Molecular Profiles Guide Colorectal Cancer Treatment
PIK3CA mutations. Phosphoinositide 3-kinase (PI3K) is a lipid kinase important for multiple cellular processes including cell growth, proliferation, survival, and apoptosis. PIK3CA encodes the catalytic subunit and is mutant in about 20% of mCRC.26 The PI3K is downstream of EGFR signaling; activation of this pathway in the setting of an oncogenic mutation might lead to resistance to anti-EGFR therapies. Sartore-Bianchi and colleagues examined 110 patients with mCRC treated with either panitumumab or cetuximab.27 Of these, 15 patient cancers featured PIK3CA mutations, and none of these responded to anti-EGFR therapies. In addition, preclinical studies have demonstrated that targeting CRC downstream of PI3K might result in significant treatment benefit.28,29
Human epidermal growth factor receptor 2 (HER2) amplification. A subpopulation of CRC with amplification of HER2, a growth factor receptor commonly used in selecting treatment options in breast cancer, has recently been described. The HERACLES phase 2 study evaluated dual HER2 targeting with lapatinib and trastuzumab in therapy-refractory mCRC with HER2 amplification.30 A RR of 35% was observed in this treatment-refractory population.
BRAF mutations. In addition to predicting a poor prognosis and resistance to EGFR-directed therapies, BRAF mutations might be predictive of treatment response using combination regimens containing RAF inhibitors. A recent phase 1B study of a combination therapy using the BRAF inhibitor vemurafenib with irinotecan and cetuximab observed a partial RR of 35%.31 This is being investigated further in the Southwest Oncology Group 1406 phase 2 trial.
Mismatch repair deficiency. Detection of microsatellite instability or the presence of mismatch repair deficiency has become standard-of-care testing for CRC. This is important for the detection of Lynch syndrome and predicting potential resistance to adjuvant 5-fluorouracil in the adjuvant setting.32,33 A recent clinical trial has demonstrated benefits for the use of programmed death 1 (PD-1) inhibitors in the setting of mismatch repair deficiency, including a RR of 40% and PFS of 5.4 months.34
Discussion
Metastatic CRC is now better understood as a collection of multiple cancer subtypes based on mutational profile. This improved understanding of the biology of CRC is altering treatment strategies to a precision medicine-based approach. It is now the standard of care for all patients with mCRC to have the cancers assayed for mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF. Anti-EGFR therapies should not be used for patients with RAS or BRAF mutations outside of a clinical trial because of a demonstrated lack of benefit in all lines of therapy. Currently, there is no evidence that these mutations significantly alter the response to the approved anti-angiogenic agents bevacizumab, aflibercept, ramucirumab, and regorafenib.
The timing of EGFR-directed therapies for patients with wild-type KRAS, NRAS, and BRAF is still being debated. According to the available data, first-line treatment with anti-EGFR agents in combination with FOLFOX or FOLFIRI (5-fluorouracil, irinotecan, and leucovorin) should be considered for all patients with KRAS, NRAS, and BRAF wild-type mCRCs. The toxicities of anti-EGFR therapies also should be considered for this setting, as some patients find that the acneiform rash, fatigue, nausea, and diarrhea that occur with these agents can have a negative impact on quality of life. As there is no improvement in OS with first-line anti-EGFR therapies for these patients, the increased toxicity from these agents limits their use. In addition, patients with mCRC with known PIK3CA mutation should consider use of EGFR-directed therapies only in the later line setting.
Research is focused on how to best use the mutational profile of the tumor to tailor therapies for mCRC. High-quality, large-volume data sets will become more important as molecular subtypes of cancer become more narrowly defined and less common. Further investigations are needed to look for other markers of resistance and to identify biomarkers predictive of treatment sensitivity.
This is an exciting time in the treatment of many cancers, especially mCRC, which significantly impacts the veteran population, because routine DNA sequencing of patient samples has allowed for rapid advances in the realization of precision medicine. This allows for improved patient selection to reduce costs and toxicities while increasing the benefit for veterans.
Acknowledgments
This work was supported by the National Institutes of Health (P30 CA014520, Core Grant, University of Wisconsin Carbone Cancer Center).
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
