Lung cancer

In 2006, Dana Reeve – actress, activist, and non-smoker – died of lung cancer. In 2009, Valerie Harper – actress and “Dancing with the Stars” contestant – was diagnosed with lung cancer that has since metastasized to the brain. They are the famous faces of a disease that is the leading cause of cancer deaths. Lung cancer is mainly caused by smoking, although prior lung disease, genetic predisposition, and environmental agents are also risk factors. Patients can be diagnosed with small-cell cell disease ([SCLC]:~14%), mesothelioma (age-adjusted incidence: 0.9 per 100,000 people, but disease has increased 50% between 1977 and 2008) or, as in the case of Valerie Harper, with non-small cell lung cancer ([NSCLC]; 85%). NSCLC tumors are further stratified into squamous-cell, adeno-, and large-cell-carcinomas. If diagnosed prior to metastasis, the 5-year survival is more than 50%. However, the majority of patients are diagnosed with advanced disease, with a 5-year survival of 16 – 18% for NSCLC and 5% for SCLC.

Effective screening to identify lung cancer in the early stages remains the holy grail of disease management. The US Preventive Services Task Force's has recommended annual low-dose computed tomography (CT) screening for high-risk individuals, ages 55 through 79, who have a 30 pack-year history of smoking or who have quit in the past 15 years. The National Framework for Excellence in Lung Cancer Screening and Continuum of Care, developed by the Lung Cancer Alliance, is geared towards screening based on best practices. Researchers have cautioned that low-dose CT-screening is associated with a propensity for over-diagnosis and possibly inappropriate treatment. This situation could potentially be remedied with the validation of biomarkers distinguishing between indolent, clinically insignificant tumors and aggressive disease. The future development of non-invasive biomarker kits (to accurately differentiate between clinically insignificant and aggressive early disease states), analogous to the non-invasive, circulating tumor DNA kits currently being evaluated for the overall detection of stage II-IV lung cancer, would be a welcome step in this regard.

Individualized treatment will depend on the stage of the disease, histologic sub-type, and molecular profile. Ideally, validated biomarkers would guide treatment decisions. Most lung tumors can be further classified according to ‘driver mutations’ in signaling molecules e.g., about 23% of adenocarcinomas harbor epidermal growth factor mutations and the frequency for some of the other known mutations range from 0.2% (N-RAS, neuroblastoma RAS viral oncogene homolog) to 6% (EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase-gene-fusion) and 25% (KRAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), respectively (1).

While chemotherapy may favor certain patients, approved genotype-directed therapies have been shown to be initially effective in patients harboring defined mutations (compared to individuals carrying the wild-type gene). However, drug resistance has emerged as a major contributor to failure of targeted therapies and standard chemotherapy (2). The development of second-, or third-generation tyrosine kinase inhibitors and other novel agents with greater potency has been spurred, partly, by the need to overcome acquired drug resistance (2). Ceritinib is one example of a promising agent associated with progression-free survival (PFS) of patients with advanced ALK-rearranged NSCLC (median PFS = 7 months, [95% CI, 5.6 to 9.5] based on phase I data; patients included those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK) (3).

In addition, the use of immunotherapies to successfully treat melanoma and renal cancers, has led to the development of agents that are also showing promise in lung cancer management. These immune checkpoint inhibitors target a host of immunosuppressive mechanisms likely to be unique to a given patient’s cancer. Depending on the therapy and study phase, 2-year overall survival rates up to 24% have been reported (4). Separate studies with promising investigational agents are currently entering preclinical or clinical accrual phases.

References

1.            Cheng L, Alexander RE, Maclennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25(3):347-369.

2.            Wangari-Talbot J, Hopper-Borge E. Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma. J Can Res Updates. 2013;2(4):265-282.

3.            Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2014;370(13):1189-1197.

4.            Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21(1):80-89.