Abstract P5-03-18: Co-occurring alterations in PALB2 germline carriers identified by liquid biopsy in patients with advanced breast cancer

Abstract Introduction: PALB2 is a BRCA complex-interacting protein and has an essential role in homologous recombination and repair (HRR). PALB2 germline (gPALB2) mutations are found in 1 – 4% of breast cancer patients and can be incidentally identified by liquid biopsy testing. Recent data has shown the efficacy for PARP inhibitors (PARPi) in breast cancer gPALB2 carriers, highlighting the importance of understanding genomic drivers in this group of patients. Here we present the genomic landscape of patients with advanced breast cancer (aBC) with incidental gPALB2 mutations identified by liquid biopsy testing. Methods: Genomic results were queried for aBC patients who had Guardant360 (G360) testing as part of routine clinical care from October 2020 – March 2022. Eligible patients had must have a diagnosis of breast cancer and an incidental gPALB2 alteration identified on G360, defined by presence of ClinVar loss-of-function single nucleotide variant (SNV)/indel mutation. Co-occurring somatic alterations in these patients were then analyzed after removing synonymous and variants of uncertain significance. Analysis of HRR-related alterations, such as loss of heterozygosity and/or copy number loss, was performed in a subset of patients. Clinical demographics and clinical status (newly diagnosed or progressing at the time of G360 testing), were extracted from test requisition forms. Results: A total of 48 patients had gPALB2 alterations: 60% had indels and 40% SNVs. gPALB2 variant allele frequencies (VAF) were >30% for all patients (median VAF: 49.7, range: 34.1-66.6). All patients were female with a median age of 59 years (range: 31-84); 29 (60%) were tested at progression whereas the rest were tested at diagnosis. 36 (75%) patients with gPALB2 had co-occurring somatic alterations across 23 genes. The most commonly mutated genes were TP53 (47%), ESR1 (23%), and PIK3CA (19%); other mutated genes had less than 7% frequency. Notably, 95% of patients with co-occurring ESR1 alterations and 70% found to harbor PIK3CA co-occurring alterations were tested at progression. Other clinically relevant findings include co-occurring somatic alterations in MTOR (4%) and HRR-related genes ATM, ARID1A, CHEK2, FANCA (4% each; one patient had both ATM and CHEK2 somatic alterations). No somatic BRCA1/BRCA2 alterations were identified in gPALB2 patients. For 33 (69%) patients with gPALB2, additional HRR-related biomarker analysis was performed resulting in identification of 3 (9%) patients with copy number loss, one who had CHEK2 and PALB2 single copy number loss, resulting in PALB2 biallelic loss. In the overall cohort, an additional 33 patients were identified with uniquely somatic PALB2 alterations. Conclusions: Carriers of gPALB2 alterations comprise a rare subset of aBC patients analyzed by liquid biopsy. These patients have co-occurring somatic alterations identified in genes that have been reported in published cohorts of aBC patients without gPALB2 alterations. Assessment of additional somatic HRR-related alterations may identify other patients with PALB2 findings who could benefit from PARPi. Clinical studies are needed to assess how patients with gPALB2 and co-occurring mutations may have altered response and/or resistance to therapies, including standard-of-care regimens and PARPi. Citation Format: Nan Chen, Rita Nanda, Frederick M. Howard, Neelima Vidula, Jennifer Yen, Leylah M. Drusbosky, Leslie Bucheit. Co-occurring alterations in PALB2 germline carriers identified by liquid biopsy in patients with advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-18.