KRAS-Mutated Metastatic CRC - Episode 1

Considerations for Managing an Atypical Patient With CRC

Cathy Eng, MD, FACP:So this is a 38-year-old female who’s been diagnosed with what appears to be a left-sided sigmoid colon carcinoma with multiple bilateral liver metastases. Her performance status is 0 and she’s treatment naïve. She appears to have undergone a sigmoid resection, and she’s been found to have aRASmutation, and she’s ready to initiate treatment.

This young woman, being 38 years old, is a bit atypical for presentation of metastatic colorectal cancer. Unfortunately this is something we are more commonly seeing nowadays, especially in large referral centers. The average-aged patient with colorectal carcinoma is in their early 60s, between ages 60 and 65. Traditionally, the standard of care for screening with colonoscopies used to be done in patients in their 50s, because we all know that with time benign polyps can become cancerous and that takes 5 to 8 years.

More recently though there’s been an alarming incidence of young patients that present with colorectal carcinoma, notably rectal tumors and left-sided tumors. It is believed that this incidence will continue to rise dramatically. As a result of these findings, and honestly this is something that we’ve all noticed in our clinics very early on, it’s now recommended that individuals start screening at the age of 45 instead of 50 years of age.

So she is completely an atypical patient, and we are concerned. Potentially, could she be associated with an inherited form of colorectal cancer? She does fit some of the typical demographics such as being a female and likely having poorly differentiated histology. But she does not have a right-sided tumor, which is more typical for HNPCC [hereditary nonpolyposis colorectal cancer], or Lynch syndrome. So this patient should definitely be tested for microsatellite instability [MSI], but my understanding is that she was MSI stable.

For any patient that presents with metastatic colorectal carcinoma, mutation analysis needs to be completed immediately, as soon as you meet with the patient. And that’s really the opportunity to do so. You don’t want to wait until the patient has failed frontline therapy before you’re trying to test their mutation status, specifically, as I mentioned earlier, MSI status, whether it be stable or high.

Next-generation sequencing is an optimal approach for some of our patients, especially if tissue is not readily available. But otherwise, we would test the tumor tissue. But the standard of care for most institutions involves aRASmutation analysis, not onlyKRAS, which is a more generalized test, but also the other rareRASmutations such asNRASandHRAS.

The patient should also be tested, as I mentioned earlier, for microsatellite instability. There’s also HER2/neu amplification, which is seen in less than 5% of all patients, but that is very critical to test for as well because that may indicate that the patient would not necessarily benefit from anti-EGFR therapy.

In addition, there’s also a new fusion protein that the patient should be tested for called NTRK, which is of great interest. That’s extremely rare. It’s seen in between 1% and 2% of all patients, but there is a drug that is available as well that targets that patient population.

We also test for theBRAFmutation. In this case, I wouldn’t necessarily order it because we already know that she isRAS-mutant, but all patients should be tested for theBRAFmutation as well. That is seen in less than 10% of all patients, and that’s a poor prognostic indicator. WhereasHER2is not a prognostic indicator but may be predictive of benefit of anti-EGFR therapy.

ForBRAF, we now have more focused treatment for those patients, and so we really want to make sure, because of the poor prognosis of those patients, that we provide targeted therapies to them whenever possible.

Transcript edited for clarity.


Case: A 38-year Old Woman WithKRAS-Mutated mCRC

Initial presentation

  • A 38-year old woman was referred to gastroenterology after experiencing several bouts of bloody diarrhea
  • PMH: unremarkable
  • PE: unremarkable

Clinical workup

  • Colonoscopy: suspicious sigmoid mass, partial obstruction
  • Biopsy: poorly differentiated adenocarcinoma
  • Imaging: CT scan of the chest/abdomen/pelvis revealed multiple small bilateral liver metastases
  • Molecular testing on tissue biopsy:
    • Positive forKRASexon 2 codon 12 mutation
    • Negative forNRAS,BRAF
    • Microsatellite-stable
  • Diagnosis: stage IV colorectal cancer
  • ECOG PS 0

Treatment

  • She underwent laparoscopic sigmoid resection
  • She was initiated on treatment with FOLFOX + bevacizumab; well-tolerated
  • Follow-up imaging at 3 and 6 months showed a partial response