Abstract 98P
Background
Data suggests that ARID1A mutations are predictive of therapeutic response to several drugs, including immune checkpoint inhibitors and PARP inhibitors. We set out to explore associations between ARID1A and other genes in cfDNA from a large, pan-cancer cohort of stage IIIB/IV patients tested via a well-validated liquid biopsy platform.
Methods
We queried sequential samples from cancer patients tested via a 73- to 74-gene cfDNA test (Guardant360®). Testing was completed from March 2016-August 2019 and included detection of sequence alterations, fusions, amplifications, and microsatellite instability (MSI-H). After excluding variants of uncertain significance and synonymous variants, mutation frequencies were compared using Fisher’s exact test.
Results
Of 62,988 patients with ≥1 cfDNA alteration detected, 3,182 patients had ≥1 functional ARID1A (fARID1A) mutation. The incidence of fARID1A varied by cancer (Table). The frequency of alterations in several genes was significantly different between patients with and without fARID1A, including PIK3CA (28% vs 16%; p<0.0001), KRAS (28% vs 21%; p<0.0001), ERBB2 (9% vs 5%; p<0.0001), BRCA1 (4% vs 2%; p<0.0001), and BRCA2 (6% vs 3%; p<0.0001). There was a significantly higher frequency of MSI-H in samples with fARID1A (12% vs 1%; p<0.0001). In colorectal cancer (CRC) patients, there were significantly more BRAF V600E alterations (17% vs 6%; p<0.0001) and NRAS alterations (10% vs 6%; p=0.017) in patients with fARID1A. Table: 98P
| Cancer Type | Frequency of Patients with fARID1A |
| Endometrial | 21% |
| Bladder | 13% |
| Gastric | 13% |
| Gallbladder | 12% |
| Cholangiocarcinoma | 11% |
| Hepatocellular carcinoma | 11% |
| Carcinoma of unknown primary | 9% |
| Esophageal | 8% |
Conclusions
In a large, pan-cancer cohort of patients we found several differences in the frequency of genes in samples with and without fARID1A. These associations may help explain the biology underlying the putative value of ARID1A as a predictive biomarker for several types of therapy and add evidence to suggest that ARID1A plays an active role in several pathways including DNA damage repair and mismatch repair.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Weipert: Shareholder/Stockholder/Stock options, Full/Part-time employment: Guardant Health. J. Saam: Shareholder/Stockholder/Stock options, Full/Part-time employment: Guardant Health; Shareholder/Stockholder/Stock options, Full/Part-time employment: Myriad Genetics. D. Gandara: Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: CellMax Life; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Inivata; Advisory/Consultancy: IObiotech; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: OncoCyte; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech. R. Kurzrock: Research grant/Funding (institution): Guardant Health; Shareholder/Stockholder/Stock options: IDbyDNA; Shareholder/Stockholder/Stock options, Officer/Board of Directors: CureMatch, Inc.; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Soluventis; Advisory/Consultancy: Gaido; Advisory/Consultancy: LOXO; Advisory/Consultancy: X-Biotech; Advisory/Consultancy: Actuate Therapeutics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: NeoMed; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Sequenom; Research grant/Funding (institution): Foundation Medicine; Research grant/Funding (institution): Grifols; Research grant/Funding (institution): Konica Minolta; Research grant/Funding (institution): DeBiopharm; Research grant/Funding (institution): Boerhringer Ingelheim; Research grant/Funding (institution): OmniSeq; Officer/Board of Directors: CureMetrix, Inc.. H.J. Lenz: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: GSK; Honoraria (self): Isofol; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: BMS.