Clinical Genomic Profiling to Identify Actionable Alterations for Very Early Relapsed Triple-Negative Breast Cancer Patients in the Chinese Population

Background: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population, and is characterized by early relapse and a complex molecular heterogeneity. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients, which are considered tumor recurrences within 24 months. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx), a next-generation-sequencing-based diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB). Results: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging 6 alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%), and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least 1 CRGA, and 87% of patients had at least 1 actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected 1 patient with ERBB2 amplification and 1 patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before. Conclusions: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.