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Studies Assess Tumor Aneuploidy to Guide Immunotherapy Treatment

NEW YORK – A pair of new studies has demonstrated the possibility of using tumor aneuploidy as a biomarker for predicting response to immunotherapy, alone or in combination with radiotherapy.

For the first of these studies, published in Nature Cancer on Monday, a team from the University of Chicago, Northwestern University, and Stanford University focused on metastatic non-small cell lung cancer (NSCLC), using data from 37 biomarker-unselected patients randomized to receive concurrent or sequential radiotherapy and immunotherapy as a first-line treatment. The immunotherapy blockade treatment involved a combination of Bristol Myers Squibb's anti-CTLA-4 drug Yervoy (ipilimumab) and its anti-PD-1 drug Opdivo (nivolumab).

"As a secondary analysis of the trial, we present a comprehensive molecular characterization of matched pretreatment and on-treatment tumor biopsies in this unique dataset to delineate the effect of radiotherapy and [immune checkpoint blockade] timing on the tumor immunogenomic milieu," senior and corresponding author Sean Pitroda, a researcher at the University of Chicago and its Ludwig Center for Metastasis Research, and his colleague wrote.

Based on exome sequencing, RNA sequencing, immune profiling, and other analyses on pre-treatment and on-treatment tumor samples, together with clinical data, the team found that NSCLC tumors marked by particularly pronounced aneuploidy were more apt to respond to combined immune checkpoint blockade immunotherapy and radiation.

In the subset of cases marked by above-average tumor aneuploidy, for example, overall survival was 100 percent after 12 months after combined radiotherapy and immunotherapy compared to 17 percent in the high-aneuploidy cases from the sequential treatment arm. The same pattern did not carry over in the low-aneuploidy cases, the researchers explained. There, overall survival at 12 months was 20 percent in the concurrent radiotherapy-immunotherapy treatment group and 17 percent in the sequential treatment group.

Those findings were backed up by the team's subsequent analyses of 58 metastatic NSCLC cases from the University of Chicago that were profiled by targeted sequencing prior to immune checkpoint treatment provided alone or in combination with radiotherapy.

Again, enhanced tumor aneuploidy appeared to correspond with better response to combined immunotherapy and radiation treatment — an effect not found in the low aneuploidy cases. After 12 months, the investigators saw 59 percent survival for NSCLC cases with aneuploidy scores above the median.

Conversely, the team saw signs that high aneuploidy scores may be linked to poorer outcomes in metastatic NSCLC patients treated with immune checkpoint blockade immunotherapy — a notion that was validated by analyses of genomic and clinical data from another 350 immunotherapy-treated individuals with metastatic NSCLC who received treatment at Memorial Sloan Kettering Cancer Center.

"We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors," the authors explained, adding that "[w]e propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and [immune checkpoint blockade]."

More broadly, the investigators analyzed the tumor and immune responses that characterized samples collected after concurrent radiotherapy and immunotherapy compared to those taken after radiotherapy but prior to immunotherapy, revealing reduced proliferation pathway activity and increased activity of certain adaptive immune, cytotoxic T cell, and other immune pathways after the concurrent treatment.

"On a practical level, aneuploidy can be readily obtained from targeted genomic sequencing panel data using existing methods," the authors noted, though they emphasized that "[f]uture trials of radiotherapy and [immune checkpoint blockade] are needed to validate aneuploidy as a biomarker."

For a related paper appearing in Nature Genetics on Monday, Pitroda and colleagues at the University of Chicago profiled aneuploidy ties to clinical outcomes in the context of tumor mutational burden (TMB) patterns in samples from 1,660 anti-CTLA4, anti-PD-1/PDL-1, or combined immunotherapy-treated primary or metastatic cancer cases from 10 cancer types ranging from NSCLC, colorectal cancer, and breast cancer to glioma, head and neck cancer, and cancers with unknown primary sites.

There, the team found that aneuploidy provided an additional level of prognostic information for immunotherapy-treated cancer cases involving low TMB tumors. In particular, the combination of low TMB and higher-than-usual aneuploidy seemed to correspond with poorer outcomes after immunotherapy treatment. The same prognostic pattern did not hold for the cancer cases with high TMB and high aneuploidy tumors.

Although enhanced aneuploidy turned up in a wide range of tumor types, the researchers noted that the proportion of high-aneuploidy tumors varied from one cancer type to the next. Aneuploidy scores were higher, on average, in head and neck cancers, cancers of unknown primary sites, or bladder cancers, for example, while gliomas and esophagogastric cancers tended to have lower aneuploidy scores.

"Taken together, we demonstrated that an elevated aneuploidy score is an independent and complementary predictor of overall survival for patients with low TMB tumors treated with ICIs," the authors reported, noting that "like TMB, aneuploidy scores can be calculated from routine tumor-only targeted DNA sequencing … indicating that this biomarker can be implemented alongside TMB using existing clinical sequencing infrastructure."

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