Colorectal cancer (CRC) is the third leading cause of cancer-related death in veterans, despite significant advances in treatment options. 1,2 Over the past 20 years, the median survival of patients with metastatic CRC (mCRC), has improved with the most recent clinical trials demonstrating a median overall survival (OS) of up to 29 months. 3
In addition to standard chemotherapeutic regimens using 5-fluorouracil, oxaliplatin, and irinotecan, biologic therapies have resulted in improved OS for patients with mCRC. These therapies include the human vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. Additional agents, including aflibercept, ramucirumab, regorafenib, and TAS-102, also have been FDA approved for mCRC, though the OS benefit for these agents as part of the series of standard-of-care treatments is less clear.
Investigators continue to determine subtypes of CRC to further advance treatment options. The histologic classification of colon cancers is actually a collection of multiple cancer subtypes. Each subtype possesses a unique biology largely dependent on the mutations present within the cancer. Recent data, reviewed below, indicate predictive and prognostic benefits to understanding the unique mutational profile of mCRC. Here, the authors present a brief updated summary of these biomarkers and a discussion of treatment strategies.
Resistance to Anti-EGFR Therapies
KRAS and NRAS are members of the RAS family of oncogenes. Activating mutations in these genes results in the propagation of growth factor signals independent of EGFR. The most common KRAS mutations are found in exon 2 (codon 12 or 13). Numerous studies over the past 10 years have confirmed that KRAS mutations at exon 2 predict resistance to cetuximab and panitumumab. 4-11 Since at least 2009, restricting use of cetuximab and panitumumab has been the standard of care for patients with KRAS exon 2 wild-type cancers. 12
Recent investigations have indicated a predictive role for extended-spectrum KRAS and NRAS mutations ( KRAS mutations at exons 2, 3, and 4 and NRAS mutations at exons 2, 3, and 4). In the OPUS clinical trial, patients whose cancers possessed extended-spectrum RAS mutations received no benefit with the addition of cetuximab to standard chemotherapy in response rate (RR), progression-free survival (PFS), or OS compared with standard chemotherapy alone. 13 Interestingly, median OS was shorter for those treated with cetuximab when a RAS mutation was present, though the difference was not statistically significant. Additional studies also have confirmed similar benefits in different settings. 8,14-18
The CALGB/SWOG 80405 phase 3 clinical trial investigated the first-line use of biologic therapies in combination with standard chemotherapy. The extendedspectrum RAS testing from this study now has been presented. 3,19 In the RAS wild-type population, the median OS was 31.2 months in the chemotherapy plus bevacizumab arm and 32.0 months in the chemotherapy plus cetuximab arm (no significant difference). No difference in PFS was observed. A significant improvement in the RR was seen in the cetuximab arm for the RAS wild-type population.
Predictive Biomarkers
BRAF is an oncogene in the RAF gene family that encodes a serine-threonine protein kinase found in the Ras-Raf-MAPK cascade. About 10% of CRC harbor a BRAF mutation. 20,21 The most significant and prevalent mutation occurs at the kinase domain from the single substitution V600E. Numerous clinical studies have suggested the presence of this mutation as a predictor of resistance to anti-EGFR therapies and a marker of poor prognosis. 6,17,22-25 In a retrospective analysis of RAS and BRAF mutation status of PRIME study data, patients without RAS and BRAF mutations showed significantly better OS and PFS when treated with FOLFOX4 (5-fluorouracil, oxaliplatin, and leucovorin) plus panitumumab, compared with FOLFOX4 alone. 8 The presence of BRAF mutations in RAS wild-type patients resulted in a worse outcome. Treatment with anti-EGFR therapy did not significantly improve median PFS or OS.