419P - Prevalence of gene rearrangement on ctDNA NGS and its targetability in patients with advanced breast cancer

Background

Gene rearrangements (fusion) have been characterized across several solid tumors as valid targets for therapy. Their prevalence and actionability in advanced breast cancer (aBC) remain underappreciated due to lower incidence as well as the uncertainty of actionability. With wider adoption of comprehensive genomic profiling (CGP) in aBC management, incidental fusion detection is a reality, and physicians need to decide its targetability.

Methods

We retrospectively analyzed results of a commercially available ctDNA NGS assay (Guardant360) ordered in patients with aBC spanning from April 2017 till April 2024. This assay not only scrutinized gene fusions but also interrogates single nucleotide variants (SNVs), insertions and deletions, and amplifications across 54-83 genes. Additionally, microsatellite instability (MSI) and blood tumor mutational burden (bTMB) were assessed in select cases. As this is real-world data this assay could have been ordered across different lines of treatments in different patients.

Results

Our analysis included over 58000 samples primarily from females (98.8%) with median age of 65 years. ctDNA detection rate was 88.7% with a median test turnaround time (TAT) of 7 days. Gene fusions were reported in 1.1% (n=641) of the total samples, FGFR3-TACC3 being most prevalent and detected in 0.13% (n=75) of samples. ALK fusions in 0.06% (n=34) of samples, were predominantly characterized by EML4-ALK, which constituted 47% (n=16) of all ALK fusion events. Among the total 16 samples positive for EML4-ALK fusion, 15 were from the United States and 1 from India. In this 58-year-old female patient with aBC from India, metastatic invasive triple-negative breast cancer was confirmed in Sep 2022. Initially, she received three cycles of Nabpaclitaxel and carboplatin and upon progression plasma ctDNA NGS was ordered and reported EML4-ALK fusion (0.7% VAF) in Nov 2022 resulting in treatment with alectinib. PET scan in Feb 2023 reported complete metabolic response (CMR). Recent scan in Feb 2024 showed two new lesions hence radiation was added to the existing regimen.

Conclusions

ctDNA CGP can provide genotyping at fast TAT for effective management of aBC. Fusions, though rare in aBC, should be considered for detection for targeted therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Bharat: Financial Interests, Personal, Full or part-time Employment: Guardant Health. S.S. Jain: Financial Interests, Personal, Full or part-time Employment: Guardant Health; Financial Interests, Personal, Stocks/Shares: Guardant Health. N. Joshi: Financial Interests, Personal, Full or part-time Employment: Guardant Health. N. Rohatgi: Financial Interests, Personal, Advisory Role: Guardant Health. All other authors have declared no conflicts of interest.