Preoperative Ribociclib and Letrozole versus Chemotherapy in HR-Positive/HER2-Negative Breast Cancer: Findings from a Correlative Analysis of the Phase 2 1402-SOLTI/CORALLEEN Trial Study

HR-positive/HER2-negative breast cancer is associated with a low percentage of stromal tumor infiltrating lymphocytes (sTILs), low immune gene expression, and poor response to immune checkpoint inhibition. Investigating the effect of letrozole and ribociclib on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches for HR-positive/HER2-negative breast cancer. The CORALLEEN trial, a randomized, exploratory study, evaluated the efficacy of ribociclib plus letrozole in patients with operable stage I-III, high-risk PAM50, luminal B breast cancer (per Prosigna®).

Patients were randomized 1:1 to receive either 6 cycles of ribociclib (600 mg; 3 weeks on/1 week off) plus daily letrozole or chemotherapy (CT): 4 cycles of doxorubicin and cyclophosphamide followed by 12 doses of weekly paclitaxel. The primary end point was rate of PAM50 Risk of Relapse–low score at surgery in each arm. Samples were collected at baseline, day 15, and at the time of surgery. sTILs score, Ki67 immunohistochemistry, and gene expression analysis were determined. Complete cell cycle arrest (CCCA) was defined as Ki67 ≤2.7%. Gene expression profiling by mRNA sequencing was evaluated, with a collection of 194 immune-gene expression signatures, representing multiple biological pathways and cell types.

Of 106 patients, 52 received neoadjuvant letrozole plus ribociclib and 54 received CT. Compared to CT, letrozole plus ribociclib achieved a significant decrease in Ki67 protein expression and led to increased rates of CCCA at 2 weeks (89.6% vs 43.2%, P <.001) and at the time of surgery (45.9% vs 25.5%, P = .054). The 11-gene PAM50 proliferative score was significantly lower in tumors with CCCA than in those without CCCA (P <.001) after letrozole plus ribociclib, but not after CT. Tumors with CCCA after CT had a significantly lower rate of tumor cellularity compared to tumors without CCCA (P = .002); this was not observed in the letrozole plus ribociclib arm (P = .141). Percentage of TILs at the time of surgery in tumors with CCCA after CT was higher than in tumors without CCCA (median, 15% vs 1%; P = .017); however, this was not observed in the letrozole plus ribociclib arm (median, 1% vs 5%; P = .584). Letrozole plus ribociclib and CT treatment at week 2 and at the time of surgery showed an increase in adaptive immune signatures indicative of activated T- and B-cell phenotypes; however, CT was uniquely associated with increased cytokine signaling, enhanced antigen presentation, and decreases in Th17, Th2, and Treg cells.

Investigators concluded that, in early-stage luminal B breast cancer, letrozole plus ribociclib induced a potent antiproliferative effect compared to CT. Both treatments increased T- and B-cell immune infiltration; however, an inverse relationship existed between immune infiltration and antiproliferative response at surgery according to treatment, where immune infiltration was increased in residual tumors without CCCA when treated with letrozole plus ribociclib, whereas the opposite was observed with CT. The prognostic value of the immune and antiproliferative effects of ribociclib plus letrozole in residual tumors is actively being assessed in the prospective RIBOLARIS phase 2 clinical trial (NCT0529746).


Pascual T, Chic N, Fernandez-Martinez A, et al. Cell-cycle inhibition and immune microenvironment in HR+/HER2- breast cancer during and after preoperative ribociclib and letrozole versus chemotherapy: a correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial. San Antonio Breast Cancer Symposium 2022. Abstract PD17-07.

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