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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104

Authors: Steffen Ormanns, Jens T Siveke, Volker Heinemann, Michael Haas, Bence Sipos, Anna Melissa Schlitter, Irene Esposito, Andreas Jung, Rüdiger P Laubender, Stephan Kruger, Ursula Vehling-Kaiser, Cornelia Winkelmann, Ludwig Fischer von Weikersthal, Michael R Clemens, Thomas C Gauler, Angela Märten, Michael Geissler, Tim F Greten, Thomas Kirchner, Stefan Boeck

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined.

Methods

Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model.

Results

Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53.

Conclusion

pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash.

Trial registration

NCT00440167 (registration date: February 22, 2007).
Appendix
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Literature
1.
Verslype C, van Cutsem E, Dicato M, Arber N, Berlin JD, Büchler MW, Cervantes A, Ciardiello F, Ducreux M, Douillard JY, Grothey A, Haller D, Haustermans K, Heinemann V, Hidalgo M, Labianca R, Li J, Marshall JL, Nordlinger B, O’Reilly EM, Roth A, Rougier P, Ryan D, Schmiegel W, Seufferlein T, Schmoll HJ, Sobrero A, Tabernero J, Tempero M, van Laethem JL, Ychou M, Zalcberg J: The management of metastatic pancreatic cancer: expert discussion and recommendations from the 14th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2012. Ann Oncol. 2013, 24 (suppl 4): iv5-iv10.CrossRef
2.
Paulson AS, Tran Cao HS, Tempero MA, Lowy AM: Therapeutic advances in pancreatic cancer. Gastroenterology. 2013, 144: 1316-1326.CrossRefPubMed
3.
Heinemann V, Haas M, Boeck S: Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev. 2012, 38: 843-853.CrossRefPubMed
4.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical trials group. J Clin Oncol. 2007, 25: 1960-1966.CrossRefPubMed
5.
Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, Davidenko I, Bondar V, Garin A, Boeck S, Ormanns S, Heinemann V, Bassi C, Evans TR, Andersson R, Hahn H, Picozzi V, Dicker A, Mann E, Voong C, Kaur P, Isaacson J, Allen A: Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 2013, 31: 4453-4461.CrossRefPubMed
6.
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M: Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011, 29: 4548-4554.CrossRefPubMedPubMedCentral
7.
Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Märten A, Winkelmann C, Klein S, Kojouharoff G, Gauler TC, Fischer von Weikersthal L, Clemens MR, Geissler M, Greten TF, Hegewisch-Becker S, Rubanov O, Baake G, Höhler T, Ko YD, Jung A, Neugebauer S, Boeck S: Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013, 62: 751-759.CrossRefPubMed
8.
Ogura T, Yamao K, Hara K, Mizuno N, Hijioka S, Imaoka H, Sawaki A, Niwa Y, Tajika M, Kondo S, Tanaka T, Shimizu Y, Bhatia V, Higuchi K, Hosoda W, Yatabe Y: Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013, 48: 640-646.CrossRefPubMed
9.
Kim ST, Lim do H, Jang KT, Lim T, Lee J, Choi YL, Jang HL, Yi JH, Baek KK, Park SH, Park YS, Lim HY, Kang WK, Park JO: Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011, 10: 1993-1999.CrossRefPubMed
10.
Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Vehling-Kaiser U, Winkelmann C, Fischer von Weikersthal L, Clemens MR, Gauler TC, Märten A, Klein S, Kojouharoff G, Barner M, Geissler M, Greten TF, Mansmann U, Kirchner T, Heinemann V: EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013, 108: 469-476.CrossRefPubMed
11.
Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, Heinemann V: KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol. 2013, 48: 544-548.CrossRefPubMed
12.
Tzeng CW, Frolov A, Frolova N, Jhala NC, Howard JH, Vickers SM, Buchsbaum DJ, Heslin MJ, Arnoletti JP: Pancreatic cancer epidermal growth factor receptor (EGFR) intron 1 polymorphism influences postoperative patient survival and in vitro erlotinib response. Ann Surg Oncol. 2007, 14: 2150-2158.CrossRefPubMed
13.
Ng SS, Tsao MS, Nicklee T, Hedley DW: Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Ther. 2002, 1: 777-783.PubMed
14.
Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles RP, Rabinovich BA, Hann B, Dankort D, Spellman PT, Phillips WA, Gray JW, McMahon M: A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012, 2: 685-693.CrossRefPubMedPubMedCentral
15.
Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Nakamori S, Monden M, Aozasa K: Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004, 10: 2846-2850.CrossRefPubMed
16.
Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, Tan D, Brattain MG, Javle MM: Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol. 2006, 13: 933-939.CrossRefPubMed
17.
Javle MM, Gibbs JF, Iwata KK, Pak Y, Rutledge P, Yu J, Black JD, Tan D, Khoury T: Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann Surg Oncol. 2007, 14: 3527-3533.CrossRefPubMed
18.
Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT: EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012, 22: 304-317.CrossRefPubMedPubMedCentral
19.
Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D: Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One. 2012, 7: e43192-CrossRefPubMedPubMedCentral
20.
Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A: PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009, 27: 2622-2629.CrossRefPubMed
21.
Da Cunha SG, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS: Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010, 116: 5599-5607.CrossRef
22.
Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD: Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010, 28: 3605-3610.CrossRefPubMedPubMedCentral
23.
Inoue K, Kurabayashi A, Shuin T, Ohtsuki Y, Furihata M: Overexpression of p53 protein in human tumors. Med Mol Morphol. 2012, 45: 115-123.CrossRefPubMed
24.
Sclafani F, Gonzalez D, Cunningham D, Hulkki Wilson S, Peckitt C, Tabernero J, Glimelius B, Cervantes A, Brown G, Chau I: TP53 status may predict benefit from cetuximab in high-risk, locally advanced rectal cancer: Results of the EXPERT-C trial. Eur J Cancer. 2013, 49 (suppl 2): abstract #7
25.
Tempero MA, Klimstra D, Berlin J, Hollingsworth T, Kim P, Merchant N, Moore M, Pleskow D, Wang-Gillam A, Lowy AM: Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. Clin Cancer Res. 2013, 19: 538-540.CrossRefPubMed
26.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011, 364: 1817-1825.CrossRefPubMed
27.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013, 369: 1691-1703.CrossRefPubMedPubMedCentral
Metadata
Title
pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104
Authors
Steffen Ormanns
Jens T Siveke
Volker Heinemann
Michael Haas
Bence Sipos
Anna Melissa Schlitter
Irene Esposito
Andreas Jung
Rüdiger P Laubender
Stephan Kruger
Ursula Vehling-Kaiser
Cornelia Winkelmann
Ludwig Fischer von Weikersthal
Michael R Clemens
Thomas C Gauler
Angela Märten
Michael Geissler
Tim F Greten
Thomas Kirchner
Stefan Boeck
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-624

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