Dr. HJ Lenz

In that clinical trial patients who underwent a curative resection for colon cancer received either FOLFOX or FOLFOX with Avastin® (bevacizumab) treatment after their surgery. Chemotherapy was given over 6 months, but patients who were randomly selected for Avastin received 6 months with chemotherapy and additional  6 months alone after chemotherapy ended for a total of 12 months of Avastin.

In our annual ASCO meeting in Chicago in 2009, we heard the results of an American trial (C-08) showing no benefit in patients who received Avastin in this setting, however there an interesting finding that during the 12 months Avastin was given there was a potential benefit. The European AVANT trial showed very similar results. Avastin did not improve outcome in patients who underwent a successful surgery for their colon cancer. There was again a hint of benefit during the time of Avastin therapy.

What does this all mean? After the negative data with Erbitux® and now with Avastin, we are coming to understand that drugs which work for metastatic disease may not have the same effect in patients who have only microscopic disease. The way these drugs work may be completely different if there only cells left or a tumor which has different infrastructure such as its own blood vessels and has overcome the defense of the immune system.

We need to get smarter and develop specific therapies for these patients and find out why the tumors in these patients come back. What makes colon cancer cells survive in some patients? How do some patients kill left over colon cancer cells?

We are back to the drawing board going beyond the pathology report to make treatment decisions but needing to understand the genetic make up of these cancers.

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.

Dr. Lenz

The short answer is YES, but obviously this depends on many factors. We usually recommend that patients complete one or two cycles of chemotherapy to see if there are many side effects or not. If patients tolerate the first two cycles well, usually there is no accumulating side effect expected except for neurotoxicity with oxaliplatin down the road.

Personally I think going back to work is important, because it gives the patient some normality and forces him or her to think about something else than the cancer. However this may not apply for everyone, so discussions with your doctor and family are critical. It is important to plan how you will continue to work while you get cancer treatment. I see patients on Mondays and Thursdays, so patients who want to continue to work or may have to continue to work to keep their insurance, usually get treatments on Thursdays, giving them the weekend to recover. Patients who want to spend the weekend with the family choose Monday treatments, giving them time to recover for the weekend. Here are some tips which might help you to better manage your time and work:

• Evaluate working hours. Can you be flexible, so that most meetings or work can be in the second week of therapy and so that you can leave early in the first week if you are feeling sick?
• Getting help at home can save more energy for work. Ask friends and family members to alternate with helping shopping, bringing kids to school or events, etc.
• Consider talking with your boss and co-workers know about your situation. They can help with your work schedule and be supportive to make your work more manageable during this time.
• Learn to delegate job duties so you can direct others in handling tasks when you’re out of the office.

You have the same rights as anyone else in the workplace and should be given equal opportunities, regardless of whether or not you tell people at work about your cancer. Hiring, promotion, and how you are treated in the workplace should depend entirely on your ability and qualifications. As long as you are able to fulfill your job duties, you cannot be fired for being sick. Also, you should not have to accept a position that you never would have considered before your illness. Some people with job problems related to cancer are protected by federal laws like the Rehabilitation Act and the Americans with Disabilities Act. Some people also benefit from the Family and Medical Leave Act (FMLA), which allows many people with serious illnesses to take unpaid leave for medical care or to manage their symptoms. The leave can take many forms, such as a part-time schedule for a limited time, or taking off 1 or 2 days per week for a while. Not all employers are required to follow FMLA. Talk to someone in your human resources department or another workplace expert to find out what your options are.

Dr. Kahn and Dr. Lenz in Their Lab

I have shared with you in the past the efforts of Dr. Michael Kahn and myself to develop novel drugs which are completely different than the existing ones.

Even the smart drugs we have such as Avastin or Erbitux, which are monoclonal antibodies that attack important targets in cancer growth and progression, have disappointed,  particularly if you are not able to select the patients who benefit the most.

Why are they not more effective?

The communications hot lines in cancer cells are extremely complicated and look like a subway/bus/tram network of large cites. Do you think when you knock out one even major intersection; it will be lethal to the city?

No. Annoying it may be, but we all know detours and ways to avoid these problem spots and so does the tumor. In fact tumor systems often  have backup communication lines which can handle these attacks.

So what do we need to do? We cannot shut down one exit or one intersection we have to shut down major lines (red, purple whatever), which are essential to maintain traffic. In cancer biology we call those major lines pathways.

Dr. Kahn has developed a novel drug which shuts down one of the most important pathways in colon cancer called Wnt (pronounced wind). This drug has shown tremendous potential to treat many cancers including leukemia and even noncancerous disease such as pulmonary fibrosis.

On September 17, 2010 we filed  an Investigational New Drug application to the FDA, which means we want approval from FDA to test this drug for the first time in patients. We expect that the trial will open in October or November.

We are very excited because this drug not only shuts down this important Wnt pathway, it also is effective treating colon cancer stem cells, which has not been possible in the past.

We all know when we treat colon cancer patients with metastases that the first chemo works usually the best, the second shorter, and with the third there is little chance. We all think this is due to the cancer adapting to the chemotherapy. However we think it is that these tumors are getting enriched with stem cell like cancer cells which are, by definition, resistant to chemotherapy. With this drug we can change that.

But this is not the best news. This drug has so far no shown any side effects, even when tested at 250 higher concentrations than needed. Obviously we need to await the clinical data but we are very excited.

USC is so excited that they gave us permission to create a new center called USC Center for Molecular Pathways and Drug Discovery because we have other hits and leads to develop and want to do it as fast as possible.

We were all convinced that when we added Erbitux and Avastin to our chemotherapy, it would work in the adjuvant setting, which means with FOLFOX for 6 months after the successful removal of colon cancer.

But it did not work. Neither Avastin nor Erbitux showed any benefit. How is that possible?

This forces us to go back to the drawing board and get smarter and learn from these experiences. What we must assume is that when you treat with these antibodies, it does not work when you only have microscopic disease.

The reason tumors recur is because some cancer cells are left behind. Some of these cells are stem cells and can’t get killed with chemotherapy.

We have demonstrated benefit in patients with metastatic disease. When you take Avastin, tumors that are visible and big and need to grow up regulate VEGF which is bound away with Avastin.  But what can Avastin do when the cancer cells are very small and don’t need VEGF to survive?

One discussion asks whether we should give adjuvant Avastin for a longer time.  However there are also side effects seen when treatment with Avastin was extended to one year.

Erbitux also did not work. Why not?

I don’t think we have the answers, but it forces us to think about the difference of cancer and its microenvironment between cancer which has spread and is active and cancer which only exists in the form of a few cells somewhere.

We need to develop smarter therapies and how to select the effective therapy like we have begun to do in metastatic patients.  Interestingly, KRAS mutation did not help to select patients who benefitted from Erbitux in the adjuvant setting . Maybe EGFR is not the right target? These results, even through disappointing will force us and industry to rethink and use our molecular biology of cancer to come up with more effective strategies.

Also, I want to mention diet, exercise and supplements in this setting. We need to invest more resources and research to understand what else we can do to reduce cancer recurrence. There are interesting data on exercise, aspirin, vitamin D and diet rich in vegetables. We need to systematically test these possible interventions.

In addition we need to develop a complete new class of medications which attack the colon cancer stem cells, because if they are not removed, they will cause recurrence. Research is going on at USC which may be successfully address this ongoing problem.

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.

Why is that?

This subtype of colorectal carcinoma accounts for 10 – 20 % of all colorectal neoplasms. Compared to the more common nonmucinous variety, mucinous tumors metastasize to lymph nodes with increased frequency and are more prone to spread to the peritoneal cavity. These mucinous colorectal adenocarcinomas (MCA) are a recognized subgroup of colon cancer and usually spread to peritoneal surface without spreading to the liver and lungs.

It is important to know that mucinous tumors are also more often associated with a genetic predisposition syndrome particular when they are located on the right side of the colon.

Since these are very complicated surgeries, these combined treatment procedures should be done only with a highly experienced surgeon.

Nevertheless, an increasing number of international treatment centers have published their results using cytoreductive surgery, and intraperitoneal chemotherapy and hyperthermia in the management of peritoneal surface malignancies of colorectal origin.

Because these patients need to be considered for this special therapy, I want to share with you some of the larger trials using this approach. In the retrospective multicenter study by Glehen et al. of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of PC of colorectal cancer, 506 patients were analyzed. Patients in whom cytoreductive surgery was complete had a significant longer survival than patients with incomplete surgery.

Recently, Elias et al performed a retrospective-cohort, multicenter French-study of peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy including 523 patients which confirmed the results obtained by Glehen.

The risk of surgery is high and should be only be performed in high volume centers familiar with this surgery. When patients with MCA with peritoneal carcinomatosis were treated either with standard therapies and standard surgery or with this novel approach called HIPEC, patients did much better with HIPEC, in fact the study was stopped early because HIPEC was doing so much better.

If you have mucinous colon cancer which is limited to the abdominal cavity please discuss this with your treatment oncologist.

The main criticism against the combined treatment is the lack of nonstandardized treatment techniques. Most of the centers are currently using HIPEC whereas only a few are using EPIC. Both procedures are not standardized and many variations exist in exposure techniques, drugs, drug doses, duration, temperature and flow rates, which may contribute to the differences in the results. Finally, a proper patient selection is essential to benefit from combined cytoreductive surgery and intraperitoneal chemotherapy.

I wanted to review with you the limitations of this test, which is  not as good by far as the test they have developed for breast cancer.

Stage II colon cancer is usually a T3 N0 lesion meaning there are no lymph nodes involved. Oncologists look very carefully at the pathology report to make sure there are no aggressive features seen such as invasion into the nerves or blood vessels or tumor cells which are poorly differentiated (which means you can’t really see where the cell comes from). These features would already indicate a higher risk of tumor recurrence.

We have other clinical features such as signs of bowel obstruction or when the surgeon removed less than 12 lymph nodes that tell us the patient has higher risk, and we usually recommend 6 months of chemotherapy.

For patients who have none of these risk factors the risk of tumor recurrence for stage II colon cancer is about 15 percent. The dilemma is what we don’t know whether the individual patient will recur or not.

The Oncotype DX®  for colon cancer measures 12 genes in the tumor tissues and separates the tumor into  low, intermediate, and high risk for recurrence. Low risk is 12%, intermediate 18% and high risk is 22%. The distinction between risk levels is much less than for breast cancer where low risk is 7% and high risk is 31%, and therefore is much less clinically helpful.

However the biggest difference between the breast and colon tests is that in the breast test the benefit from adjuvant chemotherapy is known, but for colon we don’t know if chemotherapy has any benefit in any of the risk categories.

We need a better signature to distinguish between low and high risk.  Twelve to 22 percent is only a small step, and not satisfactory to make treatment decision not knowing if there is any treatment effect. In other words your risk of 12% could mean you benefit from chemo but your risk of 22% may not.

Many companies are working on prognostic markers which can help to select patients at high risk much better for chemotherapy, I have not adapted this test for evaluation for my patients with stage II colon cancer.

Disclosure: Dr. Lenz serves as a consultant to Amgen, Bristol-Myers Squibb, Genentech, ImClone, Merck KG, Novartis, Pfizer, Response Genetics, and sanofi-aventis. He has received honoraria from Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Genentech, ICN, Imclone, Millenium, New Biotics, Novartis Chiron, Pfizer, Roche, sanofi-aventis. His research is funded by the National Cancer Institute and the National Institutes of Health

Disclosure:  Dr. Lenz is a consultant to Response Genetics which markets a genetics test to help patients and doctors make treatment decisions.

Disclosure: C3 has received funding from Genomic Health in the form of unrestricted educational grants.  C3 has ultimate authority over website content.