One compound targeting both receptors is on the market known as Tykerb® (lapatinib) which is approved for breast cancer patients in combination with Xeloda® (capecitabine).

We are utilizing our pharmacogenomic understanding of these pathways to explore genetic signatures to predict who benefits from these therapies and have initiated a global trial for patients with gastric cancer using Xeloda and Tykerb.

We have also learned that HER2 is not only found in breast cancer but also in gastric cancer, bile duct cancer and potentially ovarian and bladder cancers. We have initiated  a study with Boehringer Ingelheim Germany, together with the Massachusetts General Hospital  using these compounds for patients with different cancers who have overexpression of either EGFR or HER2.

This is another example to select patients for specific therapies more wisely to make sure we increase benefits for our patients. Almost all of our clinical trials are now designed to test tumors first to identify patients whoare  more likely to benefit from targeted therapies by testing to be sure that the target of the drug is present in the tumor.

We have seen very promising data on the HER2-overexpressing gastric and bile duct cancers which seem to have significant benefit from HER2 inhibitors such as Herceptin.

This novel compound is highly effective in inhibiting both important growth factor receptors. This trial is now open for accrual at USC and Mass General.

The function of BRCA is DNA repair, very similar to the genes associated with familial colorectal cancer known as Lynch syndrome or HNPCC (hereditary nonpolyposis colon cancer) which are the DNA mismatch repair genes.

Over the last couple of years novel drugs have been developed which are called PARP inhibitors. PARP is involved in DNA repair too. Tumors which have some DNA repair deficiencies  which are treated with PARP inhibitors seem to be particularly vulnerable to this specific therapy. PARP inhibitors attack the weakness of these tumors which are impaired in DNA repair.

Usually this gives tumors a potential advantage creating more and more aggressive mutations which are not repaired, but now we have a special smart weapon.

At this year’s American Society for Clinical Oncology meeting, PARP inhibitors showed very promising anti-tumor efficacy. Since colon cancer which is based on HNPCC or DNA mismatch repair mutations may be also more sensitive against these drugs, we have developed new clinical trials.

At the University of Southern California, we just opened a phase II trial for colon cancer patients with MIN, known as microsatellite instability, which is a landmark sign for DNA mismatch repair. We are testing a novel compound from AstraZeneca and are hoping for similar exciting results as we have seen for breast cancer.

My colleagues in breast cancer are running a number of trials using the ABT888, the PARP inhibitor from Abbott alone or in combination with chemotherapy. Since there are data that these drugs may further increase efficacy of particular cytotoxic drugs.

We are getting closer and closer to a personalized chemotherapy, testing tumors for genetic switches to select more likely effective therapies. This trial is open for accrual at USC and other institutions including Vanderbilt, New York University, and sites in Denver, Palms Springs and Miami. Call the C3 Answer Line at 877-427-2111 for more information.

Disclosure: C3 has accepted funding for projects and educational programs from AstraZeneca in the form of unrestricted educational grants. C3 has ultimate authority over website content.

These data have been discussed by Kate Murphy. However I wanted to follow up with the significance of the data. To increase the risk of recurrence from 12% to 22% is not in any way or form helpful in the clinic, particularly because this outcome is independent of treatment effect.

In other words the technology used by Genomic Health did not result in any clinically meaningful markers which are helpful to decide whether chemotherapy should be given or not.

I was surprised that the data was presented like these are positive data because they have no impact on daily practices. These data need to be improved to make a difference so that they can be used to identify the patients who are at significantly higher risk.

Patients with stage II colon cancer have on average a 15 percent chance of cancer recurring. This is a big challenge! Should we treat everyone and treat many patients with no benefit to make sure we treat everyone who really is at higher risk.?

If we had a genetic marker set which could isolate these patients who are at higher risk, we could spare the ones with very low risk  from chemotherapy for 6 months.

The Genomic Health approach was not successful partly because they did not take advantage of the whole genetic make up. The technology is able to measure 40-50 thousand genes in one test and to figure out what signature would predict recurrence would be the solution.

In breast cancer they have developed a signature to predict recurrence risk and whether chemotherapy should be given.

Last year at ASCO, Dr. Daniel Sargent presented new data that patients with stage II disease with microsatellite instability do not only not benefit from 5-FU, but they may be harmed, and it was recommended to test for MSI in all stage II colon cancer patients and in the presence of MSI-high not to give 5-FU. For stage III colon cancer that was not the case.

This year, the PETACC-3 clinical trial was analyzed for MSI and did not show the same the same findings. It seems that chemotherapy does not harm these patients, and they may benefit.

This has been an ongoing controversy over the last couple of years with some studies showing benefit and other not. Last year’s ASCO showed there even may be harm.  What MSI means is now again up in the air. We can certainly state that the presence of MSI is a GOOD prognostic marker, meaning that these patients have a lower risk of tumor recurrence. However, if chemotherapy is beneficial or not is still not clearly answered.

Another finding in this clinical trial showed that 18q deletions are not prognostic in stage II disease when MSI status is known. That is important because our clinical trial E-5202 in the US assumed that patients with an 18q deletion are at higher risk for tumor recurrence independent of MSI, which may alter the interpretation of the clinical trial.

All these data show that we are learning a tremendous amount about the molecular make up of tumors, but it also shows that it is not easy to develop clinically meaningful markers. However, there is no doubt that new markers will be identified and validated over the years to come and will make our personalized oncology care a reality.

Last year we made a significant step forward in personalized oncology with the identification of a mutation in KRAS which is found  in about 40 percent of colon cancers.  This genetic switch predicts efficacy of drugs such as Erbitux and Vectibix. Since then the European Regulatory Agency EMEA approved KRAS testing in first-line metastatic colorectal cancer treatment, and since last Monday my colleagues in Europe including England  can use Erbitux in wild-type KRAS tumors for first-line treatment t which we in the USA can not do.

The data have been submitted to FDA for review to be able to use Erbitux or Vectibix in first line treatment, and we expect a decision in the next couple of months.

More and more American physicians test for KRAS mutations, but still mainly when we consider starting Erbitux or Vectibix. Increasingly in the US we are beginning to test with the diagnosis of metastatic colon cancer because the planning of treatment strategies may significantly change.

This year’s meeting asked the question: Do we have new information on additional markers?

There was promising data on PI3K mutations and BRAF mutations as well as on PTEN loss and expression of the EGFR ligands. It seems that PI3K and BRAF mutations may be not so clear as the KRAS mutation story. Studies presented at ASCO showed that the data are not consistent indicating that testing for these markers should not be done routinely yet.

PTEN loss is complicated and not easily clinically feasible since you need tissue from the metastatic site and no one likes to biopsy liver or lung lesions for a molecular test. The concordance of PTEN loss is not great when compared between primary and metastic site. This is because the method of PTEN inactivation is not a mutation but methylation which is dependent on the tumor’s environment which obviously is different in the primary tumor and liver or lungs mets.

The most promising is the EGFR ligand expression. Additional data suggested that high levels increase the probability of response to EGFR inhibitors. The problem is methodology and how to determine the cut off level. In other words, what is high and what is low.

In an effort to prevent colon cancer but avoid the side effects of aspirin, COX-2 inhibitors such as Celebrex® (celecoxib) was developed and tested to see if they could prevent colon cancer without the side effects of aspirin. Unfortunately, we have witnessed that high doses of Celebrex can cause heart attacks which put a significant hold on the development of these drugs as chemopreventative agents.

The studies of Celebrex have been disappointing so far, and we may know why. A recent study let by Dr. Sanford Markowitz (PNAS this week) was able to show that individuals with low levels of 15-PGDH did not benefit from Celebrex therapy.  This is an important finding because it may allow selection of patients for chemoprevention (a FIRST) but also to develop novel chemoprevention strategies for individuals who have low 15-PGDH levels. There is now significant efforts to study the molecular mechanisms of 15-PGDH and resistance to Celebrex in mouse models.

How does 15-PDGH levels relate to colon cancer development? Investigators from the Dana Farber Cancer Center (Monica M. Bertagnolli) examined colon biopsies from human patients who had participated in the APC trial of Celecoxib. They found that among these individuals colon 15-PGDH levels varied by 12-fold from lowest to highest. Most importantly, they found that the patients who were resistant to Celecoxib and had developed new colon tumors were all individuals who had low levels of colonic 15-PGDH. Thus in both mice and humans, Celecoxib works to prevent colon tumors only if levels of colonic 15-PGDH are high, while low levels of 15-PGDH leads to Celecoxib resistance.

Both investigators Markowitz and Bertagnolli point out that these findings require additional studies with larger numbers of patients. In the future we need to become much more sophisticated to prevent colon cancer. We are moving away from one size fits all to a tailored strategy in chemoprevention.

We all realize that it takes a team to provide the best care, particularly with novel developments in technologies such as virtual colonoscopies, new drugs, new surgical techniques and new insights on cancer risk and prevention strategies.

This symposium looks at patients from all different angles. Today was the colorectal session. It started with the keynote lecture on epigenetics. This is a new way to control the genes within cancer cells. We are learning that this way to control genes may be very important. We have developed methods to measure the amount of methylation in the genes in a tumor.

In early human development, methylation is how cells develop into different organs. Since every body cell has the same chromosomes, genes needed to become a liver cell or kidney cells are changed. Making sure each cell develops into the right organ is partly controlled by methylation.

Tumors also take advantage of this process to grow faster and spread more easily. We are just starting to understand this process.

In leukemia, they already have developed drugs to attack this kind of methylation, or silencing of genes, and successfully treat a specific subset of leukemia. There is no doubt that we will make significant progress in the coming years and hopefully develop new drugs to attack this mechanism.

The Symposium didn’t report any new breakthrough treatments. However every session clearly showed that we have made much progress in understanding how cancer develops and grows and why some patients are more sensitive than others to treatment.

KRAS testing, which is now a standard method to decide whether EGFR inhibitors will be effective or not, is only the beginning. With better understanding of the molecular highways of cancer, we will use the novel drugs being developed in a much smarter way. There is the feeling we will make more progress in the years to come.

I am trying to change the way we treat patients with colon or rectal cancer. Over the last 10 years we have identified genetic signatures which help us choose the most effective and least toxic chemotherapy. In my practice every patient with newly diagnosed colon cancer is genetically tested for KRAS and two genes which show whether FOLFOX chemotherapy is more likely to be successful.

Today when a patient walks in with metastatic disease only in their liver, we think about a possible cure depending on number, size and location of those metastases. It is important to choose the most effective therapy since that can be the difference of a chance of curative resection or not.

Our patients at the University of Southern California (USC) have been incredibly supportive in donating their blood and tissues for our research. Our expertise in this area also is essential to understand to develop new drugs. When you know why tumors grow and escape chemotherapy, you may be able to develop a novel drug to attack  cancer more effectively. That is exactly what we are doing.

Not only our patients but foundations and private donors are helping us to change the way colorectal cancer patients will be treated in the future. Our goal is to cure more and more patients by developing better drugs. Two foundations, the Dhont Foundation and the San Pedro Guild in San Pedro, California, have supported us in the past. With their help, our research group was the first to identify critical genes for new drug development.  Based on our findings we have started to develop our own drugs.

There is no doubt that in a couple of years, every patient undergoing chemotherapy will be tested to select the most effective and least toxic therapy. We will make sure this will happen sooner than later.