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.

Researchers in the Netherlands tested both tumors for KRAS mutations in over 300 patients whose cancer had spread to their livers.

They found about a third of patients had KRAS mutations and KRAS status matched in 96 percent of the cases, making it possible to test either tumor to make decisions about treatment with Erbitux® (cetuximab) or Vectibix® (panitumumab)

Out of 305 tumors:

• 108 had a KRAS mutation in either the primary colorectal or metastatic liver tumor (35.4 percent)
• KRAS mutations didn’t match in 11 of the 108 (3.6 percent)
• Of those:
  • 5 had a wild-type (normal) primary and KRAS mutation in the liver metastasis
  • 1 had a KRAS mutated primary and the liver met was wild-type
  • 5 had different KRAS mutations in the primary and liver tumors.

Nikki Knijn and her team at the Nijmegen Medical Centre in the Netherlands concluded,

We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6–98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7–4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis.

SOURCE:  Knijn et al., British Journal of Cancer, Published online March 1, 2011.

Dr. Lenz

We are making significant progress in understanding what genetic alterations in tumors really mean.

Over the last two years, we have learned or the first time that there is an alteration in a gene called KRAS in colon cancer, and tumors which have this mutation do not respond to treatment with Erbitux® (cetuximab) or Vectibix® (panitumumab).

This is the first time we have a marker to test for sensitivity of an antibody we have to treat colon cancer.

It is very important to know that patients with tumors who carry a KRAS mutation (alteration) are not doing worse overall. They just don’t have any benefit from an antibody which targets the Epithelial Growth Factor Receptor (EGFR).

Only a few weeks ago, an international group showed for the first time that the different mutations we see in KRAS are not all the same. A mutation is usually a change in one spot (exon) on the gene, but it may happen at many different locations in the gene. The effect may be different depending on the location where it occurs.

Most of the KRAS mutations are in two areas, exon 12 and exon 13. Depending on their location these changes will have different impact on the protein function, and, therefore, maybe all will not  predict resistance to Erbitux.

The investigators have preliminary data that patients with tumor mutations in exon 13 may benefit from Erbitux. These are important findings and in the future may mean that patients with KRAS mutations in exon 13 may receive Erbitux therapy.

In my practice I am making sure that I identify all these patients, who are up to 20% of all patients with KRAS mutations. In the next couple of months, we will have more information which will give us a more conclusive answer.

I just reported in my previous blog that not all of the mutations are equal.  Some of them act like wild- type (normal), and patients with these mutations should be considered for Erbitux therapy. Patients with wild-type KRAS  have a higher chance of response from Erbitux, but that does not predict response.

There have been a lot of efforts to increase the predictive value of wild-type KRAS for response. Many potential candidates have been studied. These include PTEN, EGFR ligands, BRAF and PI3K mutations. Most of the studies revealed controversial findings. Some found an associations and other did not.

Why is that?

We need to realize that our clinical trials are designed to prove that a treatment is successful or not, but are not statistically powered to identify and validate new biomarkers. The frequency of these biomarkers, either mutations or gene expression levels, will dictate how many patients and samples you need to be able to find a biomarker. Most of the studies are too SMALL to identify biomarkers, which is the reason some of the studies are positive and others are negative. We need larger studies and national and international network to work together to validate these biomarkers.

This is independent of the question of standardization of the tests used. Some of the tests are not reproducible because they are vulnerable from the tissue handling and collection.

PI3K mutation is a great example where previous studies were sometimes positive and sometimes negative because the sample size was just too small. Then they did not consider that all mutations are not the same. Recent publication shows that exon 20 mutations are associated with sensitivity to Erbitux but exon 9 mutations are not. These may be considered in future studies to be further tested. When you do the research right, you can significantly increase the prediction of response.

When patients have tumors with wild-type KRAS, NRAS, BRAF, and PI3K, response rates go up from 20 percent to 50 percent, which is very meaningful.

Dr. Lenz

Recent data suggest that some KRAS mutations act like normal or wild-type KRAS. Maybe for those mutations, Erbitux could be used for treatment.

A recent publication in the Journal of the American Medical Association by Dr. Sabine Tejpar using an international collaboration showed that some mutations act like wild-type KRAS and that these patients actually may benefit from Erbitux therapy.

Maybe we were wrong thinking that all KRAS mutations are the same. Haven’t we learned from our mistakes before?

A G13D mutation, which means it is found in exon 13, is a relatively uncommon one. Testing cell lines with this mutation shows that these cells act like they have a wild (normal) type of KRAS, considering cell growth and sensitivity to Erbitux therapy. This held up in the animal models.

When they tested the G13D mutation in patients treated with Erbitux or Erbitux combinations, patients with this mutation did as well as those with wild-type KRAS. The interaction of sensitivity to cetuximab (Erbitux) remained significant after multivariate analyses.

Maybe we jumped too quickly to the assumption that a mutation is a mutation. We just learned a similar story about PI3K mutations, where only exon 20 mutations are associated with Erbitux sensitivity not the ones in exon 9. We need to learn to distinct the quality of mutation to make the RIGHT decision.

Please discuss your specific mutation analysis with your treating oncologist.

Previously: All KRAS Mutations May Not Be Alike

Disclosure:  The Colorectal Cancer Coalition has received funding from Eli Lilly & Company, Bristol-Myers Squibb and ImClone Systems, the companies that manufacture and market Erbitux, in the form of unrestricted educational grants.  The Coalition has ultimate authority over website content.

There is some evidence that patients having a specific type of KRAS gene mutation may respond better to Erbitux® (cetuximab) chemotherapy than others who have KRAS-gene mutations.

Previous studies have shown that people with KRAS-mutated tumors did not respond to Erbitux®, and practice guidelines now recommend testing all tumor cells for the mutation before starting Erbitux therapy in patients with recurrent, advanced colorectal cancer.

The study, reported in the Oct. 27 Journal of the American Medical Association (JAMA), examined both the data and tissue samples of 579 patients in several studies who received Erbitux® between 2001 and 2008 for chemotherapy-refractory cancer. Those patients with “codon-13” mutations had longer overall and progression-free survival by several months than those with other KRAS mutated tumor cells. Laboratory tests of tumor cell responses also showed that codon-13-mutated cells responded to cetuximab when other KRAS-mutated cells did not.

The study authors concluded that “Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.”

What it means for patients:

Current evidence has shown the codon-13 type of KRAS mutation to be relatively rare, and more research on therapy response is necessary. It is probably too soon to change recommendations for therapy for those having the codon-13 mutation.

Source: Journal of the American Medical Association, Oct. 27, 2010

Disclosure:  The Colorectal Cancer Coalition has received funding from Eli Lilly & Company, Bristol-Myers Squibb and ImClone Systems, the companies that manufacture and market Erbitux, in the form of unrestricted educational grants.  The Coalition has ultimate authority over website content.

The answer is yes, according to a pooled analysis of two large randomized clinical trials comparing chemotherapy alone to chemotherapy plus Erbitux® (cetuximab).  However, benefits depend on whether or not patient tumors have mutations of two genes, KRAS and BRAF.

Previous studies have shown that only patients with normal or wild type KRAS get any benefit from EGFR inhibitors Erbitux or Vectibix™ (panitumumab) so a combined analysis of the CRYSTAL and OPUS studies looked only a outcomes in KRAS wild type tumors.  In addition, the research team studied the effect of mutations to BRAF.

They found that adding Erbitux to initial chemotherapy improved overall survival time, time until cancers got worse (progression-free survival), the percent of tumors that shrank with treatment (overall response rate) for tumors with wild-type KRAS.  The best outcomes were in patients who had both wild-type KRAS and wild-type BRAF.

Overall, benefits were smaller for both chemotherapy and chemotherapy plus Erbitux when BRAF was mutated.  But even in patients with BRAF mutations, adding Erbitux appeared to help.

The pooled analysis of KRAS wild type patients showed:

• Adding Erbitux to chemotherapy added four months to median survival time for the entire group of KRAS wild-type patients. With chemo alone, median overall was 19.5 months while it improved to 23.5 months with chemo and Erbitux.
• Progression-free survival was 7.6 months with chemo alone and 9.6 months with the combination of chemo and Erbitux.
• 38.5 percent of chemo only patients had tumors shrink at some point during their treatment compared to 57.3 percent of patients who also got Erbitux.

When just patients with both wild type KRAS and wild type BRAF were reviewed:

• Overall survival time was 21.1 months with chemo alone and 24.8 months with chemo plus Erbitux.
• Progression–free survival was 7.7 months with chemo and 10.9 months with the combination of chemo and Erbitux.
• Overall response rate was 40.9 percent for chemo and 60.7 percent for chemo and Erbitux.

Prognosis appeared to be poorer when KRAS wild type patients had mutated BRAF, but the researchers noted that there were too few BRAF mutated tumors to make the results statistically significant.  However, adding Erbitux did improve outcomes. In those patients.

• Median overall survival was 9.9 months with chemo and 14.1 months with the addition of Erbitux.
• Progression-free survival was 3.7 months versus 7.1 months.
• Overall response was 13.2 percent for chemo alone and 21.9 percent with Erbitux and chemo.

In presenting the study results at the 2010 ASCO Annual Meeting in Chicago, Carsten Bokemeyer said,

Based on these results, BRAF mutations cannot be used as a relevant predictive marker for the use of cetuximab in first line therapy for metastatic colorectal cancer.

Bokemeyer and his colleagues concluded,

This analysis confirms that the addition of cetuximab to chemotherapy first line in patients with KRAS wild type tumors achieves a statistically significant improvement in overall response rate, progression-free survival, and overall survival compared with chemotherapy alone. The best outcome was observed in patients with KRAS wild type/BRAF wild type tumors (90% of KRAS wild type patients). BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to chemotherapy but the sample size may be too small to be reliable.

SOURCE:  Bokemeyer et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3506.

Disclosure:  C3 has received funding from Bristol Myer Squibb and ImClone Systems in the form of unrestricted educational grants.  C3 has ultimate authority over website content.