Testing for codons 12 and 13 on the KRAS gene and BRAF testing can predict whether patients with colorectal cancer will respond to anti–epidermal growth factor receptor (EGFR) therapies. However, genetic alterations not captured by testing for KRAS codon 12 and 13 mutations may play an important role in determining response to therapy for colorectal cancer.
‘Think Beyond KRAS Mutations’
“KRAS is the most dominant mutated RAS member in the tumors of patients with colorectal cancer, and it is commonly mutated in codons 12 and 13. But other mutations not routinely tested in KRAS or mutations in the NRAS gene may be present. Think beyond KRAS mutations,” said Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. “These are important mutations biologically. Genetic profiling should be expanded to include other KRAS mutations and NRAS mutations [ie, codons 12, 13, 59, 61, 117, and 146 in the KRAS and NRAS genes],” he told listeners at the Chemotherapy Foundation Symposium XXXI, held recently in New York.1
“These extended KRAS and NRAS mutations are also transforming in vitro. These mutations are mutually exclusive with KRAS codons 12 and 13 mutations. If we can better define a responsive population, then everybody wins. We can provide therapy that is more effective with less toxicity, and it would ultimately be more cost-effective. We will better deploy our weapons against colorectal cancer,” Dr. Kopetz commented.
Prevalence of KRAS Mutations
KRAS codons 12 and 13 mutations are present in 40% of patients with colorectal cancer. However, KRAS exon 3 and 4 and NRAS exon 1, 2, 3, and 4 mutations are present in about 16% of KRAS wild-type tumors and are of clinical significance.
The phase III PRIME trial evaluated treatment with FOLFOX4 (leucovorin, fluorouracil [5-FU], and oxaliplatin) with or without panitumumab (Vectibix) in patients with colorectal cancer. Extended RAS testing found that additional mutations beyond codons 12 and 13 were predictive of therapeutic outcome. Panitumumab was beneficial in patients with wild-type RAS and potentially harmful in those with extended KRAS and NRAS mutations.2
“This one study provided compelling data that when we take patients we would have considered KRAS wild-type and treat them with our current drugs, we may be harming them,” he told listeners. “As this finding has recently been replicated, we now feel confident that these data should change clinical practice.”
Data from the phase III FIRE-3 study presented at the 2013 European Cancer Congress showed that most patients with wild-type KRAS treated with FOLFIRI (leucovorin, 5-FU, and irinotecan) plus cetuximab (Erbitux) or bevacizumab (Avastin) had an overall survival benefit of 3.7 months. A retrospective analysis found that in patients with no mutations in KRAS codons 12 and 13, expanded KRAS and NRAS testing revealed other mutations associated with a trend toward a decrement in benefit. In patients found to have RAS wild-type tumors on extended profiling, the median survival difference in favor of the cetuximab-containing regimen was 7.5 months.3
“This supports the concept that if we can better profile our patients, we can improve outcomes,” Dr. Kopetz said.
Expanded KRAS and NRAS testing was found to have significance in three studies, including the PRIME trial, the FIRE-3 trial, and a study of single-agent panitumumab vs best supportive care.4 Results are awaited from the Cancer and Leukemia Group B
(CALGB)/Southwest Oncology Group (SWOG) 80405 study.
PIK3CA as Biomarker
New data suggest that PIK3CA is a potential biomarker for the benefit of aspirin in stage II/III colorectal cancer. PIK3CA mutations are present in about 15% to 20% of colorectal cancer patients, Dr. Kopetz continued. In a cohort of 964 patients with colorectal cancer from the Nurses’ Health Study and the Health Professionals Follow-Up Study, patients with mutated PIK3CA tumors who were regular aspirin users had a striking decrease in the probability of death. This effect was not seen in patients with wild-type PIK3CA tumors.5
A separate study called VICTOR confirmed that the PIK3CA mutation was associated with a reduced rate of colorectal cancer recurrence in patients taking regular aspirin after diagnosis, whereas recurrence was not reduced in those with PIK3CA wild-type who used aspirin.6
“These are intriguing data, but there are a number of questions, including how much aspirin is optimal, the required duration of treatment, and what is the mechanism,” Dr. Kopetz said.
The standard of care is to test for KRAS codons 12 and 13, BRAF, and microsatellite instability. “In my opinion, it is time to extend KRAS testing, perform NRAS testing, and start testing for PIK3CA and aspirin therapy,” he stated.
“For those who want to adopt this now, testing is available. For those who are more conservative, it is reasonable to wait for a prospective randomized controlled trial of aspirin intervention, which is being considered currently,” he added.
Breast cancer has taken the lead in developing a taxonomy based on luminal and basal cell origin, as an example. The taxonomy of colorectal cancer has lagged behind, but increasing evidence suggests that serrated adenoma, BRAF-mutated, microsatellite instability, and epithelial-mesenchymal transition are emerging subtypes.
“There may be multiple other subtypes. We struggle with this in colorectal cancer. There is no consensus yet,” he said. ■
Disclosure: Dr. Kopetz is on advisory boards for Roche/Genentech, Amgen, and Bristol-Myers Squibb.
1. Kopetz S: Molecular profiling in CRC. 2013 Chemotherapy Foundation Symposium. Presented November 6, 2013.
2. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013.
3. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013.
4. Oliner KS, Douillard J-Y, Siena S, et al: Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). 2013 ASCO Annual Meeting. Abstract 3511. Presented June 4, 2013.
5. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012.
6. Domingo E, Church DN, Sieber O, et al: Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J Clin Oncol. September 23, 2013 (early release online).