The key to treating men and women with lung cancer lies in understanding the genetic makeup of each person's tumor. A new program at Memorial Sloan Kettering Cancer Center is utilizing recent advances to pinpoint specific mutations known to play a role in more than one-third of lung cancers, with this information then being used to maximize the chance of treatment success.
Last year, Memorial Sloan Kettering began routinely testing tumor specimens of patients with non-small cell lung cancer, the most common type of the disease. In addition to the two mutations most commonly associated with it, our experts now test for 40 additional mutations. The resulting information is used by our physicians to decide whether or not to recommend specific therapies known to be effective in patients with those mutations. This molecular testing can also lead patients to one of Memorial Sloan Kettering's clinical trials investigating new medicines designed to target these specific genetic defects.
The Evolution of Molecular Diagnostics for Lung Cancer at Memorial Sloan Kettering
At the beginning of last decade, Memorial Sloan Kettering researchers helped to determine the molecular reasons why some lung adenocarcinomas (the most common type of non-small cell lung cancer) are either sensitive or resistant to two commonly used drugs, gefitinib (Iressa-) and erlotinib (Tarceva-). These drugs halt the growth of lung adenocarcinoma by zeroing in on a signaling molecule critical to tumor survival.
The scientists learned that while highly sensitive tumors harbor mutations in a gene called EGFR (found in about 15 to 20 percent of lung adenocarcinomas), resistant tumors often contain mutations in a gene called KRAS (accounting for about 25 to 30 percent of lung adenocarcinomas). As a result, testing for these mutations became a part of routine care for lung cancer patients at Memorial Sloan Kettering.
Later, our investigators participated in a federally funded, multi-institutional collaboration known as the Tumor Sequencing Project, which, in 2007, indentified more than 40 regions, located on seven genes, that are frequently altered in lung adenocarcinoma. “This effort paved the way for the successor to the Human Genome Project, called The Cancer Genome Atlas (TCGA),” says Mark Kris, Chief of the Thoracic Oncology Service at Memorial Sloan Kettering. “With our scientists as participating members, TCGA will decipher the entire genome of the cancer cell in many different tumor types, including lung cancer.”
Lung Cancer Mutation Analysis Project
In January 2009, our lung cancer disease management team initiated the Lung Cancer Mutation Analysis Project (LC-MAP). Under the LC-MAP program, Memorial Sloan Kettering pathologists look for all known mutations — including those in EGFR and KRAS, as well as the 40 additional mutations in seven genes — in tumor samples from patients diagnosed with lung adenocarcinoma. (This work is done only when enough of a patient's tumor tissue is available after the pathologist has made the initial diagnosis.) Memorial Sloan Kettering is one of only a handful of centers in the world offering such extensive testing for all patients, performed by specialists in the Department of Pathology's Laboratory of Diagnostic Molecular Pathology. As Dr. Kris explains, the knowledge gained from these tests maximizes the chance of treatment success for each patient.
Once the LC-MAP molecular analysis is completed, individuals whose cancer has spread from the chest and is found to have a mutation in the EGFR gene are offered treatment with erlotinib. The use of erlotinib before surgery (induction) and after surgery (adjuvant) is also under clinical investigation at Memorial Sloan Kettering for patients with EGFR mutations. Conversely, patients who do not have an EGFR mutation can avoid being treated with erlotinib, which would be unlikely to benefit them.
When a mutation is detected in a patient's KRAS gene, doctors can develop a treatment plan that includes drugs other than gefitinib and erlotinib. In addition, doctors may suggest clinical trials that are designed only for individuals with KRAS mutations, such as trials testing the investigational drug ridaforolimus and an adjuvant KRAS vaccine.
Testing done by the LC-MAP program may also direct patients into clinical trials designed for individuals whose cancer has recurred after initial treatment. These trials are investigating the use of drugs that are already being used as standard treatment for other cancers, as well as new agents, including targeted therapies and vaccines.
“Our Laboratory of Diagnostic Molecular Pathology has designed the LC-MAP Program for the future,” Dr. Kris notes. “As additional mutations are discovered by efforts like the Cancer Genome Atlas, these mutations can be quickly included in the 'routine' LC-MAP molecular analyses used in all appropriate patients at Memorial Sloan Kettering. At the same time, our investigators will continue to seek new therapies that target these genetic abnormalities, providing hope for the 220,000 people diagnosed with lung cancer each year.”