Breast cancer biomarkers

Immune checkpoint blockade therapy could be promising

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PHILADELPHIA & IRVING, Texas—According to research led by the Fox Chase Cancer Center, there is a small but significant percentage of patients suffering invasive breast cancer who possess at least one of three biomarkers linked to immune checkpoint blockade (ICB) therapy—a finding that suggests a role for ICB-based treatment for certain breast cancers.
“Immunotherapy is one of the most exciting advances in oncology. The objective is not to attack the cancer directly, but to tell the immune system to kill the cancer when it recognizes something unlike itself,” said Dr. David Spetzler, president and chief scientific officer of Caris Life Sciences, a Texas-based company that assesses DNA, RNA and proteins to reveal a molecular blueprint to guide more precise and personalized treatment decisions. The Fox Chase researchers analyzed microsatellite instability (MSI), tumor mutational load (TML) and PD-L1 status in molecularly profiled invasive breast cancer, using a data set of 9,627 breast cancer cases from the Caris Life Sciences database.
Caris’ database was used over a four-year period to analyze a proportion of patients with invasive breast cancer who have at least one of three biomarkers linked to ICB therapy. Recent data appear to indicate a promising response to ICB in patients with breast cancer, and Dr. Elias Obeid, director of breast, ovarian and prostate cancer risk assessment at Fox Chase Cancer Center in Philadelphia, presented related study findings at the 2017 San Antonio Breast Cancer Symposium annual meeting.
According to Obeid, “Our study follows the recent data indicating a promising response to ICB in breast cancer patients, and the FDA’s approval of pembrolizumab for all solid tumors with high microsatellite instability. We are working to identify which breast cancer patients could benefit.”
Obeid explained that pembrolizumab, a monoclonal antibody against the programmed death 1 (PD-1) receptor and one of several ICB agents in development, received FDA approval for all MSI-high solid tumors, though he added that MSI incidence in breast cancer is not fully elucidated. Other biomarkers that are being investigated in possible relationship to ICB activity include PD-1 ligand status and TML. Obeid’s study “aimed to explore the incidence of these biomarkers in invasive breast cancers.”
As noted earlier, the researchers analyzed MSI, TML and PD-L1 status in molecularly profiled invasive breast cancer in a retrospective data analysis of the Caris Life Sciences database. Not all cases were tested for all three markers, though. Of the 5,203 tested for PD-L1 status, 6.8 percent were positive. Of 1,952 tumors tested for all three biomarkers—MSI, TML and PD-L1 status—researchers found PD-L1-positivity, MSI-high or TML-high was present in 189 cases (9.7 percent).  At least one of the three biomarkers was present in 7.3 percent of hormone receptor-positive cases, 10 percent of HER2-positive cases and 13 percent of triple-negative breast cancer (TNBC). The majority of this was for PD-L1+ and TML-H (6.1 percent and 3.7 percent, respectively), while low for MSI-H distribution (0.6 percent). PD-L1 distribution was higher in TNBC cases, while TML was higher in hormone receptor-positive cases.
As the conference poster in San Antonio explained, “MSI was calculated by comparing repeat-insertions or deletions across over 7,000 microsatellite sequences in the patient sample to the hg19 reference genome … Samples with repeat variances in more than 45 microsatellites were classified as MSI-High … PD-L1 expression was evaluated using immunohistochemical analysis (IHC), with clone SP-142 (Roche Diagnostics). A sample was considered positive (PD-L1+) if there was >5% membranous staining of tumor cells … TML (tumor mutation load) was calculated as a total number of non-synonymous somatic mutations identified per megabase of genome coding area with high being greater than or equal to 17.”
According to Spetzler, “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. 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 breast cancer patients that might respond to immunotherapy.”
The Caris Comprehensive Genomic Profiling Plus (CGP+) molecular testing service assesses DNA, RNA and proteins, including MSI, TML and PD-L1, to reveal a molecular blueprint to guide more precise and personalized treatment decisions. The ADAPT Biotargeting System, an unbiased profiling platform, is currently being utilized for drug target identification, therapeutic discovery and development, fixed tissue-based companion diagnostics, blood-based cancer screening and biomarker identification.
Fox Chase was one of the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won two Nobel Prizes, the hospital’s physicians are routinely recognized in national rankings and the center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. The Center belongs to the Precision Oncology Alliance.

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