The Role of Mutation Testing in mCRC

Wells Messersmith, MD:The patient is a 71-year-old who presented with left lower quadrant pain and bloody diarrhea. He presented to his primary care physician and a colonoscopy was ordered to work this up. He was found to have a mass in the descending colon. His CEA at baseline was 6.0, and he had an excellent performance status and was able to carry on all his daily activities without assistance. The tumor was biopsied and it showed adenocarcinoma. Full mutational testing was sent, includingKRAS,NRAS,BRAF, and he was not shown to have any mutations. CT of the chest, abdomen, and pelvis showed a mass in the descending colon, and he also had 2 lesions in the liver: 1 in the right lobe and 1 on the left lobe that was abiding the left hepatic vein. Treatment was initiated with FOLFIRI and bevacizumab, and imaging at 3 and 6 months showed decreased size of the lesions, but they were still not resectable.

This is a fairly typical patient with colorectal cancer on multiple points. First, his age. In colon cancer, the median age is about age 65, depending on what database you look at. So, having a 71-year-old is fairly typical. Second, it’s left-sided. The majority of colorectal cancers are left-sided tumors. The presentation is fairly typical in the sense that it often presents with abdominal pain and bleeding. Unfortunately, many patients are diagnosed with stage 4 disease, specifically unresectable or at least initially unresectable stage 4 disease. In many ways, this is a very typical patient that any oncologist, whether in an academic setting or the community, is going to see commonly in their clinic.

Mutational testing for newly diagnosed colorectal cancer is very important. In fact, I would argue you really can’t take care of a patient without those testing results. So, let’s talk about a couple of the things that we look for. First of all, we need to knowRASstatus, especially for a left-sided tumor, because you need to know if panitumumab or cetuximab have a role in the care of the patient. And it may even be used first-line on multiple guidelines, including NCCN. Knowing the mutational status ofKRASandNRASis extremely important in terms of the choices of chemotherapy. Secondly,BRAFstatus.BRAFis also important for prognosis because patients with aBRAFmutation don’t live as long as patients who are wild-type. And secondly, it might determine what type of treatment you use. In fact, the NCCN guidelines are being updated for patients withBRAF-mutated colorectal cancer.

Third, microsatellite testing also very important. There are 2 ways of testing for that. And remember, these are basically issues with DNA repair that can either be inherited, as in hereditary nonpolyposis colorectal cancer or also called Lynch syndrome, or it can be spontaneous actually in the tumor itself. And for patients who are microsatellite high—if you test by PCR—or if they have deficient mismatch repair—if you test by immunohistochemistry—those patients are eligible to receive immunotherapy. And, again, guidelines plus the FDA package insert for several drugs were changed to reflect this.

So, you really can’t take care of a colorectal cancer patient without knowingKRASandNRAS—and by that, I mean extendedKRASandNRAStesting. It used to be we only test codon 12 and 13, and now we know we need to test other codons. You need to knowBRAF,and you need to know MSI testing. And although that doesn’t have to be back before you start your initial therapy necessarily, you’re going to want to get that as easily as you can so that you’re not scrambling as you’re making therapeutic choices.

Transcript edited for clarity.

September 2015

• A 71-year-old Caucasian male presented with severe left lower quadrant pain
  • He sought medical treatment after experiencing bloody diarrhea
• PMH: hypertension, managed with benazepril
• He is active and can perform daily activities without restrictions
• Laboratory findings: remarkable for CEA, 6.0 ng/mL
• Colonoscopy showed a mass in the descending colon which was biopsied
  • Pathological findings: Moderately differentiated adenocarcinoma
• NGS mutation testing results wereNRAS, KRAS, HRAS, HER2,andBRAFwild-type
  • Microsatellite stable
• CT of the chest, abdominal, and pelvis showed an 8-cm mass in the sigmoid colon
  • a 2-cm mass in the right lobe of the liver, and a 5-cm in the left lobe adjacent to the left hepatic vein
  • Impression: metastatic disease, borderline resectable
• Treatment was initiated with FOLFIRI + bevacizumab
• Imaging at 3 and 6 months showed decreased size of the liver nodules, but was not resectable

July 2016

• The patient complained of increased fatigue, requiring the need for frequent rest
• CT scan showed increasing size of the liver nodule (3 cm) and appearance of 3 new small liver lesions (<2 cm)
• He began therapy with FOLFOX + bevacizumab

February 2017

• The patient reported weight loss, increasing fatigue, and shortness of breath
• CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number
• A new pulmonary nodule was seen in the right lung
• He was switched to irinotecan + cetuximab
• PET/CT at 3 months showed stable disease
• At 6 months, he reported moderate improvement in fatigue