Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey

Abstract

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.

Keywords: Carcinoma; liquid biopsy; medical oncology; molecular diagnostic techniques; non-small cell lung cancer (NSCLC); pathologists.

Figure 1

CAP/IASLC/AMP recommendations for molecular diagnostics (5). ^†, ASCO and NCCN recommend BRAF testing for all patients with advanced lung adenocarcinoma (15,16). ^‡, KRAS testing may be offered as a single-gene test to exclude patients from expanded panel testing. ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; BRAF, B-Raf proto-oncogene; CAP, College of American Pathologists; EGFR, epidermal growth factor receptor; ERBB2, Erb-B2 receptor tyrosine kinase 2; HER2, human EGFR 2; IASLC, International Association for the Study of Lung Cancer; KRAS, Kirsten rat sarcoma viral oncogene; MET, MET proto-oncogene; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; RET, Ret proto-oncogene; ROS1, ROS proto-oncogene 1.

Figure 2

Proposed molecular testing strategies. LUAD, lung adenocarcinoma; NSCLC, non-small cell lung cancer.