This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Lièvre, A. Articles by Laurent-Puig, P. PubMed Articles by Lièvre, A. Articles by Laurent-Puig, P.

In Reply

Astrid Lièvre, Pierre Laurent-Puig

INSERM U775; Université Paris Descartes; and Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France

In their letter, Garassino et al stated that our study¹ did not allow us to make any conclusion regarding the prognostic value of KRAS mutations on response to cetuximab, given that the majority of the patients analyzed received a combination of cetuximab and chemotherapy (irinotecan). However, according to the US Food and Drug Administration guidelines, all of the patients who received cetuximab (± irinotecan) in our study had previously progressed under irinotecan-based chemotherapy and also, for some of them, under oxaliplatin-based chemotherapy. The prognostic value of KRAS mutations concerns, therefore, only cetuximab because all of the patients had disease progression under irinotecan. Moreover, it has been shown that KRAS mutations did not predict response to fluorouracil- based chemotherapy,^2,3 nor to bevacizumab⁴ in metastatic colorectal cancer (CRC) patients. Finally, other independent studies^5-8 also found an association between KRAS mutations and lack of response to cetuximab and/or poorer survival in chemorefractory metastatic CRC patients (Table 1). One must also take into account the results of the recent published study by Amado et al,¹¹ which tested the effect of panitumumab monotherapy according to KRAS status in 427 of the 463 patients included in a phase III randomized study comparing panitumumab with best supportive care.¹² KRAS mutations were significantly associated with lack of response to panitumumab alone and a poorer progression-free survival (hazard ratio = 0.45; 95% CI, 0.34 to 0.59), which was similar in KRAS-mutated patients receiving panitumumab and in those with best supportive care. These results led to the registration of panitumumab by the European Medicines Agency (EMEA) in chemorefractory metastatic CRC patients whose tumors are not KRAS mutated.

In our study, KRAS mutations were searched either on metastatic tissue (27%) or on primary colorectal tumor depending on the tumor tissue available for each patient. This attitude is consistent with the perfect concordance of KRAS mutations that was observed between primary tumor and liver metastases in a series of 96 metastatic CRC patients, among whom 48 were analyzed both in liver metastases and matched primary tumors.²

In conclusion, there is a convergence of relevant results concerning the prognostic and predictive value of KRAS mutations on response to cetuximab in metastatic CRC. As it was specified in the conclusion of our article, these results require confirmation in a randomized trial comparing an experimental arm containing cetuximab with a control arm without this targeted therapy.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Pierre Laurent-Puig, Amgen France (C) Stock Ownership: None Honoraria: Astrid Lièvre, Merck Lipha Santé; Pierre Laurent-Puig, Amgen France, Merck Lipha Santé Research Funding: Pierre Laurent-Puig, Amgen France, Merck Lipha Santé Expert Testimony: None Other Remuneration: Astrid Lièvre, Merck Lipha Santé; Pierre Laurent-Puig, Amgen France

NOTES

published online ahead of print at www.jco.org on April 28, 2008

REFERENCES

1. 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[Abstract/Free Full Text]

2. 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 (in press)

3. Rosty C, Chazal M, Etienne MC, et al: Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: Relationship with response to 5-fluorouracil and survival. Int J Cancer 95:162-167, 2001[CrossRef][Medline]

4. Ince WL, Jubb AM, Holden SN, et al: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981-989, 2005[Abstract/Free Full Text]

5. 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[Abstract/Free Full Text]

6. 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]

7. 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]

8. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007[Abstract/Free Full Text]

9. 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[Abstract/Free Full Text]

10. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: 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 67:2643-2648, 2007[Abstract/Free Full Text]

11. 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[Abstract/Free Full Text]

12. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007[Abstract/Free Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Lièvre, A. Articles by Laurent-Puig, P. PubMed Articles by Lièvre, A. Articles by Laurent-Puig, P.