Molecular Testing for Early Lung Cancer

Abstract

In the most recent update of the molecular testing guideline for selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors (TKIs), the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) reiterated their prior recommendation pertaining to patients with early-stage disease (stages I–III), namely “that each institution should set its own policy regarding testing patients with early-stage disease.”1 This carefully crafted recommendation attempts to strike a balance between the potential added value of molecular testing obtained from high-quality surgical material in anticipation of disease recurrence and the unnecessary cost incurred by molecular testing in a subset of patients likely cured by surgical resection alone who may never directly benefit from the test results. Although it is true that many early-stage lung cancer patients are cured by surgical resection, it is also true that many are not. For example, the disease recurrence rate ranges from 27% for patients with stage IA to almost 80% for patients with stage IIIA.2 Furthermore, nearly 60% to 70% of all recurrences predictably occur within 18 to 24 months of surgical resection.3,4 The immediate availability of molecular testing results at the time of recurrence will undoubtedly provide the patient and his or her oncologist with the necessary information to initiate timely and appropriate therapy. The absence of such information exposes patients to the unnecessary anxiety associated with treatment delays as past surgical specimens are retrieved and tested or the potential harm associated with invasive potentially harmful interventional procedures that may or may not yield informative material.Although the value of molecular testing in expediting treatment of recurrence seems apparent, the immediate therapeutic benefit to patients who had a complete surgical resection remains an open question. Two international trials randomly assigned patients with resected stage IB to IIIA to either an epidermal growth factor receptor (EGFR)–TKI (RADIANT, erlotinib; BR19, gefitinib) treatment or placebo.5,6 The results of both trials failed to show an improvement in survival in the EGFR-TKI–treated arms. It is important to recognize that neither of these trials was enriched for patients with activating EGFR mutations, a currently recognized predictive biomarker for EGFR-TKI therapy. It is interesting that in an unplanned subgroup analysis of the RADIANT trial, patients who had activating EGFR mutations had a significant improvement in disease-free survival (DFS) when treated with erlotinib compared with placebo. A more recent trial (ADJUVANT trial) randomized 222 Chinese patients with completely resected stages II/IIIA to daily gefitinib for 24 months or 4 cycles of vinorelbine and cisplatin.7 After 36 months of follow-up, median DFS was significantly higher in the gefitinib arm (28 versus 18 months, hazard ratio 0.6, P = .005).6 In North America, investigators of the SELECT trial, a single-arm phase II trial, reported a 90% 2-year DFS after adjuvant erlotinib in patients with resected stage I–IIIA whose tumors harbored activating EGFR mutations.8 Finally, the ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) trial is an ongoing federally funded randomized trial that provides National Cancer Institute funds for genetic screening of resected early lung cancer. Patients without activating oncogene mutations will be followed every 6 months for 5 years, and those with EFGR mutations and anaplastic lymphoma kinase rearrangement will be randomized to either placebo or the appropriate TKI. Given the rapidly moving landscape in the adjuvant treatment of early-stage lung cancer, the reiteration by the CAP/IASLC/AMP of the recommendation “that each institution should set its own policy regarding testing patients with early-stage disease” strikes the right balance at this time.