On Monday, April 25th, Fight Colorectal Cancer held a free patient webinar that tackled the somewhat complex but fascinating topic of personalized medicine.

Personalized medicine is what the cancer community calls treatments that are tailored to each patient’s genetic makeup. It is the future of cancer care and in some cases, it is already making a big difference in the ways patients are treated.

You can learn about these cutting edge treatments and about emerging findings in an archive of the webinar below.

Our thanks to Carolyn Grande, CRNP, AOCNP for leading the discussion. She a phenomenal educator on this topic and a member of our Medical Advisory Board. She graciously donated her time to bring this information to patients.

Medicine that is tailored to each patient’s genetic makeup is the future of cancer care. In some cases, it is already making a big difference in the ways patients are treated. Learn about these cutting edge treatments and about emerging findings that will be important for future diagnoses and treatments of colorectal cancer. Discussion led by Carolyn Grande, CRNP, AOCNP.

Patients with colon cancer have learned over the last two years that we have now a genetic marker which can predict efficacy of antibodies against EGFR which are used in patients with metastatic colon cancer.

We have learned that tumors with mutations in KRAS will not benefit from this treatment. All patients should be tested for KRAS mutation if they have advanced or metastatic disease.

However patients who have mutations of the KRAS gene don’t do worse than patients with wild type. The only difference is that the drugs which target EGFR will not work.

We really have had no marker which identifies patients who have a tumor which is very aggressive and grows independently of whatever treatment we initiate. Recent data suggest we may have identified a marker like this. The marker is called BRAF.

Only about 5 percent of patients with metastatic disease carry a mutation in this gene. Preliminary studies suggest that patients with tumors harboring this mutation do much worse. However more studies are needed to validate these findings.

The reason I am sharing this with you is because we have now therapies available which may inhibit this particular mutation. BRAF mutations are common in melanomas and bile duct cancers, and recent developments show that we may have very powerful inhibitors for patients with this mutation.

In our practice we are screening for these mutations since we have a number of clinical trials allowing patients to be tested with a BRAF inhibitor.

Please discuss these options with your oncologist if your first line therapy is not working to see  if you are eligible for clinical trials when you have either a mutant KRAS or mutant BRAF gene in your tumor.

For stage II and III colon cancer, a tumor mutation in the KRAS gene does not impact either relapse-free survival or overall survival.

BRAF mutations, which are less common, don’t help with prognosis for relapse-free survival, but do provide information about overall survival in some tumors.   Patients with BRAF mutations and microsatellite-low or stable tumors had poorer overall survival than those without mutations.

As colon cancer develops, changes in genes accumulate that affect cell division and cell death.  When cells no longer divide or die normally, tumors get larger and some cells may break off and move to new and dangerous sites.

In earlier studies, changes in the KRAS and BRAF genes have been able to predict whether or not advanced colorectal cancer would respond to drugs that target epidermal growth factor receptors (EGFR).  Patients with tumors that have mutated KRAS or BRAF don’t benefit from either Erbitux® (cetuximab) or Vectibix™ (panitumumab).

But it has been unclear whether mutations in these two genes can provide information about whether early stage II or III colon cancer would recur or what the mutations meant for eventual survival.

Using over 1,400 tumor specimens collected during a large, randomized trial of chemotherapy for stage II and III colon cancer, researchers were able to analyze KRAS and BRAF mutations and their impact on both relapse-free and overall survival.  The scientists also looked at microsatellite instability (MSI) and coordinated it with the KRAS and BRAF results.  They had good long-term information about patient relapse and survival.

About 1 in 3 tumors (37 percent) had a KRAS mutation, similar to the percentages found in other studies in metastatic colorectal cancer.  7.9 percent had a BRAF mutation, and the two mutations were mutually exclusive.  Neither KRAS nor BRAF mutations differed between stages II or III.

KRAS mutations

• Were significantly more frequent in l0w-grade tumors and right-sided tumors.
• Were borderline more common in microsatellite-low and microsatellite-stable tumors.
• Did not predict relapse-free survival or overall survival.

BRAF mutations

• Were more frequent in right-sided tumors, high-grade tumors, and tumors that were MSI-high.
• Were more frequent in patients over 60 and in women.
• Did not predict relapse-free survival.
• Did predict poorer overall survival, particularly in patients with MSI-low or MSI-stable tumors.

Arnaud D. Roth, MD and his colleagues concluded,

In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

SOURCE:  Roth et al., Journal of Clinical Oncology, Early Release, December 14, 2009.

Another mutated gene has been discovered that appears to cause resistance to treatment with the EGFR inhibitors Erbitux® (cetuximab) and  Vectibix™ (panitumumab).

Only a fraction of patients who receive Erbitux or Vectibix respond to it.  There is now convincing evidence that the 30 to 40 percent of colorectal cancer patients whose tumors have mutated KRAS genes don’t benefit, but what about others who have normal or wild-type KRAS and don’t respond either?

Scientists in Italy have found that about 12 percent of wild-type patients have a mutation in their tumor’s BRAF gene, and these patients showed no response to Erbitux or Vectibix.

Testing 113 colorectal cancer tumors from patients who had been treated with either Erbitux or Vectibix, they found 30 percent had a KRAS mutation.  Going further, they tested the remaining 79 tumors for a mutation in BRAF.  Patients with mutated BRAF showed no response to the EGFR inhibiting drugs.  None had tumors shrink, and they had a shorter time until their cancer got worse and shorter survival.

All of the patients who did respond to Erbitux or Vectibix had normal or wild-type BRAF.

Dr Federica Di Nicolantonio, from the University of Turin School of Medicine said,

None of the patients with tumours containing BRAF mutations had responded to the treatment, and in cases where the treatment did work, none of those patients had BRAF mutations. This shows that for anti-EGFR therapy to work, the BRAF gene must be the wild type and suggests that BRAF status could be a useful biomarker for selecting patients suitable for anti-EGFR treatment.

In a laboratory experiment, cells that contained mutated BRAF had a dramatically reduced response to cetuximab and panitumumab, but when they were also treated with the BRAF inhibitor sorafenib (Nexavar®), the cells died.

Dr. Di Nicolantonio said,

These findings suggest that combination therapy that simultaneously blocks EGFR and BRAF in patients with BRAF-mutated tumours may be a useful approach to increase the number of patients who could benefit from anti- EGFR therapy, but that remains to be assessed in a clinical trial.

Despite finding another gene that stops response to EGFR inhibiting drugs, the picture isn’t yet complete. More than half of patients who had no response to Erbitux or Vectibix didn’t have mutations in either KRAS or BRAF.

Dr. Di Nicolantonio adds,

This research does not complete the picture of resistance to EGFR inhibitors. In spite of the predictive value of both KRAS and BRAF mutations, in our cohort 52 per cent of non-responsive patients did not have mutations in either gene. This means further molecular markers are needed to better define patients who are unlikely to benefit from EGFR-targeted treatment.

SOURCES: The research was reported by Federica Di Nicolantonio and her colleagues on October 23, 2008 at the Molecular Targets and Cancer Therapeutics Symposium, jointly sponsored by EORTC, NCI, and AACR in Geneva.

Di Nicolantonio et al., Journal of Clinical Oncology, Online ahead of print, November 10, 2008.