β-Catenin is Independently Associated With Outcome in Pancreatic Cancer: An Analysis of NRG Oncology/RTOG 9704

Abstract

Laboratory experiments show that activation of β-catenin signaling promotes pancreatic cancer (PC) growth, but studies addressing its prognostic value in patients (pts) are scarce and with conflicting results. This question has been examined using samples from a large prospective clinical trial.NRG/RTOG 9704 was a phase III trial which compared 5-fluorouracil - to gemcitabine-based chemotherapy in pts after pancreatectomy. All pts received 5-fluorouracil -based chemoradiotherapy. Quantitative immunofluorescence analysis for β-catenin was performed on a tissue microarray developed from these pts. β-catenin and its active form (total, nuclear, and cytoplasmic) were assayed in pan-cytokeratin positive tumor cells. Assay performers were blinded to all clinical outcomes. Scores were dichotomized at their median. OS and DFS were estimated univariately with the Kaplan-Meier method and groups compared using the log-rank test. Cox proportional hazards models were used to identify the impact of expression on OS and DFS. The following variables were included in the models: β-catenin, treatment, age, gender, race, CA19-9, tumor location, nodal involvement, tumor diameter, and surgical margin status.Of 451 eligible pts, 141 samples were analyzable. There were no significant differences in baseline characteristics/outcomes for pts with and without tissue. For cytoplasmic β-catenin univariately, levels ≥ median were associated with better OS [HR (95% CI): 0.65 (0.45, 0.93); P = 0.02] and DFS [HR (95% CI): 0.70 (0.49, 0.99); P = 0.04]. On multivariable analysis, levels ≥ median were associated with better OS [HR (95% CI): 0.63 (0.43, 0.92), P = 0.02], after adjusting for CA19-9, age, and race, with a 37% risk reduction of death. There was a trend towards better DFS for pts with levels ≥ median [HR (95% CI): 0.70 (0.48, 1.01), P = 0.054], after adjusting for CA19-9. For cytoplasmic active β-catenin univariately, levels ≥ median were associated with better OS [HR (95% CI): 0.65 (0.45, 0.94); P = 0.02], that remained significant on multivariable analysis [HR (95% CI): 0.64 (0.44, 0.94); P = 0.02]. There were no associations with efficacy for nuclear or total β-catenin, nor in its active form.In this high-quality database from a prospective phase III clinical trial, cytoplasmic β-catenin and cytoplasmic active β-catenin are statistically significantly associated with OS and DFS and with OS, respectively, independent of other known prognostic factors. In agreement with one previous publication, high levels of cytoplasmic β-catenin, which is transcriptionally silent, were associated with a reduced risk of death. The significant magnitude of these effects makes them clinically relevant, warranting further investigation. This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA196067 (NRG Specimen Bank) from the National Cancer Institute (NCI).