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Appendix-derived Pseudomyxoma Peritonei (PMP): Molecular Profiling Toward Treatment of a Rare Malignancy
Elizabeth M Gleeson1, Rebecca Feldman2, Beth L Mapow1
1Drexel University College of Medicine, Philadelphia, PA.
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.
Insights
Molecular profiling of pseudomyxoma peritonei (PMP) reveals common KRAS and GNAS mutations. This analysis identifies potential targeted therapies and biomarker-guided chemotherapy options for this rare appendix cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Pathology
Background:
- Pseudomyxoma peritonei (PMP) is a rare appendiceal malignancy characterized by disseminated mucinous implants.
- Effective treatment strategies for PMP are limited due to its rarity.
Purpose of the Study:
- To investigate the utility of multiplatform molecular profiling in identifying biomarker-guided treatment strategies for appendix-derived PMP.
- To characterize the molecular landscape of PMP to inform therapeutic decisions.
Main Methods:
- Analysis of 54 patients with appendix-derived PMP.
- Utilized gene sequencing (Sanger, next-generation), protein expression (immunohistochemistry), and gene amplification (FISH).
- Assessed mutations in key oncogenes and tumor suppressor genes, protein overexpression, immune checkpoint expression, and chemosensitivity markers.
Main Results:
- High frequencies of KRAS (81%) and GNAS (74%) mutations were detected, often co-occurring (87%).
- Frequent protein overexpression of EGFR (83%), COX-2 (73%), and cMET (63%) was observed.
- Favorable rates for chemosensitivity markers (RRM1 93%, TS 87%) and elevated multidrug resistance proteins (BCRP 100%) were noted.
Conclusions:
- Multiplatform molecular profiling offers insights into potential therapies for PMP, including for KRAS-mutated cases.
- Targeted therapies for cMET and immune checkpoint inhibitors warrant further investigation.
- Biomarker-guided selection of cytotoxic chemotherapies may enhance systemic treatment efficacy in PMP.
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