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Originally published as JCO Early Release 10.1200/JCO.2008.20.1525 on December 1 2008 © 2009 American Society of Clinical Oncology.
KRAS Mutations and Anti–Epidermal Growth Factor Receptor Therapy in Colorectal Cancer With Lymph Node Metastases
Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto; and Faculty of Medicine, University of Porto, Porto, Portugal To the Editor: We read the report by Artale et al1 published last month. Their results are interesting, considering, in particular, the recent interest in applying anti–epidermal growth factor receptor (EGFR) therapy to treat metastatic colorectal cancer (mCRC). Cetuximab and panitumumab are EGFR monoclonal antibodies that, alone or in combination with chemotherapy agents, have been shown to be helpful in the treatment of patients with mCRC.2,3 Although a significant proportion of these patients have had good response rates, and increased progression-free and overall survival, with the treatment, others have had a modest or even a complete absence of response to the therapeutics.3 KRAS gene mutations are being pointed out as a possible molecular diagnostic marker to predict the sensitivity of tumors to anti-EGFR therapeutics. Patients with tumors harboring KRAS mutations show a lower response rate, and decreased progression-free and overall survival, compared with those patients with KRAS wild-type (KRAS-WT) tumors.4-12 Moreover, it has been demonstrated that the gene expression pattern of KRAS-mutant tumors overlaps with the expression pattern of cetuximab-nonresponsive tumors.13 Nevertheless, among patients with KRAS-WT tumors, a significant percentage do not respond to anti-EGFR therapeutics.4-12 With the aim of clarifying the reason for this lack of effectiveness, Artale et al analyzed the KRAS and BRAF mutational status in primary tumors and respective distant metastases in 48 CRC patients. Our view of the rationale underlying this study is that, in the context of a KRAS-WT primary tumor, the presence of a KRAS mutation in distant metastasis could represent an important and hidden factor conferring resistance to the treatment. But in contrast to this hypothesis, Artale et al reported an overall concordance regarding KRAS and BRAF mutations between the primary tumor and respective distant metastasis (92% of the patients). However, the same was not verified for primary colorectal tumors and respective lymph node (LN) metastases. Last year, our group published analyses of KRAS and BRAF mutations in a series of 250 sporadic CRCs (132 LN negative and 118 LN positive), and 45 LN metastases in 28 individual patients.14 In our series of primary CRC and LN metastases, we verified a different scenario from that described by Artale et al in primary CRC and distant metastases. LN metastases from our series displayed higher frequency (82.1%) of either concomitant or isolated mutation in KRAS and BRAF genes than primary carcinomas (55%). Furthermore, 43.5% of the LN metastases did not share the mutation pattern with the primary tumor. Two LN metastases lost a KRAS mutation, seven acquired KRAS mutations, and a single LN metastasis acquired a BRAF mutation. On the basis of these results, with a focus on KRAS mutations, we have demonstrated that a considerable fraction of CRC LN metastases do not resemble the respective primary tumors. The reasons that may underlie these findings are fully described in our article, but in summary, we believe that a KRAS mutation can either be acquired during metastasis to the LNs, as in our study, or be part of a heterogeneous population of neoplastic cells that constitutes the bulk of the primary tumor. These results are of fundamental importance, because they may represent one of the resistance mechanisms interfering with the response of patients with KRAS-WT mCRC to anti-EGFR monoclonal antibody therapy. We have written this letter because we believe that our results should be taken into consideration if KRAS screening is used as a tool to select patients for administration of this type of therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by Portuguese Foundation for Science and Technology (PTDC/SAU-OBD/68310/2006). NOTES published online ahead of print at www.jco.org on December 1, 2008 REFERENCES
1. Artale S, Sartore-Bianchi A, Veronese S, et al: Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 26:4217-4219, 2008 2. Jonker D, O’Callaghan C, Karapetis C, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040-2048, 2007 3. 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 4. Ng K, Zhu A: Targeting the epidermal growth factor receptor in metastatic colorectal cancer. Crit Rev Oncol Hematol 65:8-20, 2008[CrossRef][Medline] 5. Raponi M, Winkler H, Dracopoli N: KRAS mutations predict response to EGFR inhibitors. Curr Opin Pharmacol 8:413-418, 2008[CrossRef][Medline] 6. Lièvre A, Bachet J, 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 7. Lièvre A, Bachet J, Corre DL, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006 8. 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] 9. 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 10. Amado R, 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 11. Benvenuti S, Sartore-Bianchi A, Nicolantonio FD, 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 12. Freeman D, Juan T, Reiner M, et al: Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer 7:184-190, 2008[CrossRef][Medline] 13. de Reyniès A, Boige V, Milano G, et al: KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signature. J Clin Oncol 26:2228-2230, 2008 14. Oliveira C, Velho S, Moutinho C, et al: KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene 26:158-163, 2007[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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