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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4217-4219 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.7286
Mutations of KRAS and BRAF in Primary and Matched Metastatic Sites of Colorectal CancerFalck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy
Division of Pathology, Ospedale Niguarda Ca’ Granda, Milan, Italy
Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy
Division of Pathology, Ospedale Niguarda Ca’ Granda, Milan, Italy
Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy To the Editor: After the demonstration that KRAS or BRAF mutations in colorectal cancer (CRC) are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR) –targeted monoclonal antibodies,1-3 the clinical confirmation of these findings in independent retrospective reports4,5 as well as in a phase III trial recently published in Journal of Clinical Oncology has led the European Medicines Agency to license panitumumab and cetuximab only for patients with CRC without KRAS mutations.6,7 Nevertheless, among patients with wild-type KRAS CRC, the objective response rate is limited to 17% (v 0% in unselected patients) with panitumumab monotherapy8 and to 59% and 61% (v 43% and 33% in unselected patients) with cetuximab plus either irinotecan- or oxaliplatin-based chemotherapy, respectively.9,10 These data indicate that other mechanisms of resistance play a significant role. Moreover, evaluation of metastatic rather than primary sites could be of clinical relevance because occurrence of a mutation in the metastasis could, at least theoretically, explain resistance despite a wild-type primary tumor. Scarce and heterogeneous reports have evaluated whether KRAS status matches in primary tumor and metastatic site(s),11-14 whereas BRAF remains unexplored. For these reasons, we elected to evaluate KRAS (exon 2) and BRAF (exon 15) by DNA sequencing in a cohort of 48 CRC patients (median age, 56 years; range, 37 to 79 years; 28 men and 20 women) in primary tumor (colon, n = 32; rectum, n = 7; and sigma-rectum junction, n = 9) and matched metastases (liver, n = 39; ovary, n = 2; distant lymph nodes, n = 1; adrenal gland, n = 1; pancreas, n = 1; lung, n =2; omentum, n = 1; and pelvic mass, n = 1). DNA sequencing showed a frequency of mutation in the primary tumor or metastases of 13 (27%) of 48 and two (4%) of 48 patients for KRAS and BRAF, respectively. None of the patients carried both mutations (in primary tumor or metastasis); the occurrence of the mutations was a mutually exclusive phenomenon, as expected by literature.15 We observed an overall concordance of KRAS and BRAF mutational status (ie, mutated or wild type) between primary tumor and metastasis in 44 (92%) of 48 patients. In patients carrying a KRAS mutation, concordance between primary tumor and secondary deposits was observed in 10 (77%) of 13 patients, all but one of whom presented with synchronous metastases (Table 1). Discordance of KRAS mutational status was detected in three (23%) of 13 patients with mutations, with one patient carrying KRAS mutation in the primary tumor only and two patients carrying the mutation in the metastatic site only (pancreas and adrenal gland). Notably, occurrence of KRAS mutations with wild-type primary tumor was detected in extrahepatic sites only. In the two patients carrying BRAF mutation, one patient presented the same mutation in both primary tumor and metastasis, whereas the other patient presented the mutation in the primary tumor site only.
Controversial and heterogeneous previous reports11-14 demonstrated overall concordance between KRAS mutations in the primary tumor and secondary deposits in CRC, indicating that KRAS mutations are not essential for the attainment of metastatic capacity. In a previous study, Oudejans et al11 evaluated 39 patients and found, in three patients, a KRAS point mutation in the metastasis with a wild-type primary tumor, whereas in a single patient, a point mutation was found in a primary tumor but was absent from the metastasis. Moreover, these investigators did not find differences in frequency of KRAS mutations between 23 patients with isolated lung metastases and 20 patients with liver metastases (57% and 50%, respectively), demonstrating that KRAS oncogene activation does not have a major role in determining the frequency of lung metastases versus liver metastases. Suchy et al12 demonstrated the concordance of KRAS mutations in primary tumors and respective metastases in 15 patients, and the type of mutation was also identical in the instance of different metastases from the same primary tumor localized in different organs, indicating a stability of these mutations during metastatic progression. In a series from 1998, Al-Mulla et al13 reported that only two (8%) of 26 metastatic patients had a mutation in their primary carcinoma but none in liver metastases. In contrast with these data showing overall identity of KRAS mutations between primary tumor and matched metastatic deposits, Tórtola et al14 described discordance between KRAS mutation in bone marrow micrometastases and primary tumor. In particular, in six patients with primary tumor mutations, the pattern of KRAS mutation differed in three patients, and in one patient the same mutation plus a different one were found; moreover, in eight patients, there was a mutation in the primary tumor and none in bone marrow metastases. In the present cohort, we took into consideration KRAS and BRAF mutations because alterations of both of these cellular effectors can impair response to anti-EGFR therapy. For both genetic alterations, we observed overall concordance between primary tumor and metastasis in the vast majority of patients. Present findings represent additional knowledge supporting the notion that a concordance of KRAS and BRAF status is the most common feature in CRC. The clinical relevance of these data is that evaluation of the KRAS and BRAF mutations can be performed in either primary tumor or metastatic site(s) and that absence of such mutations could be enough to drive the selection of metastatic CRC patients who are candidates for anti-EGFR monoclonal antibody therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported in part by research grants from Oncologia Ca’ Granda Onlus Fondazione; and Associazione Italiana per la Ricerca sul Cancro, Milan, Italy. REFERENCES 1. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 2. 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 3. 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 4. 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] 5. 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 6. European Medicines Agency: Questions and answers on the marketing authorisation for Vectibix. http://www.emea.europa.eu/pdfs/human/opinion/40511307en.pdf 7. European Medicines Agency: Committee for Medicinal Products for Human Use post-authorisation summary of positive opinion for Erbitux. http://www.emea.europa.eu/pdfs/human/opinion/Erbitux_28040208en.pdf 8. 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 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. 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) 11. Oudejans JJ, Slebos RJ, Zoetmulder FA, et al: Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer 49:875-879, 1991[Medline] 12. Suchy B, Zietz C, Rabes HM: K-ras point mutations in human colorectal carcinomas: Relation to aneuploidy and metastasis. Int J Cancer 52:30-33, 1992[Medline] 13. Al-Mulla F, Going JJ, Sowden ET, et al: 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 185:130-138, 1998[CrossRef][Medline] 14. Tórtola S, Steinert R, Hantschick M, et al: Discordance between K-ras mutations in bone marrow micrometastases and the primary tumor in colorectal cancer. J Clin Oncol 19:2837-2843, 2001 15. Rajagopalan H, Bardelli A, Lengauer C, et al: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934, 2002[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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