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Researchers quantify presence of immunotherapy biomarkers in breast cancer
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SAN ANTONIO — Although a minority of patients with invasive breast cancer expressed microsatellite instability, high tumor mutational load or PD-L1 expression, these biomarkers may elucidate the benefit of immune checkpoint inhibitors for the disease, according to results of a retrospective data analysis presented at the San Antonio Breast Cancer Symposium.
“Our study follows the recent data indicating a promising response to immune checkpoint blockade among patients with breast cancer, and the FDA’s approval of pembrolizumab [Keytruda, Merck] for all solid tumors based on one biomarker, high microsatellite instability, Elias Obeid, MD, MPH, director of breast, ovarian and prostate cancer risk assessment at Fox Chase Cancer Center, said in a press release. “We are working to identify biomarkers to identify which breast cancer patients could benefit.”
The presence of microsatellite instability (MSI)-high tumors among some patients with breast cancer is not fully understood. Other biomarkers — including PD-L1 status and tumor mutational load — also are being explored to help predict patient benefit from immune checkpoint blockade.
To better understand the role of these biomarkers in breast cancer, Obeid and colleagues used databases from Caris Life Sciences to analyze next-generation sequencing of 9,627 patients (mean age, 56.8 ± 12.4 years; range 20-90) with breast cancer.
Researchers evaluated PD-L1 expression on tumor cells for 5,203 patients using immunohistochemical analysis with clone SP-142 (Roche Diagnostics).
In total, 354 (6.8%; 95% CI, 6.2-7.5) appeared positive for PD-L1, based on presence of more than 5% membranous staining of tumor cells.
Researchers defined patients as either MSI high or MSI stable by comparing repeat-insertions or deletions across over 7,000 microsatellite sequences in their sample to the hg19 reference genome. Repeat variances in more than 45 microsatellites was defined as MSI-high tumors. They found that 12 of 1,952 patient tumors were MSI high (0.6%; 95% CI, 0.3-1.1).
Researchers calculated tumor mutational load as a total number of nonsynonymous somatic mutations identified per megabase of the genome coding area. Of the 1,952 samples tested, 72 tumors (3.7%; 95% CI, 2.49-4.6) had high tumor mutational load, or a load of at least 17 mutations per megabase.
Investigators noted seven of the 12 MSI-high tumors had high tumor mutational load. Also, five of the 12 MSI-high breast cancers were triple negative. The rest were hormone receptor positive.
In this large cohort, 1,952 tumors have been tested for all three biomarkers of interest (PD-L1,microsatellite instability and tumor mutational load). Most patients (51.5%) had hormone receptor-positive disease, 37.3% had triple-negative tumors, and 11.2% were HER-2 positive.
Positive status for all three biomarkers occurred among 189 (9.7%) patients. At least one biomarker occurred among 7.3% of hormone receptor-positive cancers, 10% of HER-2-positive cancers and 13% of triple-negative breast cancers. These mostly comprised PD-L1-positive (6.1%) and tumor mutational load-high (3.7%) cases, whereas only 0.6% were MSI-high.
Moreover, the researchers observed statistically significant differences in PD-L1-positive and tumor mutational load-high distributions based on the breast cancer subtype (hormone receptor positive, HER-2 positive or triple-negative breast cancer), specimen site (primary vs. nonprimary), distant metastatic sites (eg, liver, lung or nodes) and age. However, this was not observed for microsatellite instability-high status. PD-L1-positive distribution was higher in triple-negative breast cancer cases, whereas tumor mutational load-high was higher in hormone receptor-positive cases.
Researchers observed no statistically significant differences in distribution of those biomarkers based on androgen receptor status in the triple-negative breast cancer cohort.
Tumor mutational load-high status was significantly higher in lobular breast cancers (13.7%). This warrants further research, Obeid said.
“At Caris Life Sciences, we strongly believe that tumor profiling, regardless of the site of origin, is the optimal approach to molecularly categorize tumors and inform treatment selection,” David Spetzler, MS, PhD, MBA, president and chief scientific officer of Caris Life Sciences, said in the release. “We were pleased to partner with Fox Chase Cancer Center and other leading institutions on this study to analyze a large cohort and help identify [patients with breast cancer who] might respond to immunotherapy.” – by Alexandra Todak
Reference:
Obeid E, et al. Abstract PD6-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: Authors report employment with Caris Life Sciences. Obeid reports funding from Pfizer, Merck, Sharp, Dohme Research Foundation, Eileen Jacoby Foundation, National Comprehensive Cancer Network, American Cancer Society and NIH.