Molecular profiling can accurately predict survival in colon cancer patients

Sep 25, 2007

Researchers in The Netherlands have developed a method of accurately predicting which patients with colon cancer are most likely to have their disease recur after surgery and who would, therefore, be likely to benefit from additional chemotherapy.

Led by Professor Rob Tollenaar at Leiden University Medical Center and Dr Laura Van ‘t Veer at The Netherlands Cancer Institute, they have analysed for the first time the different expressions of genes in the entire genome of tumour tissues from 121 patients with stage II colon cancer who had not received adjuvant chemotherapy.

Prof Tollenaar, who is head of sections endocrine, gastrointestinal and oncologic surgery in the department of surgery, told a news briefing at the European Cancer Conference (ECCO 14) in Barcelona, today (Tuesday) that the full-genome molecular expression profiling had identified two groups of patients that had distinct clinical outcomes.

“Patients with stage II colon cancer have an overall five-year survival of about 80%,” he explained. “So far, no randomised clinical trials has shown significant benefit from giving adjuvant chemotherapy. Three-quarters of patients are cured by surgery alone and, therefore, less than 25% of patients would benefit from additional chemotherapy.

“Our analysis showed a cluster of 75% of the patients, of whom approximately 90% were likely to survive for at least five years with no distant metastases. In the second cluster of the remaining 25% of the patients, only about 65% of them had five-year survival without distant metastases, and this is the group who would be likely to benefit from adjuvant chemotherapy.

“This is the first time that the identification of a poor survival group has been based on genome-wide expression analysis and, therefore, it relates tumour biology more accurately to the outcome of disease.”

Further analysis of the results showed that patients in the “poor outcome” group were over three times (3.2) more likely to develop metastases than the patients in the “good outcome” group. This method of identifying “poor outcome” patients was better at predicting which patients should have adjuvant chemotherapy than the commonly-used method that follows recommendations from the American Society of Clinical Oncology (ASCO).

The researchers checked their findings against information from another set of colon cancer patients that had been published in the Journal of Clinical Oncology in 2005. Prof Tollenaar said: “In these stage II colon cancer patients, the five-year metastasis-free survival prediction was confirmed; for the good outcome group, five-year survival was 90% and for the poor outcome group it was 40%. This was important validation of our own results.”

From the genome-wide analysis, the researchers identified a subset of 100 genes that were able to predict outcome equally as well as the full-genome molecular expression profile. Many of these genes are know to regulate the Epithelial-Mesenchymal transition (EMT) – a programme of cell development that is thought to be a driving force behind the development of metastases in colorectal cancer.

Prof Tollenaar said that although his research predicted outcome of disease in patients who had not received adjuvant chemotherapy, more work would need to be done to identify the molecular profile for those patients who would actually benefit from chemotherapy.

Before the results of this research could start to be used in the clinic, Prof Tollenaar said two things needed to happen: “Current, ongoing validation studies required to confirm our findings have to be completed, and the test needs to be developed into a robust diagnostic device. The molecular profiling company Agendia BV of Amsterdam has taken this up and it is likely to be available in early 2008.”

As to whether these findings would save large numbers of colon cancer patients from unnecessary chemotherapy, Prof Tollenaar said: “This depends greatly on the current practice in different European countries. For example, in Spain 60% of stage II colon cancer patients receive adjuvant chemotherapy, while in The Netherlands only 20% do. So in some countries it will result in a decrease in the number of patients receiving chemotherapy and in others, an increase; but both outcomes will result in a more accurate selection of patients.”

Source: ECCO-the European CanCer Conference

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gdpawel
not rated yet Dec 02, 2007
Chemotherapy Selection

In chemotherapy selection, Gene and Protein testing examine a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response.

Whole Cell Functional Profiling tests not only for the presence of genes and proteins but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

Genes create the blueprints for the production of proteins within the cell. A protein is a molecule that makes a cell behave in a certain way. It does so by interacting with other proteins in a complex series of steps.

The goal of Gene testing is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. However, just because a gene is present it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even Protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs.

Gene and Protein testing involve the use of dead, formaldehyde preserved cells that are never exposed to chemotherapy drugs. Gene and Protein tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene and Protein tests cannot discriminate among the activities of different drugs within the same class. Instead, Gene and Protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene and Protein tests tell us anything about drug combinations.

"Whole Cell" Functional Tumor Cell Profiling tests living cancer cells. Functional Tumor Cell Profiling assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. Functional Tumor Cell Profiling can discriminate differing anti-tumor effects of different drugs within the same class. Functional Profiling can also identify synergies in drug combinations.

Gene and Protein tests are better suited for ruling out "inactive" drugs than for identifying "active" drugs. When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect.

Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

Although Gene and Protein testing currently are limited in their reliability as clinical tools, the tests can be important in research settings such as in helping to identify rational targets for development of new anti-cancer drugs.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.