(1) Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington DC, USA
* Corresponding author Email:
Recent and rapid advancements made in our understanding of the biology of colorectal cancer (CRC) has pointed towards a more personalized way of treating cancer, utilizing targeted treatment based on the tumour molecular profile. Epidermal Growth Factor Receptor (EGFR) has been found to play an important role in CRC tumorigenesis with its activation stimulating key signal transduction cascades involved in tumour growth and progression. Cetuximab and panitumumab are monoclonal antibodies that inhibit EGFR activation, leading to inhibition of downstream signalling. Both agents have been approved in the setting of metastatic CRC. KRAS mutations have been established to be negative predictors of response to these EGFR-targeted therapies. However, 40-60% of wild-type KRAS cases do not respond to anti-EGFR therapy, suggesting the involvement of other genes that act downstream of EGFR such as BRAF, NRAS or PI3K, that may be causative for the lack of response to anti-EGFR antibodies.
In this article, we review the current literature investigating the potential predictive or prognostic values of these molecular biomarkers that are downstream of EGFR.
Tumour molecular profiling is integral to treatment personalization in CRC. Identifying predictive and prognostic biomarkers help to tailor therapy by better patient selection, in order to maximize clinical outcomes and minimize exposure to unnecessary toxicity. Most of the data presented show the need for selection strategies beyond the current reliance on KRAS to include biomarkers downstream of EGFR. However, as the data have been mostly exploratory and retrospective in nature, the clinical significance of these molecular markers will need to be validated in prospective, randomized clinical trials.