Clinical implications of Wnt signaling alterations in patients (pts) with advanced prostate cancer (aPC).
Year: 2023
Type: conference-abstract
Abstract: 229 Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis, progression, and metastasis in preclinical models. While studies have identified recurrent molecular alterations in the Wnt signaling components in about 20% of aPC pts, the clinical significance of these alterations has been incompletely characterized. Methods: PROMISE is a multi-institutional, retrospective, clinical-genomic database - inclusive of aPC pts who had tissue and/or blood-based genomic testing by commercially available CLIA-certified platforms. We evaluated outcomes in pts with alterations leading to the activation of the canonical Wnt pathway, specifically activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 (Wnt altered), compared to those lacking such alterations (Wnt wild type). Multiple endpoints were evaluated, including the frequency of metastatic disease to different sites and co-occurring alterations. Results: 1596 pts with aPC were included with a median age of 63 years at diagnosis. Wnt pathway alterations were identified in 12.4% (198/1596). Wnt altered pts had a statistically significant increase in liver and lung metastases compared with Wnt wild type pts at diagnosis (4.5% vs 2.1%, p=0.0438; 6.1% vs 2.9%, p=0.0292), at first metastatic disease (11.6% vs 5.4%, p= 0.0015; 14.8% vs 6.6%, p<0.0001), and at diagnosis of CRPC (14.2% vs 7.9%, p=0.01436; 16.1% vs 6.8%, p=0.0003). Fewer Wnt altered pts had bone metastases at CRPC compared with wild type pts (67.7% vs 75.2%, p=0.04948) without significant difference of bone metastases at the time of diagnosis or at the time of first metastatic disease. The frequency of metastases to other sites was similar between the cohorts. More Wnt altered pts had ductal features on histology at diagnosis compared with Wnt wild type pts (4.0% v 1.6%, p=0.02415) without difference in PSA, Gleason score, TNM stage, or presence of neuroendocrine or intraductal features. Co-occurring genomic alterations that were more common in Wnt altered pts included PTEN loss/mutation (25.3% vs 18.3%, p=0.0270), RB1 loss/mutation (10.6% vs 5.8%, p=0.0079), AR mutations or gain (37.9% vs 24.0%, p< 0.0001), and SPOP mutations (14.1% vs 3.9%, p< 0.0001) as compared with Wnt wild type pts. Conclusions: Wnt pathway alterations were associated with ductal histology, an increase in visceral metastases at all time points evaluated, and an increase in co-occurring PTEN, RB1, AR, and SPOP alterations. The clinical heterogeneity of aPC and differences in co-occurring mutations between the cohorts make isolating the effect of alterations in a single pathway challenging. Analysis of overall survival outcomes is currently in process, and future multivariable analysis is planned to adjust for established clinical factors and co-occurring mutations to identify the independent contributions of Wnt alterations to clinical outcomes.
Source: Journal of Clinical Oncology
Authors: Amanda Broderick, Jinju Li, Alec Chu, Clara Hwang, Pedro C. Barata, Frank Cameron Cackowski, Matthew Labriola, Alyssa Ghose, Mehmet Asim Bilen, Deepak Kilari, Laura Graham, Abhishek Tripathi, Rohan Garje, Vadim S Koshkin, Elizabeth Pan, Tanya B. Dorff, Rana R. McKay, Michael Thomas Schweizer, Ajjai Shivaram Alva, Andrew J. Armstrong
Institutions: Duke University, Duke Medical Center, Duke Cancer Institute, University of Michigan, U-M Rogel Cancer Center, Henry Ford Health, Henry Ford Hospital, University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, University Hospitals Seidman Cancer Center, Wayne State University, The Barbara Ann Karmanos Cancer Institute, Winship Cancer Institute, Medical College of Wisconsin, Medical College of Wisconsin Cancer Center, University of Colorado Cancer Center, City Of Hope National Medical Center, City of Hope, Baptist Hospital of Miami, Baptist Health South Florida, University of California, San Francisco, University of California San Diego, Moores Cancer Center, University of Washington, Fred Hutch Cancer Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4324136202