Palbociclib: randomisierte Studien und Real-World-Evidenz als Grundlage für die Therapieplanung beim metastasierten Mammakarzinom

Zusammenfassung

Die endokrin basierte Kombinationstherapie mit einem Inhibitor der cyclinabhängigen Kinasen 4 und 6 (CDK4/6-Inhibitor) gilt heute als Erstlinientherapie der ersten Wahl für Patientinnen und Patienten mit hormonrezeptorpositivem (HR+) und humaner epidermaler Wachstumsfaktor-Rezeptor 2 (HER2)-negativem lokal fortgeschrittenem bzw. metastasiertem Mammakarzinom (mBC). Wirksamkeit und Sicherheit einer Behandlung mit Palbociclib, dem ersten in dieser Indikation zugelassenen CDK4/6-Inhibitor, wurden in großen randomisierten, kontrollierten klinischen Studien (RCTs) mit streng definierten Patientinnenkollektiven belegt. Seither wurden zahlreiche relevante Fragen zur CDK4/6-Inhibition mit Palbociclib beim mBC in RCTs und Real-World-Evidenz-Erhebungen untersucht. Auf dem Boden dieser Evidenz wird Palbociclib im klinischen Alltag aufgrund der Wirksamkeit und der guten Verträglichkeit seit vielen Jahren breit eingesetzt.
Ziel des vorliegenden Reviews ist es, Ergebnisse aus RCTs einerseits und RWE andererseits unter klinisch bedeutsamen Gesichtspunkten wie Sicherheit, Verträglichkeit, Lebensqualität und Wirksamkeit mit dem Blick auf spezifische Fragestellungen und Patientencharakteristika zusammenzufassen. Die kritische Diskussion und Übersicht zur Gesamtevidenz der endokrin basierten Therapie mit dem CDK4/6-Inhibitor Palbociclib soll dazu beitragen, Therapieentscheidungen im klinischen Alltag zu stützen.

Abstract

Endocrine-based combination therapy with an inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6 inhibitors) is currently the first-line therapy of choice for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−), locally advanced or metastatic breast cancer (mBC). The efficacy and safety of the treatment with palbociclib, the first CDK4/6 inhibitor approved for this indication, have been confirmed in large randomized controlled clinical trials (RCTs) with strictly defined patient cohorts. Since then, many relevant questions about CDK4/6 inhibition with palbociclib for mBC have been investigated in RCTs and real-world studies. Based on this evidence, palbociclib is widely used in clinical practice since many years because of its efficacy and good tolerability.
The aim of this review is to summarize findings from RCTs and RWE considering clinically relevant aspects such as safety, tolerability, quality of life and efficacy with a focus on specific questions and patient characteristics. A critical discussion and review of the overall evidence for endocrine-based therapy with the CDK4/6 inhibitor palbociclib can contribute to support therapy decisions in daily clinical practice.

Schlüsselwörter

metastasiertes Mammakarzinom - CDK4/6-Inhibition - Palbociclib - Real-World-Evidenz

Keywords

metastatic breast cancer - CDK4/6 inhibition - palbociclib - real-world evidence

Publication History

Received: 19 April 2024

Accepted: 11 June 2024

Article published online:
11 June 2025

• Literatur

• 1 Mertz S, Benjamin C, Girvalaki C. et al. Progression-free survival and quality of life in metastatic breast cancer: The patient perspective. Breast 2022; 65: 84-90
• 2 Harbeck N, Penault-Llorca F, Cortes J. et al. Breast cancer. Nat Rev Dis Primers 2019; 5: 66
• 3 Leitlinienprogramm Onkologie. Interdisziplinäre S3-Leitlinie für die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms. Langversion 4.4 – Juni 2021. Office des Leitlinienprogrammes Onkologie. 2021 Accessed October 12, 2023 at: https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Mammakarzinom_4_0/Version_4.4/LL_Mammakarzinom_Langversion_4.4.pdf
• 4 Howlader N, Altekruse SF, Li CI. et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 2014; 106: dju055
• 5 Pfizer. Fachinformation. Ibrance®. 2023 Accessed October 12, 2023 at: https://www.fachinfo.de/pdf/022953
• 6 Novartis. Fachinformation. Kisquali®. 2023 Accessed October 12, 2023 at: https://www.fachinfo.de/pdf/021677
• 7 Lilly. Fachinformation. Verzenios®. 2023 Accessed October 12, 2023 at: https://www.fachinfo.de/pdf/022221
• 8 Engler T, Fasching PA, Luftner D. et al. Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients – Data from the Real-World Registry PRAEGNANT. Geburtshilfe Frauenheilkd 2022; 82: 1055-1067
• 9 Harbeck N, Bartlett M, Spurden D. et al. CDK4/6 inhibitors in HR+/HER2− advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies. Future Oncol 2021; 17: 2107-2122
• 10 Cristofanilli M, Turner NC, Bondarenko I. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17: 425-439
• 11 Finn RS, Crown JP, Lang I. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16: 25-35
• 12 Finn RS, Martin M, Rugo HS. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375: 1925-1936
• 13 Hortobagyi GN, Stemmer SM, Burris HA. et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375: 1738-1748
• 14 Slamon DJ, Neven P, Chia S. et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 2018; 36: 2465-2472
• 15 Tripathy D, Im SA, 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. Lancet Oncol 2018; 19: 904-915
• 16 Goetz MP, Toi M, Campone M. et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35: 3638-3646
• 17 Sledge GW jr., Toi M, Neven P. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 2017; 35: 2875-2884
• 18 Finn RS, Boer K, Bondarenko I. et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat 2020; 183: 419-428
• 19 Slamon DJ, Dieras V, Rugo HS. et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol 2024; 42: 994-1000
• 20 Turner NC, Slamon DJ, Ro J. et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379: 1926-1936
• 21 Cristofanilli M, Rugo HS, Im SA. et al. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study. Clin Cancer Res 2022; 28: 3433-3442
• 22 Rugo HS, Finn RS, Diéras V. et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 2019; 174: 719-729
• 23 Xu BH, Hu XC, Li W. et al. Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4. Eur J Cancer 2022; 175: 236-245
• 24 Llombart-Cussac A, Perez-Garcia JM, Bellet M. et al. Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 2021; 7: 1791-1799
• 25 Llombart-Cussac A, Perez-Garcia JM, Bellet M. et al. PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs letrozole and palbociclib in the PARSIFAL study. Cancer Res 2024;
• 26 Park YH, Kim TY, Kim GM. et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15–10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2019; 20: 1750-1759
• 27 Sonke GS, 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). J Clin Oncol 2023;
• 28 Martin M, Zielinski C, Ruiz-Borrego M. et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer 2022; 168: 12-24
• 29 Martin M, Zielinski C, Ruiz-Borrego M. et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol 2021; 32: 488-499
• 30 Kogawa T, Noguchi E, Yamanaka T. et al. Palbociclib (P) plus tamoxifen (TAM) ± goserelin in women with hormone receptorpositive (HR+)/HER2-negative (HER2−) advanced breast cancer (ABC): Primary results of NCCH1607/PATHWAY, an Asian international double-blind randomized phase 3 trial. J Clin Oncol 2023;
• 31 Bidard FC, Hardy-Bessard AC, Dalenc F. et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2022; 23: 1367-1377
• 32 Cabel L, Delaloge S, Hardy-Bessard A-C. et al. Dynamics and type of ESR1 mutations under aromatase inhibitor or fulvestrant combined with palbociclib after randomization in the PADA-1 trial. J Clin Oncol 2023;
• 33 Harbeck N, Fasching PA, Wuerstlein R. et al. Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HRD HER2L metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial. Ann Oncol 2023; 34: 660-669
• 34 Harbeck N, Fasching PA, Wuerstlein R. et al. CANKADO PRO-React eHealth support in patients with HR+HER2− metastatic breast cancer receiving palbociclib and endocrine therapy and the affect on time to deterioration of quality of life: Primary outcome analysis of the multicenter randomized PreCycle trial. J Clin Oncol 2023;
• 35 DeMichele A, Cristofanilli M, Brufsky A. et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2− metastatic breast cancer in US real-world clinical practice. Breast Cancer Res 2021; 23: 37
• 36 Rugo HS, Brufsky A, Liu X. et al. Real-world study of overall survival with palbociclib plus aromatase inhibitor in HR+/HER2− metastatic breast cancer. NPJ Breast Cancer 2022; 8: 114
• 37 Goyal RK, Chen H, Abughosh SM. et al. Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer in the United States: A SEER-Medicare population-based study. Cancer 2023; 129: 1051-1063
• 38 Trapani D, Mayer EL. What’s the reality for CDK4/6 inhibitors: Clinical trials or real-world evidence?. Cancer 2023; 129: 986-988
• 39 Ha MJ, Singareeka Raghavendra A, Kettner NM. et al. Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2− metastatic breast cancer patients compared to endocrine therapy alone in the second-line setting: A large institutional study. Int J Cancer 2022; 150: 2025-2037
• 40 El Badri S, Tahir B, Balachandran K. et al. Palbociclib in combination with aromatase inhibitors in patients ≥ 75 years with oestrogen receptor-positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A real-world multicentre UK study. Breast 2021; 60: 199-205
• 41 Taylor-Stokes G, Mitra D, Waller J. et al. Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: Results from the IRIS study. Breast 2019; 43: 22-27
• 42 Mycock K, Zhan L, Taylor-Stokes G. et al. Real-World Palbociclib Use in HR+/HER2− Advanced Breast Cancer in Canada: The IRIS Study. Curr Oncol 2021; 28: 678-688
• 43 Mycock K, Zhan L, Hart K. et al. Real-world treatment of patients with palbociclib for HR+/HER2− advanced/metastatic breast cancer: the Europe IRIS study. Future Oncol 2022; 18: 349-362
• 44 Richardson D, Zhan L, Mahtani R. et al. A prospective observational study of patient-reported functioning and quality of life in advanced and metastatic breast cancer utilizing a novel mobile application. Breast Cancer Res Treat 2021; 187: 113-124
• 45 Lux MP, Runkel ED, Glastetter E. et al. PERFORM: a non-interventional study assessing the patients’ treatment starting with 1 L palbociclib in HR+/HER2− ABC. Future Oncol 2022; 18: 3971-3982
• 46 Radosa JC, Fietz T, Wilke J. et al. Palbociclib plus endocrine therapy in HR+/HER2− advanced breast cancer patients: Interim results of the PERFORM study. Ann Oncol 2023; 34: S353-S354
• 47 Brain E, Pulido M, Paillaud E. et al. Feasibility of palbociclib in women aged 70 and older with resistant and/or pretreated advanced breast cancer in the PALOMAGE study. Cancer Res 2022; 82
• 48 Caillet P, Pulido M, Brain E. et al. PALOMAGE, a French real-world cohort of elderly women beyond age 70 with advanced breast cancer receiving palbociclib: Baseline characteristics and safety evaluation. J Clin Oncol 2021; 39
• 49 Carola E, Pulido M, Falandry C. et al. First-line systemic treatment with palbociclib in women aged ≥ 70 years presenting with hormone receptor-positive advanced breast cancer: Results from the PALOMAGE program. J Clin Oncol 2023;
• 50 Goetz MT, Toi M, Huober J. et al. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2− advanced breast cancer. Cancer Res 2024;
• 51 Hortobagyi GN, Stemmer SM, Burris HA. et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022; 386: 942-950
• 52 Berger F, Marce M, Delaloge S. et al. Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1. BMJ Open 2022; 12: e055821
• 53 Carausu M, Bidard FC, Callens C. et al. ESR1 mutations: a new biomarker in breast cancer. Expert Rev Mol Diagn 2019; 19: 599-611
• 54 Brett JO, Spring LM, Bardia A. et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021; 23: 85
• 55 Lee S, Im SA, Kim GM. et al. Patient-Reported Outcomes of Palbociclib Plus Exemestane with GnRH Agonist versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer: A Prospective, Open-Label, Randomized Phase ll Trial (KCSG-BR 15–10). Cancers (Basel) 2020; 12: 3265
• 56 Kahan Z, Gil-Gil M, Ruiz-Borrego M. et al. Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive metastatic breast cancer: Patient-reported outcomes in the PEARL study. Eur J Cancer 2021; 156: 70-82
• 57 Rugo HS, Diéras V, Gelmon KA. et al. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol 2018; 29: 888-894
• 58 Harbeck N, Iyer S, Turner N. et al. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol 2016; 27: 1047-1054
• 59 Finn RS, Rugo HS, Gelmon KA. et al. Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up. Oncologist 2021; 26: E749-E755
• 60 Karuturi MS, Rocque GB, Cappelleri JC. et al. Real-world quality of life (QoL) in patients with hormone receptor-positive (HR plus), human epidermal growth factor receptor 2-negative (HER2−), advanced breast cancer (ABC) treated with palbociclib: A patient-reported outcome (PRO) analysis from POLARIS. Cancer Res 2022;
• 61 Rocque G, Blum JL, Ji Y. et al. Real-world quality of life (QoL) in patients with HR+/HER2− advanced breast cancer (ABC) treated with palbociclib: Final clinical outcome assessment (COA) analysis from POLARIS. Ann Oncol 2022; 33: S88-S121
• 62 Tripathy D, Blum JL, Sleckman B. et al. Characterization of neutropenia in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer on palbociclib in a real-world setting: Results from POLARIS. Cancer Res 2023;
• 63 ClinicalTrails.gov. Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer. 2023 Accessed November 24, 2023 at: https://classic.clinicaltrials.gov/show/NCT03425838
• 64 Azoulay L. Rationale, Strengths, and Limitations of Real-World Evidence in Oncology: A Canadian Review and Perspective. Oncologist 2022; 27: E731-E738
• 65 Monti S, Grosso V, Todoerti M. et al. Randomized controlled trials and real-world data: differences and similarities to untangle literature data. Rheumatology (Oxford) 2018; 57: vii54-vii58
• 66 Revicki DA, Frank L. Pharmacoeconomic evaluation in the real world. Effectiveness versus efficacy studies. Pharmacoeconomics 1999; 15: 423-434
• 67 Khozin S, Blumenthal GM, Pazdur R. Real-world Data for Clinical Evidence Generation in Oncology. J Natl Cancer Inst 2017; 109
• 68 Di Maio M, Perrone F, Conte P. Real-World Evidence in Oncology: Opportunities and Limitations. Oncologist 2020; 25: e746-e752
• 69 Caffo O. Treatment sequencing in oncology: balancing clinical trial and real-world evidence Foreword. Future Oncology 2019; 15: 2887-2889
• 70 Batra A, Kong SY, Cheung WY. Eligibility of real-world patients with metastatic breast cancer for clinical trials. Breast 2020; 54: 171-178
• 71 Kraus AL, Yu-Kite M, Mardekian J. et al. Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men. Clin Pharmacol Ther 2022; 111: 302-309
• 72 Mues KE, Liede A, Liu J. et al. Use of the Medicare database in epidemiologic and health services research: a valuable source of real-world evidence on the older and disabled populations in the US. Clin Epidemiol 2017; 9: 267-277
• 73 Blonde L, Khunti K, Harris SB. et al. Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician. Adv Ther 2018; 35: 1763-1774
• 74 Sherman RE, Anderson SA, Dal Pan GJ. et al. Real-World Evidence – What Is It and What Can It Tell Us?. N Engl J Med 2016; 375: 2293-2297
• 75 Schneeweiss S. Learning from Big Health Care Data. N Engl J Med 2014; 370: 2161-2163
• 76 Yuan HB, Ali MS, Brouwer ES. et al. Real-World Evidence: What It Is and What It Can Tell Us According to the International Society for Pharmacoepidemiology (ISPE) Comparative Effectiveness Research (CER) Special Interest Group (SIG). Clin Pharmacol Ther 2018; 104: 239-241
• 77 Castelo-Branco L, Pellat A, Martins-Branco D. et al. ESMO Guidance for Reporting Oncology real-World evidence (GROW). Ann Oncol 2023; 34: 1097-1112
• 78 Cardoso F, Paluch-Shimon S, Senkus E. et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020; 31: 1623-1649
• 79 Burstein HJ. Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer. N Engl J Med 2020; 383: 2557-2570
• 80 Harbeck N, Gnant M. Breast cancer. Lancet 2017; 389: 1134-1150
• 81 Papadimitriou MC, Pazaiti A, Iliakopoulos K. et al. Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer. Biochim Biophys Acta Mol Cell Res 2022; 1869: 119346
• 82 Finn RS, Rugo HS, Dieras VC. et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL plus LET) versus placebo plus letrozole (PBO plus LET) in women with estrogen receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ER+/HER2−ABC): Analyses from PALOMA-2. J Clin Oncol 2022;
• 83 Garly R, Berg T, Jensen MB. et al. A retrospective, non-interventional study of breast cancer patients diagnosed with ER+/HER2 negative, locally advanced or metastatic breast cancer treated with palbociclib in Denmark. Acta Oncol 2023; 62: 290-297
• 84 Bedard PL, Freedman OC, Howell A. et al. Overcoming endocrine resistance in breast cancer-are signal transduction inhibitors the answer?. Breast Cancer Res Treat 2008; 108: 307-317
• 85 Dean JL, Thangavel C, McClendon AK. et al. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 2010; 29: 4018-4032
• 86 Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev 2016; 45: 129-138
• 87 Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer 2011; 18: C19-C24
• 88 Normanno N, Di Maio M, De Maio E. et al. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer 2005; 12: 721-747
• 89 Pink JJ, Bilimoria MM, Assikis J. et al. Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. Brit J Cancer 1996; 74: 1227-1236
• 90 Thangavel C, Dean JL, Ertel A. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 2011; 18: 333-345
• 91 Durairaj C, Ruiz-Garcia A, Gauthier ER. et al. Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer. Anticancer Drugs 2018; 29: 271-280
• 92 Harbeck N, Law EH, Ajmera M. et al. Prevalence of risk factors for QT prolongation and torsades de pointes among women with HR+/HER2– advanced or metastatic breast cancer treated in real-world settings in Italy and Germany. Ann Oncol 2019;
• 93 Harbeck N, Kates R, Schinköthe T. et al. Favorable impact of therapy management by an interactive eHealth system on severe adverse events in patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer treated by palbociclib and endocrine therapy. Cancer Treat Rev 2023;
• 94 Rached L, Frelaut M, Baldini C. Bridging the gap: addressing disparities of access to oncology clinical trials in the geriatric population. ESMO Open 2023; 8: 102029
• 95 RKI. Krebs in Deutschland. 2023 Accessed November 09, 2023 at: https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2021/kid_2021_c50_brust.pdf?__blob=publicationFile
• 96 Rugo HS, Turner NC, Finn RS. et al. Palbociclib plus endocrine therapy in older women with HR+/HER2− advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer 2018; 101: 123-133
• 97 Rugo HS, Liu XC, Li B. et al. Real-world comparative effectiveness of palbociclib plus letrozole versus letrozole in older patients with metastatic breast cancer. Breast 2023; 69: 375-381
• 98 Brufsky A, Liu XC, Li B. et al. Real-world treatment patterns and effectiveness of palbociclib plus an aromatase inhibitor in patients with metastatic breast cancer aged 75 years or older. Front Oncol 2023; 13
• 99 Karuturi MS, Cappelleri JC, Blum JL. et al. Measures of functional status in older patients treated with palbociclib for advanced breast cancer. J Geriatr Oncol 2024; 15: 101670
• 100 Gelmon K, Walshe JM, Mahtani R. et al. Efficacy and safety of palbociclib in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2. Breast 2021; 59: 321-326
• 101 Tripathy D, Blum JL, Karuturi MS. et al. Impact of comorbidities on real-world (rw) clinical outcomes of patients (pts) with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2−) advanced breast cancer (ABC) treated with palbociclib and enrolled in POLARIS. Ann Oncol 2023; 34: S332
• 102 Blum JL, Rocque G, Ji Y. et al. Impact of comorbidities on real-world patient-reported outcomes of patients (pts) with hormone receptor-positive human epidermal growth factor 2-negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial. Ann Oncol 2023; 34: S375
• 103 Mahtani RL, Hanson KA, Lewis K. et al. Treatment patterns and comorbidities in patients with HR+/HER2− MBC: A real-world study in five European countries. ESMO Open 2023;
• 104 Brufsky A, Liu X, Li B. et al. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases. Cancer Res 2024;
• 105 Blum JL, Dicristo C, Gordon D. et al. Outcomes of male patients with HR+/HER2− advanced breast cancer receiving palbociclib in the real-world POLARIS study. Breast Cancer Res Treat 2024; 203: 463-475
• 106 onkopedia. Mammakarzinom der Frau. 2018 Accessed November 09, 2023 at: https://www.onkopedia.com/de/onkopedia/guidelines/mammakarzinom-der-frau/@@guideline/html/index.html
• 107 Tumorregister. München ICD-10 C50: Mammakarzinom (Frauen) – Inzidenz und Mortalität. 2021 Accessed November 09, 2023 at: https://www.tumorregister-muenchen.de/facts/base/bC50f_G-ICD-10-C50-Mammakarzinom-Frauen-Inzidenz-und-Mortalitaet.pdf
• 108 Soto-Perez-de-Celis E, Li DN, Yuan Y. et al. Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol 2018; 19: E305-E316
• 109 Fietz T, Tesch H, Rauh J. et al. Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer – Results from the prospective German TMK cohort study. Breast 2017; 34: 122-130
• 110 Yildirim HC, Mutlu E, Chalabiyev E. et al. Clinical outcomes of cyclin-dependent kinase 4–6 (CDK 4–6) inhibitors in patients with male breast cancer: A multicenter study. Breast 2022; 66: 85-88
• 111 Burstein HJ, Somerfield MR, Barton DL. et al. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol 2021; 39: 3959
• 112 ClinicalTrails.gov. A Study of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer (VERITAC-3). U.S. National Library of Medicine 2024 Accessed February 21, 2024 at: https://classic.clinicaltrials.gov/ct2/show/NCT05909397
• 113 ClinicalTrails.gov. A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120). 2024 Accessed February 21, 2024 at: https://classic.clinicaltrials.gov/ct2/show/NCT04191499
• 114 Jhaveri KL, Im SA, Saura C. et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA mutated, hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. SABCS; 2023; San Antonio, Texas, U.S.A..
• 115 Mayer EL, Ren Y, Wagle N. et al. PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer. J Clin Oncol 2024; 42: 2050-2060
• 116 Llombart-Cussac A, Harper-Wynne C, Perello A. et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR [+])/human epidermal growth factor receptor 2-negative (HER2 [-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol 2023; 41: 1001-1001
• 117 Martin JM, Handorf EA, Montero AJ. et al. Systemic Therapies Following Progression on First-line CDK4/6-inhibitor Treatment: Analysis of Real-world Data. Oncologist 2022; 27: 441-446
• 118 Clifton KK, Wander SA, Ma C. et al. Abstract P4–01–18: Real-world second-line treatment patterns and associated clinical outcomes for 2795 patients with advanced HR+ HER2− breast cancer treated with first-line CDK4/6 inhibitors. Cancer Res 2023; 83: P4-01-18