Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in Chinese population.

Abstract

e13031 Background: Triple negative breast cancer (TNBC) represents about 19% of all breast cancers in Chinese population. Compared with other breast cancer subtypes, TNBC tend to be more aggressive and is associated with early relapse and worse survival. In this study, we performed comprehensive genomic profiling to explore the clinical relevant genomic alterations (CRGAs) and potential therapeutic targets in very early relapsed TNBCs, regarding as tumor recurrences within 24 months. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from 23 very early relapsed TNBC patients 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, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB). Results: In total, 137 CRGAs were detected in all the 23 TNBC patients, averaging 6 alterations per sample. The mean TMB was 4 Muts/Mb, and only one patient was MSI-Intermediate. The top ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%), BRCA1 (22%), NOTCH1 (13%), MYC (13%) and CCND1 (13%). Notable co-segregating amplifications included KAS-KDM5A and FGF3-FGF4-FGF19. Importantly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of them were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion and EGFRvIVa in the first time, which has not been reported in breast cancer before. Furthermore, we also found EGFR amplification with copy number equal to 126 in one TNBC patient. In addition, 61%, 52%, 43%, 22% and 17% TNBC patients have at least one CRGA in pathways involving PI3K/mTOR, Cell cycle, DNA repair, Growth factor receptors (GFRs) and RAS/MAPK signaling pathways, respectively. Importantly, alterations in RAS/MAP tended to occur in very early-stage, such as IA-IIB tumors, and GFRs tended to occurr in IIIA-IIIC tumors. Furthermore, 100% of these patients have at least one CRGA and 87% patients have at least one actionable alteration. Conclusions: This study demonstrated that most of TNBCs have at least one actionable alteration. In conclusion, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very early relapsed TNBC patients.