Although deaths from lung cancer have declined in the United States in recent years, this disease is still the leading cause of cancer mortality and is responsible for 27% of expected cancer deaths in 2013.1,2 Lung cancers are rarely diagnosed at an early stage, and survival traditionally has been poor.1,3

Among the different types of lung cancers currently known, adenocarcinoma is the most common form diagnosed in the United States. Research has provided significant insight into subsets of adenocarcinoma characterized by genetic alterations that present opportunities for targeted therapy.

Of these, mutations identified in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes have clinical importance in terms of treatment. The tyrosine kinases (TK) encoded by these genes are important to growth and proliferation, and have been identified as key drivers of tumor growth in associated lung tumors. Patients whose tumors bear these mutations fare poorer than other patients when treated with standard chemotherapy; therefore, they may be able to derive significant benefit from targeted TK inhibitor (TKI) treatment (Table 1).

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Table 1. Effect of Mutation on Response Rate and Progression-free Survival With EGFR Targeted Therapy2

Outcome EGFR-positive EGFR-negative
Response rate, % 68 11
PFS, months 12 ± 7.86 3.4 ± 2.59

Abbreviations: EGFR, epidermal growth factor receptor; PFS, progression-free survival.  

At the same time, targeted therapies provide little or no benefit for patients lacking the mutations.3,4 Although patients harboring EGFR mutations or ALK rearrangements have distinctive clinical profiles, particularly young age and no history of smoking, using these characteristics as screening criteria undoubtedly fails to identify patients who could benefit from TKI therapy.2 A systematic approach to identifying patients who can benefit will help improve patient care and better focus the use of TKIs in a cost-effective way.

To address the evolution of EFGR and ALK testing, the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have released evidence-based guidelines for selection of patients for EGFR (erlotinib and gefitinib) and ALK (crizotinib) TKI therapy; its authority stems from the contributions of different specialties.This effort represents a major step forward in formalizing molecular testing in lung cancer and ensuring patients receive optimal care. “The multidisciplinary aspect of this is key. Molecular testing is an evolving, important story that spans disciplines for all who care for lung cancer patients,” said David Spigel, MD, the Lung Cancer Program Director at the Sarah Cannon Research Institute in Nashville, Tennessee. A summary of the guidelines of particular interest to oncologists is shown in Table 2. 

Table 2. Selected Recommendations for EGFR and ALK Molecular Testing2

• All patients with lung adenocarcinoma should be tested to select patients for TKI  
  therapy; patients should not be excluded from testing based on clinical characteristics
EGFR and ALK testing should be done at diagnosis for patients presenting with
   advanced-stage disease and is encouraged at diagnosis for patients presenting with
   stage I-III disease
• Priority is given to EGFR testing, followed by ALK testing, over other molecular tests
• Rapid turnaround (within 10 working days) of results is recommended; labs that
   cannot meet the timeline should use outside labs
EGFR PCR tests that can detect all individual mutations reported with a frequency of
   ≥1% are recommended
ALK FISH dual-probe, break apart assays are considered the standard; carefully
   validated ALK IHC may be considered to screen specimens for FISH testing
EGFR and ALK test reports should include results and interpretation easily
   understandable by oncologists and nonspecialist pathologists

Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PCR, polymerase chain reaction; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.