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Lung Cancer in ‘Never-Smokers’: Beyond EGFR Mutations and EGFR-TK Inhibitors

Lung Cancer in ‘Never-Smokers’: Beyond EGFR Mutations and EGFR-TK Inhibitors

Lung cancer is the leading cause of cancer death worldwide, responsible for over a million deaths annually. In the United States in 2009, it is estimated that 219,440 cases will be diagnosed and 159,390 deaths will be attributable to lung cancer.[1] The vast majority of these deaths are cigarette-smoking associated. However, an estimated 10% to 15% of these deaths will occur in “never-smokers.” The estimated 16,000 to 24,000 deaths in never-smokers per year in the United States alone would make lung cancer in never-smokers the sixth leading cause of cancer death if considered as an independent entity from lung cancer in “ever-smokers.”[2] In this issue of ONCOLOGY, Subramanian and Govindan provide a comprehensive review of the epidemiology, molecular genetics, and therapeutic targets in lung cancer in never-smokers.

Compared to former and current smokers with lung cancer, never-smokers with lung cancer present at an earlier age, are more likely to be women, more frequently have adenocarcinoma histology and appear to have a better prognosis.[3] At least one retrospective analysis found that never-smokers in the US with advanced lung cancer treated in the first-line setting with standard cytotoxic therapy had an improved overall survival.[4]

Molecular Changes

The development of targeted therapy against the epidermal growth factor receptor (EGFR) signaling pathway spurred great interest in lung cancer in never-smokers. Retrospective and subgroup analyses of several landmark trials looking at the use of the EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Iressa) and erlotinib (Taraceva) demonstrated that compared to ever-smokers, never-smokers were more likely to respond and had a survival advantage (reviewed in reference 3). The observed response to EGFR-TKIs in several studies appeared to be primarily driven by the presence of activating mutations in EGFR.

A recent trial (the Iressa Pan Asia Study) in East Asian never and light smokers with advanced non–small-cell lung cancer (NSCLC) found that the patients with an EGFR mutation treated in the first-line setting had a significantly higher response rate and longer progression-free survival on gefitinib than on standard cytotoxic therapy. Conversely, never-smokers without the EGFR mutation did significantly worse with gefitinib treatment.[5] The greatest benefit from treatment with EGFR tyrosine kinase inhibitors appears to be in cancers with activating EGFR mutations, which are more common among never-smokers with lung cancer.

Although never-smokers with lung cancer represent an enriched population for EGFR mutations, EGFR mutations are present in only 40% of never-smokers in Caucasian populations.[6,7] Clearly, other molecular changes must be driving tumorigenesis in lung cancer that develops in never-smokers. One candidate gene is the constitutively active oncogenic KRAS. Previous small studies had suggested that KRAS mutations, found in about 20% of adenocarcinomas overall, were rare in never-smokers.[3] Recent data from Riley et al have challenged this notion: In a predominantly Caucasian population, KRAS mutations were found at a similar frequency in smokers vs never-smokers, although the type of mutation is likely different (transversion vs transition mutations).[8] Interestingly, KRAS and EGFR mutations appear to be mutually exclusive in NSCLC, and multiple studies have suggested that TKIs are ineffective when KRAS mutation is present (reviewed in reference 3). Two other major oncogenic pathways—amplification of HER2 and chromosomal translocation between the EML4 and ALK genes—are likely drivers of tumorigenesis in a small fraction of lung cancer cases in never-smokers. In the remaining 40% to 50% of lung cancers in never-smokers, the dominant oncogene(s) or signaling pathway(s) have not been elucidated.


Lung cancer in never-smokers is a significant cause of cancer mortality, and despite recent progress remains an understudied clinical entity. In a significant minority of cases, molecular markers (EGFR, KRAS, EML4-ALK) have been discovered that can guide treatment decisions. Testing for these mutations is rapidly becoming a standard of care in many cancer centers. Emerging data strongly suggest that EGFR-TKI therapy should be considered first-line treatment in patients with EGFR mutations. However, a standard treatment algorithm for lung cancers in never-smokers has not been defined. There is a great need for clinic trials aimed at testing both standard cytotoxic therapy and targeted therapeutics, in both the adjuvant and advanced setting, in this understudied population. Collection of relevant tissue from never-smokers needs to be a key component of these trials, as it is the critical substrate for further insights into the molecular pathogenesis of lung cancer in never-smokers.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.



1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-249, 2009.

2. Thun MJ, Henley SJ, Burns D, et al: Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 98:691-699, 2006.

3. Rudin CM, Avila-Tang E, Harris CC, et al: Lung cancer in never smokers: Molecular profiles and therapeutic implications. Clin Cancer Res 15:5646-5661, 2009.

4. Tsao AS, Liu D, Lee JJ, et al: Smoking affects treatment outcome in patients with advanced nonsmall cell lung cancer. Cancer 106:2428-2436, 2006.

5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.

6. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004.

7. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005.

8. Riely GJ, Kris MG, Rosenbaum D, et al: Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 14:5731-5734, 2008.

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