We have entered a new era in the management of patients with non–small cell lung cancer (NSCLC). To select the optimal therapy we must now distinguish between the histologic subtypes of NSCLC and we must know the genetic alterations in these cancers. Adequate biopsies are now required to ensure the right histologic diagnosis and to have sufficient DNA for genetic testing.

Activating Mutations, Corresponding Inhibitors

As outlined in the accompanying TAP on Technology article that begins on page 6, patients with activating EGFR mutations fare better on an EGFR tyrosine kinase inhibitor such as erlotinib (Tarceva) or gefitinib (Iressa) compared with combination platinum-based therapy in the first-line setting. In contrast, NSCLC patients without these mutations fare better on first-line chemotherapy—hence, the need for testing. For patients with activating mutations, erlotinib or gefitinib can be expected to produce response rates of about 70%, with median progression-free survival of about a year or more and median survival times exceeding 2 years.

Patients with an EML4/ALK fusion gene treated with the ALK inhibitor crizotinib in any line of therapy also have a response rate of about 70% and a median progression-free survival approaching 1 year. Although crizotinib is not yet approved by the FDA, clinical trials are widely available and FDA approval will hopefully come soon. Thus, advanced NSCLC patients should have their tumors tested for the EML4/ALK fusion as well as EGFR mutations.

Genetic studies have informed us that up to 50% of lung adenocarcinomas may harbor an activating mutation driving the tumor for which there are known specific inhibitors. Among these are KRAS, NRAS, BRAF, HER2, MEK1, PIK3CA, and AKT1 in addition to EGFR. Non–small cell lung cancers may also be driven by amplification of MET as well as fusion of ALK, with both being assessable by fluorescence in situ hybridization (FISH).

Consortium Protocols

To determine the precise frequency of these genetic alterations, their relation to clinical features and to one another, and to place patients harboring these genetic changes on clinical trials of specific inhibitors, the NCI has funded the Lung Cancer Mutation Consortium through a Grand Opportunities grant mechanism. The members of the consortium are listed in the sidebar on page 8. A summary of the genetic testing and some of the activated protocols are shown in Fig. 1. To date, more than 900 of the expected 1,000 cases have been enrolled, and more than 50% of these have a genetic alteration in one of the genes tested. There will be presentations of the data at the ASCO Annual Meeting in Chicago in June and at the World Conference on Lung Cancer in Amsterdam in July.

With the finding that lung cancer mortality can be reduced by 20% or more by annual spiral CT scans in high-risk subjects as well as these improvements in therapy, we can expect a continued reduction in lung cancer mortality—a tribute to scientific advances. ■