bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022‒01‒02
two papers selected by
Piotr Okupski
  1. Updated Overall Survival of Ribociclib Plus Endocrine Therapy vs Endocrine Therapy Alone in Pre- and Perimenopausal Patients With HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.
  2. Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer-findings from the RIBECCA trial.
  1. Clin Cancer Res. 2021 Dec 29. pii: clincanres.3032.2021. [Epub ahead of print]
    Updated Overall Survival of Ribociclib Plus Endocrine Therapy vs Endocrine Therapy Alone in Pre- and Perimenopausal Patients With HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.
    Yen-Sen Lu, Seock-Ah Im, Marco Colleoni, Fabio Franke, Aditya Bardia, Fatima Cardoso, Nadia Harbeck, Sara Hurvitz, Louis Chow, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Rafael Villanueva Vazquez, Kyung Hae Jung, K Govind Babu, Paul Wheatley-Price, Michelino De Laurentiis, Young-Hyuck Im, Sherko Kuemmel, Nagi El-Saghir, Ruth O'Regan, Claudia Gasch, Nadia Solovieff, Craig Wang, Yongyu Wang, Arunava Chakravartty, Yan Ji, Debu Tripathy.
      PURPOSE: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase 3 MONALEESA-7 trial of pre-/perimenopausal patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).PATIENTS AND METHODS: Patients were randomized to receive ET (goserelin plus nonsteroidal aromatase inhibitor [NSAI] or tamoxifen) with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods.
    RESULTS: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo (HR, 0.76; 95% CI, 0.61-0.96). Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged <40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of CDK4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI.
    CONCLUSIONS: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged <40 years, with HR+/HER2- ABC with 53.5 months of median follow-up. (ClinicalTrials.gov, NCT02278120).
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3032
  2. Eur J Cancer. 2021 Dec 22. pii: S0959-8049(21)01245-4. [Epub ahead of print]162 45-55
    Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer-findings from the RIBECCA trial.
    Caroline A Peuker, Sarvenaz Yaghobramzi, Corinna Grunert, Luisa Keilholz, Enio Gjerga, Steffen Hennig, Sigrid Schaper, Il-Kang Na, Ulrich Keller, Sara Brucker, Thomas Decker, Peter Fasching, Tanja Fehm, Wolfgang Janni, Sherko Kümmel, Andreas Schneeweiss, Martin Schuler, Diana Lüftner, Antonia Busse.
      BACKGROUND: Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies.METHODS: Here, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib.
    RESULTS: Gene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients.
    CONCLUSIONS: We show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer.
    Keywords:  Adaptive immunity; Breast cancer; CDK4/6 inhibitors; Immunomodulation; Ribociclib
    DOI:  https://doi.org/10.1016/j.ejca.2021.11.025
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