Genetic and epigenetic variations ensure that no two people are exactly alike, and the same holds true for any two cancers.
Now, researchers have the tools and the knowledge to help predict how individuals will respond to
cancer therapies, enabling them to create more effective therapies for individual cancers personalized medicine. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new
biomarkers , and techniques for determining biomarkers , that could determine how an individual might respond to drug or
radiation therapy.
Molecular predictors of drug response in breast cancer: Abstract 4963
Researchers at Lawrence Berkeley National Laboratory have identified gene expression signatures that could serve as biomarkers to predict how individuals will respond to the breast cancer drugs lapatinib and CI-1040. Their findings could help in individualizing treatments for women, and their methodologies could aid in identifying similar biomarkers for responses to other drugs and for other types of cancer.
"Individuals respond differently to different therapeutics because there are substantial differences in the spectrum of genetic, biological and epigenetic characteristics between breast cancers, although some recurrent abnormality patterns are emerging that define breast cancer subtypes" said Joe W. Gray, Ph.D., staff scientist and director of the Life Sciences Division at Lawrence Berkeley National Laboratory. "We need better ways to identify how we can best tailor existing therapies to individuals and how to target experimental agents."
Gray and his colleagues have developed a system to evaluate drug response comprised of a panel of 50 breast cancer cell lines. Each of these cell lines represents a single variant among the different genomic abnormalities found among breast cancers. They measured molecular profiles of each cell line and used these to identify subsets of cell lines that represent the subtypes observed in analyses of primary tumors.
By correlating the responses of these cells to targeted therapeutic drugs, the researchers were able to identify the molecular characteristics of cells that were most sensitive to the drugs. They tested their approach by analyzing responses of the cell line panel to lapatinib, a duel inhibitor of EGFR and ErbB2 and CI-1040, a MEK enzyme inhibitor. These studies defined molecular signatures that predicted individual responses among the cell lines to the drugs. For Lapatinib, the strongest correlate of response was amplification and over expression of ErBB2, consistent with clinical experience. For CI-1040, changes in the MEK pathway were most strongly associated with response. Predictors based on combinations of molecular correlates of response were able to quantitatively predict individual cell line responses.
"The concordance of our markers of response to lapatinib with those observed clinically suggests that the molecular markers identified in the cell line collection can be used to guide the use and testing of other approved and experimental drugs," Gray said. "This is important since it is logistically and financially impossible to test all of the experimental medicines in each cancer subtype. This 'systems, approach suggests a way to prioritize drugs for use in patients and for initial clinical tests."
According to Gray, a large of number of emerging therapeutic agents should be prioritized for testing in the subtypes of breast cancer along with other cancers and their subtypes. When therapies are ineffective, they may produce harmful side effects and decrease a patient's quality of life.
KRAS mutation in colorectal cancer is a predictive factor of response and progression free survival in patients treated with Cetuximab: Abstract 5671
Mutations in the KRAS oncogene could predict a lack of response to the drug cetuximab in patients with colorectal tumors. For those with the mutations, the drug is likely to be inefficient and possibly harmful, according to researchers at France's Institut National de la Sante et de la Recherche Medicale (INSERM).
"Because a variety of different effective agents may now be available for any given type of cancer, deciding which treatment regimen is likely to be the most effective and the least toxic is more complicated than ever," said Pierre Laurent-Puig, M.D., PhD, a professor of Oncology at University of Paris-Decartes. "Characterizing the factors that are predictive of toxicity and efficacy could lead to significant improvement in both the quality of treatment and outcomes."
Cetuximab, an antibody that attacks the ability of cells to respond to the epidermal growth factor, has been previously shown to be effective in treating metastatic colorectal cancer.
Dr. Laurent-Puig and his colleagues studied 114 patients who had been given cetuximab in combination with another drug, irinotecan.
According to the researchers, approximately 30 percent of patients may have a poor response to the drug. Almost none of the patients who responded to the drug had an activating KRAS mutation, as compared to 35 percent of the patients with stable disease or 55 percent of the patients with progressive disease.
According to Dr. Laurent-Puig, this might be due to the cascade of molecular interactions that occur after epidermal growth factor meets its receptor, EGFR. The KRAS enzyme is a key component to these molecular actions, but mutations in the KRAS gene could allow the enzyme to function whether or not it receives the commanding signal from EGFR. Therefore, the inhibition of EGF receptor by cetuximab will not block the molecular signals that are activated farther down the cascade.
The researchers also determined that KRAS mutations are independent of another predictive marker of cetuximab response, skin toxicity, which appears through a variety of forms including rashes, eczema and fissures. Skin toxicity also indicates a poor response to cetuximab. The study indicated that median survival is 15.6 months for patients with skin toxicity and without a KRAS mutation; whereas the survival is only 5.6 months for patients with the mutation, but no skin toxicity.
Dr. Laurent-Puig and colleagues are continuing to investigate the molecular biomarkers associated with cetuximab, including in tumors without the KRAS mutation that do not respond to the drug.
Recombinant peptides as biomarkers for cancer response to tyrosine kinase inhibitors combined with radiation: Abstract 4657
A new method for determining biomarkers could allow physicians to personalize lung or brain cancer therapy and lower the risk of unnecessary radiation treatments. Researchers at Vanderbilt University are using a biomarker library of peptides to determine whether or not tyrosine kinase inhibitor therapy, combined with radiation therapy, is indeed effective against lung or brain cancer.
"It is difficult to assess the response of cancer in the brain or lung to treatment, since those neoplasms are difficult to access safely," said Roberto Diaz, M.D., Ph.D., a resident in Radiation Oncology at the Vanderbilt-Ingram Cancer Center. "With the proper biomarkers physicians may be able to tell if a patient is not responding to the therapy and alter their treatment strategy accordingly."