostic role on multivariate analysis.
  
  
  CONCLUSIONS
  Our analysis confirms the favorable prognosis of metastatic gastric cancer patients with a defective MMR system and suggests that expression of TILs might also be linked to better outcome. Because of the correlation between defective MMR status and measures of immune system activity, this group of patients would be the best candidates for novel immunotherapy-based therapies.
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Giampieri
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy. elena.maccaroni@live.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Maccaroni
authors.affiliation: Department of Pathology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mandolesi
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Del Prete
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Andrikou
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Faloppi
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bittoni
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Bianconi
authors.affiliation: Department of Pathology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scarpelli
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bracci
authors.affiliation: Department of Medical Oncology, Università di Cagliari, Cagliari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008214:Lymphocytes / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009504:Neutrophils / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000556:secondary; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin; D005472:Fluorouracil
keywords: Chemotherapy; Gastric cancer; Microsatellite instability; Mismatch repair; Prognosis