Abstract
Simple SummaryNext-generation sequencing (NGS) has revolutionized care for patients with advanced and metastatic non-small cell lung cancer through the identification of specific oncogenic driver mutations and pairing with matched targeted therapies. The application of NGS technologies also has the potential to improve outcomes in patients with earlier-stage disease who undergo surgery as their first line of treatment. We review clinically relevant topics in this patient cohort, for whom NGS technologies have spearheaded our understanding of tumor heterogeneity, the underlying genomic features associated with lung adenocarcinoma histologic subtypes, the prediction of recurrence after surgery, the identification of minimal residual disease by circulating tumor DNA, the discernment of intrapulmonary metastases versus synchronous or metachronous disease, and the identification of patients with early-stage non-small cell lung cancer who are likely to benefit from induction or adjuvant therapies.During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of “targeted therapy” in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as EGFR, ALK, ROS1, BRAF V600E, MET, and NTRK mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.
Highlights
The identification of specific oncogenic drivers through next-generation sequencing (NGS) and the development of matched targeted therapies have revolutionized cancer care and associated outcomes for patients with locoregionally advanced and metastatic non-small cell lung cancer (NSCLC)
Examples of important areas relevant to early-stage NSCLC include (1) a better understanding of tumor heterogeneity, (2) the underlying genomic features associated with the tumor biology of lung adenocarcinoma (LUAD) histologic subtypes, (3) prediction of recurrence of disease after surgery, (4) identification of minimal residual disease (MRD), (5) discernment of intrapulmonary metastases (IPMs) from synchronous or metachronous disease, and (6) identification of patients with early-stage NSCLC who are likely to benefit from induction or adjuvant targeted therapies
Upcoming clinical trials of adjuvant therapy based on MRD detection include MERMAID I, which will evaluate the effect of adjuvant durvalumab plus chemotherapy versus chemotherapy alone on disease-free survival (DFS) in patients with completely resected stage II–III NSCLC and MRD
Summary
The identification of specific oncogenic drivers through next-generation sequencing (NGS) and the development of matched targeted therapies have revolutionized cancer care and associated outcomes for patients with locoregionally advanced and metastatic non-small cell lung cancer (NSCLC). The subsequent clinical trials in stage IV NSCLC have demonstrated markedly improved patient outcomes with TKI approaches that target NGS-identified drivers, compared with platinum-based chemotherapy alone [5]. Despite NGS-driven advances in cancer care for locoregionally advanced and metastatic NSCLC, fewer efforts have been made to leverage tumor genomic profiling for earlier-stage NSCLC, where surgery plays a prominent diagnostic and therapeutic role. As care paradigms for advanced-stage lung cancer are rapidly changing, there is an expectation, and actual anticipation, that the use of similar genomic- and molecular-based approaches will improve outcomes among patients with earlier-stage disease. We discuss the emerging role of NGS-based technologies and their applications in early-stage NSCLC, with a focus on patients undergoing surgery with curative intent
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