Scope of the Problem
In colorectal cancer (CRC), Kristen rat sarcoma (KRAS) has been the most notable biomarker advance in terms of predictive value for treatment with epidermal growth factor receptor inhibitors (EGFRIs). Retrospective analysis across several randomized clinical trials, suggest that EGFRIs are not effective in treating metastatic CRC (mCRC) patients with KRAS mutant tumors (Amado et al, 2008). The National Comprehensive Cancer Network (NCCN) identifies KRAS as a predictive biomarker and has incorporated recommendations for the determination of the KRAS gene status of either the primary tumor or a site of metastasis for a patient with mCRC at diagnosis. KRAS mutations occur early in the formation of CRC and there is strong concordance between mutation status of the primary and metastatic tumor (NCCN, 2011). Baas and colleagues (2011) conducted a literature search of studies that tested concordance of mutational status between primary tumors and metastases in CRC patients, particularly focusing on KRAS BRAF, PIK3CA and loss of PTEN in order to make recommendations for mutational testing in standard clinical practice.
- Twenty-one studies reported concordance of KRAS with an overall concordance rate of 93% (range = 76% - 100%)
- A subanalysis of KRAS in primary tumors and hepatic versus extrahepatic metastasis showed a concordance rate of 95% for hepatic and 86% for extrahepatic metastasis. Concordance of hepatic metastases and lymph node metastases was 95% versus 84% suggesting a discordance with the primary tumor occurs more frequently with lymph node metastases
- An additional subanalysis was performed with regard to concordance in patients with primary wild-type (WT) versus primary mutation (MT) to ascertain whether the primary tumor mutational status predicts discordance. Discordance was found to occur in 14% of patients with KRAS MT compared with 5% of patients with KRAS WT tumors
- Overall concordance of BRAF status and loss of PTEN were 98% and 68% respectively
- The range of PIK3CA status concordance was 89% - 94%
The authors (Baas et al, 2011) concluded that discordance of KRAS status can occur albeit infrequently. They also noted that testing the primary tumor or any tumor tissue available is adequate for clinical decision making regarding use of EGFRIs.
In 2008, the advent of data supporting the KRAS mutational status as influential to mCRC patients’ response to EGFRI therapy was practice-changing. More remarkable was that the standard of care in treating these patients changed based on retrospective data leading to the American Society of Clinical Oncology (ASCO) Provisional Clinical Opinion (PCO) recommendation that KRAS testing be performed for all patients with mCRC who are candidates for EGFRI therapy (Allegra, 2009). Both ASCO and NCCN guidelines recommend that cetuximab or panitumumab should only be given to patients with KRAS wild-type tumors. The question of whether there is concordance of KRAS in primary and metastatic tumor is imperative as some patients with metastatic disease, particularly those with recurrent disease, may not have readily accessible tissue or may not be able to undergo a procedure to access tumor sampling. As research continues to evaluate the impact of predictive biomarkers on comprehensive clinical treatment decision – making, treatment will be designed based on unique disease characteristics. This approach will enable greater certainty of the potential of therapeutic response.
Allegra, C., Jessup, J.M., Somerfield, M.R., Hamilton, S.R., Hammond, E.H., Hayes, D.F., …Schilsky, R.L. (2009). American Society of Clinical Oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor monoclonal antibody therapy. Journal of Clinical Oncology, 27, 2091-2096. doi: 10.1200/JCO.2009.21.9170 Link to free full text http://jco.ascopubs.org/content/27/12/2091.full.pdf+html
Amado, R.G., Wolf, M., Peeters, M., VanCutsem, E., Siena, S., Freeman, T.J.,…Chang, D.D. (2008). Wild-type K-ras is required for panitumumab efficacy in patients with metastatic colon cancer. Journal of Clinical Oncology, 26:1626-1634. doi:10.1200/jco.2007.14.7116 Link to free full text http://jco.ascopubs.org/content/26/10/1626.full.pdf+html
Baas, J.A., Krens, L.L., Guchelaar, H-J., Morreau, H., Gelderblom, H. (2011). Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: A review. Oncologist, July 8; epub ahead of print. doi: 10.1634/theoncologist.2011-0024 Link to free full text: http://theoncologist.alphamedpress.org/content/early/2011/07/08/theoncologist.2011-0024.long Free registration required.
National Comprehensive Cancer Network (NCCN). (2011). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) Colon Cancer v 1.2012. Available at https://subscriptions.nccn.org/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf Free registration required.