LAUSR

The adequate histologic subtyping of non–small cell lung cancer (NSCLC) secondary to the clinical need of tailoring systemic therapies has been challenged by small sample sizes of primary or metastatic lung tumors obtained through fineneedle aspiration cytology or tiny bronchoscopy biopsies in which the precise tumor definition may be hampered because of scant viable cells and/or poor tumor differentiation. Several studies have demonstrated how a limited panel of immunohistochemistry markers may reliably refine NSCLC subtyping or, at least, provide the most likely differentiation lineage of poorly differentiated lung cancers originally diagnosed as NSCLC, not otherwise specified. It is anticipated that the application of precision medicine will improve all areas of medicine, including predicting an individual’s risk of disease, disease prognosis, and risk of side effects versus positive response to disease treatment approaches. Tissue, even more relevantly, remains the issue in the era of targeted therapies and immunotherapy because of the clear need to identify which subset of patients will benefit most from these tailored approaches. Histologic and biologic heterogeneity are well known phenomena that may significantly impact our capability to detect specific molecular targets and our ability to predict sensitivity to specific molecular targeted agents. The heterogeneity of response and outcome associated with specific molecular features is more likely a reflection of biologic heterogeneity than technical issues, which might not be captured in small biopsies, fine-needle aspirates, or tissue microarrays consisting of small, selected tissue cores. The unit in precision medicine is a biomarker ensemble, which includes a predictive biomarker that is hypothesized to play a crucial role in the disease pathway; a diagnostic assay, which is used to determine a patient’s biomarker status; and finally a therapeutic agent, which is intended to be more effective for patients who are biomarker-positive. If 1 of 3 basic elements is lacking, then we are lying down outside the framework of precision medicine. With the current emphasis on biomarker-driven drug development and the increasing inclusion of integral and integrated biomarkers in our trials, it is necessary to ensure that fit-for-purpose assays of these biomarkers are incorporated into study protocols. Briefly, markers are integral when they are essential for conducting the study, because they define eligibility, stratification, and monitoring of the disease or study endpoints. Markers are considered integrated when they actually are testing a hypothesis based on pre-existing data and not simply generating hypotheses. Such integrated markers need to be performed ideally on all patients in a trial, and the assay already should have been tested in humans with the disease in question and should have demonstrated reproducible analytic qualities. Tissue procurement is definitively more critical for integral biomarkers than for integrated biomarkers. In contrast, exploratory biomarkers may not be performed on all participants in a trial, and the collection of these exploratory markers by trial investigators may be voluntary. Currently, in the field of thoracic malignancies, although we count some outstanding breakthrough therapeutic successes, these can be numbered on the fingers of 1 hand and include epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for EGFR-sensitizing mutations and the re-arrangement of anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, with the recent addition of inhibitors of the immune-checkpoint pathways, as either second-line or front-line treatment for NSCLC. It is noteworthy that these immunotherapy approaches require matching known antigens or pathways with the antibodies; consequently, coupling diagnostics and therapeutics is also a major feature of immunotherapy. Although we are currently lagging behind the original expectations, most researches still believe that these advances enable the routine molecular study of every tumor at the point of care and, over time, will redefine clinical management