Dataset Information

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.

ABSTRACT:

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Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR).

Patients and methods

We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics.

Results

Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS.

Conclusion

In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

SUBMITTER: Raghav KP

PROVIDER: S-EPMC3868421 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.

Raghav Kanwal P S KP Shetty Aditya V AV Kazmi Syed M A SM Zhang Nianxiang N Morris Jeffrey J Taggart Melissa M Fournier Keith K Royal Richard R Mansfield Paul P Eng Cathy C Wolff Robert A RA Overman Michael J MJ

The oncologist 20131022 12

<h4>Unlabelled</h4>Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR).<h4>Patients and methods</h4>We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the follo ...[more]

PMID: 24149137

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Project description:BackgroundMucinous appendiceal adenocarcinoma (MAA) is a rare, heterogeneous disease. Patients with unrespectable mucinous appendiceal adenocarcinoma presenting with peritoneal spread are treated by intraperitoneal chemotherapy, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy, or targeted therapy. However, there are no guidelines for efficacious drugs against mucinous appendiceal adenocarcinoma. Therefore, relevant high-fidelity models should be investigated to identify effective drugs for individual therapy.MethodsSurgical tumor specimens were obtained from a mucinous appendiceal adenocarcinoma patient. The tissue was digested and organoid culture was established. H&E and immunohistochemistry staining as well as DNA sequencing was performed on tissue and organoid. The pathological characteristics and gene mutations of the organoid were compared to those of the original tumor. Drug sensitivity tests were performed on organoid and the patient clinical responds to chemotherapy and targeted therapy was compared.ResultsOrganoids were successfully established and stably passaged. Pathological characteristics of organoids including H&E staining and expression of protein markers (CK20, CDX-2, STAB2, CD7, PAX8) were consistent to those of the original tumor. Moreover, the organoids carried the same gene mutations as the primary tumor. Sensitivity of the organoids to chemotherapeutic drugs and tyrosine kinase inhibitors included: 5-FU (IC50 43.95 μM), Oxaliplatin (IC50 23.49 μM), SN38 (IC50 1.02 μM), Apatinib (IC50 0.10 μM), Dasatinib (IC50 2.27 μM), Docetaxel (IC50 5.26 μM), Regorafenib (IC50 18.90 μM), and Everolimus (IC50 9.20 μM). The sensitivities of organoid to these drugs were comparable to those of the patient's clinical responses.ConclusionThe mucinous appendiceal adenocarcinoma organoid model which retained the characteristics of the primary tumor was successfully established. Combined organoid-based drug screening and high throughput sequencing provided a promising way for mucinous appendiceal adenocarcinoma treatment.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

Dataset Information

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.

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Patients and methods

Results

Conclusion

Publications

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.

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