In Case of Invasive Nodule, Break Ground Glass.

After decades of stagnation, lung cancer survival is trending upward with numerous reports of long-term survival in patients with advanced lung adenocarcinoma (LUAD) treated with targeted therapeutics and of overall 5-year survival rates exceeding 20% (1). Much of the improvement is attributed to the introduction of genomic biomarker–based targeted therapeutics in advanced disease, starting after the approval of EGFR (epidermal growth factor receptor) tyrosine kinase receptor therapy for first-line treatment of EGFR-mutated lung cancer in 2013 (2). Trends in advanced disease survival are expected to continue with the standard use of immunotherapy and with ongoing development of drugs targeted to drivers and to the immune response.

Appropriately, attention is being directed toward repurposing these approaches to early-stage disease, with notable benefits demonstrated by adjuvant use of osimertinib in resected early-stage EGFR-mutant lung adenocarcinoma (3) and by neoadjuvant immunotherapy trials in early-stage lung cancer (4). These advances are welcome because the 5-year survival for early-stage lung cancer is 60%, which is lower than the overall 5-year survival rates for breast and prostate cancer.

Importantly, there are subtypes of early-stage lung adenocarcinoma that routinely have survival rates of 95–100% after resection (5). Advances in the clinical, pathological, and biological understanding of these tumors contributed to the updated International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma that featured identification of pathological subtypes of adenocarcinoma in situ, minimally invasive carcinoma, and lepidic predominant carcinoma, that are composed entirely of or in part by a noninvasive lepidic morphology component that is correlated with a ground-glass opacity radiographic pattern on computed tomography (CT) imaging (6). The 5-year survival rates after resection of these lepidic-containing tumors is high and is associated with the pathological extent of invasion and with the morphological subtype of the invasive solid component (7).

Reassured by the experience accumulated from managing patients with early-stage lung adenocarcinoma tumors detected incidentally or through lung cancer screening programs, guidance has been developed that suggests that “active surveillance” with follow-up chest CT imaging is an appropriate strategy for selected patients with chest imaging findings of lung nodules with a ground-glass component that is purely nonsolid or part-solid (8, 9). Cohort studies such as the Early Lung Cancer Action Program consortium have reported 100% lung cancer survival rates following a surveillance strategy for nonsolid and part-solid lesions (10).

In this issue of the Journal, Chen and colleagues (pp. 1180–1191) address the important question as to whether chest CT–detected nodules with a ground-glass component mirror the biology and genomics of resected tumors with a lepidic component (11). In a prospective study of 101 patients with lung cancer, 31 had nodules with ground-glass components identified by high-resolution CT three-dimensional volumetric analysis. Pathology showed that no tumor was adenocarcinoma in situ and that 11 were classified as either minimally invasive lung adenocarcinoma or lepidic predominant adenocarcinoma, and these were appropriately analyzed together as “low-grade” LUAD.

As expected, the major somatic mutation in this cohort of tumors acquired from Asian, predominantly nonsmoking patients was in EGFR, with a prevalence of 63%. This may impact the generalizability of findings to Western populations that have lower prevalence of EGFR mutant tumors. Importantly, none of the somatic mutations correlated with ground-glass extent, which differs from reports from Qian and colleagues that showed an increasing frequency of mutations in KRAS, NF1, and TP53 in solid LUAD compared with adenocarcinoma in situ and minimally invasive carcinoma tumors (12). Tumor mutation burden was increased in high-grade LUAD, and consequently, cell-free DNA and circulating tumor DNA levels were increased in high-grade blood specimens as well.

Transcriptomic and TCR (T-cell receptor) sequencing of tumors provided insights into tumor metabolic activity and activation of the immune system within the tumor microenvironment. Accumulating evidence supported by murine models of lung cancer suggests a paradigm for progression and invasion for part-solid lung adenocarcinoma (13–15). Nonsolid tumors acquire persistent activating mutations, escape immune surveillance, and activate microenvironment processes to promote angiogenesis, invasion, epithelial–mesenchymal transition, and subsequent progression to advanced-stage metastatic tumors. Of particular interest is the role of the immune system in this process. Using concomitant analysis of tumor DNA and inferred analysis of RNA sequencing data, HLA loss of heterozygosity and TCR clonality were increased in solid nodules compared with part-solid nodules, and this was associated with increased expression of immunomodulatory genes and of CD4+, CD8+, and Treg cell infiltration. Recent work using single-cell analysis of early lung adenocarcinoma builds on these findings to show promise of more precise deconvolution of the immune landscape in these tumors and a better understanding of the ongoing biological tension between antitumor immunity and immune evasion within these nodules (16, 17).

Albeit limited by a modest sample size, Chen and colleagues’ analysis does demonstrate intertumor heterogeneity within the low-grade subtype nodules. This is important because it is likely that the genomic and immune heterogeneity within these tumors with similar radiographic and pathologic appearance will drive subsequent progression, invasion, and metastasis in a small subset of tumors. Prospective analysis of nodule biomarkers associated with invasion and progression will be required to confirm this hypothesis and to determine if concomitant biomarker analysis will enhance outcomes in patients managed using guidelines that are driven predominantly by nodule imaging characteristics. In other words, breaking the ground glass to better understand the biological activity within these part-solid nodules promises to enhance our understanding of lung adenocarcinoma progression and to improve strategies to manage and treat these common tumors.