Gene expression profiling in early breast cancer treated with neoadjuvant ribociclib plus letrozole (R plus L) versus chemotherapy (CT): A correlative analysis of the SOLTI-1402/CORALLEEN phase II trial

In the CORALLEEN trial, R+L achieved similar response rates to multi-agent CT. We present a comprehensive gene expression analysis done before, during, and after therapy to fully characterize the biology behind the primary results of the trial. CORALLEEN was a randomized study in postmenopausal women with stage I-IIIA hormone receptor positive (HR+)/HER2-negative Luminal B breast cancer by PAM50. Patients (pts) received either 6 cycles of R+L or 4 cycles of AC followed by 12 doses of paclitaxel. Primary endpoint was rate of PAM50 Risk of Relapse (ROR) low disease at surgery. Baseline, week 2, and surgical specimens were collected. Expression of 770 genes and 31 signatures were determined using the Breast360TM nCounter-based codeset. Response was defined as ROR-low disease at surgery, relative/absolute changes in ROR between baseline/week 2 and surgery, RCB-0/I or levels of Ki67 at surgery. To identify genes associated with response, a significance of microarrays (SAM) analysis with a false discovery rate (FDR) <5% was performed. A total 297/318 (93.4%) samples were available. No genes or signatures at baseline, or week 2, were found to be associated with response at surgery in each arm. At week 2, 146 (14.6%) genes or signatures were found significantly up-regulated (n=47) and down-regulated (n=99) in the R+L arm compared to CT. R+L induced higher expression of genes related to DNA damage repair and immune activation (e.g. TP53, RAD52, GZMM and CD19) and lower expression of cell-cycle and hormone-related genes (e.g. PGR, CDK1 and MKI67). At surgery, 102 (10.2%) genes or signatures were found significantly up-regulated (n=4) and down-regulated (n=98) in the R+L arm compared to CT. R+L induced higher downregulation of estrogen- and proliferation-related genes and signatures (e.g. PGR, ER signaling, and MKI67). No genes were able to predict response. Compared to CT, R+L induced higher downregulation of proliferation-related genes and signatures at week 2 and surgery. These results support the strategy to use the neoadjuvant setting to select patients who achieve a large molecular downstaging following CDK4/6 inhibition.