title: GNAS mutations as prognostic biomarker in patients with relapsed peritoneal pseudomyxoma receiving metronomic capecitabine and bevacizumab: a clinical and translational study.
abstract: There is lack of evidence about systemic treatment of pseudomyxoma peritonei (PMP) relapsing after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. There is also lack of biomarkers able to predict outcomes beyond known clinical and pathological prognostic features.
  
  
  
  Fifteen patients with relapsed PMP and progressive disease within the last 6 months were included and received metronomic capecitabine (625 mg/mq/day b.i.d.) and bevacizumab (7.5 mg/Kg three-weekly) until progressive disease/unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Ion Torrent(®) next generation sequencing technology (Hot-spot Cancer Panel) was used to characterize molecular features.
  
  
  
  At a median follow up of 12 months, median PFS was 8.2 months and 1-year overall survival was 91 %. Partial responses were observed in 20 % of cases, but a significant reduction of tumor markers in up to 79 %. Treatment was very well tolerated without no new safety signals. All tumor samples except one had KRAS mutations. Patients with GNAS mutations had a significantly shorter median PFS as compared to GNAS wild-type ones (5.3 months vs. not reached; p < 0.007). The results were externally validated on our previous series of PMP patients. GNAS mutations were rare in a parallel cohort of 121 advanced colorectal cancers (2.5 %), but were associated with peculiar clinical-pathological features and aggressive course.
  
  
  
  Metronomic capecitabine and bevacizumab is an active and well tolerated option in patients with relapsed PMP. The negative prognostic effect of GNAS mutations in gastrointestinal cancers warrants further confirmatory studies and may prompt the development of effective targeted strategies.
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy. filippo.pietrantonio@istitutotumori.mi.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maggi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Caporale
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Milione
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Surgery Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Baratti
authors.affiliation: Surgery Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kusamura
authors.affiliation: Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Niger
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Mennitto
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bossi
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Settanni
authors.affiliation: Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Busico
authors.affiliation: Department of Cancer Surgery, Humanitas Clinical and Research Center, Milan, Rozzano, Italy.
authors.forename: Pietro Francesco
authors.initials: PF
authors.lastname: Bagnoli
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: Surgery Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Deraco
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
mesh_terms: D059250:Administration, Metronomic; D000368:Aged; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002864:Chromogranins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D011553:Pseudomyxoma Peritonei / Q000188:drug therapy* / Q000235:genetics; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; D000068258:Bevacizumab; D000069287:Capecitabine; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Appendiceal cancer; Bevacizumab; GNAS; Metronomic capecitabine; Next-generation sequencing; Peritoneal pseudomyxoma