Abstract 58P
Background
The clinical significance of HRD in breast cancer, ovarian cancer and prostate cancer has been established, but the value of HRD in NSCLC has not been fully and thoroughly investigated.
Methods
FFPE samples from 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assesses through AmoyDx Genomic Scar Score (GSS), cases with a GSS score > 50 were considered as HRD-positive. Differences in genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed.
Results
Of the 355 patients, 89 (25.1%) were HRD-positive. Compared with HRD-negative patients, HRD-positive patients were likely to have more somatic pathogenic HRR mutations, higher TMB (p < 0.001) and less driver gene mutations (p < 0.001). Further, in EGFR/ALK mutant patients, HRD positive NSCLC harbored more amplification in oncogenic genes, like MYC, MET, RICTOR, and CDK6. In EGFR/ALK wild type patients, more amplifications in PI3K pathway genes, like PIK3CA, AKT3 and cell cycle genes, AURAK, CCND1 were occurred in HRD positive NSCLC. Regardless of EGFR/ALK mutation status, HRD-positive NSCLC displayed higher activity of tumor proliferation and enrichment of “Type 2 T helper cell”. HRD-negative NSCLC showed pro-inflammatory and anti-tumor immunity characteristics, “MHC Ⅱ”, and “Effector memory CD8 T cell”. The PFS of HRD-positive patients who received target therapy were significantly shorter than HRD-negative patients (mPFS: 12 vs 16 months, p = 0.042), and 3rd-generation TKI showed limited improvement of efficacy in HRD-positive patients. HRD-positive, EGFR/ALK wild-type patients responded poorly to platinum-free immune combination regimens (mPFS, HRD-positive, Plt+ vs HRD-positive, Plt-, 18.0 vs 5.0 months, p = 0.09).
Conclusions
Unique genomic and transcriptional characteristics were disclosed in HRD positive NSCLC. Unfavored prognosis and poor response to EGFR-TKIs, immunotherapy was revealed in HRD-positive NSCLC. This study suggested a potential strategy combining PARP inhibitors with targeted or immuno-therapy.
Legal entity responsible for the study
The authors.
Funding
National High Level Hospital Clinical Research Funding, Grant/ Award Number: BJ-2019-195.
Disclosure
All authors have declared no conflicts of interest.