Ribociclib plus letrozole alters the blood immune profile in older patients with HR+/HER2- metastatic breast cancer

Authors

  • Yentl Lambrechts Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven, Belgium
  • Sigrid Hatse Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven, Belgium
  • Cindy Kenis Department of General Medical Oncology and Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium - Department of Public Health and Primary Care, Academic Centre for Nursing and Midwifery, KU Leuven, Leuven, Belgium
  • Lore Decoster Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
  • Evandro de Azambuja Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), Brussels, Belgium
  • Patrick Neven Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium
  • Claire Quaghebeur Medical Oncology, UCLouvain, CHU Namur Site Sainte-Elisabeth, Namur, Belgium
  • Frank Cornelis Medical Oncology Department, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc and Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
  • Didier Verhoeven Department of Medical Oncology, AZ KLINA, Brasschaat, University of Antwerp, Antwerp, Belgium
  • Annelore Barbeaux Department of Medical Oncology, CHR Verviers East Belgium, Verviers, Belgium
  • Jeroen Mebis Department of Medical Oncology, Jessa Hospital, Hasselt, Belgium
  • Julie Van Dievel Department of General Medical Oncology and Hematology, Imelda hospital, Bonheiden, Belgium
  • Vincent Verschaeve Department of Medical Oncology, GHDC Grand Hôpital de Charleroi, Charleroi, Belgium
  • Lionel Duck Department of Oncology, Clinique Saint-Pierre, Ottignies, Belgium
  • Eveline De Cuypere Department of Medical Oncology, AZ Sint-Jan Hospital Bruges, Bruges, Belgium
  • Giuseppe Floris Laboratory for Cell and Tissue Translational Research, Department of Imaging and Radiology, KU-Leuven - Department of Pathology, University Hospitals Leuven, Leuven, Belgium
  • Christine Desmedt Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
  • Annouschka Laenen Leuven Biostatistics and Statistical Bioinformatics Center, KU Leuven, Leuven, Belgium
  • Noam Pondé Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
  • Hans Wildiers Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven, Belgium; Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium; Medical Oncology, UCLouvain, CHU Namur Site Sainte-Elisabeth, Namur, Belgium

DOI:

https://doi.org/10.37155/2972-4759-2024-02-01-3

Keywords:

breast cancer, biomarkers, immunity, translational research, Geriatric oncology

Abstract

Background – The combination of CDK4/6 inhibitors and endocrine therapy (ET) is a standard firstline therapy for hormone receptor positive (HR+)/HER2- metastatic breast cancer (mBC). Preliminary data suggest that CDK4/6 inhibitors can 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 on this phenomenon. Material and methods – This biomarker substudy of the RibOB trial (NCT03956654) evaluated the impact of ribociclib and letrozole on circulating immune cell subsets and protein markers in older ( ≥ 70 years) patients with HR+/HER2- mBC. Peripheral blood mononuclear cell subtyping and analysis of plasma immune response and checkpoint markers were performed using flow cytometry at baseline and after three months of ribociclib + ET. Frailty status was assessed at baseline using G8 score. Results – 20 patients (median age: 76 years, range: 70–87 years), 8 considered fit (G8>14), and 12 frail (G8 ≤ 14), were included. After three months of treatment, the immune subset composition showed significant increases in naïve B-, T-regulatory (Tregs), and CD4+ T-cells, while memory B-cells and Tregs were significantly decreased. In addition, consistent upregulation was seen in costimulatory receptors CD27 and CD28. Plasma immune checkpoint markers B7.2 (CD86) and PD-1 were significantly decreased. The immune subset profiles of fit versus frail persons showed no statistically significant difference. Conclusions – The study shows that the combination of ribociclib and ET modulates the immune system in older patients, potentially reversing the age-related immunosenescence process by increasing naïve T-cell and B-cell populations and decreasing memory populations.

References

Derhovanessian E, Solana R, Larbi A, et al. Immunity, ageing and cancer[J]. Immunity & Ageing, 2008, 5: 1-16. https://doi.org/10.1186/1742-4933-5-11

López-Otín C, Blasco M A, Partridge L, et al. The hallmarks of aging[J]. Cell, 2013, 153(6): 1194-1217. https://doi.org/10.1016/j.cell.2013.05.039

Berben L, Floris G, Wildiers H, et al. Cancer and aging: two tightly interconnected biological processes[J]. Cancers, 2021, 13(6): 1400. https://doi.org/10.3390/cancers13061400

López-Otín C, Blasco M A, Partridge L, et al. Hallmarks of aging: An expanding universe[J]. Cell, 2023, 186(2): 243-278. https://doi.org/10.1016/j.cell.2022.11.001

White M C, Holman D M, Boehm J E, et al. Age and cancer risk: a potentially modifiable relationship[J]. American journal of preventive medicine, 2014, 46(3): S7-S15. https://doi.org/10.1016/j.amepre.2013.10.029

Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674. https://doi.org/10.1016/j.cell.2011.02.013

Bailur J K, Pawelec G, Hatse S, et al. Immune profiles of elderly breast cancer patients are altered by chemotherapy and relate to clinical frailty[J]. Breast Cancer Research, 2017, 19: 1-10. https://doi.org/10.1186/s13058-017-0813-x

Freedman R A, Vaz-Luis I, Barry W T, et al. Patterns of chemotherapy, toxicity, and short-term outcomes for older women receiving adjuvant trastuzumab-based therapy[J]. Breast cancer research and treatment, 2014, 145: 491-501. https://doi.org/10.1007/s10549-014-2968-9

Jenkins E O, Deal A M, Anders C K, et al. Age-specific changes in intrinsic breast cancer subtypes: a focus on older women[J]. The oncologist, 2014, 19(10): 1076-1083. https://doi.org/10.1634/theoncologist. 2014-0184

Argyriou A A, Polychronopoulos P, Koutras A, et al. Is advanced age associated with increased incidence and severity of chemotherapy-induced peripheral neuropathy?[J]. Supportive Care in Cancer, 2006, 14: 223-229. https://doi.org/10.1007/s00520-005-0868-6

Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology[J]. The lancet oncology, 2007, 8(12): 1101-1115. https://doi.org/10.1016/S1470-2045(07)70378-9

Hortobagyi G N, Stemmer S M, Burris H A, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer[J]. New England journal of medicine, 2016, 375(18): 1738-1748. https://doi.org/10.1056/NEJMoa1609709

Hortobagyi G N, Stemmer S M, Burris H A, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer[J]. Annals of Oncology, 2018, 29(7): 1541-1547. https://doi.org/10.1093/annonc/mdy155

Tripathy D, Im S A, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial[J]. The lancet oncology, 2018, 19(7): 904-915. https://doi.org/10.1016/S1470-2045(18)30292-4

Goetz M P, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer[J]. J clin oncol, 2017, 35(32): 3638-3646. https://doi.org/10.1200/JCO.2017.75.6155

Goel S, DeCristo M J, Watt A C, et al. CDK4/6 inhibition triggers anti-tumour immunity[J]. Nature, 2017, 548(7668): 471-475. https://doi.org/10.1038/nature23465

Braal C L, Jongbloed E M, Wilting S M, et al. Inhibiting CDK4/6 in breast cancer with palbociclib, ribociclib, and abemaciclib: similarities and differences[J]. Drugs, 2021, 81: 317-331. https://doi.org/10.1007/s40265-020-01461-2

Sonke G S, Hart L L, Campone M, et al. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial[J]. Breast cancer research and treatment, 2018, 167: 659-669. https://doi.org/10.1007/s10549-017-4523-y

Battisti N M L, De Glas N, Sedrak M S, et al. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper[J]. Therapeutic Advances in Medical Oncology, 2018, 10: 1758835918809610. https://doi.org/10.1177/1758835918809610

Howie L J, Singh H, Bloomquist E, et al. Outcomes of older women with hormone receptor–positive, human epidermal growth factor receptor–negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: An FDA pooled analysis[J]. Journal of Clinical Oncology, 2019, 37(36): 3475-3483. https://doi.org/10.1200/JCO.18.02217

Deng J, Wang E S, Jenkins R W, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation[J]. Cancer discovery, 2018, 8(2): 216-233. https://doi.org/10.1158/2159-8290.CD-17-0915

Berben L, Floris G, Kenis C, et al. Age‐related remodelling of the blood immunological portrait and the local tumor immune response in patients with luminal breast cancer[J]. Clinical & translational immunology, 2020, 9(10): e1184. https://doi.org/10.1002/cti2.1184

Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Journal of Clinical Oncology,2018, 36(20):2105-2122. https://doi.org/10.1200/JCO.2018.77.8738 PMID: 29846122.

Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations[J]. Annals of Oncology, 2015, 26(2): 288-300. https://doi.org/10.1093/annonc/mdu210

Kenis C, Decoster L, Van Puyvelde K, et al. Performance of two geriatric screening tools in older patients with cancer[J]. J Clin Oncol, 2014, 32(1): 19-26. https://doi.org/ 10.1200/JCO.2013.51.1345

Bellera C A, Rainfray M, Mathoulin-Pélissier S, et al. Screening older cancer patients: first evaluation of the G-8 geriatric screening tool[J]. Annals of Oncology, 2012, 23(8): 2166-2172. https://doi.org/10.1093/annonc/mdr587

Saatci O, Huynh-Dam K T, Sahin O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies[J]. Journal of Molecular Medicine, 2021, 99(12): 1691-1710. https://doi.org/10.1007/s00109-021-02136-5

Hanker A B, Sudhan D R, Arteaga C L. Overcoming endocrine resistance in breast cancer[J]. Cancer cell, 2020, 37(4): 496-513. https://doi.org/10.1016/j.ccell.2020.03.009

Koch S, Larbi A, Derhovanessian E, et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people[J]. Immunity & Ageing, 2008, 5: 1-12. https://doi.org/10.1186/1742-4933-5-6

Elyahu Y, Hekselman I, Eizenberg-Magar I, et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes[J]. Science advances, 2019, 5(8): eaaw8330. https://doi.org/10.1126/sciadv.aaw8330

Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?[J]. Frontiers in immunology, 2018, 8: 328099. https://doi.org/10.3389/fimmu.2017.01960

Chen L, Flies D B. Molecular mechanisms of T cell co-stimulation and co-inhibition[J]. Nature reviews immunology, 2013, 13(4): 227-242. https://doi.org/10.1038/nri3405

Khan M, Arooj S, Wang H. Soluble B7-CD28 family inhibitory immune checkpoint proteins and anti-cancer immunotherapy[J]. Frontiers in Immunology, 2021, 12: 651634. https://doi.org/10.3389/fimmu.2021.651634

Oner G, Altintas S, Canturk Z, et al. The immunologic aspects in hormone receptor positive breast cancer[J]. Cancer Treatment and Research Communications, 2020, 25: 100207. https://doi.org/10.1016/j.ctarc.2020.100207

Criscitiello C, Curigliano G. Immunotherapy of breast cancer[J]. Immuno-Oncology, 2015, 42: 30-43. https://doi.org/10.1159/000437183

Bailly C, Thuru X, Quesnel B. Soluble programmed death ligand-1 (sPD-L1): a pool of circulating proteins implicated in health and diseases[J]. Cancers, 2021, 13(12): 3034. https://doi.org/10.3390/cancers13123034

Scirocchi F, Scagnoli S, Botticelli A, et al. Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: relief from immunosuppression is associated with clinical response[J]. EBioMedicine, 2022, 79:104010. https://doi.org/10.1016/j.ebiom.2022.104010

Wildiers H, Highley M S, de Bruijn E A, et al. Pharmacology of anticancer drugs in the elderly population[J]. Clinical pharmacokinetics, 2003, 42: 1213-1242. https://doi.org/10.2165/00003088-200342140-00003

Huang H, Zhou J, Chen H, et al. The immunomodulatory effects of endocrine therapy in breast cancer[J]. Journal of Experimental & Clinical Cancer Research, 2021, 40: 1-16. https://doi.org/10.1186/s13046-020-01788-4

Sellegounder D, Ferrucci L, Anbazhagan R, et al. Molecular crosstalk between endocrine factors, paracrine signals, and the immune system during aging[J]. Frontiers in Endocrinology, 2023, 14: 1203755. https://doi.org/10.3389/fendo.2023.1203755

Sonke G S, Van Ommen-Nijhof A, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Journal of Clinical Oncology, 2023. 41(17_suppl): p. LBA1000-LBA1000. https://doi.org/10.1200/JCO.2023.41.17_suppl.LBA1000

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Published

2024-05-24

Issue

Vol. 2 No. 1 (2024): Vol 2 No 1 (2024)

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Original Research Article

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Copyright (c) 2024 Yentl Lambrechts, Sigrid Hatse, Cindy Kenis, Lore Decoster, Evandro de Azambuja, Patrick Neven, Claire Quaghebeur, Frank Cornelis, Didier Verhoeven, Annelore Barbeaux, Jeroen Mebis, Julie Van Dievel, Vincent Verschaeve, Lionel Duck, Eveline De Cuypere, Giuseppe Floris, Christine Desmedt, Annouschka Laenen, Noam Pondé, Hans Wildiers

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