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Appendix-derived Pseudomyxoma Peritonei (PMP): Molecular Profiling Toward Treatment of a Rare Malignancy

Gleeson, Elizabeth M., MD, MPH*; Feldman, Rebecca, PhD; Mapow, Beth L., DO*; Mackovick, Lynn T., DO*; Ward, Kristine M., MD*; Morano, William F., MD*; Rubin, Rene R., MD*; Bowne, Wilbur B., MD*

American Journal of Clinical Oncology: August 2018 - Volume 41 - Issue 8 - p 777–783
doi: 10.1097/COC.0000000000000376
Original Articles: Gastrointestinal

Objectives: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

*Drexel University College of Medicine, Philadelphia, PA

Carolinas HealthCare System, Charlotte, NC

E.M.G., R.F., and W.B.B.: designed and performed the research. E.M.G, R.F., and W.B.B.: performed the statistical analysis. E.M.G., R.F., K.M.W., W.F.M., R.R.R., and W.B.B.: wrote the paper.

This work was presented in part at the American Society of Clinical Oncology—Gastrointestinal Cancers Symposium (ASCO GI), San Francisco, CA, January 21-23, 2016 and at the 11th International Symposium on Regional Cancer Therapies, Chandler, AZ, February 13-15, 2016.

R.F. was an employee of Caris Life Sciences. R.F. was an employee in the Medical Affairs Department, a research-focused entity that is separate and distinct from the Sales Department. The other authors declare no conflicts of interest.

Reprints: Wilbur B. Bowne, MD, Department Surgery, Division of Surgical Oncology, Drexel University College of Medicine, 254N. 15th Street, MS 413, Philadelphia, PA 19102. E-mail:

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