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PDL1 Amplifications Mark Subset of Solid Tumors, May Point to Checkpoint Blockade Response

NEW YORK (GenomeWeb) – A subset of solid tumors containing PDL1 amplifications appear more prone to respond to immune checkpoint blockade immunotherapy, even in the absence of high PD-L1 protein expression, microsatellite instability (MSI), or enhanced tumor mutational burden (TMB).

As they reported yesterday in JAMA Oncology, researchers from the University of California at San Diego and Foundation Medicine retrospectively analyzed nearly 118,200 de-identified tumors that had been profiled with FoundationOne and FoundationOneHeme assays, narrowing in on 843 tumors — from more than 100 cancer types or subtypes — that contained at least six PDL1 copy number alterations apiece.

Although the majority of the PDL1-amplified tumors had low or intermediate levels of TMB and variable expression of the PD-L1 protein by immunohistochemistry, the team reported, there were clues that these cases may have more robust checkpoint blockade responses. In a small subset of nine checkpoint blockade-treated tumors with PD-L1 amplification, for example, half a dozen patients had progression-free survival stretching out between a few months and more than two years.

"Our data suggest that PDL1 [copy number alterations] are found in a small subgroup of diverse solid tumors and may correlate with responses to checkpoint blockade," corresponding author Aaron Goodman, a hematologist and medical oncologist at the UC San Diego Moores Cancer Center for Personalized Cancer Therapy, and his co-authors wrote. "Additional prospective studies are needed to validate this finding and to determine whether routine testing for this alteration is warranted."

Past studies have highlighted a few of the tumor and/or immune cell features — such as tumor MSI, TMB, mismatch repair deficiency, or increased PD-L1 expression — that may signal enhanced tumor response to drugs targeting PD-L1/PD-1 or CTLA4 immune checkpoint pathways. But the search for checkpoint blockade response biomarkers continues.

For the latest study, Goodman and colleagues considered PDL1 amplification as a possible response feature. They began by tracking the prevalence of these copy number changes using de-identified data for 118,187 tumors profiled at Foundation Medicine between October 2012 and October 2017.

The team also looked at complementary clinical information for a subset of individuals treated at the UCSD Moores Center, offering a glimpse at checkpoint blockade response in nine individuals with PDL1-amplified tumors who received that form of treatment.

All told, the analysis unearthed 843 tumors with PDL1 amplifications — roughly 0.7 percent of the complete collection of genetically profiled samples. The alteration was particularly common in mixed hepatocellular cholangiocarcinomas, the team noted, where it turned up in nearly 11 percent of samples.

But the amplification was also enriched in kidney sarcomatoid carcinoma, thyroid anaplastic carcinoma, lung squamous cell carcinoma, head and neck squamous cell carcinoma, and other tumor types. At the other end of the spectrum, the researchers saw relatively few tumors with PDL1 amplifications in melanoma or in colorectal, pancreatic, or prostate cancer types.

All but 15 percent of tumors with these amplifications fell in the low or intermediate TMB categories, they noted, while 0.7 percent of the 741 PDL1-amplified tumors tested for MSI were considered MSI-high.

Across the nine checkpoint blockade-treated UCSD patients with PDL1-amplified tumors and available clinical data, the team had access to PD-L1 protein expression information for six tumors. Four of the tumors did express the protein, though checkpoint blockade response also turned up in two individuals with no detectable PD-L1 protein.

Six of the nine patients — two with head and neck squamous cell carcinoma, two with metastatic basal cell cancer, and one apiece with glioblastoma or urothelial cancer — responded to anti-PD-1/PD-L1 treatment alone or in combination with an investigational drug or a CTLA4 inhibitor, the researchers reported, with a median progression-free survival time of 15.2 months. The median overall survival time was not reached in these responders.

Though such results appeared promising, the authors cautioned that larger prospective studies are need to verify the potential ties between PDL1 amplification and response to checkpoint blockade therapy.

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