Management of Oncogene Driven Locally Advanced Unresectable Non-small Cell Lung Cancer.

INTRODUCTION: The current standard of care of locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation, followed by consolidation durvalumab. However, there is evidence that the efficacy of chemoradiation and also immunotherapy in many oncogene-positive LA-NSCLC are attenuated, and dependent on the subgroup. AREAS COVERED: We will firstly review the outcomes of standard-of-care therapy in oncogene-driven LA-NSCLC. We looked at various oncogene driven subgroups and the tumor microenvironment that may explain differential response. Finally, we review the role of targeted therapy in the treatment of LA-NSCLC. EXPERT OPINION: Each oncogene-positive subgroup should be treated as its own entity, and continued efforts should be undertaken to incorporate targeted therapy, which is likely to yield superior survival outcomes if trial design can be optimized and toxicities can be managed.

BRCA sequencing of tumors: understanding its implications in the oncology community.

In the current era of personalized medicine, much more information can be gleaned through genetic testing and tumor sequencing. Unfortunately, this comes at a price of obtaining results that may beget more uncertainties. Sequencing for mutations on tumor samples is increasingly performed, more commonly to guide treatment for oncology patients, and occasionally as a proxy for germline testing when the ideal index patient to initiate genetic testing in a family at risk for hereditary cancer syndrome is no longer alive. Next-generation sequencing (NGS) involving tens to hundreds of genes as a testing platform is being used more routinely in the clinic now. However, one should keep in mind that the larger number of genes included in an NGS panel will yield a correspondingly higher probability of finding an incidental germline pathogenic mutation, which will have both clinical and ethical implications for patients and their families. The probability of identifying a tumor pathogenic BRCA1/2 variant is about 3-4%, with the majority (~80%) being germline in nature; thus, patients should be counselled accordingly prior to having their tumor samples sequenced. On the flip side, caution should be exercised when tumor sequencing is intended to be a surrogate for germline testing. This is because false negative rate is high at ~30%, making it an inadequate tool to sufficiently dismiss the presence of a germline BRCA1/2 mutation, especially in a setting where there is already a high clinical suspicion for a hereditary condition.