Lower levels of cancer aneuploidy were associated with more favorable outcomes after immune checkpoint inhibition in patients with non–small cell lung cancer (NSCLC), according to data presented by Alessi et al at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract 26).

“Cancer aneuploidy, which is an unbalanced number of chromosomes in cancer cells, is a widespread alteration in NSCLC and is associated with altered immune signaling; however, the functional significance of cancer aneuploidy remains unclear,” said presenting author João Alessi, MD, a research clinical fellow at Dana-Farber Cancer Institute, Boston. Despite the availability of predictive biomarkers, such as PD-L1 expression and tumor mutational burden, fewer than 50% of patients with NSCLC respond to immune checkpoint inhibition, highlighting the need for additional markers to identify patients likely to respond to the treatment, he explained.

Aneuploidy and Response to Immunotherapy

In this study, Dr. Alessi and colleagues retrospectively analyzed the association between cancer aneuploidy and response to anti–PD-1/PD-L1 immune checkpoint inhibition in patients with NSCLC. The analysis included data from 279 patients who were treated with this therapy and whose tumors underwent next-generation sequencing. Tumors were assigned an aneuploidy score, which was defined as the total number of altered chromosome arms and ranged from 0 (no altered chromosome arms) to 39 (alterations in all examined chromosome arms).

The researchers found that patients with complete or partial responses to immune checkpoint inhibition had a significantly lower aneuploidy score compared with those with stable or progressive disease (median aneuploidy score of 4 vs 7). Patients with cancer aneuploidy scores less than or equal to 2 had significantly higher overall response rates (43.0% vs 19.8 %), significantly longer progression-free survival (6.2 vs 2.9 months), and significantly longer overall survival (19.8 vs 13.8 months) than patients with aneuploidy scores greater than 2.

Aneuploidy score was significantly associated with progression-free and overall survival, even after adjusting for other factors such as performance status, oncogenic driver mutation, PD-L1 expression, tumor mutational burden, and line of treatment. After adjustment, patients with aneuploidy scores less than or equal to 2 were 28% and 36% more likely to have improved progression-free and overall survival, respectively, compared with patients with aneuploidy scores greater than 2.

Dr. Alessi and colleagues also found that tumors with low aneuploidy scores had significantly higher numbers of immune cells positive for CD8, Foxp3, and PD-1. The presence of these inflammatory markers indicates that tumors with low aneuploidy may be more immunogenic than those with higher aneuploidy levels, which could contribute to increased responses to immune checkpoint inhibition. Aneuploidy score was not associated with PD-L1 expression or tumor mutational burden, suggesting that aneuploidy score could serve as an independent predictive biomarker.

“Given the burgeoning number of recommended molecular tests for NSCLC, next-generation sequencing offers an opportunity for aneuploidy assessment,” said Dr. Alessi. “Incorporating aneuploidy score in molecular testing may aid treatment decisions and clinical trial design.”

A limitation of the study was that it was a retrospective analysis of cases from a single cancer center. Dr. Alessi cautioned that further data from prospective studies are needed to validate the associations the researchers observed and to determine the optimal aneuploidy score threshold for predicting responses. Sample purity and the lack of a standard method to measure aneuploidy were additional limitations, though Dr. Alessi noted that samples with low purity were removed from the analysis.

Disclosure: The study was supported by the Dana-Farber Cancer Institute. For full disclosures of the study authors, visit abstractsonline.com.