Physician attitudes and prevalence of molecular testing in lung cancer

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.