Gynecologic-cancer analysis of ARID1A alterations detected in tissue and liquid biopsies.

person Natalie Danziger Foundation Medicine, Inc., Cambridge, MA info_outline Natalie Danziger, Elise C. Kohn, Julia C. F. Quintanilha, Gerald Li, Julia A Elvin, Douglas I. Lin

Authors person Natalie Danziger Foundation Medicine, Inc., Cambridge, MA info_outline Natalie Danziger, Elise C. Kohn, Julia C. F. Quintanilha, Gerald Li, Julia A Elvin, Douglas I. Lin Organizations Foundation Medicine, Inc., Cambridge, MA, National Cancer Institute, Rockville, MD, Foundation Medicine, Inc., Boston, MA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Foundation Medicine Inc Background: The tumor suppressor gene ARID1A is an emerging target for new cancer treatment strategies including ATR inhibition. This study aimed to describe the landscape of ARID1A alterations ( ARID1A mut) in gynecologic malignancies. Methods: Patients (pts) with a diagnosis of ovarian (OC) or uterine cancer (UC) of different histologies and comprehensive genomic profiling (CGP) by Foundation Medicine Inc. were included in this study. CGP of solid tissue biopsies (Tbx; FoundationOneCDx) included evaluation of genomic loss of heterozygosity (gLOH; gLOH-high as ≥16% as validated in OC), microsatellite instability (MSI), and tumor mutational burden (TMB; high as ≥10 mutations/Megabase). CGP of peripheral whole-blood liquid biopsies (Lbx; FoundationOneLiquidCDx) included evaluation of MSI and tumor fraction (TF), a measure of the relative quantity of circulating tumor DNA (ctDNA). TF was calculated by measures of aneuploidy and allele frequency and binned as TF < 1%, TF 1 to < 10%, or TF ≥10%. Results: Tbx Cohort: 5,778/30,212 (19.1%) cases were ARID1A mut. Pts had a median age of 63 (range 21-89) years. ARID1A mut were observed across many subtypes and most frequently in endometrial endometrioid (n = 3,052, 57.7%) and ovarian clear cell (n = 982, 57.6%) but rarely in serous (OC, n = 12,258, 2.8%; UC, n = 2,682, 8.9%). Pts frequently harbored more than one ARID1A mut (2,360/5,778, 40.8%). Of the 8,484 observed ARID1A mut, 97.6% were short variants (SV), 0.5% were deletions, and 1.9% were inactivating rearrangements. SV were primarily frameshifts (68.5%) and nonsense mutations (27.6%). The most frequent alterations observed were frameshifts at the D1860 codon. SV were predicted to be homozygous in 11.9%, heterozygous in 65.3%, or unknown zygosity in 22.8%. Overall, 16.6% of ARID1A mut cases with SV had at least one homozygous alteration. 6.6% of pts with homozygous ARID1A mut were MSI-high (MSI-H), while 39.4% of pts with only heterozygous or unknown zygosity ARID1A mut were MSI-H (p < 0.0001). Overall, 1,905 (33.0%) of ARID1A mut cases were MSI-H, and 2,183 (37.8%) were TMB high. For ARID1A mut cases with evaluable gLOH (n = 4745), the median gLOH was 2.7%, and 5.9% pts were gLOH-high. The most frequently altered co-occurring genes were PTEN (62.2%), PIK3CA (54.2%), and TP53 (27.6%). 8.7% of ARID1A mut also harbored a BRCA alteration. Lbx Cohort: 59/967 (6.1%) cases were ARID1A mut. 17 (28.8%) were MSI-H. Frequency of ARID1A mut increased as TF increased, with a detected frequency of 1.3%, 6.7%, and 14.0% among Lbx with TF < 1%, TF 1 to < 10%, or TF ≥10% respectively. Conclusions: ARID1A mut are observed across a variety of Gynecologial cancer subtypes but are enriched in clear cell and endometrioid histologies and detected in both tissue and liquid biopsies. ARID1Amut were not associated with elevated gLOH but were often MSI-H and TMB ≥10mut/Mb. Clinical trials targeting ARID1 A may wish to consider the context of co-occuring biomarkers.