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Published in: Journal of Translational Medicine 1/2012

Open Access 01-12-2012 | Research

Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study

Authors: Paola Ulivi, Laura Capelli, Martina Valgiusti, Wainer Zoli, Emanuela Scarpi, Elisa Chiadini, Paola Rosetti, Sara Bravaccini, Daniele Calistri, Luca Saragoni, Andrea Casadei Gardini, Angela Ragazzini, Giovanni Luca Frassineti, Dino Amadori, Alessandro Passardi

Published in: Journal of Translational Medicine | Issue 1/2012

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Abstract

Background

KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen.

Methods

67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry.

Results

BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively) and OS (p = 0.008 and p = 0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations.

Conclusions

BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.
Appendix
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Literature
1.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.CrossRefPubMed
2.
go back to reference Meyerhardt JA, Mayer RJ: Systemic therapy for colorectal cancer. N Engl J Med. 2005, 352: 476-487. 10.1056/NEJMra040958.CrossRefPubMed Meyerhardt JA, Mayer RJ: Systemic therapy for colorectal cancer. N Engl J Med. 2005, 352: 476-487. 10.1056/NEJMra040958.CrossRefPubMed
3.
go back to reference Pessino A, Artale S, Sciallero S, Guglielmi A, Fornarini G, Andreotti IC, Mammoliti S, Comandini D, Caprioni F, Bennicelli E, Andretta V, Siena S, Sobrero A: First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol. 2008, 19: 711-716.CrossRefPubMed Pessino A, Artale S, Sciallero S, Guglielmi A, Fornarini G, Andreotti IC, Mammoliti S, Comandini D, Caprioni F, Bennicelli E, Andretta V, Siena S, Sobrero A: First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol. 2008, 19: 711-716.CrossRefPubMed
4.
go back to reference Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ: Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007, 357: 2040-2048. 10.1056/NEJMoa071834.CrossRefPubMed Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ: Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007, 357: 2040-2048. 10.1056/NEJMoa071834.CrossRefPubMed
5.
go back to reference Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004, 351: 337-345. 10.1056/NEJMoa033025.CrossRefPubMed Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004, 351: 337-345. 10.1056/NEJMoa033025.CrossRefPubMed
6.
go back to reference Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66: 3992-3995. 10.1158/0008-5472.CAN-06-0191.CrossRefPubMed Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66: 3992-3995. 10.1158/0008-5472.CAN-06-0191.CrossRefPubMed
7.
go back to reference Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67: 2643-2648. 10.1158/0008-5472.CAN-06-4158.CrossRefPubMed Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67: 2643-2648. 10.1158/0008-5472.CAN-06-4158.CrossRefPubMed
8.
go back to reference Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008, 26: 1626-1634. 10.1200/JCO.2007.14.7116.CrossRefPubMed Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008, 26: 1626-1634. 10.1200/JCO.2007.14.7116.CrossRefPubMed
9.
go back to reference Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008, 359: 1757-1765. 10.1056/NEJMoa0804385.CrossRefPubMed Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008, 359: 1757-1765. 10.1056/NEJMoa0804385.CrossRefPubMed
10.
go back to reference Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009, 360: 1408-1417. 10.1056/NEJMoa0805019.CrossRefPubMed Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009, 360: 1408-1417. 10.1056/NEJMoa0805019.CrossRefPubMed
11.
go back to reference Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009, 27: 663-671. 10.1200/JCO.2008.20.8397.CrossRefPubMed Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009, 27: 663-671. 10.1200/JCO.2008.20.8397.CrossRefPubMed
12.
go back to reference Yan J, Roy S, Apolloni A, Lane A, Hancock JF: Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 1998, 273: 24052-24056. 10.1074/jbc.273.37.24052.CrossRefPubMed Yan J, Roy S, Apolloni A, Lane A, Hancock JF: Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 1998, 273: 24052-24056. 10.1074/jbc.273.37.24052.CrossRefPubMed
13.
go back to reference Zhang BH, Guan KL: Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. Embo J. 2000, 19: 5429-5439. 10.1093/emboj/19.20.5429.CrossRefPubMedPubMedCentral Zhang BH, Guan KL: Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. Embo J. 2000, 19: 5429-5439. 10.1093/emboj/19.20.5429.CrossRefPubMedPubMedCentral
14.
go back to reference Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S: Multi-determinants analysis of molecular alterations for predicting clinical benefit to egfr-targeted monoclonal antibodies in colorectal cancer. Plos One. 2009, 4: e7287 4-CrossRef Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S: Multi-determinants analysis of molecular alterations for predicting clinical benefit to egfr-targeted monoclonal antibodies in colorectal cancer. Plos One. 2009, 4: e7287 4-CrossRef
15.
go back to reference Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008, 26: 5705-5712. 10.1200/JCO.2008.18.0786.CrossRefPubMed Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008, 26: 5705-5712. 10.1200/JCO.2008.18.0786.CrossRefPubMed
17.
go back to reference Samuels Y, Diaz LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005, 7: 561-573. 10.1016/j.ccr.2005.05.014.CrossRefPubMed Samuels Y, Diaz LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005, 7: 561-573. 10.1016/j.ccr.2005.05.014.CrossRefPubMed
18.
go back to reference Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994, 370: 527-532. 10.1038/370527a0.CrossRefPubMed Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994, 370: 527-532. 10.1038/370527a0.CrossRefPubMed
19.
go back to reference Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007, 97: 1139-1145. 10.1038/sj.bjc.6604009.CrossRefPubMedPubMedCentral Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007, 97: 1139-1145. 10.1038/sj.bjc.6604009.CrossRefPubMedPubMedCentral
20.
go back to reference Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, Bertario L, Leo E, Pierotti MA, Pilotti S: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009, 20: 84-90.CrossRefPubMed Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, Frattini M, Riva C, Andreola S, Bajetta E, Bertario L, Leo E, Pierotti MA, Pilotti S: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009, 20: 84-90.CrossRefPubMed
21.
go back to reference Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009, 69: 1851-1857. 10.1158/0008-5472.CAN-08-2466.CrossRefPubMed Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009, 69: 1851-1857. 10.1158/0008-5472.CAN-08-2466.CrossRefPubMed
22.
go back to reference Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008, 68: 1953-1961. 10.1158/0008-5472.CAN-07-5659.CrossRefPubMedPubMedCentral Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008, 68: 1953-1961. 10.1158/0008-5472.CAN-07-5659.CrossRefPubMedPubMedCentral
23.
go back to reference Kaplan EL, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc. 1958, 53: 457-481. 10.1080/01621459.1958.10501452.CrossRef Kaplan EL, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc. 1958, 53: 457-481. 10.1080/01621459.1958.10501452.CrossRef
24.
go back to reference Lawkess JS: Statistical models and methods for life-time data. 1982, John Wiley and Sons, New York Lawkess JS: Statistical models and methods for life-time data. 1982, John Wiley and Sons, New York
25.
go back to reference Cox DR: Regression models and life tables. J Royal Stat Soc. 1972, 34: 187-220. Cox DR: Regression models and life tables. J Royal Stat Soc. 1972, 34: 187-220.
26.
go back to reference Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouché O, Reid J, Stone S, Penault-Llorca F: Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009, 27: 5924-5930. 10.1200/JCO.2008.21.6796.CrossRefPubMed Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouché O, Reid J, Stone S, Penault-Llorca F: Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009, 27: 5924-5930. 10.1200/JCO.2008.21.6796.CrossRefPubMed
27.
go back to reference Razis E, Briasoulis E, Vrettou E, Skarlos DV, Papamichael D, Kostopoulos I, Samantas E, Xanthakis I, Bobos M, Galanidi E, Bai M, Gikonti I, Koukouma A, Kafiri G, Papakostas P, Kalogeras KT, Kosmidis P, Fountzilas G: Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer. 2008, 8: 234-10.1186/1471-2407-8-234.CrossRefPubMedPubMedCentral Razis E, Briasoulis E, Vrettou E, Skarlos DV, Papamichael D, Kostopoulos I, Samantas E, Xanthakis I, Bobos M, Galanidi E, Bai M, Gikonti I, Koukouma A, Kafiri G, Papakostas P, Kalogeras KT, Kosmidis P, Fountzilas G: Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer. 2008, 8: 234-10.1186/1471-2407-8-234.CrossRefPubMedPubMedCentral
28.
go back to reference Matallanas D, Romano D, Al-Mulla F, O'Neill E, Al-Ali W, Crespo P, Doyle B, Nixon C, Sansom O, Drosten M, Barbacid M, Kolch W: Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell. 2011, 44: 893-906. 10.1016/j.molcel.2011.10.016.CrossRefPubMed Matallanas D, Romano D, Al-Mulla F, O'Neill E, Al-Ali W, Crespo P, Doyle B, Nixon C, Sansom O, Drosten M, Barbacid M, Kolch W: Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell. 2011, 44: 893-906. 10.1016/j.molcel.2011.10.016.CrossRefPubMed
29.
go back to reference De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O'Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010, 304: 1812-1820. 10.1001/jama.2010.1535.CrossRefPubMed De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O'Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010, 304: 1812-1820. 10.1001/jama.2010.1535.CrossRefPubMed
30.
go back to reference Al-Mulla F, Going JJ, Sowden ET, Winter A, Pickford IR, Birnie GD: Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J Pathol. 1998, 185: 130-138. 10.1002/(SICI)1096-9896(199806)185:2<130::AID-PATH85>3.0.CO;2-M.CrossRefPubMed Al-Mulla F, Going JJ, Sowden ET, Winter A, Pickford IR, Birnie GD: Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J Pathol. 1998, 185: 130-138. 10.1002/(SICI)1096-9896(199806)185:2<130::AID-PATH85>3.0.CO;2-M.CrossRefPubMed
31.
go back to reference Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, Beranek M, Jandik P, Benamouzig R, Jullian E, Laurent-Puig P, Olschwang S, Muller O, Hoffmann I, Rabes HM, Zietz C, Troungos C, Valavanis C, Yuen ST, Ho JW, Croke CT, O'Donoghue DP, Giaretti W, Rapallo A, Russo A, Bazan V, Tanaka M, Omura K, Azuma T, Ohkusa T, Fujimori T, Ono Y, Pauly M, Faber C, Glaesener R, de Goeij AF, Arends JW, Andersen SN, Lövig T, Breivik J, Gaudernack G, Clausen OP, De Angelis PD, Meling GI, Rognum TO, Smith R, Goh HS, Font A, Rosell R, Sun XF, Zhang H, Benhattar J, Losi L, Lee JQ, Wang ST, Clarke PA, Bell S, Quirke P, Bubb VJ, Piris J, Cruickshank NR, Morton D, Fox JC, Al-Mulla F, Lees N, Hall CN, Snary D, Wilkinson K, Dillon D, Costa J, Pricolo VE, Finkelstein SD, Thebo JS, Senagore AJ, Halter SA, Wadler S, Malik S, Krtolica K, Urosevic N: Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer. 2001, 85: 692-696. 10.1054/bjoc.2001.1964.CrossRefPubMedPubMedCentral Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, Beranek M, Jandik P, Benamouzig R, Jullian E, Laurent-Puig P, Olschwang S, Muller O, Hoffmann I, Rabes HM, Zietz C, Troungos C, Valavanis C, Yuen ST, Ho JW, Croke CT, O'Donoghue DP, Giaretti W, Rapallo A, Russo A, Bazan V, Tanaka M, Omura K, Azuma T, Ohkusa T, Fujimori T, Ono Y, Pauly M, Faber C, Glaesener R, de Goeij AF, Arends JW, Andersen SN, Lövig T, Breivik J, Gaudernack G, Clausen OP, De Angelis PD, Meling GI, Rognum TO, Smith R, Goh HS, Font A, Rosell R, Sun XF, Zhang H, Benhattar J, Losi L, Lee JQ, Wang ST, Clarke PA, Bell S, Quirke P, Bubb VJ, Piris J, Cruickshank NR, Morton D, Fox JC, Al-Mulla F, Lees N, Hall CN, Snary D, Wilkinson K, Dillon D, Costa J, Pricolo VE, Finkelstein SD, Thebo JS, Senagore AJ, Halter SA, Wadler S, Malik S, Krtolica K, Urosevic N: Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer. 2001, 85: 692-696. 10.1054/bjoc.2001.1964.CrossRefPubMedPubMedCentral
32.
go back to reference Tol J, Nagtegaal ID, Punt CJ: BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009, 361: 98-99. 10.1056/NEJMc0904160.CrossRefPubMed Tol J, Nagtegaal ID, Punt CJ: BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009, 361: 98-99. 10.1056/NEJMc0904160.CrossRefPubMed
33.
go back to reference Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA: Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009, 101: 465-472. 10.1038/sj.bjc.6605164.CrossRefPubMedPubMedCentral Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, Silver J, Ogino S, Hooshmand S, Kwak E, Freed E, Meyerhardt JA, Saridaki Z, Georgoulias V, Finkelstein D, Fuchs CS, Kulke MH, Shivdasani RA: Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009, 101: 465-472. 10.1038/sj.bjc.6605164.CrossRefPubMedPubMedCentral
34.
go back to reference Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, Giovannucci EL, Fuchs CS: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009, 58: 90-96. 10.1136/gut.2008.155473.CrossRefPubMedPubMedCentral Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, Giovannucci EL, Fuchs CS: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009, 58: 90-96. 10.1136/gut.2008.155473.CrossRefPubMedPubMedCentral
35.
go back to reference Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6: 279-286. 10.1016/S1470-2045(05)70102-9.CrossRefPubMed Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6: 279-286. 10.1016/S1470-2045(05)70102-9.CrossRefPubMed
36.
go back to reference Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S: PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009, 15: 3184-3188. 10.1158/1078-0432.CCR-08-2961.CrossRefPubMed Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S: PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009, 15: 3184-3188. 10.1158/1078-0432.CCR-08-2961.CrossRefPubMed
37.
go back to reference 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. 10.1200/JCO.2008.20.2796.CrossRefPubMed 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. 10.1200/JCO.2008.20.2796.CrossRefPubMed
Metadata
Title
Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study
Authors
Paola Ulivi
Laura Capelli
Martina Valgiusti
Wainer Zoli
Emanuela Scarpi
Elisa Chiadini
Paola Rosetti
Sara Bravaccini
Daniele Calistri
Luca Saragoni
Andrea Casadei Gardini
Angela Ragazzini
Giovanni Luca Frassineti
Dino Amadori
Alessandro Passardi
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2012
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-10-87

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