Clinical and mutational profile of ARID1A-mutated gastrointestinal cancers: Duration of response to platinum-based chemotherapy.
Authors: Khosrowjerdi Sara J. , Horick Nora K. , Clark Jeffrey William , Parikh Aparna Raj , Allen Jill N. , Nipp Ryan David , Franses Joseph Wang , Goyal Lipika , Wo Jennifer Yon-Li , Roeland Eric , Giantonio Bruce J. , Weekes Colin D. , Blaszkowsky Lawrence Scott , Murphy Janet E. , Corcoran Ryan Bruce , Klempner Samuel J , Ryan David P. , Hong Theodore S. 
Published: June 2021

e15611

Background: ARID1A is mutated in several cancer types, with studies reporting mutations in up to 10% of colorectal cancers (CRC) and as high as 35% of gastric and pancreatic cancers. The ARID1A gene encodes a member of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex and functions as a tumor suppressor. ARID1A has also been implicated in double-stranded DNA repair via both homologous recombination and non-homologous end-joining, potentially conferring platinum sensitivity. We sought to characterize this subset of gastrointestinal (GI) malignancies. Methods: We identified patients with locally advanced or metastatic ARID1A-mutated GI malignancies treated at Massachusetts General Hospital (MGH) by next-generation sequencing. Patients were selected who gave consent to molecular testing and who were enrolled on to a study. We evaluated clinical characteristics and outcomes for patients undergoing treatment at MGH between 2009 and May 2020. The Kaplan-Meier method was used to calculate progression free survival (PFS) to first-line platinum-based chemotherapy. Results: We captured 38 patients with ARID1A-mutated tumors. Median age at diagnosis was 66 (range 31-87) and 63.2% of patients were male (n = 24). Tumor types varied, including CRC (n = 13, 34.2%), esophagogastric (n = 13, 34.2%), pancreatic (n = 6, 15.7%), cholangiocarcinoma (n = 2, 5.3%), small bowel (n = 1, 2.6%), anal (n = 1, 2.6%), and unknown GI primary (n = 2, 5.3%). Most were metastatic at diagnosis (n = 23, 60.5%). The identified ARID1A mutations were each distinct, occurring along the length of the gene and were comprised of missense (n = 10, 26.3%), nonsense (n = 12, 31.6%), frameshift (n = 13, 34.2%), and splice-site (n = 3, 7.9%) mutations. We observed on average 4-5 co-mutations per tumor, with TP53 (n = 25, 65.8%), KRAS (n = 14, 36.8%), APC (n = 11, 28.9%), BRCA2 (n = 7, 18.4%) and BRAF (n = 7, 18.4%) occurring most frequently. Tumors were both microsatellite stable (n = 23, 60%) and microsatellite unstable (n = 7, 18.4%). Most patients (n = 37, 97.4%) received a platinum-based chemotherapy as first-line therapy including FOLFOX (n = 23, 60.5%), FOLFIRINOX (n = 10, 26.3%), gemcitabine/cisplatin (n = 2, 5.3%), carboplatin/5-FU (n = 1, 2.6%), and carboplatin/etoposide (n = 1, 2.6%). Median PFS for first-line platinum based chemotherapy was 14.0 months (CI 8.2-34.7) overall. For patients with CRC, PFS to platinum-based therapy was 14.0 months (CI 4.8-not reached) compared with 9.6 months for non-CRC (CI 7.4-not reached). Conclusions: To our knowledge, this is the first assessment of clinical characteristics and outcomes for ARID1A-mutated GI malignancies. Mutations in ARID1A are highly diverse, without a clear association with tumor type. Future studies assessing response to platinum-based chemotherapy are warranted.