Caris Life Sciences' Multiplatform Tumor Profiling of Hepatocellular and Biliary Tract Carcinomas Yields Insights into Novel and Conventional Therapeutic Options

Research Presented at 2015 Gastrointestinal Cancers Symposium Highlights Clinical Utility of Caris Molecular Intelligence in Elucidating Disease Biology and Identifying Potential Treatment Options

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Caris Life Sciences

Jan 15, 2015, 12:00 ET

IRVING, Texas, Jan. 15, 2015 /PRNewswire/ -- Caris Life Sciences® today announced the presentation of data from two studies in which Caris Molecular Intelligence™, the company's panomic, comprehensive tumor profiling service, yielded insights into the biology of hepatocellular and biliary tract carcinomas, while also identifying potential treatment options for patients living with these tumor types.

In a presentation at the 2015 Gastrointestinal Cancers Symposium in San Francisco, Calif., the researchers reported that Caris Molecular Intelligence revealed the molecular heterogeneity of hepatocellular carcinoma (HCC) and facilitated identification of potential therapies targeting molecular subtypes of this disease, for which treatment options have heretofore been extremely limited.

In a separate presentation, use of Caris Molecular Intelligence reportedly uncovered distinct targetable biomarkers in biliary tract carcinomas such as extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC), and gallbladder carcinoma (GBCA), while also suggesting the potential sensitivity of these rare, aggressive tumor types to novel and conventional therapies.

Both studies, presented during poster sessions on Friday, January 16, utilized Caris Molecular Intelligence's multi-platform approach, which included gene sequencing (Sanger and next-generation sequencing [NGS]), protein expression analysis (immunohistochemistry [IHC]), and gene copy number analysis (chromogenic or fluorescence in situ hybridization [CISH or FISH]). Investigators in each study examined tumor samples for underlying molecular alterations that may yield potentially different therapeutic options for patients with these tumor types.

"For patients with hepatocellular and biliary tract carcinomas, the limitations of currently available treatment options underscore a great need to identify new therapies," commented Sandeep K. Reddy, M.D., chief medical officer at Caris Life Sciences, and a co-investigator in each of the two studies. "The data presented at the Gastrointestinal Cancers Symposium demonstrate how multiplatform molecular profiling with Caris Molecular Intelligence can yield a better understanding of tumor subtypes and their biological makeup as a means to provide therapeutic guidance."

HCC Study Highlights
Researchers evaluated 313 HCC samples using Caris Molecular Intelligence, which revealed the molecular heterogeneity of HCC while identifying different potential treatment options for molecular subtypes. The tumor suppressor gene p53 (TP53) was mutated in 28% of samples, which exhibited significantly higher expression of topoisomerase 2A (TOPO 2A; 89% vs. 39%; p<0.0001), thymidylate synthase (TS; 70% vs. 32%; p=0.0057) and ribonucleotide reductase M1 (RRM1; 40% vs. 12%; p=0.017), implying high rates of tumor proliferation and DNA synthesis, compared to non-TP53-mutated tumors. This finding suggests that cytotoxic chemotherapeutics such as anthracyclines may be therapeutically relevant in TP53-mutated HCC while fluoropyrimidines and gemcitabine may be more likely to benefit non-TP53-mutated patients, according to the investigators.

Tumors carrying the catenin (cadherin-associated protein), beta 1 (CTNNB1) mutation showed significantly higher expression of the secreted protein acidic and rich in cysteine (SPARC; 67% vs. 21%; p=0.0013) and androgen receptor (AR; 53% vs. 22%; p=0.025) than non-CTNNB1-mutated HCCs, suggesting the potential benefit of agents that target the WNT signaling pathway in combination with nab-paclitaxel or anti-androgen therapy. Additionally, primary HCCs (N=209) showed significantly higher expression of the programmed cell death protein 1 (PD-1; 89% vs. 33%; p=0.01) and TS (35% vs. 13%; p <0.001) than metastatic HCCs (N=105), suggesting the potential viability of immunomodulatory agents in patients with primary HCC. Although there is no evidence of the effectiveness of cytotoxics in patients with HCC, the investigators surmised that irinotecan, alkylating agents, fluoropyrimidines, anthracyclines, nab-paclitaxel, gemcitabine, or taxanes may be therapeutically relevant in subsets of patients expressing these tumor markers.

"Currently available therapies for HCC produce only marginal improvements in overall survival, highlighting the urgent need to identify effective treatment strategies," noted lead investigator Ghassan K. Abou-Alfa, MD, who is a board-certified medical oncologist at Memorial Sloan Kettering Cancer Center. "By revealing numerous biomarker changes of interest in HCC, our data suggest that targeted therapies that inhibit tyrosine kinase, PD-1 and the PI3 kinase pathway may be effective in selected patients."

Biliary Tract Carcinoma Study Highlights
Investigators used Caris Molecular Intelligence to evaluate 815 cases of biliary tract cancer (126 EHCC, 434 IHCC, 244 GBCA, 11 Not Otherwise Specified) to delineate different molecular alterations within those tumors as a means to identify potential therapeutic options. Twenty-four of 47 genes tested had mutations, with the highest rates of mutation observed in TP53 (28%), KRAS (18%), isocitrate dehydrogenase 1 (IDH1, 9%), and SMAD4 (6%). Mutations of the tumor suppressor proteins BRCA1 and 2 were seen in 7.3% and 12.5% of cases, respectively. IHC showed low expression of RRM1 (82% of cases) and TS (79%), as well as high expression of TOPO1 (56%), TOPO2A (49%), PD-1 (40%), SPARC (39%), and the PD-1 ligand (PD-L1, 15%), suggesting the potential utility of chemotherapeutic and immunomodulatory agents targeting these alterations in selected cases.

Comparing the three types of carcinoma, researchers found that EHCC had the highest KRAS mutation rate (28%), IHCC had the highest IDH1 mutation rate (14%), and GBCA and EHCC had significantly higher TP53 mutation rates (44% and 41%, respectively, vs. 8%) and HER2 amplification rate (15% and 18% respectively, vs. 1.5%) than IHCC. IDH1 and TP53 mutations were mutually exclusive, and IDH-1 mutated IHCC had higher P-glycoprotein (Pgp) expression than TP53-mutated IHCC (82% vs. 37%; p<0.01). GBCA showed high expression of TOPO2A via FISH (21%) and IHC (71%), as well as a high loss of PBRM1 (53%). According to the investigators, this study highlights the molecular differences identified by multiplatform tumor profiling on biliary cancers arising in different locations, which may translate into different sensitivities to novel and conventional therapies.

"The challenges of treating rare, aggressive biliary tract carcinomas are compounded by the fact that the underlying molecular alterations and their correlation with responses to therapies are not well understood," remarked lead investigator Randall F. Holcombe, MD, Chief Medical Officer, Cancer, at Mount Sinai Health System. "By revealing distinct biomarker characteristics of biliary tract carcinomas, multiplatform tumor profiling offers insights into disease biology and suggests potential sensitivity to novel and conventional therapies for these tumor types, which have tended to be chemo-resistant."

About Caris Life Sciences® and Caris Molecular Intelligence™
Caris Life Sciences® is a leading biosciences company focused on fulfilling the promise of precision medicine through quality and innovation. Caris Molecular Intelligence™, the industry's leading tumor profiling service with more than 68,000 patients profiled, provides oncologists with the most potentially 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 correlates biomarker data generated from a tumor with biomarker-drug associations supported by evidence in the relevant clinical literature. The company is also developing a series of 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 Europe, the U.S., Australia and other international markets. To learn more, please visit www.CarisLifeSciences.com.

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