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In the setting of advanced NSCLC, the paradigm has shifted from treating a single disease with very few options to understanding NSCLC as a multitude of different diseases with different optimal approaches.[1,2] We have to understand the nuances of each patient’s disease to determine the optimal therapy. In this activity, I will review biomarkers that help us identify different NSCLC subtypes and discuss new targeted therapies for patients with specific mutations, as well as recent findings from clinical trials of immunotherapies.
The first revelation was the discovery of differential benefit for nonsquamous and squamous histologies from pemetrexed. In the modern era, it is important to understand specific DNA alterations that drive the tumor. This pie chart highlights the many alterations that have been identified, many of which have targeted therapies that are either approved or in advanced clinical trials and will soon be options for our patients.
Obtaining a biopsy remains fundamental to understanding the tumor of patients with advanced NSCLC. First, we establish the histologic subtype, either squamous or nonsquamous. Then, we conduct molecular testing—which is just as important—to choose the correct treatment for our patients. To conduct molecular testing, it is important to ensure that sufficient biopsy tissue is obtained. The primary tumors and metastatic lesions are equally suitable for molecular testing. Bone biopsies are suboptimal due to decalcification and degradation of DNA. Liquid biopsies using cell-free tumor DNA in the plasma are an option when tissue is not available, which will be discussed shortly.
For nonsquamous NSCLC, it is recommended to test for EGFR, ALK, ROS1, BRAF, MET, and RET aberrations, because these targets have therapies that are approved by the FDA. We should also consider using broad molecular testing by NGS to detect a wider range of mutations from the beginning using a single test.
For squamous disease, there are fewer actionable mutations, but broad testing by NGS is still recommended and Medicare does cover it, as well as most private insurers. At the very least, we should consider molecular testing in young, never, or light smokers or if the biopsy specimen is small or has mixed histology.
It is also important to determine the PD-L1 expression level in all patients with advanced NSCLC, because it guides clinicians on using immunotherapy in their patients.
The advent of liquid biopsies is changing the diagnostic landscape in NSCLC and other tumor types. We have known for quite some time that tumors shed DNA into the blood and that this might be part of the metastatic process; detecting cell-free tumor DNA and characterizing it has become possible in recent years.
Liquid biopsy is an excellent choice when molecular testing is needed but the tumor biopsy is insufficient. It is also useful in second-line and third-line therapy to establish the mechanism of resistance, especially to tyrosine kinase inhibitor (TKI) treatment.
The obvious advantage is that a liquid biopsy is minimally invasive. It is a blood draw done in the lab, and the results are returned faster than with a tissue-based biopsy. Another theoretical advantage is that a liquid biopsy addresses the issue of tumor heterogeneity. A tissue biopsy is just 1 specimen of 1 single tumor. The liquid biopsy represents sampling of the entire tumor burden across the body.
Liquid biopsy is also associated with limitations such as lower sensitivity vs tissue biopsy, although it has improved over time. That said, the specificity of liquid biopsy is excellent. So a positive result on liquid biopsy can be trusted, but a negative result—especially from a patient with a high pretest probability of an actual mutation—would suggest the need for a tissue biopsy. Likewise, gene fusions such as ALK and ROS1 rearrangements might be somewhat harder to find by liquid biopsy, but if identified, that result can be trusted.