19 Molecular alterations occurring in other cancers can also present in a small proportion of NSCLC, such as NTRK gene rearrangements that are amenable to treatment with NTRK TKIs. There are also a number of emerging molecular targets and therapies in NSCLC, some likely nearing clinical practice (and already helpful for selection for clinical trials), such as RET rearrangements, 17 MET exon 14 skipping mutations, 18 and activating HER2 mutations. 16 These guidelines were endorsed by the major oncology societies of China, Japan, Korea, Malaysia, Singapore, and Taiwan. 14 The addition of PD-L1 immunohistochemistry (IHC) staining is based upon the improved outcomes with the immune checkpoint inhibitor pembrolizumab both in the second line for tumors with PD-L1 1% or more 15 and in the first line for patients with PD-L1 expression 50% or higher. In 2018, ESMO and the Chinese Society of Clinical Oncology issued joint Pan-Asian guidelines recommending routine testing of all advanced nonsquamous NSCLC for EGFR mutation, ALK rearrangement, ROS1 rearrangement, and BRAF mutation, as well as PD-L1 immunohistochemistry. The 2018 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines similarly recommend routine testing for EGFR, ALK, and ROS1 13 and commented that BRAF-targeting drugs were gaining approval in some European countries. There is also general concordance between guidelines in the United States and international organizations. 11 Another commonly accessed source of recommendations is the National Comprehensive Cancer Network guidelines, 12 which currently mirror the ASCO recommendations. Shortly afterward, ASCO issued an endorsement of the CAP/IASLC/AMP guidelines, but further extended the recommendations to include routine BRAF mutation testing. The guidelines also recommended routine testing for T790M mutation in all patients with EGFR mutations who progressed on first- or second-generation EGFR TKIs and added endorsement of the use of cell-free DNA for testing when tissue was unavailable. 9 However, the guideline committee completed its formal review just before the approval of dabrafenib and trametinib therapy for BRAF+ NSCLC in June 2017, 10 and thus, this population was not included in the recommendations. In 2018, the CAP/IASLC/AMP guidelines were updated to add the recommendation for routine testing for ROS1 gene rearrangements 8 given the efficacy of TKIs such as crizotinib in this population. This guideline established the standard of care for molecular testing in NSCLC that stands today, although now with expanded targets. 7 Beyond the biomarkers themselves, these guidelines also made detailed recommendations about the target population (all patients with advanced lung adenocarcinoma regardless of clinical indicators such as smoking status, race, or sex), the recommended testing approaches, and a recommended turnaround time of less than 14 days. In 2013, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly issued guidelines for routine testing of patients with lung cancer for EGFR mutations and ALK gene fusions. 5 In that same year, crizotinib was approved for treatment of anaplastic lymphoma kinase (ALK)–rearranged NSCLC, 6 illustrating the rapid pace of adoption of targeted therapies and the challenges guidelines would have keeping pace. Although sensitizing mutations in the EGFR gene were first described in 2004, 1, 2 followed by multiple trials showing that EGFR tyrosine kinase inhibitors (TKIs) were superior to chemotherapy in this subgroup of patients, 3, 4 it was not until 2011 that the first provisional recommendation was issued by ASCO endorsing routine testing of all patients with lung adenocarcinoma for EGFR mutations. This practice has its own set of challenges in keeping up with a rapidly changing field. As the treatment of lung cancer has become progressively more biomarker-driven, and with the rapid emergence of effective matched targeted therapies, organizations have made attempts to define best practices for which tests are necessary and in what target population.
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