Molecular Profiling Defines New Potential Targets for Lung Cancer Treatment

Appropriate patient selection might influence cost of care, further study needed

The collaborative efforts of members of the Lung Cancer Mutation Consortium (LCMC) demonstrate that although lung cancer may be a disease with one name, genetically it is very heterogeneous. Preliminary results of a study conducted by the LCMC (Abstract CRA7506) are the initial reports of the occurrance of 10 driver mutations for lung adenocarcinoma in 1,000 patients.

Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, presented findings at yesterday’s Oral Abstract Session: Lung Cancer — Metastatic/Non-small Cell. In addition to quantifying the presence or absence of driver mutations, the information was used in real time either to select erlotinib for patients with EGFR mutations or to recommend an appropriate clinical trial of an agent targeting the specific mutation identified. "Understanding the biology of the tumor can lead to better, more effective treatment for the patient," Dr. Kris said.

Investigators tested tumors from patients with lung adenocarcinoma in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using standard multiplexed assays and FISH for EML4-ALK rearrangements and MET amplifications. All patients had stage IIIB/IV lung cancer and a performance status of 0 to 2.

"Understanding the biology of the tumor can lead to better, more effective treatment for the patient."
— Mark G. Kris, MD

In this group of 516, a single driver mutation was detected in 54% (280) of tumors. The most common mutations found were KRAS (114, 22%), EGFR (89, 17%), and EML4-ALK rearrangements (38, 7%). Other mutations found included BRAF (9), PIK3CA (6), MET amplifications (3), HER2 (3), MEK1 (2), NRAS (2); no AKT1 mutations were found. Ninety-seven percent of mutations were mutually exclusive.

The network of 14 participating institutions was established quickly, and the ability to test for these mutations consistently around the United States is a benefit that will outlive the grant.

"Our goal was to develop testing capability at every site," Dr. Kris said. He noted that seven of the 14 sites developed this capability specifically for the trial, and that this testing will continue. "This is the only time that every test for every mutation on every sample was done.”

In his discussion, Ramaswamy Govindan, MD, of the Alvin J. Siteman Cancer Center and Washington University School of Medicine, noted that knowledge in the area of cancer genetics is growing rapidly, as is the number of targeted therapies. An appropriate match between the two is critical, and the work of the LCMC is an important step.

"If you give targeted drugs to targeted patients, they do quite well," he said.

The link between patients with mutations and appropriate trials is an important component, as is the development of trials testing targeted agents. Only 8% of non-small cell lung cancer studies are currently biomarker driven.

The cost of cancer care might be contained if targeted agents are used only for patients who are appropriate candidates. A French study of EGFR testing for patients prior to treatment with gefitinib showed a cost savings, even with the cost of testing factored in. More studies of new potential targets and personalized adjuvant therapy also are needed, Dr. Govindan concluded.