Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas

Kanwal P.S. Raghav, Aditya V. Shetty, Syed M.A. Kazmi, Nianxiang Zhang, Jeffrey Morris, Melissa Taggart, Keith Fournier, Richard Royal, Paul Mansfield, Cathy Eng, Robert A. Wolff, Michael J. Overman

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background. 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.

Original languageEnglish (US)
Pages (from-to)1270-1277
Number of pages8
JournalOncologist
Volume18
Issue number12
DOIs
StatePublished - Dec 16 2013

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Molecular Targeted Therapy
Cyclooxygenase 2
Adenocarcinoma
Microsatellite Instability
Mutation
Survival
Epidermal Growth Factor Receptor
Celecoxib
Phosphatidylinositol 3-Kinases
Kaplan-Meier Estimate
Neoplasms
Histology
Immunohistochemistry

Keywords

  • Appendix adenocarcinoma
  • Celecoxib
  • Cetuximab
  • COX-2
  • KRAS
  • MSI

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Raghav, K. P. S., Shetty, A. V., Kazmi, S. M. A., Zhang, N., Morris, J., Taggart, M., ... Overman, M. J. (2013). Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. Oncologist, 18(12), 1270-1277. https://doi.org/10.1634/theoncologist.2013-0186

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. / Raghav, Kanwal P.S.; Shetty, Aditya V.; Kazmi, Syed M.A.; Zhang, Nianxiang; Morris, Jeffrey; Taggart, Melissa; Fournier, Keith; Royal, Richard; Mansfield, Paul; Eng, Cathy; Wolff, Robert A.; Overman, Michael J.

In: Oncologist, Vol. 18, No. 12, 16.12.2013, p. 1270-1277.

Research output: Contribution to journalArticle

Raghav, KPS, Shetty, AV, Kazmi, SMA, Zhang, N, Morris, J, Taggart, M, Fournier, K, Royal, R, Mansfield, P, Eng, C, Wolff, RA & Overman, MJ 2013, 'Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas', Oncologist, vol. 18, no. 12, pp. 1270-1277. https://doi.org/10.1634/theoncologist.2013-0186
Raghav, Kanwal P.S. ; Shetty, Aditya V. ; Kazmi, Syed M.A. ; Zhang, Nianxiang ; Morris, Jeffrey ; Taggart, Melissa ; Fournier, Keith ; Royal, Richard ; Mansfield, Paul ; Eng, Cathy ; Wolff, Robert A. ; Overman, Michael J. / Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. In: Oncologist. 2013 ; Vol. 18, No. 12. pp. 1270-1277.
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abstract = "Background. 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.",
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T1 - Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas

AU - Raghav, Kanwal P.S.

AU - Shetty, Aditya V.

AU - Kazmi, Syed M.A.

AU - Zhang, Nianxiang

AU - Morris, Jeffrey

AU - Taggart, Melissa

AU - Fournier, Keith

AU - Royal, Richard

AU - Mansfield, Paul

AU - Eng, Cathy

AU - Wolff, Robert A.

AU - Overman, Michael J.

PY - 2013/12/16

Y1 - 2013/12/16

N2 - Background. 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.

AB - Background. 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.

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