Patients with Early-Stage NSCLC See Higher TMB Versus Those with Advanced Stage NSCLC

According to study findings presented at the MAP 2020 Virtual Congress, held October 9-10, 2020, the tumors of patients with stage I and II early-stage non-small cell lung cancer (NSCLC) demonstrate the highest tumor mutational burden (TMB) and most often display the mutational signature associated with tobacco smoking.

Guus Van den Heuvel, MD, of the Radboud University Medical Center in Nijmegen, Netherlands explained in a presentation of the findings that recent studies demonstrate varying therapeutic effects of immune checkpoint inhibitors in patients with NSCLC and high TMB, prompting the current study which examined the link between high TMB in a large series of clinical NSCLC samples irrespective of tumor stage. In addition, Van den Heuvel and colleagues looked to establish the particular mutational processes involved by assessing mutational signatures.

In this retrospective observational descriptive study, researchers extracted DNA from cytological samples and formalin-fixed, paraffin-embedded tissue sections of tumor samples collected from patients with stages I, II, III, and IV NSCLC. DNA sequencing was performed using the TruSight™ Oncology 500 panel consisting of 523 cancer-related genes.

For the purposes of this study, TMB was defined as the number of somatic mutations per megabase (mut/Mb) in each sample. Moreover, tumor samples which contained a minimum of 30 somatic variants were utilized for mutational signature profiling.

Overall, sequencing was performed on 197 samples. The median non-synonymous TMB was found to be 8.7 mut/Mb (range, 0-85.4). When compared with this median, stage I and II tumors had a TMB of 67% and the TMB in stage III and IV tumors was 47.5% (P = .01).

An evaluation of mutational signatures was also performed in 76 (39%) tumor samples with a median TMB of 15.2 mut/Mb. The study revealed that the single base substitution (SBS) signature 4, which is associated with tobacco smoking, was displayed in 34 of the 76 samples (45%). Even further, the SBS4 signature was found to be significantly more present in early stages I and II disease compared with advanced stages III and IV (P = .003).

Additionally, the signatures SBS2 and SBS13, which are associated with activity of the AID/APOBEC family of DNA deaminases and might possibly be associated with cancer development, were observed in 30 of the 76 samples (39%). One tumor with TMB 26 mut/Mb also contained SBS7a and SBS7b signatures that are associated with UV light exposure.

With the overall study findings considered, the researchers concluded that patients with early stage NSCLC generally have a higher TMB in comparison to advanced stages and more often show a SBS4 signature, which is associated with tobacco smoking. They went on to advise these study findings may have clinical implications for a subpopulation of patients that could benefit from adjuvant immuno-oncology.

Reference:

PATIENTS WITH EARLY STAGE NSCLC HAVE A HIGHER TMB IN COMPARISON TO ADVANCED STAGE DISEASE [news release]. Published October 9, 2020. Accessed October 27, 2020. https://www.esmo.org/oncology-news/patients-with-early-stage-nsclc-have-a-higher-tmb-in-comparison-to-advanced-stage-disease