Structurally-oriented classification of FOXA1 alterations identifies prostate cancers with opposing clinical outcomes and distinct molecular and immunologic subtypes.

10-15% of prostate cancers (PCa) harbor recurrent FOXA1 aberrations whereby the alteration type and the effect on the forkhead( FKH) domain impacts protein-function. We developed a FOXA1 classification system to inform clinical management.

5,014 PCa were examined using whole exome and transcriptome sequencing from the Caris database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain: these were in the first part of the FKH domain (class 1A: amino acids [AA] 168-246), within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted-truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269, class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.

FOXA1 alterations did not influence survival when considered in aggregate, but had distinct prognostic effects when stratified by class. Class 1A alterations were associated with overall improved survival (HR=0.57, p=0.03); a similar trend was seen with Class 1B (HR=0.88, p=0.07). Conversely, class 1C exhibited worse survival upon 2nd-generation androgen receptor signaling inhibitor (ARSI) treatment (HR=1.93, p<0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR=2.05, p<0.001) and worse outcomes to first-line androgen-deprivation therapies (HR=2.5, p<0.001). Class 3A alterations indicated improved survival (HR=0.70; p=0.01) whereas class 3B alterations portended poor outcomes (HR=1.50; p<0.001). Amplifications (class 4) indicated poor outcomes (HR=1.48; p=0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European-Americans, African-Americans had increased class 1C alterations whereas Asian-Pacific patients had increased class 1B alterations.

FOXA1alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision making for PCa patients and uncovers important racial differences.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Jan 02 [Epub ahead of print]

Justin Hwang, Pornlada Likasitwatanakul, Sachin Kumar Deshmukh, Sharon Wu, Jason J Kwon, Eamon Toye, David Moline, Mark G Evans, Andrew Elliott, Rachel Passow, Christine Luo, Emily John, Nishant Gandhi, Rana R McKay, Elisabeth I Heath, Chadi Nabhan, Natalie Reizine, Jacob J Orme, Josep M Domingo Domenech, Oliver Sartor, Sylvan C Baca, Scott M Dehm, Emmanuel S Antonarakis

University of Minnesota, Minnesota, MN, United States., University of Minnesota, Minneapolis, MN, United States., Caris Life Sciences (United States), Phoenix, Arizona, United States., Caris Life Sciences (United States), Phoenix, AZ, United States., Broad Institute, United States., University of Pennsylvania, Philadelphia, Pennsylvania, United States., University of Minnesota, Minneapolis, United States., University of California, San Diego, La Jolla, CA, United States., Karmanos Cancer Center, Detroit, MI, United States., Caris Life Sciences (United States), Deerfield, United States., University of Illinois at Chicago, Chicago, IL, United States., Mayo Clinic, Rochester, MN, United States., Hungarian Academy of Sciences, Boston, United States.