1277P - HRD status of patients with early stage non-small cell lung cancer

Background

There is an unmet need for post-surgical therapeutic options in early-stage NSCLC patients. PARP inhibitors (PARPi) have shown efficacy in cancer patients harboring germline or/and somatic BRCA1/BRCA2 mutations and homologous recombination deficiency (HRD). Patient selection for targeted treatment is of crucial importance. Thus, the assessment of HRD status in patients with early-stage NSCLC may pave the way for the use of PARPi in an adjuvant setting.

Methods

Tumor specimens and peripheral blood samples were analyzed for somatic and germ-line mutations with a customized panel of 58 genes. To assess HRD status the genomic scar score (GSS) was calculated using the AmoyDx® HRD Focus Panel or AmoyDx® HRD Complete Panel. The effect of PARP inhibition on tumour growth was assessed in patient-derived xenografts, where RAD51 foci were quantified by immunofluorescence.

Results

Six of 85 patients (59 men/26 women) with operable NSCLC, carried germline mutations in BRCA1 (n=1), BRCA2 (n=1), ATM (n=3), and PALB2 (n=1) genes. Pathogenic somatic mutations were detected in BRCA1 (n=8), BRCA2 (n=9), ATM (n=8), PALB2 (n=3), CHEK1 (n=3), CHEK2 (n=6), RAD50 (n=5) and TP53 (n=49) genes. Based on GSS, 25 (29.4%) patients were characterized as HRD and at least one somatic HRR mutated gene was observed in 15 (57.7%) of them [BRCA1 (n=4), BRCA2 (n=4), ATM (n=3), PALB2 (n=2), CHEK2 (n=1) ]. Preliminary functional experiments in HRP (HR proficient, n=5) and HRD (n=4) PDX and organoids (n=3 and n=3 for HRD and HRP respectively) indicate that HRD tumors present low RAD51 foci count (p=0.03 after damage induction) and favorable response to Olaparib and CDDP.

Conclusions

These data suggest that homologous recombination may be deficient in a substantial proportion of early-stage NSCLC patients, supporting the potential use of PARPi in HRD patients in the adjuvant or maintenance setting.

Clinical trial identification

N/A

Editorial acknowledgement

N/A

Legal entity responsible for the study

The authors.

Funding

Amoy Diagnostics.

Disclosure

All authors have declared no conflicts of interest.