Predictive biomarkers for immune checkpoint inhibitor (ICI) and poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) in advanced-stage breast carcinoma

Abstract

Purpose

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have demonstrated antitumoral activity in cancers with a homologous recombination deficiency (HRD) and have been approved in 2018 by the U.S. Food and Drug Administration (FDA) for the treatment of germline BRCA1/2-mutation-associated breast cancer (BC). Clinical trials evaluating the combination of the immune checkpoint inhibitor (ICI) and PARPi are on-going. PD-L1-immunohistochemistry (IHC) and tumor mutation burden (TMB) are FDA approved predictive markers for ICI therapy in a subset of patients with breast cancer. We investigated the associations between these two biomarkers and HRD parameters in advanced stage BC.

Methods

Patients diagnosed with invasive BC between 2014 and 2022 whose tumors underwent a PD-L1 22C3 assay and/or comprehensive genomic profiling by NGS were identified. TMB, homologous recombination repair (HRR) gene mutations, and the loss of heterozygosity (LOH) score were collected. PD-L1 IHC and TMB were considered as markers for ICI. The BRCA1/2 gene, BRCAwt-HRR genes, and the LOH score were flagged as HRD criteria.

Results

Sixty-eight patients with locally advanced or metastatic BC were included. There were no significant difference in LOH status, BRCAwt-HRR gene mutations or BRCA1/2 mutations between PD-L1-positive and PD-L1-negative groups. The TMB score was not significantly associated with BRCAwt-HRR or BRCA1/2 gene mutations. LOH-high tumors showed a slightly higher TMB score than the LOH-low tumors.

Among the 68 patients, two received both ICIs and PARPi therapies sequentially, one had a complete response (CR) (TMB: 5 muts/Mb; BRCA1 mutated) and the other had progressive disease (BRCA VUS, variants of uncertain significance).

Conclusions

Our study failed to show significant associations between PD-L1 IHC and HRD parameters. The TMB score was positively associated with LOH-high status, but not a HRR gene mutation. Independently evaluating these markers needs to be considered to select patients for targeting therapies. Clinical outcome needs further evaluation.