Adjuvant systemic therapy following surgical resection of a stage II colorectal cancer (CRC) has long been an area of controversy. The National Comprehensive Cancer Network recommends that decision making regarding adjuvant chemotherapy for stage II CRC patients should be discussed with the patient and include individual disease characteristics and treatments, including clinical trials and their possible toxicities.1 As the era of personalized medicine continues to expand, researchers are attempting to identify tumor characteristics that can predictively identify patients who would receive the greatest benefit from adjuvant therapy.
Hutchins and colleagues recently published an original report evaluating the usefulness of defective mismatch repair (dMMR), BRAF and KRAS mutation in predicting tumor recurrence and sensitivity to chemotherapy.2 Immunohistochemistry for dMMR and pyrosequencing for KRAS and BRAF were conducted on 1,913 patients in the Quick and Simple and Reliable (QUASAR) trial, which was a CRC randomized trial evaluating fluorouracil and folinic acid chemotherapy or no chemotherapy in low-risk (node negative) stage II CRC.
Of the 1,913 patients analyzed for MMR status, 218 (11%) were dMMR. KRAS status of 1,583 patients revealed 542 (34%) were KRAS mutant and 1,041 (66%) wild-type. BRAF status was obtained for 1,584 patients, 125 (8%) patients were mutant and 1,459 (92%) were wild-type. A summary of the risk of recurrence among the groups were as follows:
- Defective MMR tumors were about half that for MMR-proficient (pMMR) (11% vs. 26%)
- KRAS mutant tumors were significantly higher than wild-type tumors (28% vs. 21%)
- BRAF mutant and wild-type tumors did not differ significantly (19% v. 24%)
- Those who received fluorouracil and folinic acid had significantly lower risk than the observation group
- The reduced risk of recurrence with chemotherapy was not significantly different in dMMR and pMMR, KRAS mutant and wild-type, or BRAF mutant and wild-type
The authors concluded that MMR assays identified patients with a low risk of recurrence and that KRAS status provides useful information to guide use of chemotherapy.
Retrospective analysis across several randomized clinical trials, suggested that epidermal growth factor receptor inhibitors (EGFR-Is) are not effective in treating metastatic CRC patients with KRAS mutant tumors.3,4 These results led to the change in drug labeling for both cetuximab and panitumumab indicating that use of these agents was not recommended in treatment of CRC with KRAS mutations. Additionally, it was the springboard for moving research forward in rightly identifying the appropriate patients for the appropriate therapy.
In the midst of challenging economic times, skyrocketing drug therapy costs and the desire for the most optimal medical outcomes, progress in identifying predictive markers is integral to achieving the desired results for patients while minimizing undue risk. To that end, Hutchins and colleagues have continued to move the bar forward through their work with biomarkers to predict recurrence and therapy response in stage II CRC patients, where it has traditionally been challenging to determine who would derive the most benefit from adjuvant therapy.
National Comprehensive Cancer Network. Colorectal Cancer Version 3.2011. Available at: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf Free registration required.
Hutchins, G, Southward, K, Handley, K, et al. Value of mismatch repair, KRAS and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011; 29: 1261-1270. doi:10.1200/JCO.2010.30.1366 Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/21383284
Amado, RG, Wolf, M, Peeters, M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colon cancer. J Clin Oncol 2008; 26:1626-1634. doi:10.1200/jco.2007.14.7116 Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/18316791
DeRoock, W, Piessevaux, H, DeSchutter, J et al. (2008). KRAS wild-type state predicts survival and is associated with early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol, 2008; 19:508-515. doi:10.1093/annonc/mdm496 Link to free full text article: http://annonc.oxfordjournals.org/content/19/3/508.long