Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

Abstract

Background: Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. Methods: Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55). Sixty-two percent of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% Results: Profiling across all appendiceal cancer histological subtypes for IHC revealed: 97% BRCP, 81% MRP1, 81% COX-2, 71% MGMT, 56% TOPO1, 5% PTEN, 52% EGFR, 40% ERCC1, 38% SPARC, 35% PDGFR, 35% TOPO2A, 25% RRM1, 21% TS, 16% cKIT, and 12% for TLE3. NGS revealed mutations in the following genes: 50.4% KRAS, 21.9% P53, 17.6% GNAS, 16.5% SMAD4, 10% APC, 7.5% ATM, 5.5% PIK3CA, 5.0% FBXW7, and 1.8% BRAF.Conclusions: Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. The incidence of low TS (79%) could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). Therapeutic options includeTOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), KRAS, p53, GNAS, SMAD4, APC, ATM, PIK3CA, FBXW7, and BRAF may be also considered. Overall, appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers (can we say this, any statistical analysis done?) and have differential expression from colorectal cancers. These findings indicate the need to evaluate patient 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 (supported by a grant from Caris Life Sciences). MGMT (temozolomide). Clinical trials targeting pathways involving IntroductionCancers arising from the appendix are rare. In reports of appendectomy specimens, the incidence of malignancy has been reported to be between 0.58% to 0.9% (1,2). The histological spectrum is quite varied, with recent reports through large database studies indicating adenocarcinoma being the most common subtype (3,4). Other histological variants include carcinoid or neuroendocrine and a mixed histology tumor of both carcinoid and adenocarcinoma subtype termed goblet cell carcinoma (5). Finally, another epithelial variant of appendiceal cancer is pseudomyxoma peritonei (PMP), a mucinous neoplasm that clinically presents as gelatinous ascites (6,7). Due to the rarity of these malignancies limited prospective trials exist gu...

Correlation of molecular and morphological features of appendiceal epithelial neoplasms

“…The results indicate that BRAF ‐mutated serrated polyps are non‐progressive lesions and are not likely to be the precursor of other tumour types. In contrast to our results, previous studies have reported much lower frequencies of BRAF mutations in the serrated lesions of the appendix . Yantiss et al identified BRAF mutations in 11 of 33 (33%) non‐dysplastic serrated lesions and five of 23 (22%) dysplastic serrated lesions .…”

GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

“…13,26,30,33,34 The diagnosis of ocular melanoma is particularly strongly associated (OR = 2.09, p < 0.0001) which is consistent with previous literature findings. 21,22,31 …”

Adenocarcinoma Ex-Goblet Cell: a Retrospective Experience

“…As we embark on these prospective studies, it is important to recognize just how little insight we possess about the intrinsic characteristics of the disease. We have yet to identify prognostic or predictive biomarkers, potential molecular drivers or immune signatures that could impact targeted-or immune-therapy selection and clinical trial eligibility for AGCC patients [12, 13]. Gaining more information about the disease through powerful tools such as next-generation sequencing remains an area of need.…”