The number of alterations detected in the DNA collected from blood samples (liquid biopsies) of cancer patients treated with immune checkpoint inhibitors was associated with response to the treatment.
Using blood samples from 69 patients with different types of cancer treated with immune checkpoint inhibitor therapy, investigators at the University of California San Diego Moores Cancer Center analyzed the ctDNA by next-generation sequencing (Guardant360 assay). Specifically, they counted the number of variants of unknown significance (VUS, alterations/mutations in the DNA whose association with disease risk is unknown).
Of the 69 patients, 29 percent had more than three VUS alterations and 71 percent had three or fewer VUS in their ctDNA.
After being treated with an immune checkpoint inhibitor, patients with more than three VUS in their ctDNA had significantly higher response rates (45 percent) compared with those who had three or fewer VUS (15 percent).
Among patients who had higher numbers of alterations of the VUS type, the median survival was not reached while those who had lower numbers of alterations of the VUS type had a median survival of only about 11 months.
Landmark analyses of PFS at 2 months for responders and nonresponders,
VUS >3 versus ≤3 groups
A, A 2-month landmark study for PFS is shown for 15 patients treated with checkpoint inhibitor–based immunotherapy who had >3 VUS ctDNA alterations. B, A 2-month landmark study for PFS is shown for 26 patients treated with checkpoint inhibitor–based immunotherapy who had ≤3 VUS ctDNA alterations. Comparison groups are those who achieved response (CR or PR; in blue) versus those who did not achieve response (SD or PD; in red). C, A 2-month landmark study for PFS is shown for 15 patients treated with checkpoint inhibitor–based immunotherapy who had achieved response (CR or PR). D, A 2-month landmark study for PFS is shown for 26 patients treated with checkpoint inhibitor–based immunotherapy who had not achieved response (SD or PD). Comparison groups are those with >3 VUS ctDNA alterations (in blue) versus ≤3 VUS ctDNA alterations (in red).
“Immune checkpoint inhibitors, a class of immunotherapy, are transforming cancer treatment; however, overall only about 20 percent of patients respond to these drugs, and the drugs sometimes have significant side effects,” said senior authos Razelle Kurzrock. “Therefore, it is important to have biomarkers that can help predict response to these relatively new drugs.
Most biomarkers used to predict response to checkpoint inhibitors are measured on tumor biopsy specimens and have limitations, said lead author Yulian Khagi. “Biopsies can be painful, expensive, risky, and not always representative of the tumor characteristics overall,” he said. “We wanted to identify an easily obtainable and easily interpretable biomarker that can predict response to checkpoint inhibitor therapy utilizing genomic sequencing of DNA that is shed from cancer cells into the bloodstream.”
“Our study demonstrated that high circulating tumor DNA [ctDNA, tumor DNA derived from a blood sample] alteration number was associated with response to checkpoint inhibitor therapy,” Kurzrock said.
“Though the study was small, a significant difference could also be identified for a longer survival without progression of cancer and even a longer overall survival in the high versus low VUS alteration group,” noted Khagi. “It is likely that, with larger studies, this difference will become more significant.”
“Mutations lead to the production of abnormal proteins; the more mutations and abnormal proteins the tumors produce, the better the chance that one or more of these proteins will be ‘detected’ by the immune system,” explained Kurzrock. “We showed that counting the mutations in the DNA floating in the bloodstream could help predict response to these new and exciting drugs that boost the immune system to attack cancer.”
Khagi noted, “If verified by further studies, clinicians will be able to utilize the objective results of this simple blood test to make determinations about whether to use checkpoint inhibitor-based immune therapy in a variety of tumor types. It should also be noted that the cutoff points might be different as these blood tests evolve to detect more mutations in more genes.”
Source – Eurekalert