Abstract P4-01-29: Ribociclib plus letrozole alters the immune subset composition in older (≥70 yrs.) patients with HR+/HER2- metastatic breast cancer
Authors: Lambrechts Yentl , Hatse Sigrid , Kenis Cindy , Decoster Lore , de Azambuja Evandro , Jerusalem Guy , Neven Patrick , Lago Lissandra Dal , Denys Hannelore , Vuylsteke Peter , Cornelis Frank , Punie Kevin , Floris Giuseppe , Desmedt Christine , Laenen Annouschka , Pondé Noam , Wildiers Hans 
Published: March 2023

Abstract
Background The combination of CDK4/6 inhibitors and endocrine therapy is the current standard first-line therapy for patients with HR+/HER2- metastatic breast cancer (mBC). Preliminary data suggest that CDK4/6 inhibitors not only induce tumor response by blocking CDK-dependent cell growth but that they can also alter the host immune function and stimulate tumor cell-directed immunity. However, clinical data are scarce, and no data exist about the impact of age and frailty, which are known to impact host immunity (immunosenescence). Materials and methods This prospective ongoing study is evaluating the efficacy and toxicity of the CDK4/6 inhibitor ribociclib and letrozole in older (≥ 70 years) patients with HR+/HER2- mBC (RIBOB, NCT03956654). In the associated blood biomarker sub-study, we investigate the impact of ribociclib and letrozole on the immune subset composition. Immune cell subsets were analyzed using flowcytometry (BD FACSVerse™) of peripheral blood mononuclear cells isolated at baseline (before ribociclib administration) and after three months of ribociclib treatment. In total, six multicolor flow cytometry staining panels were set up to investigate the changes in the immune cell subsets (CD4+ T-cell subsets, CD8+ T-cell subsets, general immune cell subsets, T-regulatory cell subsets, T-cell activation status subsets, and myeloid-derived suppressor cells subsets). Frailty status was assessed at baseline using the G8 screening tool (range score: 0-17) as a proxy. The paired t-test and matched-pairs Wilcoxon signed-rank test are used to evaluate changes in immune subset composition between baseline and after three months. The unpaired t-test and Mann-Whitney U test are used to evaluate differences in immune subset composition between frail and fit patients. Results Immune cell subset distribution and evolution were available for 15 older patients (median age: 77 yrs.; IQR 74-83), 4 considered fit (G8-score &gt;14), and 11 frail (G8-score ≤14). Firstly, we analyzed the difference in immune subset composition between baseline and three months for the whole cohort. There was a significant increase of naïve T-regulatory cells (p=0.0012) and a significant increase in CD8+ T-cell activation indicated by an upregulation of HLA-DR+ (p=0.0055) and CD38+ (p=0.0203). Secondly, the difference in immune subset composition between fit and frail persons was assessed showing a lower activation status of CD4+ and CD8+ T-cell subsets in frail persons at baseline, as assessed by several activation markers: CD4+PD1+ (p=0.0051), CD4+PD1+CD69+ (p=0.0013), CD8+PD1+ (p=0.0073), and CD8+PD1+CD69+ (p=0.0339). These significant differences between fit and frail disappeared after three months, largely because of increased T-cell activation in the frail subset. Conclusion Ribociclib plus letrozole treatment for three months results in an upregulation of the T-regulatory cells’ naïve subset, suggesting an expansion of the T-cell repertoire, which is compatible with immune cell activation. Furthermore, the activation status of the CD8+ T-cells was upregulated. These observations confirm recent findings reported by Scirocchi F. et al. (Lancet, 2022). In addition, frail older patients show a lower baseline T-cell activation status compared to fit older patients but seem to have increased T-cell activation after treatment exposure. In the future, correlations with treatment response will be evaluated when follow-up data matures. Our data encourage the further assessment of immune cell modulation in combination with CDK4/6 inhibitors in the treatment of patients with metastatic breast cancer.
Citation Format: Yentl Lambrechts, Sigrid Hatse, Cindy Kenis, Lore Decoster, Evandro de Azambuja, Guy Jerusalem, Patrick Neven, Lissandra Dal Lago, Hannelore Denys, Peter Vuylsteke, Frank Cornelis, Kevin Punie, Giuseppe Floris, Christine Desmedt, Annouschka Laenen, Noam Pondé, Hans Wildiers. Ribociclib plus letrozole alters the immune subset composition in older (≥70 yrs.) patients with HR+/HER2- metastatic breast cancer [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 P4-01-29.