title: Appendix-derived Pseudomyxoma Peritonei (PMP): Molecular Profiling Toward Treatment of a Rare Malignancy.
abstract: Pseudomyxoma peritonei (PMP) is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy.
  
  
  
  A total of 54 patients with appendix-derived PMP were included in the study. Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing), protein expression (immunohistochemistry), and gene amplification (C/fluorescent in situ hybridization).
  
  
  
  Targeted sequencing of 47 genes detected variants in KRAS (81%), GNAS (74%), SMAD4 (16%), and ATM (16%). Mutations were found at low frequencies (n=1 to 2) in APC, BRAF, PIK3CA, MLH1, and TP53. GNAS and KRAS co-occurrence was found in 87%. Protein overexpression was found in epidermal growth factor receptor (83%), cyclooxygenase-2 (73%), cMET (63%), cKIT (58%), and platelet-derived growth factor receptor alpha (58%). Immune checkpoint expression was found in 36% (programmed cell death protein 1) and 18% (programmed death-ligand 1). Surrogate markers of cell proliferation were found at low rates (TLE3 23%, TOP2A 22%), consistent with the slow-growing biology of PMP. Phosophatase and tensin homolog was intact (wild type [100%]) and positive (immunohistochemistry [80%]). Patients exhibited stable microsatellite status and mismatch repair proficiency (93%). Importantly, multidrug resistance protein expression was elevated (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1), and irinotecan (TOPO1) chemosensitivities were detected at favorable rates: 93%, 87%, 77% and 65%, respectively.
  
  
  
  Molecular profiling by multiple platforms identified potential therapies for the nontargetable KRAS-mutated population. The role of cMET-targeted therapeutics and immune checkpoint inhibitors merits further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate efficacy to systemic treatment.
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Gleeson
authors.affiliation: Carolinas HealthCare System, Charlotte, NC.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feldman
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Mapow
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Lynn T
authors.initials: LT
authors.lastname: Mackovick
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Ward
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: William F
authors.initials: WF
authors.lastname: Morano
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Rene R
authors.initials: RR
authors.lastname: Rubin
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Wilbur B
authors.initials: WB
authors.lastname: Bowne
mesh_terms: D000368:Aged; D001065:Appendix / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011553:Pseudomyxoma Peritonei / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor