Pan-cancer landscape of FOXA1 alterations: Insights and clinical implications.

3090 Background: Forkhead box A1 ( FOXA1) is a pioneer transcription factor that regulates organogenesis and is associated with progression in breast and prostate cancers. To explore its role more broadly in oncogenesis, we characterize FOXA1 genomic alterations and clinical correlates in a large pan-cancer cohort from the American Association for Cancer Research project Genomics, Evidence, Neoplasia, Information, Exchange (AACR-GENIE) database. Methods: Using AACR-GENIE, FOXA1 mutations (in frame insertions/deletions (indel-inframe), frameshift insertions/deletions (indel truncating), point mutations (missense), fusions, and amplifications) were characterized across >30 cancer types for primary and metastatic tumors with patient characteristics and clinical outcomes. FOXA1 alterations were queried in the MSK-MET cohort, a subset of GENIE cohort, allowing the definition of hazard ratios (HRs) and overall survival estimates based on Cox proportional hazard models. Results: Among 120,625 samples queried from the AACR GENIE data, FOXA1 was profiled in 87,706 samples: 30,268 metastases, 49,228 primary tumors, and 8,210 not specified. FOXA1 mutations were present in 1,869 samples (2.1%), mostly in the forkhead DNA-binding domain. Prostate tumors were enriched with indel-inframe alterations whereas breast cancers were enriched with missense mutations. F266, R261, and D226 mutations in the Wing2 region were common in breast and prostate cancers. In the GENIE cohort, FOXA1 copy number profiles were collected for 74,715 samples, with amplification detected in 834 (1.1%) and deletion in 96 samples (0.1%). FOXA1-amplification was most common in non-small cell lung cancer (NSCLC, 3%, n=190, in primary; 6%, n=264, in metastatic), followed by small cell lung cancer (SCLC) (4.1%, n=10, in primary; 3.5%, n=10, in metastatic), breast (2%, n=80 in primary; 1.6%, n=73, in metastatic) and prostate cancers (2.2%, n=49, in primary; 1.6%, n=27 in metastatic). In the MSK-MET cohort, FOXA1 amplifications were associated with poorer outcomes in primary breast (HR: 3.04, 95% CI: 1.89-4.89, p=4e -6 ), primary NSCLC (HR: 1.45, 95% CI: 1.06-1.99, p=0.02), and prostate cancer (HR: 1.94, 95% CI: 1.03-3.68, p=0.04). FOXA1 amplifications were associated with wide-spread metastases in primary breast, NSCLC, and prostate cancer. Conclusions: In this observational study of pan-cancer FOXA1 mutant specimens from the GENIE database, we found that FOXA1 alterations in prostate cancer (primary and metastatic tumors) were predominantly indels versus missense in other cancers. We also observe a consistent association between FOXA1 amplification and enhanced metastatic potential regardless of tissue of origin. Our findings suggest that FOXA1 amplifications could serve as a potential prognostic and therapeutic target, particularly for breast, prostate, and non-small cell lung cancer.