Genomic characterization of anal canal squamous cell carcinoma (ASCC) and outcomes on matched targeted therapy.

Abstract

3526 Background: Anal canal squamous cell carcinoma (ASCC) is uncommon but increasing in incidence. 5-year survival of patients (pts) with metastatic ASCC is only 36%; new therapies are an unmet medical need. Genomic alterations (GA) in phosphoinositol-3-kinase (PI3K) signaling pathway have been reported in small datasets of ASCC. Data on clinical outcomes with therapies targeting these GA in pts with ASCC are lacking. Methods: Tumor genomic data of pts with ASCC at Memorial Sloan Kettering Cancer Center (MSK) were obtained using a targeted next generation sequencing assay (MSK IMPACT) from cBioPortal database. GA were annotated for biological significance using the OncoKB database, and only GA with known oncogenic potential were included. GA were categorized as mutations (mut), amplifications (amp), deletions (del) and fusions (fus). Clinical annotations were abstracted from electronic health records and outcomes of pts who participated in clinical trials were assessed. Data were summarized using descriptive statistics and survivals were estimated using Kaplan-Meier method. Results: Of 92,711 pts in cBioPortal, 218 (0.2%) pts had ASCC (male n = 65, 30%). Of these 218 pts, 179 (82%) had at least 1 oncogenic GA. Oncogenic GA were most frequently identified in PIK3CA 40% (87 pts; mut 67, amp 36, with overlap), KMT2D 19% (mut 42), BCL6 17% (amp 37), PTEN 12% (mut 18, del 9), EP300 11% (mut 24), KMT2C 11% (mut 20, del 3), and FBXW7 10% (mut 20, del 1). Oncogenic GA were most frequent in the PI3K-AKT-mTOR signaling pathway (121 pts, 55%). Amps were also seen in FGF3 , FGF4, FGF19 and CCND1 in 4% pts each. Thirteen pts with metastatic treatment refractory ASCC participated in early phase clinical trials; 3 pts enrolled in > 1 studies (total 18 trial participations). GA-matched targeted therapy was administered to 8 pts: oncogene inhibitors in 6 pts (targeting PIK3CA E545K in 3, PIK3CA Q546K in 1, HER2 I767M in 1, FGFR2 amp in 1), and drugs selected for tumor suppressor gene GA in 3 pts (PTCH1 loss in 1, TP53-wild in 1, FBXW7 in 1). Six pts received immunotherapy and 3 pts were treated with antivirals drugs targeting Human Papillomavirus. Out of 4 pts treated with PI3K signaling inhibitors, 1 had partial response and 2 had stable disease, with median progression free survival of 3.6 (95% CI 0-8.6) months and median overall survival of 9.1 (95% CI 5.7-12.5) months. Two out of four pts treated with PI3K pathway inhibitors were on treatment for > 6 months. No response was seen in pts treated with drugs targeting GA other than PIK3CA or with immunotherapy; and one of three pts treated with anti-viral agents had best response of stable disease. Conclusions: This is the largest characterization of GA with known oncogenic potential in ASCC. The PI3K signaling pathway is altered in over half of ASCC, and PI3K-AKT-MTOR inhibitors have the potential for further investigation in pts with activating GA in PIK3CA gene.