João Alessi, MD, on the Ability for Cancer Aneuploidy to Predict Immunotherapy Response in NSCLC

João Alessi, MD, research clinical fellow at Dana-Farber Cancer Institute, spoke with CancerNetwork® to discuss his work presented at the American Association for Cancer Research (AACR) Annual Meeting 2021 focusing on cancer aneuploidy scores and the potential for aneuploidy to predict immunotherapy response in a patient with non–small cell lung cancer.

CancerNetwork®: Could you give a brief background on exactly what cancer aneuploidy is and why you were interested in reviewing it?

João Alessi, MD: Cancer aneuploidy is an unbalanced number of chromosomes, and it’s associated with somatic mutation rates, expression of proliferative genes, and altered immune signaling. Whether aneuploidy correlates to a distinct [number] of phenotypes or impacts clinical outcomes to immune checkpoint inhibitors in non–small cell lung cancer is unclear.

Looking at the poster that was a part of the recent AACR Annual Meeting, could you talk about the study design and what the patient requirements were to be included in this research?

We collected clinicopathological data from patients from the Dana-Farber Cancer Institute and retrospectively we analyzed an overall cohort of 1582 patients. We also examined a subset of 300 patients who received immunotherapy for advanced disease. Patients in the immunotherapy cohort were included if they had advanced non–small cell lung cancer, which was treated with at least 1 dose of PD-L1 inhibitor alone or in combination with CTLA-4 inhibitor. We excluded patients who received PD-L1 inhibitors as consolidation after concrete chemoradiation for unresectable stage III [disease].

With that main cohort, what results did you find, and what would you say was the main takeaway for you and your colleagues with this research?

First, we calculated the aneuploidy score, as I mentioned, [which] is the number of alternate chromosome arms for each tumor. That was calculated as the sum total of alternate arms from a range of 0 to 39 that we examined in this study. And, as we know, the aneuploidy score highly correlates with a fraction of genomes altered by aneuploidy.

As a main finding of our study, we’ve seen that overall response rate, progression-free survival, and overall survival were improved among patients with a low aneuploidy score that was defined as equal to or lower than 2 compared with those tumors with an aneuploidy score was greater than 2.

The rationale behind this association with improving clinical outcomes to immunotherapy, we looked into a separate cohort of cases that eliminated the tumor microenvironment of tumors. And we’ve seen that tumors with a low aneuploidy score were enriched with tumor-infiltrating cells [and] that means a higher proportion of CD8- and PD-1–positive immune cells compared with tumors with higher aneuploidy score.

With this interesting data, do you have any research planned to build off these data?

In conclusion, this study provides a sizable advance [in understanding] how aneuploidy correlates with clinical, pathologic, and genomic factors and a distinct tumor microenvironment. A strength is its association with benefits to treatment checkpoint inhibitors. It may represent another biomarker for immunotherapy efficacy among those with non–small cell lung cancer.

Therefore, additional strategies to impact aneuploidy levels on immune signature, and to correlate pathways may define a viable secondary therapeutic approach to embrace immune checkpoint inhibitor treatment outcomes. Furthermore, incorporating the aneuploidy score in specific arm level events may have implications for this decision-making treatment and study design. We intend to increase the number of cases in our cohort and perhaps validate our findings in a separate cohort.

Reference

Alessi JV, Ricciuti B, Li YY, et al. Association of aneuploidy score with clinical outcomes to immunotherapy in NSCLC. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract 26.