Oct. 1, 2007 Determining the genetic profile of a particular lung tumor can help clinicians make the crucial decision about which chemotherapy treatment to try first.
A new study led by researchers from the Duke University Comprehensive Cancer Center and the Duke Institute for Genome Sciences & Policy (IGSP) found distinct differences in the susceptibility different tumors have to widely used chemotherapy drugs.
"We were able to predict which tumors would be most likely to respond to standard first-line therapy and which would respond better to what has traditionally been a second-line therapy, based on gene expression profiling," said David Hsu, M.D., Ph.D. an oncologist at Duke and lead author on the publication. "This represents a big step in the move toward individualized medicine. This could also make a huge difference in the treatment of patients with late-stage lung cancer, as most of these patients gain the most benefit from their initial treatment strategy."
Researchers looked at the sensitivity of multiple cancerous cell lines to cisplatin, the most commonly used agent in the treatment of lung cancer. After determining which cell lines were responsive to cisplatin they looked at the RNA of these tumors and generated a genomic signature -- a pattern of gene expression particular to each individual sample.
They were able to draw conclusions about which genes were turned on and which were turned off in these samples, and subsequently created a genomic map for cisplatin sensitivity. The genomic map was then applied to 91 non-small cell lung cancer (NSCLC) tumor samples to determine which tumors were most likely to be responsive to cisplatin, Hsu said.
"We found that tumors known to be sensitive to cisplatin expressed certain genes that were not expressed in tumors that were resistant to cisplatin," said senior author Anil Potti, M.D., an oncologist at Duke and a researcher in the IGSP. "The reverse was true, as well; genes that were not expressed in tumors resistant to cisplatin seemed to be turned on in tumors that were sensitive to it."
The important second part of this project was to come up with a therapy option for the tumors that weren't sensitive, Potti said.
"It's one thing for a doctor to tell a patient that he won't respond to cisplatin," he said, "but we have to know what to do when he asks 'what do you have for me"'"
The researchers then examined several common second-line therapies, such as a drug called pemetrexed which uses a different mechanism of action to attack NSCLC tumors.
"We found the strongest inverse correlation between tumors that were sensitive to cisplatin and those that were sensitive to pemetrexed," Potti said. "This suggests that some patients who are not likely to respond to cisplatin should perhaps be treated with pemetrexed first."
A clinical trial -- the first of its kind in lung cancer -- based on the findings of genomics studies is currently underway at Duke. "These are not experimental drugs, we know they work," Potti said. "It's just a matter of giving each patient the right one on the first try."
Almost 180,000 people are diagnosed with lung cancer each year in the United States, and about 160,000 patients die from the disease yearly, according to the American Cancer Society. Non-small cell lung cancer is the most common form of the disease -- accounting for 80 percent of all cases.
Almost half of NSCLC patients are found to have stage four disease, meaning the cancer has spread beyond the lung into other areas of the body. Currently, only 15 to 30 percent of people treated for stage four lung cancer will be alive a year later and only two percent are alive after five years, making this the deadliest form of cancer.
Standard therapy often includes administration of what is called platinum-based chemotherapy, which works by damaging DNA and interrupting the chain of cellular events that leads to cancer proliferation. Response rate to this type of chemotherapy, however, is about 20 to 30 percent, meaning that up to 80 percent of patients getting this treatment do not see their tumors shrink in response to therapy. Those patients may go on to receive what is known as second-line therapy: drugs such as pemetrexed or docetaxel, which work by interrupting the cellular machinery of tumor cells.
The researchers published their findings in the October 1, 2007 issue of the Journal of Clinical Oncology. The study was funded by the Jimmy V Foundation and the National Cancer Institute.
Other researchers involved in this study were Bala Balakumaran, Chaitanya Acharya, Vanja Vlahovic, Kelli Walters, Katherine Garman, Carey Anders, Richard Riedel, David Harpole, Holly Dressman, Joseph Nevins and Phillip Febbo of Duke; and Johnathan Lancaster of the H. Lee Moffitt Cancer Center at the University of South Florida.
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