Molecular Testing Strategies in Non-Small Cell Lung Cancer

Optimizing the Diagnostic Journey

Jeffrey P. Gregg; Tianhong Li; Ken Y. Yoneda


Transl Lung Cancer Res. 2019;8(3) 

In This Article

Abstract and Introduction


Molecular testing identifies patients with advanced non-small cell lung cancer (NSCLC) who may benefit from targeted therapy or immunotherapy (i.e., immune checkpoint inhibitor treatment for patients with high tumor mutational burden (TMB), microsatellite instability-high or mismatch repair-deficient tumors). Current guidelines state that molecular testing should be conducted at the time of initial diagnosis and tumor progression on targeted therapy. In real-world clinical practice in the United States (US), molecular testing is often not conducted or happens late in the diagnostic journey, resulting in delayed or inappropriate treatment. Herein, we review the rationale for molecular testing in advanced NSCLC, along with best-practice guidelines based on published recommendations and our own clinical experience, including a case study. We propose three strategies to optimize molecular testing in newly diagnosed patients with advanced NSCLC: (I) pulmonologists, interventional radiologists, or thoracic surgeons order molecular tests as soon as advanced NSCLC with an adenocarcinoma component is suspected; (II) liquid biopsies conducted early in the diagnostic pathway; and (III) pathologist-directed reflex testing, as conducted in other areas of oncology. To help facilitate these strategies, we outline our recommendations for optimal sample collection techniques and stewardship. In summary, we believe that implementation of these individual strategies will allow clinicians to effectively leverage available treatment options for advanced NSCLC, reducing the time to optimal treatment and improving patient outcomes.


Lung cancer continues to be the leading cause of cancer death in the United States (US), with 209,703 new cases predicted in 2020.[1,2] Lung cancer is categorized as either small-cell lung cancer in approximately 10% to 15% of cases or non-small cell lung cancer (NSCLC) in approximately 80% to 85% of cases.[2] Lung cancer is diagnosed at an advanced stage in 72% to 76% of patients in the UK and 57% in the US, precluding curative treatment, and is associated with poor prognosis.[3,4]

Primary care providers, emergency medicine physicians, and pulmonologists are often the first point of contact for patients. From initial presentation, patients have a long journey that includes referral, clinical work-up, biopsy, molecular testing, formal diagnosis and treatments. There is an unmet need for strategies to improve efficiency in this process. One step in disease diagnosis where improvements can be made is molecular testing, used to identify specific molecular characteristics treatable with targeted therapies.[5] Without appropriate molecular testing and corresponding results, empiric therapy will likely be initiated, which may be inappropriate and detrimental to patients with targetable mutations.[6–8] Herein, we review the role of molecular testing in advanced NSCLC, along with current guidelines and recommended methodologies, and propose three strategies to optimize current practices.