Supplement

Biomarkers and Molecular Profiling in Non-Small Cell Lung Cancer: An Expanding Role and Its Managed Care Implications

Published Online: December 30, 2013
Robert T. Adamson, PharmD, FASHP
Lung cancer is the leading cause of cancerrelated mortality in the world. The American Cancer Society estimated that in 2013, the disease will account for almost 159,500 deaths in the United States, or approximately 27% of all cancer deaths in the country. Lung cancer accounts for about 14% and 12% of all new cancer diagnoses in males and females, respectively, and nearly 70% of patients with lung cancer will present with locally advanced or metastatic disease at initial diagnosis. Despite evidence-based recommendations and clinical guidelines that support the utility of epidermal growth factor receptor (EGFR) mutation testing in improving targeted therapy in non-small cell lung cancer (NSCLC), the most common form of lung cancer, EGFR testing continues to be underutilized, as the procedure may cost up to $1000 and require up to 2 weeks for results. Additional research and data collection will be needed to ascertain the costeffectiveness and role of molecular testing and targeted therapies in the management of NSCLC. This article reviews the current testing strategy and treatment guidelines, and provides a pharmacoeconomic evaluation of the use of EGFR testing to guide the management of NSCLC in today’s cost-constrained healthcare environment.

Am J Manag Care. 2013;19:S398-S404
Lung cancer is a highly prevalent malignancy that is associated with substantial morbidity and mortality. Histologically, it is divided into non-small cell lung cancer (NSCLC), the more common form, and smallcell carcinoma. Numerous clinical studies evaluating treatment efficacy have been conducted in the therapeutic space for NSCLC, but areas of uncertainty for the disease that continue to persist include the benefit of targeted agents in unselected and general patient populations, the value and appropriate timing of testing to guide the appropriate use of specific agents, and the optimal sequencing of agents (ie, first-line, second-line, etc).1 In the first article in this supplement, the epidemiology, pathophysiology, and treatment options for NSCLC are examined, focusing on the epidermal growth factor receptor (EGFR).2 This article provides an overview of the biomarkers that are associated with clinical outcomes in NSCLC and the recommendations for molecular profiling in NSCLC, as a means to effectively implement targeted therapies, individualize treatment regimens, and ensure optimal and cost-effective disease management in NSCLC.

Biomarker Testing

The healthcare system has entered a transitional period during which clinicians and health plans are under increasing pressure to deliver the most therapeutically effective treatments—which are often the most expensive options—in the most cost-effective manner.3,4 Strategies to help limit healthcare spending include the implementation of utilization management programs and/ or cost agreements to control the prices of treatments.3 These strategies should incorporate the results of comparative effectiveness research to provide treatment in a cost-effective manner.4 Biomarker testing for patients with NSCLC is one strategy that may help improve cost-effectiveness. By utilizing biomarker testing judiciously, clinicians may design optimal treatment regimens for their patients with NSCLC.1,5-7

Many different types of methodologies are available to classify lung cancer and to determine EGFR abnormalities.1,8-17 Tissue sampling for histology reveals the subtype of NSCLC, with adenocarcinoma being more likely to reveal the presence of EGFR and V-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) mutations.8 Although certain factors are predictive of EGFR abnormalities, such as Asian ethnicity, adenocarcinoma, nonsquamous pathology, no history of smoking, and female gender, testing is necessary to ensure the presence and type of EGFR abnormality.1,5-7 For example, EGFR mutations have been found in up to 20% to 40% of Caucasians and 40% to 50% of Asians.9

Tsao and colleagues examined tumor samples from patients enrolled in the BR.21 study for EGFR mutations and the number of EGFR genes to examine whether responsiveness to erlotinib and its impact on survival were associated with EGFR expression, gene amplification, or mutations. Participants in the BR.21 study had NSCLC and had previously been treated with and failed first- or second-line chemotherapy.10,11 Tissue samples were collected from paraffin blocks or 10 to 20 unstained slides for each patient, and then tested for EGFR protein expression using immunohistochemistry through Dako EGFR PharmDx kits. Samples containing more than 10% staining were considered positive for EGFR. Specimens with cellularity of more than 50% were scraped from the slides for isolation of DNA and mutational analysis. For specimens with less tumor cellularity, enriched DNA was isolated using microdissection, then amplified with polymerase chain reaction (PCR) assays via AmpliTaq Gold and primer sets. Purified PCR products were then sequenced in both directions using a BigDye Terminator Cycle Sequencing Kit and an ABI Genetic Analyzer, and further analyzed using SeqScape software, followed by manual review. Fluorescence in situ hybridization (FISH) was performed using dual color DNA probes to determine the number of EGFR copies. The samples with a high number of copies were considered FISHpositive.11 A total of 325 tumors were evaluated for immunohistochemistry, of which 184 (57%) were positive for EGFR, including 50% of the adenocarcinoma samples and 63% of the other samples. FISH was attempted in 221 tumors and was successful in 125 (57%) of the cases. Forty-five percent of the successful cases demonstrated high polysomy or amplification (48% of adenocarcinoma and 41% of the other samples), indicating presence of multiple EGFR genes in tumors. Mutational analysis was attempted in 197 samples, of which 110 samples yielded sufficient DNA for amplification of exons 18, 19, 20, and 21. Of these, 107 were successfully analyzed, and 24 (22%) contained 1 or more mutations. Investigators were able to amplify exons 19 and 21 in 70 of the 87 samples that did not contain sufficient material for a testing of exons 18 to 21. The net result was successful mutational analysis for 90% of the samples.11

Investigators found a total of 45 mutations in 40 patients. Mutations were present in 28% of samples of those with adenocarcinoma and 16% of the samples with other types of NSCLC.11 The presence of a mutation did not correlate with the expression of EGFR or the number of copies of EGFR. Neither patient survival nor disease severity was predicted by EGFR mutation status, the number of copies of EGFR, the presence of EGFR mutations, or the status of protein expression. However, a subgroup of patients with EGFR overexpression who were treated with erlotinib demonstrated significantly longer survival than patients who had received placebo (hazard ratio [HR], 0.68; 95% confidence interval [CI] 0.49-0.95; P = .02). There was no survival benefit with erlotinib in patients with EGFR negative tumors (HR, 0.93; 95% CI 0.63-1.36; P = .70). Further, among patients with high polysomy or EGFR amplification, survival was significantly longer in the erlotinib treatment arm (HR, 0.44; 95% CI 0.23-0.82; P = .008). There was no significant survival advantage associated with the use of erlotinib in the subgroup of patients without high polysomy or EGFR amplification (HR, 0.85; 95% CI 0.48-1.51; P = .59).11 These results demonstrated the feasibility of using mutation testing to guide EGFR-directed therapy in second- or third-line treatment for patients with NSCLC.

In a study published in 2009, large-scale screening of EGFR mutations in patients with advanced NSCLC was undertaken to determine its feasibility and practicality.12 From 2005 to 2008, 2105 specimens of lung cancer from Spain were screened for EGFR mutations, and as expected, mutations were found in a low percentage of the sample population (16.6%), with a higher frequency of occurrence among women (69.7%), patients who had never smoked (66.6%), and those with adenocarcinomas (80.9%). In patients receiving erlotinib, median progression-free survival (PFS) was 14 months and median overall survival was 27 months. In this trial, male gender and the presence of an L858R mutation (compared with patients with del 19 or without the L858R mutation) predicted longer PFS.12

As outlined in the preceding article in this supplement, while the presence of a EGFR mutation is a predictor of treatment efficacy in NSCLC, tumor histology is also an important component for therapeutic consideration, as it helps to identify the appropriate patients for mutational testing.2 Consequently, tissue samples should be obtained for reasons beyond just confirming the presence of malignancy and differentiating the malignancy type. Testing should begin with the planning of specimen collection. Cytologic specimens from needle biopsies can be used, but this method may not be representative of the patient’s whole tissue architecture. Small volume, core needle, or endoscopically obtained forceps biopsies offer a more complete characterization of the tumor and surrounding area. Large volume tissue and paraffin blocks afford improved reliability for evaluation of the tumor and its surrounding area. Depending on the location of the tumor itself, core needle biopsies are also a viable alternative.13,14 The criteria for cytological sampling have been recently reviewed in detail, and recommendations for testing are summarized in the section below.14

Recent Recommendations on Molecular Profiling

The American Society of Clinical Oncology


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