Response Signatures

Conventional chemotherapy of solid human tumors has moderate effects on clinical outcome and is associated with severe toxic side effects. The introduction of targeted drugs with reduced toxicity was accompanied by high hopes. Pharmaceutical companies and clinical oncologists expected that these drugs would lead to a dramatic improvement of therapy results in overall survival of patients, time to progression as well as a better quality of live. However, the clinical results were moderate or even disappointing and by far did not meet the expectations. One possible reason for these disappointing results was that patients were not pre-selected for the expression of the target molecule. However, even when the expression was verified using in-situ hybridization or immunohistochemistry as is the case for HER2 and EGFR, the results are rather moderate. For example, only 26% of the breast cancer patients expressing HER2 in the tumor will benefit from the therapy with Herceptin. Obviously, the expression of a single marker even if it is the target molecule, is insufficient for treatment prediction.

When lung cancer patients were treated with Iressa in several phase III clinical studies the response rates of patients were rather disappointing. However, a small subgroup of approximately 10% showed a dramatic clinical benefit. Further molecular analysis of the tumors of these responders showed that the response was partially due to activating mutations in the kinase domain of the target molecule. This could also be demonstrated for the drug Tarceva. Although mutation analysis of the EGFR may soon become a mandatory diagnostic assay for the treatment of patients with certain tyrosine kinase inhibitors this assay is not sufficient for the majority of patients. Therefore, clinicians are presently looking for mutations, activation status and other alterations in downstream effectors of EGFR pathway. Signature Diagnostics believes that this approach might be too narrow and does not reflect the complexity of signaling events in tumor cells with aberrant expression of genes. In order to identify effective therapy response signatures a genome wide approach will be more successful. At present ten thousands of genes can be examined for molecular alterations in a single experiment. Such an approach opens the window for the clinical discovery of new marker combinations (signature) in the primary tumor of the patient.

Prognostic Signatures

Key to increasing survival of cancer patients is the ability to accurately identify which of them is at high risk of relapse and would require extensive treatment. The surgical resection of the tumor for patients with early stage colon cancer is highly effective. However, around 25% percent of these patients would later develop recurrence and die from the disease.

The incidence of relapse points to the need for more accurate methods for predicting recurrence. Prognostic correlations with individual genetic abnormalities are poor, given the genetic complexity of tumors. The use of gene expression profiles could result in more accurate and objective prognosis. Recent publications of breast and colon cancer microarray studies suggest that the aggressiveness of the tumor can be revealed by gene expression patterns already present in the primary tumor. These results confirm the value of gene expression signatures for predicting disease outcome.