Genomic and transcriptomic analyses of residual invasive triple-negative breast cancer after neoadjuvant chemotherapy in the prospective MIRINAE trial (a randomized phase II trial of adjuvant atezolizumab plus capecitabine compared to capecitabine; KCSG-BR18-21)

Abstract

Background: Profiling residual disease after neoadjuvant chemotherapy (NAC) might identify molecular target and tumor microenvironmental features to guide adjuvant therapy. We explored the characteristics of residual triple-negative breast cancer (TNBC) in the prospective MIRINAE trial (KCSG-BR18-21), a phase II study evaluating adjuvant atezolizumab plus capecitabine versus capecitabine in TNBC without pathological complete response after NAC (NCT03756298) through multi-omics analyses. Materials and methods: Residual TNBC samples were analyzed for tumor-infiltrating lymphocytes (TILs), programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC), and Lunit SCOPE IO immune phenotype (IP). Mutations were assessed by FoundationOne (R) CDx, and RNAseq was conducted for molecular subtyping and gene expression analyses. Results: Three hundred and five patients were analyzed, and ypTNM (post-neoadjuvant pathological tumor-node - -metastasis) stages were stage I (28.0%), II(48.7%), and III (23.3%). High TILs were observed in 27.1% and PD-L1 IHC was positive in 39.5%. Pathogenic alterations in TP53, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and homologous recombination repair (HRR) pathways were observed in 86.3%, 27.1%, and 11.9%. Most patients were basal-like (51.1%) by PAM50, and mesenchymal (MES; 36.7%) or basal-like immune suppressed (BLIS; 30.3%) by TNBC molecular classification. TIL-high group was enriched with the basal-like immune-activated (BLIA) subtype (37.5%), with up-regulation of immune response-related gene sets. Nineteen patients (6.2%) recurred within 6 months of surgery (6.2%), mostly being basal-like (85.7%) or BLIS (64.3%), with low TILs and desert IP. Up-regulations of CCNE1, CD44, and BRD4 along with DNA replication-related gene sets were associated with early recurrence. Conclusion: Residual TNBCs after standard NAC were predominantly basal-like or MES/BLIS subtypes with variable tumor microenvironment (TME). Early recurrence was associated with immune-cold TME, and further analyses on each treatment arm will provide deeper insights into the role of adjuvant immunotherapy.