Identifying early breast cancer (eBC) patients that require adjuvant chemotherapy is defined by clinical features, which do not accurately identify high-risk patients. The USO01062 Phase 3 study enrolled 2,611 high-risk patients based on clinical features, with a 13% event rate observed. Comparing the genomic landscape of tumors between patients who had a recurrence event and those who did not may uncover genomic aberrations associated with recurrence that may be used to identify high-risk patients. The genomic landscape of TNBC subtypes is also largely unknown and NGS profiling may shed light on novel therapeutic opportunities.
The USO01062 study failed to show a benefit for the addition of capecitabine to adjuvant chemotherapy (O'Shaughnessy J. et al. 2015). Arms were pooled and DNA and RNA were extracted from 1,181 tumor samples, of which 145 patients had a DFS event, and were matched demographically to a set of 146 patients without an event for targeted NGS profiling using FoundationOne®. Gene expression was previously run using a breast cancer specific 800-gene panel (Wilson T.R. et al. 2016).
Analysis of somatic alterations within IHC subtypes identified unique prognostic factors, e.g. alterations in ATM, ERCC4 and IGF2R correlated with a worse HR in HR+ disease, whereas alterations in MAP3K1, RPTOR and LYN correlated with a worse HR in TNBC. Analysis of tumor mutational burden (TMB) revealed TNBC tumors had the highest burden, which did not correlate with clinical outcome or expression of PDL1 and CD8 genes. Molecular subtyping of TNBC (Lehmann B.D. et al. 2011) found distinct genetic drivers in each subtype, e.g. alterations in TP53 and MYC were the most frequent in BL1 and BL2 tumors. IM tumors expressed alterations in TP53, CREBBP and BRCA1. LAR tumors expressed alterations in PIK3CA and PTEN.
TMB was not prognostic and did not correlate with PDL1 or CD8 gene expression, suggesting that TMB in TNBC may not be a surrogate for the immune activated subtype. TNBC molecular subtyping identified different genomic drivers providing evidence for genomic heterogeneity within subtypes. Lastly, comparison of patients that experienced a DFS event identified genomic alterations that may be used to identify high-risk patients.
Clinical trial identification
Patients were enrolled onto the parent study USO01062, (NCT00089479).
Legal entity responsible for the study
T.R. Wilson, A.R. Udyavar, C-W. Chang, J. Giltnane, J.M. Spoerke, J. Aimi, H. Savage, A. Daemen, R. Bourgon, M.R. Lackner: Employed by Genentech, Inc. Stocks in Roche