Molecular Profiling of Lung Cancer

Lung cancer is the leading cause of cancer related mortality in the United States, with an estimated 224,210 new cases and 159,260 deaths anticipated in 2014 (ACS 2014). Classically, treatment decisions have been empiric and based upon histology of the tumor. Platinum based chemotherapy remains the cornerstone of treatment. However, survival rates remain low. Novel therapies and treatment strategies are needed.

Lung cancer is comprised of two main histologic subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Over the past decade, it has become evident that subsets of NSCLC can be further defined at the molecular level by recurrent 'driver' mutations that occur in multiple oncogenes, including AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1 (Table 1). Another altered kinase gene involves MET. 'Driver' mutations lead to constitutive activation of mutant signaling proteins that induce and sustain tumorigenesis. These mutations are rarely found concurrently in the same tumor. Mutations can be found in all NSCLC histologies (including adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma) and in current, former, and never smokers (defined by individuals who smoked less than 100 cigarettes in a lifetime). Never smokers with adenocarcinoma have the highest incidence of EGFR, HER2, ALK, RET, and ROS1 mutations. Importantly, targeted small molecule inhibitors are currently available or being developed for specific molecularly defined subsets of lung cancer patients.

Historically, efforts at characterizing the molecular underpinnings of SCC of the lung have lagged behind those of adenocarcinoma of the lung. Many of the 'driver' mutations found in lung adenocarcinoma are only rarely found in lung SCC. Moreover, newer agents, such as bevacizumab (Avastin) and pemetrexed (Alimta) are not approved for or exhibit diminished efficacy in SCC (Sandler et al. 2006; Scagliotti et al. 2008). Thus, patients with metastatic SCC have fewer treatment options than those with non-squamous NSCLC. Despite these caveats, however, 'driver' mutations that may be linked to outcomes with targeted therapies in SCC are emerging. Altered genes include FGFR1 and DDR2 as well as PIK3CA. In addition, results from a recent large genomic study in lung SCC have added a variety of potential therapeutic targets that await validation in prospective clinical trials (Hammerman et al. 2012).

The following text is meant to provide a broad overview of several of the oncogenes known to be important for lung cancer pathogenesis. Where possible, the presence of a specific mutation is correlated to clinical parameters as well as response to both conventional chemotherapy and targeted agents. At present, only data for treatment of advanced (stage IIIB/IV) disease is presented.


Table 1. Frequency of Mutations and Availability of Targeted Therapies in NSCLC.
Gene Alteration Frequency in NSCLC
AKT1 Mutation 1%
ALK Rearrangement 3–7%
BRAF Mutation 1–3%
DDR2 Mutation ~4%
EGFR Mutation 10–35%
FGFR1 Amplification 20%
HER2 Mutation 2–4%
KRAS Mutation 15–25%
MEK1 Mutation 1%
METa Amplification 2–4%
NRAS Mutation 1%
PIK3CA Mutation 1–3%
PTEN Mutation 4–8%
RET Rearrangement 1%
ROS1 a Rearrangement 1%

Key:
Drugs approved in NSCLC.
Drugs approved in NSCLC but for other molecular subtype.
Drugs approved in other cancer.
Drugs in clinical development.

Note: a Crizotinib is a dual ALK/MET tyrosine kinase inhibitor which is currently only FDA approved for ALK positive NSCLC. However, there is a case report of a patient with NSCLC harboring MET amplification who responded to this agent (Ou et al. 2011). In addition, one patient with NSCLC harboring a ROS1 gene rearrangement had a partial response to crizotinib, which has ‘off-target’ anti-ROS1 activity (Bergethon et al. 2012).

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. Molecular Profiling of Lung Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer/ (Updated March 31).

Last Updated: March 31, 2014

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