IRVING, Texas, May 28, 2015 /PRNewswire/ -- Caris Life Sciences®, a leading biotechnology company focused on fulfilling the promise of precision medicine, today announced the presentation of data from two large cohort studies that demonstrate the utility of Caris Molecular Intelligence®, the company's panomic comprehensive tumor profiling service, in characterizing mechanisms of drug resistance and pathway alterations in solid tumors. The two studies, presented May 31 in poster sessions at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Ill., highlight the importance of drug efflux pump expression (n=51,939) and PIK3CA pathway aberrations (n=19,784) as biomarkers that can inform the development of targeted treatment strategies for patients with various types of solid tumors.
"The large cohort analyses provide robust, actionable information about biomarkers in solid tumors, potentially aiding community oncologists in devising treatment regimens based on the molecular characteristics of individual patients' tumors," said Sandeep K. Reddy, M.D., Chief Medical Officer at Caris Life Sciences. "Such an approach to targeted therapy is advancing the personalization of cancer care across a wide range of malignancies."
Caris Molecular Intelligence is a multi-platform tumor profiling service that includes gene sequencing (Next-Generation Sequencing [NGS] and Sanger), protein expression analysis (Immunohistochemistry [IHC]), gene copy number and translocation analysis (Chromogenic or Fluorescence in situ Hybridization [CISH or FISH]). Investigators in both of the large cohort studies used these methods to examine tumor samples for underlying molecular alterations that may yield insights into selection of therapeutic options for patients with solid tumors.
Drug Efflux Pump Expression Analysis
In one ASCO poster presentation (abstract #11108), researchers presented an analysis of drug efflux pump expression in more than 50,000 molecularly profiled patients with solid tumors. "Drug efflux pumps are membrane proteins that extrude cytotoxic drugs from the cell, thereby decreasing the intracellular concentration of a drug to sub-therapeutic levels, and contributing to drug resistance," explained lead investigator Michael P. Castro, M.D., Medical Oncologist at the Queen's Medical Center in Honolulu, Hawaii. "The multidrug resistance phenotype, or MDR, is a major cause of resistance to chemotherapy. We examined protein expression patterns of drug efflux pumps in a large cohort of patients with solid tumors for insight on how to exploit MDR status to circumvent treatment dilemmas."
Dr. Castro and colleagues assessed protein expression in 51,939 tumor samples, and queried the Caris Registry™, a prospective, observational database of clinicopathologic and outcome variables from consenting patients whose tumors underwent multi-technology profiling by Caris Molecular Intelligence, for available clinical outcomes. They reported broad and overlapped expression patterns for three drug efflux pumps that are commonly implicated in chemotherapy resistance: the multidrug resistance protein 1 (MRP1), the breast cancer resistance protein (BCRP), and P-glycoprotein (PGP). Of the three, MRP1 had the highest expression rate, at 81% across all tumor types, followed by BCRP at 66%, and PGP at 23%. Gastrointestinal cancers exhibited the most abundant expression of all three drug pumps (80%, 90%, and 53%, respectively), with the highest average combined expression observed in liver cancers (81%). In contrast, brain, thymic, and head and neck cancers exhibited the lowest average combined expression of the three drug pumps (39%, 40%, and 42%, respectively). Of the 6,002 patients evaluable for co-expression, 29% were ATP-binding cassette-positive (ABC+), meaning they were positive for all three drug pumps; ABC positivity was most frequently expressed in colon, pancreas, ovarian, breast, and lung cancers. Forty-two percent of evaluable patients were positive for two of the three drug pumps, and 21% were positive for one of the three. Only 9% exhibited negative status for all three drug pumps (ABC-); the highest frequencies of ABC negativity were in breast, lung, ovarian, skin, and endometrial cancers.
To determine the prognostic role of the drug pumps on patient survival, the investigators assessed the differences in median survival between a cohort of 31 ABC+ and 27 ABC- patients with breast (n=6 and 2, respectively), ovarian (n=12 and 6, respectively), and lung (n=13 and 19, respectively) cancers. For the ABC+ patients, median survival since specimen collection was 596 days, compared to 855 days for the ABC- patients.
"Our analysis is notable for the data demonstrating more favorable outcomes for patients who were triple-negative for drug efflux pumps, compared to the triple-positive patients," commented Dr. Castro. "Whereas further study is needed to more conclusively determine how drug transporter expression may impact clinical outcomes, these data provide important clues."
Pathway Aberration Analysis
In the other large cohort poster presentation (abstract #11042), researchers reported on an analysis of aberrations in the PI3K/PTEN/Akt/mTOR signaling pathway and the co-incidence of hormone receptors and HER2 protein expression in 19,784 diverse solid tumors, encompassing more than 40 cancer types.
"Molecular aberrations in the phosphatidylinositol 3-kinase, or PI3K, pathway have been documented across cancers, especially mutations in the PIK3CA gene and mutation or loss of the tumor suppressor protein PTEN," explained Razelle Kurzrock, M.D., Chief of the Division of Hematology & Oncology and Director of the Center for Personalized Cancer Therapy at the University of California San Diego (UCSD) Moores Cancer Center. "Such alterations may be relevant to therapies targeting the PI3K/PTEN/Akt/mTOR pathway."
Dr. Kurzrock and colleagues reported the highest PIK3CA mutation rates in endometrial (37%, n=1,600), breast (31%, n=2,282), cervical (29%, n=284), anal squamous cell (28%, n=67), and bladder cancers (22%, n=303). Patterns in AKT1 and PTEN mutation rates differed by type of cancer, as did PTEN loss, which was observed in 57% of patients with hepatocellular carcinoma (HCC), 52% of those with prostate cancer, and 50% of those with endometrial cancer. The researchers observed co-mutation of PTEN and PIK3CA in 1.5% of patients with breast cancer, none of the patients with prostate cancer, and 12% of those with endometrial cancer. Notably, co-occurrence of PIK3CA mutations and PTEN loss was frequent; for example, 31% of patients with PIK3CA mutations also had loss of PTEN.
Forty-three percent of the PIK3CA mutations were distributed in exon 9, 33% in exon 20, and 24% in other exons. The distribution of PIK3CA mutations varied by cancer type and occurred more frequently in the absence of HER2 protein expression or copy number increase (p=0.0001) and more frequently in the presence of hormone receptor overexpression such as androgen receptor (AR), progesterone receptor (PR), and estrogen receptor (ER) (p=0.0335). The investigators observed PTEN loss in 27% of patients with and in 30% of patients without HER2 overexpression or amplification (p=0.004).
"Patterns of biomarker co-alterations, as observed in this large cohort analysis, may provide new insights relevant to selection of targeted anticancer therapy, particularly with regard to the PIK3CA pathway," commented Dr. Kurzrock. "Such insights may be crucial to optimizing combination treatment regimens for patients with solid tumors."
About Caris Life Sciences®
Caris Life Sciences® is a leading biotechnology company focused on fulfilling the promise of precision medicine through quality and innovation. Caris Molecular Intelligence®, the company's healthcare information and comprehensive tumor profiling service with more than 70,000 patients profiled, provides oncologists with the most clinically actionable treatment options available to personalize cancer care today. Using a variety of advanced profiling technologies to assess relevant biological changes in each patient's tumor, Caris Molecular Intelligence connects biomarker data generated from a tumor with biomarker-drug associations supported by evidence in the relevant clinical literature. Since 2009, Caris has tracked clinical and outcome data for certain patients undergoing tumor molecular profiling, for which Caris has observed that patients treated with drugs consistent with their molecular profile show a significant increase in overall survival. The company is developing its Carisome® TOP™ technology, a revolutionary and proprietary blood-based platform for the development of novel therapeutics, drug delivery and drug target identification. The technology is also being developed for diagnosis, prognosis, and theranosis of cancer and other complex diseases. Headquartered in Irving, Texas, Caris Life Sciences offers services throughout Europe, the U.S., Australia and other international markets. To learn more, please visit www.CarisLifeSciences.com.
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