Chromosomal Abnormality and Immunotherapy Response

Patients with non-small cell lung cancer (NSCLC) whose cancer cells have low levels of aneuploidy—an abnormal number of chromosomes—tend to respond better to immune checkpoint inhibitor drugs than patients with higher levels, Dana-Farber Cancer Institute researchers will report at the virtual AACR Annual Meeting 2021.

In analyzing data from hundreds of patients with NSCLC who were treated with these drugs, the researchers found that those whose cancer receded tended to have less aneulploidy in their tumor cells than those whose disease remained stable or worsened. These findings suggest that aneuploidy testing can have an important role in determining which treatment is most likely to benefit patients, according to the researchers.

Immunotherapy results could be related to chromosomal abnormalities

“Aneuploidy is a widespread feature of non-small cell lung cancer and is associated with altered immune signaling; however, the functional significance of cancer aneuploidy remains unclear,” said João Alessi, MD, of Dana-Farber who will be presenting the study findings. “Despite the availability of biomarkers for predicting which patients are most likely to respond to checkpoint-inhibiting drugs, less than 50 percent do respond, highlighting the need for new and better markers.”

The checkpoint inhibitors used to treat NSCLC target the proteins PD-1 or PD-L1, which deter immune system T cells from attacking tumor cells. By blocking these proteins, the drugs allow the attack to proceed. The discovery by Dana-Farber scientists that PD-1 and PD-L1 can stymie an immune attack on cancer cells laid the foundation for the development of a new generation of checkpoint inhibitors.

For this study, Alessi and his colleagues analyzed data from 279 patients with NSCLC who had been treated with PD-1 or PD-L1 inhibitors. Each tumor was assigned an aneuploidy score from 0-39 based on the number of altered chromosome arms within its cells. The researchers used this information to explore whether aneuploidy score was linked to the effectiveness of treatment.

They found that patients with complete or partial responses (complete or partial shrinkage of their tumors) to checkpoint inhibitors had significantly lower aneuploidy scores than those with stable or progressive disease. Patients with cancer aneuploidy scores less than or equal to 2 had significantly higher overall response rates (43% 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.