Abstract PD17-07: Cell-Cycle Inhibition and Immune Microenvironment in HR+/HER2- Breast Cancer During and After preoperative ribociclib and letrozole vesus chemotherapy: A correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial
Authors: Pascual Tomás , Chic Nuria , Fernandez-Martinez Aranzazu , González-Farré Blanca , Paré Laia , Saura Cristina , Hernando Cristina , Muñoz Montserrat , Arumí Míriam , Galván Patricia , Gonzalez-Farré Xavier , Oliveira Mafalda , Gil Miguel Gil , Ciruelos Eva , Villagrasa Patricia , Gregori Joaquin Gavila , Prat Aleix , Perou Charles M. 
Published: March 2023

Abstract
Background Hormone receptor–positive/HER2-negative (HR+/HER2-) breast cancer (BC) is associated with low % of stromal tumor-infiltrating lymphocytes (sTIL) and immune gene expression and poor response to immune checkpoint inhibitors. Evaluating the effect of letrozole and ribociclib (L+R) on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches for HR+/HER2- BCs. Here, we present an exploratory correlative analysis from CORALLEEN, a trial that evaluated the efficacy of L+R (vs. chemotherapy [CHT]) in patients with high-risk PAM50 Luminal B BC (Prat et al. Lancet Oncology. 2022). Methods CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, HR+/HER2- and Luminal B by Prosigna®. Patients were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole or CHT: 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint was the rate of PAM50 Risk of Relapse (ROR)-low score at surgery in each arm. Samples were prospectively collected at baseline, day 15, and surgery. sTILs score, ki67 IHC and gene expression analysis were determined in all available samples. Complete cell cycle arrest (CCCA) was defined as Ki67≤2.7%. Gene expression profiling by mRNA sequencing (RNAseq) was evaluated. We applied a collection of 194 immune- gene expression signatures (iGES), representing multiple biological pathways and cell types, including. Results 106 patients were randomly assigned to receive neoadjuvant L+R (n=52) or CTH (n=54). Overall, Ki67, sTILs and RNA-seq was available in 95.4%, 96.7% and 83.1% of the samples across the 3 time-points. In terms of cell-cycle inhibition, L+R achieved a significant decrease in Ki67 protein expression and led to higher rates of CCCA at 2 weeks (89.6% vs. 43.2%, p&lt; 0.001) and surgery (45.9% vs 25.5%, P=0.054) compared with CHT. Interestingly, the 11-gene PAM50 proliferative score was significantly lower in tumors with CCAA than in those with non-CCCA (p&lt; 0.001) after L+R, but not after CTH (p = 0.682). In contrast, tumors with CCCA after CHT had a significantly lower rate of tumor cellularity compared to tumors with non-CCAA (p = 0.002). This was not observed in the L+R arm (p=0.141). Compared to baseline, no clear and significant patterns in % of sTILs were observed at week 2 and surgery. However, % of TILs at surgery in tumors with CCCA after CHT was higher than in tumors with non-CCCA (median 15% versus 1%, p=0.017). This was not observed in the L+R arm (median 1% and 5%, p=0.584). Interestingly, this inverse relationship between immune infiltration and CCAA was further confirmed by RNA- CHT compared to tumors with non-CCCA, whereas 174 (89.7%) of iGES were upregulated (FDR&lt; 5%) in tumors with non-CCCA after L+R compared to tumors with CCCA. Finally, L+R and CTH treatment at week 2 and surgery showed an increase in adaptive immune signatures indicative of activated T-cell and B-cell phenotypes; however, CTH was uniquely associated with increased cytokine signaling, enhanced antigen presentation, dendritic, granulocyte, macrophage and NK cells and decrease in Th17, Th2 and Treg cells. Conclusion In early-stage Luminal B breast cancer, L+R induce a potent anti-proliferative effect compared to CHT. Both treatments generally increased T- and B-cell immune infiltration; however, an inverse relationship between immune infiltration and anti-proliferative response at surgery exists according to treatment, where immune infiltration is increased in residual tumors with non-CCAA when treated with L+R, but the opposite is observed with CHT. The prognostic value of immune and anti-proliferative effects of L+R in residual tumors is currently being evaluated in the prospective RIBOLARIS phase II clinical trial (NCT05296746).
Citation Format: Tomás Pascual, Nuria Chic, Aranzazu Fernandez-Martinez, Blanca González-Farré, Laia Paré, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Míriam Arumí, Patricia Galván, Xavier Gonzalez-Farré, Mafalda Oliveira, Miguel Gil Gil, Eva Ciruelos, Patricia Villagrasa, Joaquin Gavila Gregori, Aleix Prat, Charles M. Perou. Cell-Cycle Inhibition and Immune Microenvironment in HR+/HER2- Breast Cancer During and After preoperative ribociclib and letrozole vesus chemotherapy: A correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-07.