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Molecular Profiling in CRC
My Thoughts on Molecular Profiling in Colorectal Cancer

Released: May 03, 2016

Expiration: May 02, 2017

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For most oncologists who treat patients with a wide range of malignancies, it can be a challenge to learn the unique genetic story for each tumor type. Because I specialize in gastrointestinal tumors, including colon cancer, my colleagues routinely ask me for advice on using molecular profiling to inform frontline treatment decisions for patients with colon cancer. Here is my approach for patients with unresectable, metastatic colorectal cancer.

In my practice, I perform molecular profiling on every patient with metastatic colon cancer. In fact, I recommend molecular profiling for all patients with colon cancer. My reasoning is 2-fold. First, it is important to identify very early on those patients with microsatellite instability and mismatch repair deficiency because they are candidates for an ongoing clinical trial of frontline therapy with single-agent pembrolizumab, which is an immune checkpoint inhibitor. Second, I want to know my patients’ RAS and BRAF status, as both of these may help determine the optimal frontline treatment. Once I know the results of these genetic tests, I can then proceed with a decision on first-line treatment.

In the absence of any of the above molecular alterations, my starting point for frontline treatment is oxaliplatin and fluoropyrimidine plus bevacizumab. I like this regimen because there is not much hair loss with oxaliplatin, and starting here somewhat forces me to proceed to a maintenance therapy, which I think is a good long-term strategy. Another practical reason that I favor this regimen is that I want my patients to remain eligible for second-line clinical trials if necessary, and most of these include irinotecan and exclude patients with previous irinotecan. Thus, by choosing oxaliplatin for frontline treatment, I am preserving the possibility of referring my patients who might need subsequent treatment to a clinical trial.

If a patient with unresectable metastatic colorectal cancer tests positive for microsatellite instability and mismatch repair deficiency, I currently refer the patient to an ongoing clinical trial of single-agent pembrolizumab or any number of other immune therapy–based trials. Previous trials have demonstrated that single-agent immune checkpoint inhibitors provide substantial benefit for patients with microsatellite instability and mismatch repair deficiency who are refractory to other treatments. Based on these findings and other successful frontline trials of immune checkpoint inhibitors in melanoma, lung cancer, and kidney cancer, I am hopeful that these drugs will be effective enough in the frontline setting that patients will be able to avoid or postpone chemotherapy. Although this is a rare subgroup of patients with colorectal cancer (approximately 10%), it is important to know this information right from the start.

By now, we all understand that patients with RAS mutations are unlikely to benefit from treatment with EGFR inhibitors (cetuximab and panitumumab). Thus, for patients who test positive for RAS mutations, bevacizumab is the biologic of choice. For those with a RAS wild-type tumor, I then decide between bevacizumab or an EFGR inhibitor. To this end, I consider comorbidities and patient preferences. I inform my patients that rash is the primary adverse event of EGFR inhibitors, but they have excellent response rates. For patients with cardiovascular problems or those who are at risk of perforation, I might favor an EGFR inhibitor.

BRAF mutations are associated with a poor prognosis. Although these mutations are not common (5% to 10% of patients with colorectal cancer), there is growing evidence that a combination of bevacizumab and FOLFIRINOX is an optimal frontline option for these patients. I would certainly consider this regimen for patients with BRAF mutations, particularly given that this combination has been shown to be superior even in an unenriched patient population.

Your Thoughts?
How do you use molecular profiling when selecting first-line therapy for patients with unresectable metastatic colorectal cancer? I invite you to post your thoughts and questions in the comments section below, and check back soon for my next ClinicalThought™ commentary on metastatic colorectal cancer.