It was originally hoped that the presence of mutations in KRAS and other related genes would provide an easy answer as to whether to administer anti-EGFR antibody therapy to a given metastatic colorectal cancer patient. However, in nature nothing is simple, and there are a number of issues that practicing clinicians should be made aware of.
Colorectal cancer (CRC) continues to be a major public health problem in the United States and throughout the world. In 2014, in the United States, CRC will be diagnosed in nearly 148,000 new patients and will account for close to 50,000 deaths.
As reviewed very nicely by Sridharan et al in this issue of ONCOLOGY, over the past 10 to 15 years, impressive advances have been made in the medical treatment of metastatic CRC (mCRC). Three new cytotoxic agents, five new targeted agents, and a whole host of combination regimens have been introduced. Great advances have also been made in our understanding of the critical signaling pathways that mediate the growth and proliferation of tumors, and we are now able to apply the latest advances in molecular diagnostic techniques to determine the molecular characteristics of a given tumor type, which can, increasingly, guide treatment selection.
With respect to mCRC, the presence of KRAS mutations has been shown to be a highly specific negative predictive biomarker of clinical response to anti-EGFR (epidermal growth factor receptor) antibody therapy. However, it should be emphasized that the presence of a wild-type (WT) KRAS genotype does not ensure that a patient will respond to anti-EGFR antibody therapy. In fact, it is estimated that up to 65% of patients whose tumors express WT KRAS will still be resistant to anti-EGFR antibody therapy. As a result of all of the clinical data collected, several other molecular biomarkers, in addition to KRAS, have been identified that should be used as part of the decision-making process. Based on these studies, our molecular diagnostic lab is routinely testing for BRAF, NRAS, and PIK3CA mutations, as there is now growing evidence that the presence of each of these genetic mutations is associated with a significantly reduced response to anti-EGFR antibody therapy. In the absence of mutations in these four genes, our lab is subsequently performing next-generation sequencing using the Ion Torrent AmpliSeq Cancer Panel, a process in which > 2,000 mutations in a panel of 50 genes are interrogated in order to identify the presence of other mutational events.
It was originally hoped that the presence of mutations in KRAS and other related genes would provide an easy answer as to whether to administer anti-EGFR antibody therapy to a given mCRC patient. However, in nature nothing is simple, and there are a number of issues that practicing clinicians should be made aware of. First and foremost is the issue of tumor heterogeneity, which is present on several different levels. Although not well investigated, there is growing evidence that there can be discordant mutational status between the primary and metastatic tumors. There certainly can also be heterogeneity of KRAS genotype within the same tumor, much as has been recently reported in renal cell cancer. Over time and in response to treatment with chemotherapy with or without biological agents, there can be a shift in KRAS mutational status. Another important issue to consider relates to the potential for artifactual mutations, which can occur, in large part as a result of fragmentation of DNA during tissue processing. In this regard, the experience and reliability of the molecular pathology laboratory is critically important. Finally, one needs to consider accessibility of tumor tissue so that this type of genetic analysis can be performed. For this reason, serious efforts are now focused on using peripheral blood as a “liquid biopsy” to determine the presence of circulating mutated tumor DNA prior to and during therapy.
There remain several technical hurdles to overcome with respect to mutational analysis, and the complicated tumor biology requires further elucidation. However, the hope is that the tremendous advances in molecular tumor profiling will eventually enable us to prescribe individually tailored therapy to our patients with mCRC. Even so, a critical rate-limiting factor for the ultimate success of personalized medicine is the ready availability of novel targeted agents directed at specific tumor mutations, and in this regard, much work remains to be done.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Sridharan M, Hubbard JM, Grothey A. Colorectal cancer: how emerging molecular understanding affects treatment decisions. Oncology (Williston Park). 2014;28:110-8.