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Originally published as JCO Early Release 10.1200/JCO.2008.20.3224 on February 17 2009 © 2009 American Society of Clinical Oncology.
The Marriage of Growth Factor Inhibitors and Chemotherapy: Bliss or Bust?Division of Hematology Oncology, Department of Medicine, University of Florida, Gainesville, FL
National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA
Division of Hematology Oncology, Department of Medicine, University of Florida, Gainesville, FL
Many clinical trials have demonstrated a benefit associated with the combination of growth factor, growth factor receptor, or signaling pathway inhibitors with cytotoxic chemotherapy; however, there are instances where such combinations have proven futile or antagonistic. Among the most successful combinations have been those utilizing antibodies targeting the extracelluar domain of the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER-2) with cetuximab and trastuzumab, respectively. As our ability to screen individual tumors for specific receptor and signaling pathway alterations becomes more facile, patterns that can serve to effectively guide our therapy are emerging. Recent investigations in patients with advanced colorectal cancer have identified KRAS mutation as a critical predictor of lack of clinical benefit from the anti-EGFR antibodies panitumumab and cetuximab.1–5 On further analysis, these same studies suggest a possible negative interaction between these antibodies and the fluoropyrimidines fluorouracil (FU) or capecitabine (CAP), which is most apparent in KRAS-mutated patients. Activating mutations in KRAS, a key regulator of cellular growth and proliferation, have been identified in 30% to 50% of patients with advanced colorectal cancer.6 The benefit of anti-EGFR antibodies is almost entirely associated with patients whose colon cancers develop in the absence of KRAS mutation. Amado et al1 enrolled 423 patients with advanced and refractory colorectal cancer treated with either single-agent panitumumab or best supportive care with the option to cross over to panitumumab at the time of disease progression. Patients with wild-type KRAS enjoyed a median progression-free survival (PFS) of 12.3 months and an overall response rate of 17% in those treated with panitumumab versus a PFS of 7.3 months for the best supportive care group (HR, 0.45). Those with mutant KRAS enjoyed no benefit in PFS from the use of panitumumab (HR, 0.99) and had an overall response rate of 0%. Additional phase II investigations2–5 using cetuximab alone or with various chemotherapeutic agents in patients with advanced colorectal cancer also reported a negligible response rate in patients whose cancers contained mutant KRAS. Clinical results have recently been reported from four large, mature, multi-institutional, randomized clinical trials in which anti-EGFR antibodies were added to chemotherapy in approximately 1,500 untreated patients with advanced colorectal cancer and with defined KRAS status. The relevant outcomes data from these trials are listed in Table 1.
The Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS)7 and Capecitabine, Irinotecan, Oxaliplatin (CAIRO II)8 studies used oxaliplatin combined with fluoropyrimidine-based chemotherapy with or without cetuximab. Both studies demonstrate a reduction in response rate and PFS, as well as survival for CAIRO II, with the addition of the anti-EGFR antibody in patients whose cancers possess mutant KRAS and little if any additional benefit in PFS for patients with wild-type KRAS. Both the Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL)9 and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE)10 investigations, using irinotecan-based chemotherapy, similarly demonstrate a decrement in benefit with the addition of the anti-EGFR antibody in patients with mutant KRAS tumors, although the effect is more modest, particularly with regard to PFS. Why might there be a decrement in benefit with the addition of anti-EGFR antibodies to chemotherapy in patients with mutant KRAS–containing cancers, particularly with oxaliplatin-based chemotherapy? Given that the negative trends occur in four independent trials with only two invariable constituents, namely a fluoropyrimidine and the anti-EGFR antibody, one hypothesis that could explain the clinical observation is a negative interaction at the cellular level between EGFR inhibition and the fluoropyrimidine. The greater negative effect with oxaliplatin versus irinotecan may be the result of oxaliplatin's greater dependence on FU for its clinical activity. Preclinical investigations, as well as the study in the second-line setting reported by Rothenberg et al,11 clearly support the concept that the addition of FU to oxaliplatin results in greater than an additive interaction, whereas the single-agent activity of oxaliplatin is modest, particularly in contrast to irinotecan, which has respectable single-agent activity in patients with advanced colorectal cancer.12 The additional benefit of adding cetuximab to single-agent irinotecan in the Bowel Oncology Cetuximab Antibody (BOND) trial13 also suggests that any negative interaction between the anti-EGFR antibody and chemotherapy is related to the presence of a fluoropyrimidine in the regimen. The proposed antagonistic interaction between fluoropyrimidines and anti-EGFR antibodies may be explained by the fact that FU requires metabolically active cells in which to undergo the requisite multistep anabolism to the active forms of the drug.14 In wild-type KRAS cells, the anti-EGFR antibody may effectively control malignant cell growth, overshadowing a possible negative interaction between the antibody and chemotherapy. In KRAS-mutated cells, with no benefit from the anti-EGFR antibody, antagonism with chemotherapy becomes more apparent. KRAS-activating mutation might be expected to prevent growth inhibition by EGFR inhibitors, given that the mutation occurs downstream of the normal activating events at the EGFR receptor. If KRAS mutation is sufficient to drive rapid cell growth and division, then EGFR inhibitors would not interfere with fluropyrimidine-mediated cell death. Data from the laboratory indicate that this is not the case; cetuximab is able to effectively slow the growth of some KRAS-mutated cell lines.15 EGFR signaling activates SRC and STAT proteins as well as the MAPK and PI3K/AKT pathways16; growth inhibition by EGFR antagonists could operate by downregulation of one or more of these pathways. Thus, the normal EGFR-mediated activation of additional signaling pathways may be necessary for continued tumor cell growth. Resistance to cetuximab growth inhibition was seen in both cell lines and a single-agent cetuximab clinical trial when pathway-activating mutations in both the KRAS and PI3K/AKT pathway were present.15,17 The PI3K/AKT pathway is mutated in 40% of colorectal tumors.18 Identifying subsets of colon cancer patients by additional mutations will doubtless yield additional predictive data. Of note, sensitivity to FU was unaffected by KRAS status both in cell lines16 and in patients treated with FU alone.19 There are clinical trials of combined growth factor inhibitors and chemotherapy in rectal, breast, and lung cancer that emphasize the potential risks of such combinations. Cetuximab added to capecitabine plus oxaliplatin (CAPOX) and radiotherapy has an apparently inferior rate of pathologic complete remission (pCR) when compared with CAPOX/radiotherapy-alone trials for rectal cancer. Phase II neoadjuvant CAPOX/radiotherapy studies yielded pCR rates of 16% to 23%,20,21 whereas the pCR rate decreased to 9% with cetuximab.22 A decrease in pCR from 20%23 to 5%24 also apparently results from adding cetuximab to capecitabine/radiotherapy. With the caution that these are cross-trial comparisons and there is no information on KRAS mutation status presented, these results support a possible negative interaction between cetuximab and fluoropyrimidines. An analogous scenario has been reported with breast cancer therapy. Tamoxifen, targeting the estrogen receptor (ER), has been studied both concurrently and sequentially with a variety of chemotherapeutic agents. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-0925 compared tamoxifen added to melphalan (L-PAM) and FU versus chemotherapy alone in the adjuvant breast setting. There was a trend toward a negative effect of tamoxifen in those ER-positive patients younger than 50 years, a population where a weaker clinical impact of tamoxifen could be overshadowed by interference with the benefit of chemotherapy. Antagonism between tamoxifen and both L-PAM and FU was subsequently demonstrated in vitro,26 probably related to interference with cellular uptake of the former, and tamoxifen-induced growth arrest interfering with cell cycle–dependent killing by the latter. More recently, the INT0100/SWOG-881427 trial examined the concurrent versus sequential use of tamoxifen with adjuvant breast cancer chemotherapy, clearly favoring the latter approach. The data in metastatic breast cancer are less clear,28 but there is little evidence for an additive benefit to concurrent chemotherapy/ER blockade in ER-positive patients, suggesting an antagonism between the biologic and cytotoxic agents. Trastuzumab, targeting HER-2, has been combined with a number of chemotherapy agents, all of which have demonstrated an apparent clinical benefit with the addition of the antibody. Preclinical investigation of trastuzumab and chemotherapy combinations using breast cancer cell lines led to the identification of synergistic, additive, and antagonistic interactions.29,30 Not surprisingly, FU was the only drug which was antagonized by trastuzumab in vitro and failed to show additional benefit from antibody addition against xenograft tumors versus FU alone. A separate study demonstrated antagonism between trastuzumab and both FU and 5'dFUrd, the initial metabolite of capecitabine, in a HER-2–positive/ER-negative cell line. Interestingly, the data with capecitabine are contradictory; one study showed lack of antagonism using a HER-2–positive/ER-positive cell line, but this finding could not be repeated by others.30,31 Clinically, capecitabine/trastuzumab combinations have been more effective than either agent alone, but it remains an open issue as to whether the combination is more or less than additive. A recently reported phase III comparison of capecitabine versus capecitabine and trastuzumab favored the latter.32 Lapatinib, which inhibits the tyrosine kinase activity of both EGFR and HER-2, augments the benefit of capecitabine when administered to herceptin-refractory metastatic breast cancer patients.33 The potential antagonism between FU and trastuzumab has not been tested clinically. There is a large clinical experience with combined cytotoxic chemotherapy and the tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and more recently, sorafenib in the treatment of lung cancer.34–38 These trials used continuous TKI administration with simultaneous chemotherapy (except for the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC [ESCAPE] trial, which paused sorafenib for chemotherapy administration) to no advantage. Foreshadowing the above hypothesis from the colon cancer trials, subset analysis of KRAS-mutated lung tumors in the Tarceva Responses in Conjunction With Paclitaxel and Carboplatin (TRIBUTE) trial demonstrated a worse outcome if erlotinib was added to carboplatinum and paclitaxel,39 although this conclusion is hedged by the limited number of patients in each arm. The failure of TKIs to augment the cytotoxicity of chemotherapy in lung cancer led back to the bench, where studies demonstrated the importance of the schedule association of the TKI and paclitaxel, with a 2-day exposure to the TKI followed by paclitaxel providing the best benefit in a xenograft model of this combination.40 Other drug combinations favor cytotoxic chemotherapy first, then the TKI, to maximize response.41 These studies emphasize the need to consider the impact of cell cycle arrest by biologic agents when combined with cytotoxics. Even with separation of therapy, there are unexpected results. For example, the paradoxical 1-year shortening of overall survival with the addition of gefitinib after definitive chemoradiotherapy for stage III lung cancer in Southwest Oncology Group (SWOG) 0023, a phenomenon that was not a result of drug toxicity, is difficult to rationalize.42 The growth inhibitory effects of the anti-EGFR agents are well established. Cetuximab and erlotinib, as well as trastuzumab and tamoxifen, have been shown to induce G1 arrest in treated cancer cells.43–46 Although this is the most likely cause for any negative interaction with cell cycle–dependent chemotherapy, other interactions have been observed. Trastuzumab-treated cells have been shown to downregulate DNA repair, potentially accounting for the synergistic effect observed with carboplatinum.47 Cetuximab has also been shown to downregulate an EGFR-stimulated endonuclease, resulting in increased toxicity of topoisomerase 1 inhibitors, a phenomenon that has been observed clinically with irinotecan.13,48 Further adding to the complexity of interaction between biologic therapies and cytotoxics, chemotherapy can affect the targets of growth factor inhibitors, as demonstrated by chemotherapy-mediated upregulation of EGFR increasing sensitivity to anti-EGFR therapy in vitro.49 Combinations of biologically based targeted agents and more traditional chemotherapeutic agents are increasingly the norm, but the history of such combinations includes both successes and failures, generating as many questions as answers.50,51 The interactions between biologics and cytotoxics will vary with the different agents applied and the distinctive biology of the patient's tumor. Preclinical data using artificial systems do not necessarily predict clinical results; as new knowledge and trial results emerge, the availability of stored patient materials that will expedite analysis of tissues with well-documented clinical data sets will be essential. The recent colon cancer trials, with the suggestion of antagonism between cetuximab and fluoropyrimidines, particularly in the KRAS-mutated population, remind us of the need to anticipate possible adverse outcomes when combining biologic and cytotoxic therapy. Clinical results with growth factor inhibitors also raise questions about the significance of their target pathways in the cancer cell—questions best explored in the laboratory.
The author(s) indicated no potential conflicts of interest.
Conception and design: Stephen Staal, Carmen J. Allegra Administrative support: Stephen Staal Collection and assembly of data: Stephen Staal Data analysis and interpretation: Stephen Staal, Michael J. O'Connell, Carmen J. Allegra Manuscript writing: Stephen Staal, Michael J. O'Connell, Carmen J. Allegra Final approval of manuscript: Stephen Staal, Michael J. O'Connell, Carmen J. Allegra
1. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634, 2008. 2. De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515, 2008. 3. Di Fiore F, Blanchard F, Charbonnier F, et al: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166–1169, 2007.[CrossRef][Medline] 4. Lièvre A, Bachet JB, Boige V, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379, 2008. 5. Lièvre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995, 2006. 6. Vogelstein B, Fearon ER, Hamilton SR, et al: Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532, 1988.[Abstract] 7. Bokemeyer C, Bondarenko I, Hartmann JT, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:178s; 2008 (suppl) abstr 4000. 8. Punt CJ, Tol J, Rodenburg CJ, et al: Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC): The CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 26:180s; 2008 (suppl) abstr LBA4011. 9. Van Cutsem E, Lang I, D'Haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:5s; 2008 (suppl) abstr 2.[CrossRef] 10. Hecht Jr, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin (ox)/bevacizumab (bev) +/– panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE) Presented at American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, Orlando, FL, January 25-27, 2007. 11. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059–2069, 2003. 12. Rothenberg ML: CPT-11: An original spectrum of clinical activity. Semin Oncol 23:21–26, 1996.[Medline] 13. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345, 2004. 14. Grem JL: 5-fluorouracil: Forty-plus and still ticking—A review of its preclinical and clinical development. Invest New Drugs 18:299–313, 2000.[CrossRef][Medline] 15. Jhawer M, Goel S, Wilson AJ, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961, 2008. 16. Scaltriti M, Baselga J: The epidermal growth factor receptor pathway: A model for targeted therapy. Clin Cancer Res 12:5268–5272, 2006. 17. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145, 2007.[CrossRef][Medline] 18. Parsons DW, Wang TL, Samuels Y, et al: Colorectal cancer: Mutations in a signalling pathway. Nature 436:792; 2005.[CrossRef][Medline] 19. Etienne-Grimaldi MC, Formento JL, Francoual M, et al: K-ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 14:4830–4835, 2008. 20. Rödel C, Liersch T, Hermann RM, et al: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:110–117, 2007. 21. Koeberle D, Burkhard R, von Moos R, et al: Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer 98:1204–1209, 2008.[CrossRef][Medline] 22. Rödel C, Arnold D, Hipp M, et al: Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70:1081–1086, 2008.[Medline] 23. Dupuis O, Vie B, Lledo G, et al: Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: A GERCOR phase II study. Oncology 73:169–176, 2007.[CrossRef][Medline] 24. Machiels JP, Sempoux C, Scalliet P, et al: Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738–744, 2007. 25. Fisher B, Redmond C, Brown A, et al: Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project trial. J Clin Oncol 4:459–471, 1986. 26. Osborne CK, Kitten L, Arteaga CL: Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens. J Clin Oncol 7:710–717, 1989.[Abstract] 27. Albain KS, Green SJ, Ravidin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37a; 2002 abstr 143. 28. Fossati R, Confalonieri C, Torri V, et al: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16:3439–3460, 1998.[Abstract] 29. Pegram M, Hsu S, Lewis G, et al: Inhibitory effects of combinations of HER-2. Oncogene 18:2241–2251, 1999.[CrossRef][Medline] 30. Pegram MD, Konecny GE, O'Callaghan C, et al: Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 96:739–749, 2004. 31. Fujimoto-Ouchi K, Sekiguchi F, Tanaka Y: Antitumor activity of combinations of anti-HER-2 antibody trastuzumab and oral fluoropyrimidines capecitabine. Cancer Chemother Pharmacol 49:211–216, 2002.[CrossRef][Medline] 32. Von Minckwitz G, Vogel P, Schmidt M, et al: Trastuzumab treatment beyond progression in patients with HER-2 positive metastatic breast cancer. Breast Cancer Res Treat 106: 2007 (suppl) abstr 4056. 33. Cameron D, Casey M, Press M, et al: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543, 2008.[CrossRef][Medline] 34. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non–small-cell lung cancer: A phase III trial–INTACT 1. J Clin Oncol 22:777–784, 2004. 35. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non–small-cell lung cancer: A phase III trial–INTACT 2. J Clin Oncol 22:785–794, 2004. 36. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol 23:5892–5899, 2005. 37. Gatzemeier U, Pluzanska A, Szczesna A, et al: Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non–small-cell lung cancer: The Tarceva lung cancer investigation trial. J Clin Oncol 25:1545–1552, 2007. 38. Scagliotti G, von Pawel J, Reck M, et al: Sorafenib plus carboplatin/paclitaxel in chemonaive patients with stage IIIB-IV non-small cell lung cancer: Interim analysis results from the phase III randomized, double-blind, placebo-controlled, ESCAPE trial. J Thoracic Oncol 3:1s; 2008 (suppl) abstr 2750.[CrossRef] 39. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900–5909, 2005. 40. Solit DB, She Y, Lobo J, et al: Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 11:1983–1989, 2005. 41. Mahaffey CM, Davies AM, Lara PN Jr, et al: Schedule-dependent apoptosis in K-ras mutant non–small-cell lung cancer cell lines treated with docetaxel and erlotinib: Rationale for pharmacodynamic separation. Clin Lung Cancer 8:548–553, 2007.[CrossRef][Medline] 42. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450–2456, 2008. 43. Sutherland RL, Green MD, Hall RE, et al: Tamoxifen induces accumulation of MCF 7 human mammary carcinoma cells in the G0. Eur J Cancer Clin Oncol 19:615–621, 1983.[CrossRef][Medline] 44. Peng D, Fan Z, Lu Y, et al: Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res 56:3666–3669, 1996. 45. Lenferink AE, Busse D, Flanagan WM, et al: ErbB2. Cancer Res 61:6583–6591, 2001. 46. Ling YH, Li T, Yuan Z, et al: Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and nuclear translocation in association with cell growth inhibition and G1. Mol Pharmacol 72:248–258, 2007. 47. Pegram MD, Slamon DJ: Combination therapy with trastuzumab (herceptin) and cisplatin for chemoresistant metastatic breast cancer: Evidence for receptor-enhanced chemosensitivity. Semin Oncol 26:89–95, 1999.[Medline] 48. Vigneron A, Gamelin E, Coqueret O: The EGFR-STAT3 oncogenic pathway up-regulates the Eme1 endonuclease to reduce DNA damage after topoisomerase I inhibition. Cancer Res 68:815–825, 2008. 49. Van Schaeybroeck S, Karaiskou-McCaul A, Kelly D, et al: Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res 11:7480–7489, 2005. 50. Johnson DH: Targeted therapies in combination with chemotherapy in non–small-cell lung cancer. Clin Cancer Res 12:4451s–4457s, 2006. 51. Milano G, Spano J, Leyland-Jones B: EGFR-targeting drugs in combination with cytotoxic agents: From bench to bedside, a contrasted reality. Br J Cancer 99:1–5, 2008.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
AUTHORS' DISCLOSURES OF...
