Abstract 133P
Background
ARID1A encodes a key component of the SWI–SNF chromatin remodeling complex, participating in the control of PI3K/AKT/mTOR pathway. No data are available for patient populations whose tumors harbor multiple ARID1A mutations. A variety of compounds are being tested in ARID1A-altered cancers, without any drug approval so far.
Methods
Molecular and clinical characteristics of patients evaluated at Phase I Unit of Fondazione Policlinico Gemelli and harboring at least one ARID1A alteration were collected. Clinical data were retrieved from hospital records. Molecular analysis was performed by FoundationOne on tissue (primary diagnosis or relapsed tissue) or blood.
Results
Among the 207 patients that received the molecular analysis at our site, 19 (9.1%) had at least one pathogenic alteration in ARID1A: 15 (79%) had molecular alterations in solid tissue, 4 (21%) in liquid biopsy. Half of the solid archival tissue (8/15, 53%) was from the primary diagnosis, the others from the relapsed disease. ARID1A alterations were prevalent in ovarian cancer (clear cell histotype, 5/19, 26%) and endometrial cancer (endometrioid subtype, 5/19=26%), followed by cervical cancer (10.5%), colon cancer (10.5%) and breast (luminal type) cancer (10.5%). The most frequent co-occurent molecular alterations were: TP53 (8/19=42%), PIK3CA (8/19=42%), PTEN (6/19=31.5%), CTNNB1 (4/19=21%), ASXL1 (4/19=21%), MLL2 (4/19=21%). The most common pathogenic alteration in ARID1A was Q372fs*19 (3/19=16%), identified only in solid tissue, both alone or in combination with another mutation in ARID1A. Microsatellite instability status was detected in 26% (5/19) of the samples; the median value of TMB was 7.57 mut/MB. Double molecular alterations in ARID1A were identified in 5/19 (26%) patients; the majority of them (4/5, 80%) were endometrial carcinoma of endometrioid subtype, with at least a co-occurent mutation in PTEN or PIK3CA.
Conclusions
The high frequency of co-occurent mutations in PIK3CA and PTEN with ARID1A in some subtypes of gynecological cancers (endometrioid endometrial cancers and clear cell ovarian cancers) supports the proposal of a new treatment strategy based on the combination of ATR inhibitor and PIK3CA inhibitors.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.