Lung cancer in the era of precision medicine

Abstract

The past decade has been transformative for lung cancer patients, physicians, and scientists. The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer. Indeed, it precipitated concerted efforts by many investigators to define molecular subgroups of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and define mechanisms of sensitivity and resistance to targeted therapies. The fruits of these efforts are visible every day now in lung cancer clinics: Patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Ongoing and future efforts to find new vulnerabilities of lung cancers, unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with lung cancer.

Figure 1

Timeline of major discoveries in lung cancer in recent years (above the arrow) and related clinical trials (below the arrow).

Figure 2

Schema of a potential process for incorporating molecular profiling and repeat biopsies into the treatment of lung cancer. The initial diagnostic biopsy is evaluated using histopathology, immunohistochemistry and molecular profiling to determine therapy. A repeat biopsy is collected at the time of acquired resistance and re-analyzed using the same methods to identify changes between the pre-treatment specimen and that collected at resistance. The process is repeated through each different line of therapy. When possible cell lines and patient-derived xenografts should be generated to facilitate functional studies of resistance mechanisms and therapeutic testing.

Figure 3

Novel clinical trial designs to test precision-medicine approaches in cancer. Examples of trials that fall under the Umbrella and Basket trial categories are shown. Reprinted from Herbst and colleagues (24).