408P - Characterizing the genomic landscape of breast cancer in an Irish cohort of patients

Background

Breast cancer (BC) is a heterogeneous disease, with many molecular subsets, and the advent of next generation sequencing (NGS) which allows for the detection of biomarkers to guide patient (pt) selection and systemic treatment, has enhanced our understanding of the genomic landscape of BC with subsequent improvement in clinical outcomes. We aimed to assess the frequency of clinically relevant biomarkers in an Irish cohort of breast cancer patients.

Methods

A total of 327 breast cancer pts were analysed using the commercially available Oncomine™ Focus panel from 2021 to 2024 in St. James’s Hospital. Analysis of DNA was performed to detect single nucleotide variants and indels across 35 genes, excluding BRCA1/2.

Results

265/327 cases had DNA of sufficient quality and quantity for analysis (81%). Activating PIK3CA mutations were the most frequently observed mutations (40%, n=106) with 4.9% of cases (n=13) exhibiting double PIK3CA mutation. The most frequently affected PIK3CA codons were codons 1047, 545 and 542 (n=56, 23 and 12 respectively). Clinically relevant mutations observed included ESR1 (8.8%, n=23), AKT1 (6.8%, n=18) and ERBB2 (3%, n=8). PIK3CA mutation co-occurred with ERBB2 (n=4), ESR1 (n=10) mutations and AKT1 (n=2). 50% (4/8) of cases with ERBB2 mutations were invasive lobular carcinoma subtype; 1pt harbored ERBB2 amplification with the acquired ERBB2 gatekeeper mutation (L869R). Among confirmed triple negative BC cases (n=8), one case harbored dual mutations in PIK3CA (Y1021C and C378F located in the kinase and helical domains) and ERBB2 (class III D769Y and class I S310F).

Conclusions

We present the largest study of BC variant frequencies in a cohort of Irish breast cancer patients to date and confirm NGS is feasible and identifies clinically relevant and actionable variants. We confirm that the frequency of PIK3CA alterations, in addition to codon specificity, are comparable to those observed in European and US cohorts and demonstrate that the detection of clinically relevant biomarkers is not confined to ER positive HER2 negative BC. The tissue failure rate (19%) underscores the need for cfDNA testing to identify the expanding range of actionable targets in BC to improve access to emerging targeted therapies and biomarker-driven clinical trials.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Cancer Molecular Diagnostics, St James’s Hospital, Dublin 8.

Funding

National Cancer Control Programme.

Disclosure

All authors have declared no conflicts of interest.