3398 - Homology-directed repair (HDR)-defective lung adenocarcinomas (LUACs) in circulating tumor DNA (ctDNA)

Background

Tumors lacking key HDR regulators, such as, BRCA1, BRCA2 and AT-rich interaction domain 1A (ARID1A), are hypersensitive to PARP inhibitors. Also, mutations in HDR have been associated with response to PD-1 or PD-L1 blockade. ARID1A is one of the genes with the highest mutation rate across several types of tumors. We aim to identify if HDR mutations and alterations occurred in advanced LUAC patients (p).

Methods

The Spanish Lung Liquid versus Invasive biopsy Program (SLLIP), from August 2016 to June 2017, performed genomic profiling from plasma in 185 treatment-naïve advanced LUAC p on a 73-gene ctDNA assay (Guardant360). SLLIP (NCT03248089) validated Guardant360 for the detection of LUAC targetable activating alterations. Median age 66, 64% male and 81% smokers/ex-smokers. A secondary aim was the discovery of additional drivers and actionable mutations, particularly in the absence of EGFR, KRAS, ALK and ROS alterations. Determination of deleterious mutation status was based on public databases (ClinVar and BRCA Exchange) and expert curation.

Results

25.4% of LUAC p had any genomic alteration in DDR genes and ARID1A (BRCA1, 12; BRCA2, 13; ATM, 4; MLH1, 2; ARID1A, 24). Greater than 90% of the variants in BRCA1, BRCA2, and MLH1 were of unknown significance or likely benign. The 12 BRCA1-mutant p had a median number of 3 (range 1-15) co-occurring genetic alterations. One p had an EGFR mutation, and 4 p had KRAS mutations. The 13 BRCA2-mutant p had a median number of 4 (range 1-14) co-occurring genetic alterations. One p had EGFR, 1 p MET exon 14 and 4 p KRAS mutations. Three of 4 ATM-mutant p had co-occurring EGFR or KRAS alterations, while 3 of the ATM mutations were likely pathogenic. The 2 MLH1-mutant p had co-occurring KRAS alterations. The 24 ARID1A-mutant p had a median number of 4 (range 1-15) co-occurring genetic alterations. Six p had EGFR and 8 p KRAS mutations. More than half of the ARID1A alterations were loss-of-function mutations. The majority of SLIPP p received 1st line platinum-based chemotherapy.

Conclusions

For the first time ARID1A mutant p have been identified in LUAC. ctDNA could identify HDR-defective LUACs, which could aid in the use of PARP inhibitors and response to PD-1/PD-L1 blockade.

Clinical trial identification

NCT03248089.

Legal entity responsible for the study

Guardant Health Inc.

Funding

Guardant Health Inc.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.