ASCO Presentations Highlight Expression of Biomarkers PD-1 and PD-L1 Linked to Response to Novel Immunotherapeutic Agents for Treatment of Colorectal Cancer, Triple Negative and Metaplastic Breast Cancers
Irving, Texas, June 10, 2014 – Caris Life Sciences®, a leading biosciences company focused on fulfilling the promise of precision medicine, announced today the presentation of data from multiple studies in which Caris Molecular Intelligence™, Caris’ comprehensive tumor profiling service, was used to identify biomarkers of response to novel classes of immunotherapeutic agents. The data, presented last week at the 50th annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Ill., shed light on potential immunotherapeutic targets in a broad range of malignancies, including colorectal cancer, triple negative breast cancer (TNBC), and metaplastic breast cancer.
“As the field of immunotherapy continues to evolve, Caris understands the importance of identifying patients who are likely to respond to the newer classes of immunotherapeutic agents that are being investigated and developed, as evidenced by our integration of routine PD-1 and PD-L1 testing in Caris Molecular Intelligence™,” commented Sandeep K. Reddy, M.D., Chief Medical Officer at Caris Life Sciences. “Because PD-1 and PD-L1 cannot be found through DNA analysis alone, identification and characterization of novel, actionable targets through use of multi-technology molecular profiling is critical to enhancing our understanding of these markers of response to immunotherapy. For treating physicians, this comprehensive analysis potentially expands treatment options for a wide range and larger number of patients with various types of cancer.”
PD-1 and PD-L1 in Colorectal Cancer
In a poster presentation last week, a team led by Zoran Gatalica, M.D., DSc, Executive Medical Director at Caris Life Sciences, presented data demonstrating the value of Caris Molecular Intelligence™ as a means to completely characterize colorectal tumors. In particular, the data highlight the importance of the programmed cell death protein 1 (PD-1) and its ligand, PD-L1, as markers of potential response to novel immune checkpoint inhibitors in patients with colorectal cancer (CRC) with microsatellite instability (MSI). Microsatellites are short repetitive sequences of DNA; MSI, which is detected by polymerase chain reaction (PCR)-based assays that reveal the mutated microsatellites, results from impaired DNA mismatch repair (MMR) mechanisms(i.e., when DNA errors that spontaneously occur during DNA replication are not corrected).
Dr. Gatalica and colleagues profiled 87 CRC cases for the presence of PD-1- and PD-L1-expressing cells, MMR proteins, DNA-MSI, and select cancer gene sequences (detected via next-generation sequencing [NGS]). They detected PD-1-positive intraepithelial lymphocytes (PD-1+ IEL) in 77% of MSI-H CRCs and in 38% of microsatellite-stable (MSS) CRCs. Similarly, the proportion of PD-L1+ CRCs was significantly higher in MSI-H than in MSS CRC groups, (38% vs. 13%; p=0.02); though the expression of PD-L1 in cancer cells was described as “patchy” in most cases. Expression of both PD-1+ IEL and PD-L1 cancer cells were seen in 30% of MSI-H CRCs and in 5% of MSS cancers (p=0.008).
“Immune checkpoint-inhibiting drugs interrupt interactions between immune-modulating PD-1-positive lymphocytes and the cancer-expressing ligand PD-L1, leading to tumor reduction and disease control,” noted Dr. Gatalica. “Clinicians considering initiation of immune checkpoint therapy should therefore check for the presence of PD-1 lymphocytes and cancer cell-specific PD-L1 expression, as a guide to administering these agents to appropriate patients.”
Dr. Gatalica noted that his findings are similar to those from a Phase 2 study of PD-1 antibody in patients with MSI tumors, conducted at Johns Hopkins University School of Medicine, and that more than five PD-1/PD-L1 trials are ongoing, although the data thus far are exploratory and early. “PD-1 and PD-L1 markers are not elevated at the same levels across all cancer types, meaning that the effectiveness of the anti-PD-1 immunomodulatory agents may depend on specific elevation levels,” he cautioned. “Moreover, immunotherapies are not appropriate for every solid tumor; some tumors are not associated with these specific immune responses. PD-1/PD-L1 status, however, should be evaluated before embarking upon clinical trial enrollment, as this analysis can significantly inform the patient recruitment process, and can be done easily and inexpensively via gold-standard immunohistochemistry testing.”
Read the study here: https://www.carislifesciences.com/media/pdf/Programmed-death-1-(PD-1)-lymphocytes-and-ligand-(PD-L1)-in-colorectal-cancer-and-their-relationship-to-microsatellite-instability_ASCO2014-Gatalica.pdf
PD-L1 and Other Novel Biomarkers in Triple Negative Breast Cancer
A separate oral presentation focused on expression of PD-L1 and other immunotherapeutic biomarkers in TNBC, an aggressive form of breast cancer in which the cancer cells lack estrogen receptors (ER), progesterone receptors (PR), and large amounts of the HER2/neu protein. This research revealed how expression of immune regulatory targets in the TNBC population suggests that immune-targeted therapies may be effective in certain patients. These findings are considered especially timely, given the growing interest in immunotherapy as a potential treatment option in TNBC and other tumor types. In the study, 511 TNBC samples underwent multiplatform molecular profiling by Caris Molecular Intelligence, which included whole genome messenger RNA (mRNA) expression, protein expression via immunohistochemistry (IHC), gene copy number changes via in situ hybridization (ISH), and gene sequencing. The researchers, led by Barbara Pockaj, M.D., of the Mayo Clinic in Phoenix, Ariz., reported an inverse correlation between PD-L1 and BRCA1, suggesting that certain TNBC patients may benefit from a combination of immunotherapy and platinum agents or PARP inhibitors. Additionally, patients with quadruple-negative breast cancer (i.e., lacking the AR protein as well as ER, PR and HER-2) were identified as another population that may benefit from immunotherapeutic agents. In particular, patients with androgen receptor (AR)-negative TNBC may benefit from therapies designed to inhibit the activity of molecules such as PD-L1, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and indoleamine 2,3-dioxygenase 1 (IDO-1).
Genomic and Protein Alterations in TNBC and Metaplastic Breast Cancer
In a poster highlight session on Monday, June 2, Joyce O’Shaughnessy, MD, of Texas Oncology – Baylor Charles A. Sammons Cancer Center presented results of a comparison of the genomic and protein expression profiles of patients with TNBC and those with metaplastic breast cancer (MpBC), a rare subtype (less than 1%) of breast cancer that is generally ER-, PR- and HER2-negative, with a claudin-low gene expression profile. Of the 2000 TNBCs included in the analysis since 2009 from all 50 states and 59 countries, 126 were found to be triple-negative MpBCs. Dr. O’Shaughnessy and colleagues used a multiplatform approach, including sequencing (Sanger or NGS), protein expression (IHC) and/or gene amplification (chromogenic or fluorescence in situ hybridization [CISH/FISH]), to detect several notable differences between the two breast cancer subtypes. Although there are even fewer approved treatment options available for patients with MpBC than for those with TNBC, 97 percent of MpBC cases were found to have clinically relevant alterations, 84 percent of which were based on changes in protein expression or gene number increase only, with no gene mutations identified. Additionally, more than half of the MpBC cases were found to have alterations and/or loss of PTEN in the PI3K pathway, an area in which several experimental therapies are being investigated in clinical trials. In a small subset of cases evaluated for PD-1/PD-L1 protein levels, all had overexpression, suggesting PD-1/PD-L1 immunomodulatory agents might be efficacious.
About Caris Molecular Intelligence™
Caris Molecular Intelligence™, the industry’s leading cancer molecular profiling service, helps oncologists treat cancer smarter by delivering the most potential treatment options for patients. This service has been used by more than 6,000 oncologists to develop individualized and actionable treatment plans for more than 60,000 cancer patients in 59 countries across the globe. Caris Molecular Intelligence integrates the latest relevant panomics data – the combination of genes, proteins, molecular pathways, and unique patient characteristics – from clinical studies in cancer and cancer biology to identify the most clinically actionable drug associations approved by the U.S. Food & Drug Administration or in active clinical trials in the United States. Beyond standard DNA analysis, Caris Molecular Intelligence assesses all relevant biological components, such as RNA, protein expression and gene amplification levels, to provide oncologists with the most treatment options for their patients. Currently, Caris can identify therapeutic guidance for up to 51 drug associations, far exceeding the 19 that can be identified using next-generation sequencing alone. This therapeutic guidance is electronically delivered to the ordering physician in an easy-to-read report that enables development of tailored treatment plans. For more information on Caris Molecular Intelligence, visit www.carismolecularintelligence.com.
About Caris Life Sciences
Caris Life Sciences is a leading biosciences company focused on fulfilling the promise of precision medicine. Caris Molecular Intelligence™, the industry’s first and largest tumor profiling service, provides an oncologist with the most potentially clinically actionable treatment options available to personalize care today. Using a variety of advanced and clinically-relevant technologies that assess all relevant biological components of a patient’s cancer, Caris Molecular Intelligence correlates molecular data generated from a tumor with biomarker/drug associations derived from clinical cancer literature. The company is also developing a series of blood tests based on its proprietary Carisome® TOP™ platform, a revolutionary blood-based testing technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. Headquartered in Irving, Texas, Caris Life Sciences offers services throughout the U.S., Europe, Australia and other international markets. To learn more, please visit www.carislifesciences.com.
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