Guest blogger, John Tentler, Ph.D. from the University of Colorado School of Medicine highlights the importance of biomarkers in colorectal cancer treatment decisions with the hope of advancing the science as researchers have in other cancers.
All Cancers are Not the Same
With the emergence of new technologies, such as next generation DNA sequencing, the complex molecular landscapes of cancer are being revealed and it is becoming ever more apparent that all cancers are not the same, even within a particular cancer type.
Indeed, it has long been appreciated that there are several types of breast cancer, with further subtypes within those categories. These discoveries have in turn dramatically changed oncology practice with regard to diagnosis, prognosis, and treatment decisions. For example, all breast cancer patients are now routinely tested for expression of the estrogen receptor, progesterone receptor and HER2 to guide treatment options. These genes are examples of biological markers, or “biomarkers,” which are increasingly being used by oncologists to stratify patients into subgroups to help guide treatment strategies, effectively implementing a “personalized medicine” approach.
Colorectal Cancer Biomarkers
More recently, concerted efforts have been directed towards identifying predictive biomarkers of response to therapeutics in colorectal cancer (CRC), some of which are now being incorporated into oncology practice. Currently, the following biomarkers are being used to guide treatment decisions for CRC patients:
The RAS oncogenes: KRAS and NRAS
Most frequently mutated genes in CRC, with KRAS in up to 50% of cases.
RAS is a molecular on/off switch regulating a key pathway controlling cell division.
Typically RAS is activated by a cell surface receptor such as the epidermal growth factor receptor or EGFR. However, if RAS is mutated it is stuck in the “on” state and therapies directed at EGFR such as cetuximab and panitumumab will be ineffective as EGFR is no longer controlling RAS.
Another signaling enzyme downstream of RAS in this pathway is BRAF (pronounced B-RAF).
While mutations in BRAF are less common than RAS, it is a biomarker of poor prognosis in CRC. Because of this, more aggressive chemotherapy regimens, as well as surgery and radiation may be considered.
Patients who have microsatellite instability or MSI (high) have a defect in normal DNA repair mechanisms that result in high mutation rates.
A patient with MSI may have Lynch syndrome which needs to be confirmed by formal laboratory testing.
If the MSI CRC patient is stage II or III, the prognosis is better and they may not benefit from adjuvant (additional) chemotherapy such as 5-FU. If they are MSI and stage IV, studies have shown that they may be responsive to immunotherapies, such nivolumab (anti-PD-1).
Finally, PI3 kinase (PI3CK) mutations are present in approximately 15-20% of colorectal cancers. Studies have indicated that these patients may benefit from aspirin therapy following surgical resection. However, testing for this mutation is not standard of care at present.
It should be noted that while these biomarkers have resulted in more effective and longer-lasting responses to therapies, not all patients will respond predictably to treatment.
Despite our advances in biomarker discovery in CRC, ongoing research is actively seeking to identify additional markers to bring this disease to the point that breast oncology has reached. We anticipate further study results of predictive biomarkers to best identify individuals who will benefit from specific forms of treatment. The breast cancer community has done an excellent job with standardizing biomarker testing to make it widely uniform and available for patients. By learning from these successes, we hope to make these advances a reality in the CRC community.
Fight Colorectal Cancer is involved in all areas of colorectal cancer research, ranging from basic biology, prevention, treatment and survivorship. It’s our commitment to stay on top of the most pressing issues. Learn more about how to get involved in colorectal cancer research and sign up for the latest updates.