Abstract
Background Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. 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. Methods Formalin-fixed paraffin-embedded (FFPE) tumour 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) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB). Results In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six 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 one CRGA, and 87% of patients had at least one 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 one patient with ERBB2 amplification and one 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.
Highlights
Breast cancer is the most frequently diagnosed cancer and results in the second most common cancer mortality among the Chinese female population [1]
Formalin-fixed paraffin-embedded (FFPE) biopsy specimens from 36 Triple-negative breast cancer (TNBC) patients, including 23 very-early-relapsed TNBC patients and 13 no-recurrence TNBC patients were obtained with the approval of the Sun Yat-set University Cancer Center (SYSUCC) Institutional Review Board
Inclusion criteria were patients histologically confirmed ER-negative, PR-negative, and human epidermal growth factor receptor type 2 (HER2) nonover expressing by immunohistochemistry (IHC) (0, 1) or non-amplified by fluorescence in situ hybridization (FISH)
Summary
Breast cancer is the most frequently diagnosed cancer and results in the second most common cancer mortality among the Chinese female population [1]. TNBC is regarded as the most aggressive breast malignancy and accounts for approximately 19% of all breast cancers in the Chinese population [3]. Because of the lack of specific targets for therapy, TNBC represents a particular treatment challenge. Patients with early TNBC experience the peak risk of recurrence within 3 years of diagnosis [6]. 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. 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
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