CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Oncology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy

Division of Medical Oncology, Fatebenefratelli San Pietro Hospital, 00189 Rome, Italy

Medical Oncology Unit B, Policlinico Umberto I, 00161 Rome, Italy

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Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy

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Department of Medical Oncology, Catholic University of Sacred Heart, 00168 Rome, Italy

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Medical Oncology, Sandro Pertini Hospital, 00157 Rome, Italy

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Medical Oncology Unit, Belcolle Hospital, 01100 Viterbo, Italy

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Phase 1 Unit and Pre+cision Medicine, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy

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Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy

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San Giovanni Addolorata Hospital, 00184 Rome, Italy

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Department of Oncology, University Campus Biomedico of Rome, 00155 Rome, Italy

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Medical Oncology Unit, Department of Systems Medicine, Tor Vergata Clinical Center University Hospital, 00133 Rome, Italy

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Medical Oncology, S.M. Goretti Hospital, 04100 Latina, Italy

¹⁴

Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00185 Rome, Italy

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Cancers 2021, 13(2), 332; https://doi.org/10.3390/cancers13020332

Received: 14 December 2020 / Revised: 7 January 2021 / Accepted: 12 January 2021 / Published: 18 January 2021

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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Simple Summary

The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to endocrine therapy have remarkably improved the outcome of patients with HR+ advanced breast cancer. However, some points of reflections are still undiscussed. To answer these questions, we revised the mechanism of action of CDK4-6 inhibitors, clinical data available from pivotal studies, and summarized potential future strategies to overcome resistance to CDK4-6 inhibitors, thus improving patient’s survival.

Abstract

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC. View Full-Text

Keywords: CDK4/6 inhibitors; breast cancer; endocrine therapy (ET); advanced breast cancer (ABC); endocrine resistance

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MDPI and ACS Style

Roberto, M.; Astone, A.; Botticelli, A.; Carbognin, L.; Cassano, A.; D’Auria, G.; Fabbri, A.; Fabi, A.; Gamucci, T.; Krasniqi, E.; Minelli, M.; Orlandi, A.; Pantano, F.; Paris, I.; Pizzuti, L.; Portarena, I.; Salesi, N.; Scagnoli, S.; Scavina, P.; Tonini, G.; Vici, P.; Marchetti, P. CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives. Cancers 2021, 13, 332. https://doi.org/10.3390/cancers13020332

AMA Style

Roberto M, Astone A, Botticelli A, Carbognin L, Cassano A, D’Auria G, Fabbri A, Fabi A, Gamucci T, Krasniqi E, Minelli M, Orlandi A, Pantano F, Paris I, Pizzuti L, Portarena I, Salesi N, Scagnoli S, Scavina P, Tonini G, Vici P, Marchetti P. CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives. Cancers. 2021; 13(2):332. https://doi.org/10.3390/cancers13020332

Chicago/Turabian Style

Roberto, Michela, Antonio Astone, Andrea Botticelli, Luisa Carbognin, Alessandra Cassano, Giuliana D’Auria, Agnese Fabbri, Alessandra Fabi, Teresa Gamucci, Eriseld Krasniqi, Mauro Minelli, Armando Orlandi, Francesco Pantano, Ida Paris, Laura Pizzuti, Ilaria Portarena, Nello Salesi, Simone Scagnoli, Paola Scavina, Giuseppe Tonini, Patrizia Vici, and Paolo Marchetti. 2021. "CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives" Cancers 13, no. 2: 332. https://doi.org/10.3390/cancers13020332

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CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

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