Individualized Treatment Needed for Patients With NRAS-Mutated mCRC

Maria Ignez Braghiroli, MD

Activating, hotspot mutations in the NRAS gene occur in a small subset of patients with metastatic colorectal cancer (mCRC). These mutations are now being identified in routine clinical practice by extended RAS genotyping.

Maria Ignez Braghiroli, MD, and her colleagues recently published the results of a study in which the investigators sought to identify the clinical and molecular characteristics of patients with NRAS-mutated mCRC. These findings were presented at the 2016 ESMO Congress.

The results demonstrated that NRAS-mutant mCRC is an aggressive subset of CRC, with worse overall survival rates than that of patients with RAS wild-type tumors or KRAS-mutant mCRC.

The researchers also found that NRAS mutations define a clinically distinct subgroup of mCRC with increased left-sided colon primary tumors.

OncLive: Can you tell us about clinical characteristics of patients with mCRC harboring NRAS mutations?

You excluded patients with KRAS mutations. How would that have affected the results?

What would you say the current treatment paradigm is for NRAS-mutant metastatic colorectal cancer?

How much would you say mutation status affects the individual treatment of patients with colorectal cancer?

In an interview with OncLive, Braghiroli, medical oncologist, Instituto do Câncer do Estado de São Paulo, discusses the current treatment paradigm for these patients and the need for more individualized treatment approaches in this setting.Braghiroli: We've been trying to molecularly characterize the type of tumors, and possibly try to individualize treatment. What we did is we selected all the colorectal cancer patients that were found to have NRAS mutations from 2008 to 2015 that were treated at Memorial Sloan Kettering. We found a total of 87 patients, and we had to exclude 3 patients because they had concurrent KRAS mutations and we wanted the patients with NRAS mutations only. Then we compared this population in terms of clinical characteristics, molecular characteristics, and outcomes to treatment in the population with KRAS mutations and all RAS wild type tumors.We don't really know, and that's why we excluded only 3 that had both the NRAS and KRAS mutations. That's why we didn't include them in the NRAS-mutated patients only.Basically, we know that anti-EGFR medications don't work for KRAS-mutant patients and also the NRAS-mutant patients. These are the smaller proportion of patients with colorectal cancer, around 3% to 7%. That's why we don't really know what happens to this specific subtype of RAS mutation patients, and that is why we were looking into it.Specifically for the RAS-mutated patients, we know that they do not respond to the anti-EGFR mutations. In general, we know that maybe BRAF-mutated patients have a much worse prognosis, and the studies currently focused on BRAF inhibitors or MEK inhibitors, or a combination of BRAF, MEK, and anti-EGFR inhibitors in these patients. That is actually being performed at Memorial Sloan Kettering also. A small subtype of patients actually have an amplification of HER2, for example, and they might benefit from anti-HER2 treatment.

Are there any ongoing or planned studies in this space that you are particularly excited about?

What do you hope to see in the next 5 to 10 years in the treatment of colorectal cancer?

What role does sidedness play in CRC?

There is also a sub-population that has its microsatellite stability, and maybe this population benefits from immunotherapy. So we are tending to find a small, specific subtypes of tumors, and then individualize their treatment in this way.There are many studies in immunotherapy. I think this is very interesting, and so far for the sporadic type of colorectal cancer, we seem to not have very good results, so I think studies focusing on that will be very interesting.Immunotherapy is one thing. I think we might understand left or right sided, and if this is really important for patients and if that has any implication for treatment. Hopefully, we'll have newer medications with more consistent improvement in survival, and maybe earlier detection via colonoscopy. It's not an easy procedure to perform for the patients, and there have been ongoing studies on fecal identification of tumor cells. That, or maybe blood identification of tumor cells to try to find them earlier.There has been some evidence that patients with right-sided tumors may have a worse prognosis than patients with left-sided tumors. In our population with NRAS-mutated patients, the patients did worse than all RAS wild-type tumors, but interestingly, they had more left-sided tumors than right-sided tumors. This is still a matter of research.

Braghiroli MI, Chou JF, Hechtman JF, et al. Clinical characteristics and outcomes of patients with metastatic colorectal cancer (CRC) harboring NRAS mutations. Poster presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark.