Potential actionable targets in appendiceal cancer detected by immunohistochemistry (IHC), fluorescent in situ hybridiza & on (FISH) and mutational analysis


Erkut Borazanci, Jeffery Kimbrough, Jasgit C. Sachdev, Sherri Z. Millis, Samuel Ejadi, Ken Burnett, Stephanie Ratliff, Daniel D. Von Hoff, Ramesh K. Ramanathan


Appendiceal cancers are very rare and consist of various histologies such as carcinoid, mucocele, psuedomyxoma peritonei, goblet cell carcinoma, lymphoma, and adenocarcinoma. Current standard treatment involves surgical resection or debulking but no standard exists regarding adjuvant chemotherapy or treatment for metastatic disease.


Samples were identified from >50,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory (Caris Life Sciences) for biomarkers of drug sensitivity, under an approved protocol. 285 samples with primary tumor sites of appendix were identified (male/female raTo of 38%/62%; mean age of 55). Approximately 80% of samples were adenocarcinomas, 10% carcinoids, and 10% of indeterminate histology. IHC assays were performed on 273 samples with up to 30 biomarkers; 39 samples underwent FISH for cMyc, cMET, EGFR, HER2 and/or TOPO2A gene copy amplifications; and KRAS, EGFR, PIK3CA, and BRAF were sequenced on 223 samples.


IHC-idenTfied targets included: 97% high BCRP; 16% high KIT; 80% high COX-2; 50%high EGFR; 30% low MGMT, 81% high MRP1, 35% high PDGFR, 82% low PTEN, 27% high RRM1, 39% high SPARC; 67% high TLE3, 27% high TOPO2A ; 63% high TOPOI and 99% negaTve TS. FISH yielded 5% amplified EGFR and 0% amplified Her2/Neu. Sequencing results indicated 53% mutated KRAS and 2% mutated BRAF.


Appendiceal cancers show considerable heterogeneity and the high levels of drug resistance proteins (BCRP and MRP1) highlights the difficulty in treating these tumors. The incidence of KRAS mutations (53%) and low expression of TS (99%) is noteworthy. The almost global incidence of low TS could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). potential targets are so varied this would lead to an individualized approach to treatment. therapeutic options possible based upon the targets noted above include TOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temozolamide), BRAF inhibitors (Vemurafenib, dabrafenib) and SPARC (nab-paclitaxel). These findings indicate the need to evaluate paTent samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers, and to pursue whole genomic sequencing. (Supported by a grant from Caris Life Sciences).

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