Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis 

Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis Palma Fedele, Matteo Landriscina, Federica Fumai, Lucia Moraca, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6594505/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: The management of metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer in elderly patients, particularly those aged 80 years and older, remains an area of significant clinical uncertainty due to limited representation in clinical trials. Given the anticipated rise in the oldest-old population, real-world data are urgently needed to inform therapeutic strategies in this setting. This study aimed to evaluate the effectiveness and safety of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) in patients aged ≥ 80 years. Methods: We conducted a retrospective, multicenter analysis across seven Italian oncology centers. Eligible patients were aged 80 years or older and had initiated CDK4/6i therapy for HR+/HER2- metastatic breast cancer between January 2020 and May 2024. Data on demographics, comorbidities, frailty (G8 score), treatment regimens, and adverse events were collected. Primary endpoints included progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan–Meier method. Safety was assessed according to CTCAE v5.0 criteria. Results: A total of 39 patients were included. The median age was 83 years. Visceral metastases were present in 53.8% of cases, and 41.1% of patients were classified as frail (G8 ≤ 14). A reduced starting dose was adopted in 43.6% of patients. Median PFS was 13 months, and median OS was 15 months. Hematologic toxicities were the most frequent adverse events: neutropenia occurred in 62% of patients (grade ≥ 3 in 25%), and anemia in 13% (grade ≥ 3 in 6%). Non-hematologic toxicities included asthenia (16%), diarrhea (8%, mainly with abemaciclib), and elevated liver enzymes (24%). No cases of thrombocytopenia or QTc prolongation were observed. Temporary treatment interruptions were necessary in a substantial proportion of patients. Conclusions: In this real-world cohort of patients aged ≥ 80 years, CDK4/6 inhibitors combined with endocrine therapy demonstrated clinically meaningful outcomes with an acceptable safety profile. Individualized treatment approaches, including dose adjustments based on frailty and comorbidities, appear critical for optimizing outcomes. These findings support the feasibility of CDK4/6i-based therapy in the oldest-old population and highlight the need for prospective geriatric-focused studies. Metastatic breast cancer Elderly patients HR+/HER2- breast cancer CDK4/6 inhibitors Real-world evidence Geriatric oncology Treatment tolerability Figures Figure 1 Figure 2 Introduction The therapeutic landscape for metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC) has undergone significant advances over the past decade, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET), now firmly established as the standard of care [ 1 – 8 ]. These agents have substantially improved progression-free survival (PFS) and, in many settings, overall survival (OS), thereby reshaping clinical practice. However, pivotal trials leading to the approval of CDK4/6 inhibitors predominantly enrolled younger, fitter patients, often excluding those with significant comorbidities or frailty. Consequently, data regarding the efficacy and safety of CDK4/6 inhibitors in the elderly, and particularly in patients aged 80 years and older, remain scarce [ 9 – 12 ]. This lack of data represents a growing clinical challenge, particularly in light of the global demographic trend toward an aging population [ 13 ]. Indeed, individuals aged ≥ 80 years are projected to represent a substantial and growing proportion of the oncology population in the coming decades. Within this group, HR+/HER2- BC remains the most frequent subtype, accounting for approximately 75% of all breast cancer cases [ 14 ], and its incidence tends to remain high with advancing age. Despite this, the old-old and oldest-old are often undertreated in clinical practice, due to concerns regarding frailty, polypharmacy, and reduced physiological reserves, which can impact both treatment choices and outcomes. The management of metastatic breast cancer in this particularly vulnerable group poses unique challenges. The need to balance therapeutic efficacy against the risk of toxicity is heightened, often leading clinicians to adopt cautious strategies, including initial dose reductions and more intensive toxicity monitoring. Yet, the real-world effectiveness and safety of CDK4/6 inhibitors in this setting have not been well characterized, and there remains uncertainty regarding the optimal treatment approach. Although recent real-world studies, including a large Italian retrospective analysis, have begun to address the role of CDK4/6 inhibitors in elderly patients with metastatic breast cancer [ 15 ], specific evidence focusing exclusively on patients aged 80 years and older remains scarce. Recognizing this critical gap, we conducted a retrospective, multicenter study aimed at evaluating the real-world outcomes of CDK4/6 inhibitor therapy combined with ET in patients aged 80 years and older with HR+/HER2- metastatic breast cancer. Our objectives were to assess survival outcomes, characterize the safety profile, and explore patterns of treatment adaptation, with particular attention to the use of dose modifications and their potential impact on clinical results. Materials and Methods This retrospective, multicenter observational study was conducted across seven Italian oncology centers. The study included patients aged 80 years or older with a histologically confirmed diagnosis of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) who initiated treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) between January 2020 and May 2024. Eligibility criteria allowed inclusion of patients who had previously received treatment for early-stage disease, provided that CDK4/6i therapy was started in the metastatic setting. No specific restrictions were placed regarding performance status or comorbidity burden, reflecting a real-world patient population. Clinical and demographic information was systematically collected from electronic medical records. Variables included age at treatment initiation, body mass index (BMI), comorbidity status, Eastern Cooperative Oncology Group Performance Status (ECOG PS), histological subtype, and extent of metastatic disease (visceral versus non-visceral involvement). Therapeutic details encompassed the choice of endocrine partner (aromatase inhibitors or fulvestrant), the specific CDK4/6 inhibitor administered, and the starting dose strategy (standard versus reduced). Frailty was assessed using the G8 screening tool, a validated measure of vulnerability in elderly oncology patients. HER2 status was classified according to local pathological assessments as either positive or negative, without further stratification into HER2-low categories, in keeping with the diagnostic standards at the time of patient enrollment. CDK4/6 inhibitors were administered following standard clinical practice, with treatment continuation until evidence of disease progression, the onset of unacceptable toxicity, or death. No patients had been exposed to CDK4/6 inhibitors in the adjuvant setting. Patient confidentiality was ensured in accordance with the European General Data Protection Regulation (GDPR) (Regulation EU 2016/679), with each patient assigned a unique anonymized code. Ethical approval for the study protocol was obtained from the Ethics Committee of the Puglia Region n (protocol code 0072095—19 September 2024). . The primary outcomes were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from CDK4/6i initiation to disease progression or death from any cause, whichever occurred first. OS was defined as the time from treatment initiation to death from any cause. Patients without progression or death at the time of the last follow-up were censored for survival analyses. Safety was evaluated by recording adverse events (AEs) throughout the treatment course, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 [ 16 ]. Events were further categorized by System Organ Class (SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0. When multiple events occurred in a single patient, only the highest grade was reported. Descriptive statistics were used to summarize baseline characteristics and adverse events, with continuous variables expressed as medians and ranges and categorical variables as absolute frequencies and percentages. Survival distributions were estimated using the Kaplan–Meier method, and follow-up time was calculated using the reverse Kaplan–Meier technique. Statistical analyses were performed using R software, version 4.4.1. Given the retrospective design, no formal sample size calculation was conducted; the study cohort reflects the total number of eligible patients treated across the participating centers during the study period. Results A total of 39 patients aged 80 years or older with HR+/HER2– metastatic breast cancer were included in the analysis. The demographic and clinical characteristics of the cohort are summarized in Table 1. Table 1. Clinical and demographic characteristics of patients undergoing CDK4/6 inhibitor therapy. N° of patients 39 (%) Characteristics 12(30,7%) 27(69,3%) Stage at the diagnosis I-III IV 18(46,2%) 21 (53.8%) N° metastasis site Soft Tissue/Bone Visceral 19 (48,7%) 20 (51,3%) BC subtype Luminal A Luminal B 4(10,2%) 27(69,2%) 8(20,6%) Comorbidities 0 1 2 or more 1(2,5%) 22 (56,4%) 16(41,1%) ECOG PS 0 1 2 23(58,9%) 16(41,1%) G8 score >14 ≤14 20(51,3%) 19(48,7%) Endocrine therapy Letrozole orAnastrozole Fulvestrant 7(17,9%) 21(53,8%) 11(28,3%) CDK4/6i Abemaciclib Palbociclib Ribociclib 22(56,4%) 17(43,6%) Starting Dose Standard Reduced 35 (21.87%) 44(27.50%) 46 (28.75%) Toxicities G1 G2 G3 21 (53,8%) 8 (20,5%) 10(25,5%) 1(2,5%) Temporary Suspensions 1 2 3 16(41,1%) 23(58,9%) BMI BMI=25 Overall, 69.3% of patients had been diagnosed at stage IV, and 53.8% presented with visceral metastases. In terms of tumor subtypes, 51.3% of patients had a luminal B phenotype, while 48.7% had a luminal A phenotype. Regarding comorbidities, 10.2% of patients had no comorbidities, 69.2% had one comorbidity, and 20.6% had two or more comorbidities. Considering body mass index (BMI), 41.1% of patients had a BMI below 25 kg/m², whereas 58.9% were overweight or obese (BMI ≥25 kg/m²). The performance status assessment showed that 97.5% of patients had an ECOG PS of 1 or 2, and 41.1% had a G8 score of ≤14, indicating significant frailty. Regarding systemic therapy, 51.3% of patients received an aromatase inhibitor (letrozole or anastrozole) and 48.7% received fulvestrant as endocrine partner. Among the CDK4/6 inhibitors, palbociclib was the most frequently used (53.8%), followed by ribociclib (28.3%) and abemaciclib (17.9%). A reduced starting dose was adopted in 43.6% of cases. Survival outcomes were estimated using Kaplan–Meier analysis. The median progression-free survival (PFS) for the entire cohort was 13 months. The PFS rate at 12 months was approximately 52%. The median overall survival (OS) was 15 months, with an estimated OS rate of 60% at 12 months and 30% at 24 months. The survival curves for PFS and OS are shown in Figures 1 and 2. Safety and tolerability were assessed throughout the treatment period. Hematologic toxicities were the most frequent adverse events: neutropenia occurred in 62% of patients, with 25% experiencing grade ≥3 events. Anemia was reported in 13% of patients, with 6% experiencing grade ≥3 severity. Asthenia was observed in 16% of patients (8% grade ≥3), while diarrhea was recorded in 8% of cases, notably more frequent among patients treated with abemaciclib (43% any grade, but only 3% grade ≥3). Elevations in liver enzymes (ALT/AST) occurred in 24% of patients (3% grade ≥3). No cases of thrombocytopenia or QTc interval prolongation were documented (Table 2). Table 2 AEs Any Grade n° (%) Grade ³ 3 n° (%) Total Patients n °39 Abemaciclib N°7 Ribociclib N°11 Palbociclib N°21 Abemaciclib N°7 Ribociclib N°11 Palbociclib N°21 Any Grade Grade ³ 3 Anemia No Yes 6(86) 1(14) 10(90) 1(10) 18(85) 3(15) 6(86) 1(14) 11(100) 0(0) 20(95) 1(5) 34(87) 5(13) 37(94) 2(6) Neutropenia No Yes 5(71) 2(29) 5(45) 6(55) 5(24) 16(76) 6(86) 1(14) 9(81) 2(19) 14(67) 7(33) 15(38) 24(62) 29(75) 10(25) Thrompocytopenia No Yes 7(100) 0(0) 11(100) 0(0) 21(100) 0(0) 7(100) 0(0) 11(100) 0(0) 21(100) 0(0) 39(100) 0(0) 39(100) 0(0) Asthenia No Yes 6(86) 1(14) 10(90) 1(10) 17(80) 4(20) 6(86) 1(14) 10(90) 1(10) 20(95) 1(5) 33(84) 6(16) 36(92) 3(8) Diarrhea No Yes 4(57) 3(43) 11(100) 0(0) 21(100) 0(0) 6(86) 1(14) 11(100) 0(0) 21(100) 0(0) 36(92) 3(8) 38(97) 1(3) ALT/AST increased No Yes 6(86) 1(14) 4(36) 7(64) 20(95) 1(5) 0(0) 0(0) 11(100) 0(0) 20(95) 1(5) 30(76) 9(24) 38(97) 1(3) Qtc prolungation No Yes 7(100) 0(0) 11(100) 0(0) 21(100) 0(0) 7(100) 0(0) 11(100) 0(0) 21(100) 0(0) 39(100) 0(0) 39(100) 0(0) Discussion The findings of this real-world study provide important insights into the management of HR+/HER2- MBC in patients aged 80 years and older, a population critically underrepresented in pivotal clinical trials. In our cohort, treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) achieved clinical outcomes that appear comparable to those reported in younger elderly populations [ 9 – 11 ]. The observed median progression-free survival (PFS) of 13 months and median overall survival (OS) of 15 months are particularly noteworthy given the advanced age, elevated comorbidity burden, and significant proportion of patients classified as frail according to the G8 screening tool. These results suggest that meaningful disease control is attainable even in the oldest-old patients when systemic therapies are carefully tailored to individual patient characteristics. The safety profile observed in this study aligns with existing data on CDK4/6i toxicity but also reflects the particular vulnerabilities of an ultra-elderly population. Hematologic toxicities, especially neutropenia, remained the most frequent adverse events, although the incidence of grade ≥ 3 events was manageable. Non-hematologic toxicities such as asthenia, diarrhea, and liver enzyme elevations were also observed but rarely reached high-grade severity. Importantly, no cases of thrombocytopenia or QTc prolongation were recorded, underscoring the overall feasibility of CDK4/6i therapy in this setting. One of the salient features of our cohort was the high proportion of patients (43.6%) who initiated treatment with an upfront dose reduction. This approach likely reflects a cautious clinical strategy to minimize the risk of severe toxicities in a frail, comorbid population [ 17 ].While this individualized dosing strategy may be associated with favorable safety outcomes, its impact on efficacy parameters such as PFS and OS remains uncertain. Prospective studies specifically evaluating the role of dose intensity in the oldest-old are needed to address this critical question. Several strengths of our study merit attention. First, to our knowledge, this represents one of the few real-world analyses specifically focusing on patients aged ≥ 80 years treated with CDK4/6 inhibitors, addressing a major gap in the current literature [ 9 – 11 ]. Second, the multicenter nature of the study enhances the generalizability of the findings, capturing heterogeneous clinical practices across different institutions. Third, the systematic collection of geriatric parameters, such as the G8 frailty score, provides valuable context for interpreting outcomes in a population characterized by significant biological heterogeneity. However, important limitations must be acknowledged. The retrospective design inherently introduces the risk of selection bias, missing data, and unmeasured confounding variables. Additionally, the relatively small sample size limited the statistical power of the analyses and precluded the performance of multivariate models to identify independent prognostic factors. As a result, associations between clinical variables (e.g., frailty status, initial dose reduction) and survival outcomes could not be formally assessed. Moreover, the absence of detailed geriatric assessment beyond the G8 score—such as evaluations of cognitive status, functional dependence, or social vulnerability—limits the granularity of frailty characterization. Despite these limitations, the consistency of our findings with those reported in broader real-world settings, combined with the manageable toxicity profile observed, supports the use of CDK4/6 inhibitors in carefully selected oldest-old patients with metastatic HR+/HER2- BC. Importantly, our results reinforce the need for individualized treatment approaches based not solely on chronological age, but incorporating comprehensive assessments of physiological reserves, comorbidities, and patient preferences. Future prospective studies specifically designed to include ultra-elderly patients, ideally incorporating comprehensive geriatric assessment tools and frailty-stratified treatment algorithms, are urgently needed to optimize the management of this growing and vulnerable patient population. Conclusion In this retrospective, real-world study focusing on patients aged 80 years and older with HR+/HER2- metastatic breast cancer, treatment with CDK4/6 inhibitors combined with endocrine therapy demonstrated meaningful clinical benefits and a manageable safety profile. Despite the presence of frailty and comorbidities, survival outcomes were comparable to those reported in younger elderly populations, suggesting that age alone should not preclude the use of CDK4/6 inhibitors when appropriate patient selection and individualized management strategies are employed. The high proportion of initial dose reductions underscores the need for careful tailoring of therapy in the oldest-old. Personalized treatment decisions, based on comprehensive evaluation of comorbidities, functional status, and frailty, appear essential to optimize clinical outcomes while minimizing toxicity. Prospective studies incorporating detailed geriatric assessments and evaluating different dosing strategies are warranted to further refine the therapeutic approach in this growing and vulnerable patient population. Declarations Author Contribution Author Contributions: Conceptualization, P.F. and M.L.; methodology F.F, ; software F.F, ; validation, V.C.; formal analysis, G.G-C.; investigation L.C, ; resources, L.C..; data curation F.F ,; writing—original draft preparation F.G; writing— review and editing, A.C.; visualization ; supervision, P.F.; and project administration, P.F.All authors have read and agreed to the published version of the manuscript. References Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73 , 17–48. https://doi.org/10.3322/caac.21763. Cardoso, F.; Kyriakides, S.; Ohno, S.; Penault-Llorca, F.; Poortmans, P.; Rubio, I.T.; Zackrisson, S.; Senkus, E. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019, 30 , 1674–1705. https://doi.org/10.1093/annonc/mdz173. 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Fedele P, Landriscina M, Moraca L, Gadaleta-Caldarola A, Cusmai A, Giuliani F, Chiuri V, Giotta F, Pinto A, Mirisola V, Gadaleta-Caldarola G. Standard Versus Reduced CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: An Observational Multicenter Study. J Clin Med. 2024 Dec 6;13(23):7441. doi: 10.3390/jcm13237441. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6594505","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457851697,"identity":"80480fbe-4539-46c5-92ba-dadbd04474b9","order_by":0,"name":"Palma Fedele","email":"data:image/png;base64,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","orcid":"","institution":"Oncology Unit, “Dario Camberlingo” Hospital,","correspondingAuthor":true,"prefix":"","firstName":"Palma","middleName":"","lastName":"Fedele","suffix":""},{"id":457851698,"identity":"9835c752-8105-4cc0-9394-6b27733085a9","order_by":1,"name":"Matteo Landriscina","email":"","orcid":"","institution":"University of Foggia","correspondingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Landriscina","suffix":""},{"id":457851700,"identity":"1735420b-797d-438d-ae10-15d953e1fff3","order_by":2,"name":"Federica Fumai","email":"","orcid":"","institution":"Oncology Unit, “Dario Camberlingo” Hospital,","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Fumai","suffix":""},{"id":457851701,"identity":"003eb83c-c308-4573-945b-5675a69a7412","order_by":3,"name":"Lucia Moraca","email":"","orcid":"","institution":"Oncology Unit, “Teresa Masselli Mascia” Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Moraca","suffix":""},{"id":457851702,"identity":"9284942f-b8e0-40ff-ab66-1c2f75a4f9f0","order_by":4,"name":"Antonio Cusmai","email":"","orcid":"","institution":"Oncology Unit, I.R.C.C.S. “Giovanni Paolo II”","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Cusmai","suffix":""},{"id":457851703,"identity":"d3719fed-1ac3-4101-9ac5-b21855f66404","order_by":5,"name":"Francesco Giuliani","email":"","orcid":"","institution":"Oncology Unit, “San Paolo” Hospital","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Giuliani","suffix":""},{"id":457851704,"identity":"6aa06c23-f54c-4a6c-9a6a-8455a828a635","order_by":6,"name":"Vincenzo Emanuele Chiuri","email":"","orcid":"","institution":"Oncology Unit, “Sacro Cuore di Gesù” Hospital","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"Emanuele","lastName":"Chiuri","suffix":""},{"id":457851705,"identity":"87518f79-bd20-46a9-bcfc-cfaa4e6ec308","order_by":7,"name":"Francesco Giotta","email":"","orcid":"","institution":"Oncology Unit, I.R.C.C.S. “Giovanni Paolo II”","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Giotta","suffix":""},{"id":457851706,"identity":"1c66c99c-ef0d-45a0-8fa6-266bd0a99e3b","order_by":8,"name":"Gennaro Gadaleta-Caldarola","email":"","orcid":"","institution":"Oncology Unit, “Mons. A. R. Dimiccoli” Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gennaro","middleName":"","lastName":"Gadaleta-Caldarola","suffix":""}],"badges":[],"createdAt":"2025-05-05 12:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6594505/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6594505/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83108315,"identity":"01ec930a-9e27-4f6e-b3c6-f355d5e55778","added_by":"auto","created_at":"2025-05-20 06:47:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10158,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier progression-free survival curve for the entire cohort of patients receiving CDK4/6 inhibitor therapy.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6594505/v1/dfd9a3981338600ee45a9b40.png"},{"id":83108316,"identity":"009d2a8e-1061-442f-be5c-00e24d58d912","added_by":"auto","created_at":"2025-05-20 06:47:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10392,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier overall survival (OS) curve for the entire cohort of patients receiving CDK4/6 inhibitor therapy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6594505/v1/c83d41c97d85aa83e7106bdc.png"},{"id":87068943,"identity":"79d941c6-debf-4a32-8041-00686f074491","added_by":"auto","created_at":"2025-07-18 19:23:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1171939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6594505/v1/5ce0aaef-87e5-4af3-bae4-2e2fffe295df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis ","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe therapeutic landscape for metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC) has undergone significant advances over the past decade, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET), now firmly established as the standard of care [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These agents have substantially improved progression-free survival (PFS) and, in many settings, overall survival (OS), thereby reshaping clinical practice.\u003c/p\u003e \u003cp\u003eHowever, pivotal trials leading to the approval of CDK4/6 inhibitors predominantly enrolled younger, fitter patients, often excluding those with significant comorbidities or frailty. Consequently, data regarding the efficacy and safety of CDK4/6 inhibitors in the elderly, and particularly in patients aged 80 years and older, remain scarce [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This lack of data represents a growing clinical challenge, particularly in light of the global demographic trend toward an aging population [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIndeed, individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years are projected to represent a substantial and growing proportion of the oncology population in the coming decades. Within this group, HR+/HER2- BC remains the most frequent subtype, accounting for approximately 75% of all breast cancer cases [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and its incidence tends to remain high with advancing age. Despite this, the old-old and oldest-old are often undertreated in clinical practice, due to concerns regarding frailty, polypharmacy, and reduced physiological reserves, which can impact both treatment choices and outcomes.\u003c/p\u003e \u003cp\u003eThe management of metastatic breast cancer in this particularly vulnerable group poses unique challenges. The need to balance therapeutic efficacy against the risk of toxicity is heightened, often leading clinicians to adopt cautious strategies, including initial dose reductions and more intensive toxicity monitoring. Yet, the real-world effectiveness and safety of CDK4/6 inhibitors in this setting have not been well characterized, and there remains uncertainty regarding the optimal treatment approach.\u003c/p\u003e \u003cp\u003eAlthough recent real-world studies, including a large Italian retrospective analysis, have begun to address the role of CDK4/6 inhibitors in elderly patients with metastatic breast cancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], specific evidence focusing exclusively on patients aged 80 years and older remains scarce.\u003c/p\u003e \u003cp\u003eRecognizing this critical gap, we conducted a retrospective, multicenter study aimed at evaluating the real-world outcomes of CDK4/6 inhibitor therapy combined with ET in patients aged 80 years and older with HR+/HER2- metastatic breast cancer. Our objectives were to assess survival outcomes, characterize the safety profile, and explore patterns of treatment adaptation, with particular attention to the use of dose modifications and their potential impact on clinical results.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis retrospective, multicenter observational study was conducted across seven Italian oncology centers. The study included patients aged 80 years or older with a histologically confirmed diagnosis of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) who initiated treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) between January 2020 and May 2024.\u003c/p\u003e\u003cp\u003eEligibility criteria allowed inclusion of patients who had previously received treatment for early-stage disease, provided that CDK4/6i therapy was started in the metastatic setting. No specific restrictions were placed regarding performance status or comorbidity burden, reflecting a real-world patient population.\u003c/p\u003e\u003cp\u003eClinical and demographic information was systematically collected from electronic medical records. Variables included age at treatment initiation, body mass index (BMI), comorbidity status, Eastern Cooperative Oncology Group Performance Status (ECOG PS), histological subtype, and extent of metastatic disease (visceral versus non-visceral involvement). Therapeutic details encompassed the choice of endocrine partner (aromatase inhibitors or fulvestrant), the specific CDK4/6 inhibitor administered, and the starting dose strategy (standard versus reduced). Frailty was assessed using the G8 screening tool, a validated measure of vulnerability in elderly oncology patients.\u003c/p\u003e\u003cp\u003eHER2 status was classified according to local pathological assessments as either positive or negative, without further stratification into HER2-low categories, in keeping with the diagnostic standards at the time of patient enrollment.\u003c/p\u003e\u003cp\u003eCDK4/6 inhibitors were administered following standard clinical practice, with treatment continuation until evidence of disease progression, the onset of unacceptable toxicity, or death. No patients had been exposed to CDK4/6 inhibitors in the adjuvant setting.\u003c/p\u003e\u003cp\u003ePatient confidentiality was ensured in accordance with the European General Data Protection Regulation (GDPR) (Regulation EU 2016/679), with each patient assigned a unique anonymized code. Ethical approval for the study protocol was obtained from the Ethics Committee of the Puglia Region n (protocol code 0072095\u0026mdash;19 September 2024). .\u003c/p\u003e\u003cp\u003eThe primary outcomes were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from CDK4/6i initiation to disease progression or death from any cause, whichever occurred first. OS was defined as the time from treatment initiation to death from any cause. Patients without progression or death at the time of the last follow-up were censored for survival analyses.\u003c/p\u003e\u003cp\u003eSafety was evaluated by recording adverse events (AEs) throughout the treatment course, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Events were further categorized by System Organ Class (SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0. When multiple events occurred in a single patient, only the highest grade was reported.\u003c/p\u003e\u003cp\u003eDescriptive statistics were used to summarize baseline characteristics and adverse events, with continuous variables expressed as medians and ranges and categorical variables as absolute frequencies and percentages. Survival distributions were estimated using the Kaplan\u0026ndash;Meier method, and follow-up time was calculated using the reverse Kaplan\u0026ndash;Meier technique. Statistical analyses were performed using R software, version 4.4.1.\u003c/p\u003e\u003cp\u003e Given the retrospective design, no formal sample size calculation was conducted; the study cohort reflects the total number of eligible patients treated across the participating centers during the study period.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 39 patients aged 80 years or older with HR+/HER2\u0026ndash; metastatic breast cancer were included in the analysis. The demographic and clinical characteristics of the cohort are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003eTable 1. Clinical and demographic characteristics of patients undergoing CDK4/6 inhibitor therapy.\u003c/p\u003e\n\u003ctable dir=\"rtl\" border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"502\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eN\u0026deg; of patients 39 (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCharacteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e12(30,7%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;27(69,3%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eStage at the diagnosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eI-III\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eIV\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e18(46,2%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e21 (53.8%) \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eN\u0026deg; metastasis site\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSoft Tissue/Bone\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eVisceral\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e19 (48,7%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e20 (51,3%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBC subtype\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eLuminal A\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eLuminal B\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e4(10,2%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e27(69,2%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;8(20,6%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eComorbidities\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e2 or more\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1(2,5%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e22 (56,4%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e16(41,1%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eECOG PS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e23(58,9%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;16(41,1%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eG8 score\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026gt;14\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026le;14\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e20(51,3%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e19(48,7%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eEndocrine therapy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eLetrozole orAnastrozole\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFulvestrant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;7(17,9%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;21(53,8%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;11(28,3%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCDK4/6i\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAbemaciclib\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePalbociclib\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRibociclib\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e22(56,4%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e17(43,6%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eStarting Dose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eStandard\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eReduced\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e35 (21.87%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e44(27.50%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e46 (28.75%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eToxicities\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eG1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eG2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eG3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e21 (53,8%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e8 (20,5%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e10(25,5%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1(2,5%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTemporary Suspensions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 250px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e16(41,1%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e23(58,9%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBMI\u0026lt;25\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBMI\u0026gt;=25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOverall, 69.3% of patients had been diagnosed at stage IV, and 53.8% presented with visceral metastases. In terms of tumor subtypes, 51.3% of patients had a luminal B phenotype, while 48.7% had a luminal A phenotype. Regarding comorbidities, 10.2% of patients had no comorbidities, 69.2% had one comorbidity, and 20.6% had two or more comorbidities.\u003c/p\u003e\n\u003cp\u003eConsidering body mass index (BMI), 41.1% of patients had a BMI below 25 kg/m\u0026sup2;, whereas 58.9% were overweight or obese (BMI \u0026ge;25 kg/m\u0026sup2;). The performance status assessment showed that 97.5% of patients had an ECOG PS of 1 or 2, and 41.1% had a G8 score of \u0026le;14, indicating significant frailty.\u003c/p\u003e\n\u003cp\u003eRegarding systemic therapy, 51.3% of patients received an aromatase inhibitor (letrozole or anastrozole) and 48.7% received fulvestrant as endocrine partner. Among the CDK4/6 inhibitors, palbociclib was the most frequently used (53.8%), followed by ribociclib (28.3%) and abemaciclib (17.9%). A reduced starting dose was adopted in 43.6% of cases.\u003c/p\u003e\n\u003cp\u003eSurvival outcomes were estimated using Kaplan\u0026ndash;Meier analysis. The median progression-free survival (PFS) for the entire cohort was 13 months. The PFS rate at 12 months was approximately 52%. The median overall survival (OS) was 15 months, with an estimated OS rate of 60% at 12 months and 30% at 24 months. The survival curves for PFS and OS are shown in Figures 1 and 2.\u003c/p\u003e\n\u003cp\u003eSafety and tolerability were assessed throughout the treatment period. Hematologic toxicities were the most frequent adverse events: neutropenia occurred in 62% of patients, with 25% experiencing grade \u0026ge;3 events. Anemia was reported in 13% of patients, with 6% experiencing grade \u0026ge;3 severity. Asthenia was observed in 16% of patients (8% grade \u0026ge;3), while diarrhea was recorded in 8% of cases, notably more frequent among patients treated with abemaciclib (43% any grade, but only 3% grade \u0026ge;3). Elevations in liver enzymes (ALT/AST) occurred in 24% of patients (3% grade \u0026ge;3). No cases of thrombocytopenia or QTc interval prolongation were documented (Table 2).\u003c/p\u003e\u003cp\u003eTable 2\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"641\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 202px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny Grade\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en\u0026deg; (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 32.1467%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026sup3;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en\u0026deg; (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 16.1488%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Patients\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en \u0026deg;39\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eAbemaciclib\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN\u0026deg;7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp; Ribociclib\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN\u0026deg;11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 68px;\"\u003e\n \u003cp\u003ePalbociclib\u003c/p\u003e\n \u003cp\u003eN\u0026deg;21\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003eAbemaciclib\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN\u0026deg;7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eRibociclib\u003c/p\u003e\n \u003cp\u003eN\u0026deg;11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003ePalbociclib\u003c/p\u003e\n \u003cp\u003eN\u0026deg;21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003eAny Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eGrade\u0026nbsp;\u0026sup3;\u0026nbsp;3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10(90)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(10)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e18(85)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3(15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e20(95)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e34(87)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5(13)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e37(94)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2(6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeutropenia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5(71)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2(29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5(45)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(55)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5(24)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e16(76)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e9(81)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2(19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e14(67)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(33)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e15(38)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e24(62)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e29(75)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10(25)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThrompocytopenia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e39(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e39(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAsthenia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10(90)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e17(80)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4(20)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10(90)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e20(95)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e33(84)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e36(92)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3(8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiarrhea\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4(57)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3(43)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e36(92)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3(8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e38(97)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALT/AST increased\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6(86)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4(36)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(64)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e20(95)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e20(95)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e30(76)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e9(24)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e38(97)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1(3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQtc prolungation\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"\" valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e11(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e21(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.9159%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e39(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e39(100)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0(0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe findings of this real-world study provide important insights into the management of HR+/HER2- MBC in patients aged 80 years and older, a population critically underrepresented in pivotal clinical trials. In our cohort, treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) achieved clinical outcomes that appear comparable to those reported in younger elderly populations [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observed median progression-free survival (PFS) of 13 months and median overall survival (OS) of 15 months are particularly noteworthy given the advanced age, elevated comorbidity burden, and significant proportion of patients classified as frail according to the G8 screening tool. These results suggest that meaningful disease control is attainable even in the oldest-old patients when systemic therapies are carefully tailored to individual patient characteristics.\u003c/p\u003e \u003cp\u003eThe safety profile observed in this study aligns with existing data on CDK4/6i toxicity but also reflects the particular vulnerabilities of an ultra-elderly population. Hematologic toxicities, especially neutropenia, remained the most frequent adverse events, although the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events was manageable. Non-hematologic toxicities such as asthenia, diarrhea, and liver enzyme elevations were also observed but rarely reached high-grade severity. Importantly, no cases of thrombocytopenia or QTc prolongation were recorded, underscoring the overall feasibility of CDK4/6i therapy in this setting.\u003c/p\u003e \u003cp\u003eOne of the salient features of our cohort was the high proportion of patients (43.6%) who initiated treatment with an upfront dose reduction. This approach likely reflects a cautious clinical strategy to minimize the risk of severe toxicities in a frail, comorbid population [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].While this individualized dosing strategy may be associated with favorable safety outcomes, its impact on efficacy parameters such as PFS and OS remains uncertain. Prospective studies specifically evaluating the role of dose intensity in the oldest-old are needed to address this critical question.\u003c/p\u003e \u003cp\u003eSeveral strengths of our study merit attention. First, to our knowledge, this represents one of the few real-world analyses specifically focusing on patients aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years treated with CDK4/6 inhibitors, addressing a major gap in the current literature [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Second, the multicenter nature of the study enhances the generalizability of the findings, capturing heterogeneous clinical practices across different institutions. Third, the systematic collection of geriatric parameters, such as the G8 frailty score, provides valuable context for interpreting outcomes in a population characterized by significant biological heterogeneity.\u003c/p\u003e \u003cp\u003eHowever, important limitations must be acknowledged. The retrospective design inherently introduces the risk of selection bias, missing data, and unmeasured confounding variables. Additionally, the relatively small sample size limited the statistical power of the analyses and precluded the performance of multivariate models to identify independent prognostic factors. As a result, associations between clinical variables (e.g., frailty status, initial dose reduction) and survival outcomes could not be formally assessed. Moreover, the absence of detailed geriatric assessment beyond the G8 score\u0026mdash;such as evaluations of cognitive status, functional dependence, or social vulnerability\u0026mdash;limits the granularity of frailty characterization.\u003c/p\u003e \u003cp\u003eDespite these limitations, the consistency of our findings with those reported in broader real-world settings, combined with the manageable toxicity profile observed, supports the use of CDK4/6 inhibitors in carefully selected oldest-old patients with metastatic HR+/HER2- BC. Importantly, our results reinforce the need for individualized treatment approaches based not solely on chronological age, but incorporating comprehensive assessments of physiological reserves, comorbidities, and patient preferences.\u003c/p\u003e \u003cp\u003eFuture prospective studies specifically designed to include ultra-elderly patients, ideally incorporating comprehensive geriatric assessment tools and frailty-stratified treatment algorithms, are urgently needed to optimize the management of this growing and vulnerable patient population.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn this retrospective, real-world study focusing on patients aged 80 years and older with HR+/HER2- metastatic breast cancer, treatment with CDK4/6 inhibitors combined with endocrine therapy demonstrated meaningful clinical benefits and a manageable safety profile. Despite the presence of frailty and comorbidities, survival outcomes were comparable to those reported in younger elderly populations, suggesting that age alone should not preclude the use of CDK4/6 inhibitors when appropriate patient selection and individualized management strategies are employed.\u003c/p\u003e \u003cp\u003eThe high proportion of initial dose reductions underscores the need for careful tailoring of therapy in the oldest-old. Personalized treatment decisions, based on comprehensive evaluation of comorbidities, functional status, and frailty, appear essential to optimize clinical outcomes while minimizing toxicity.\u003c/p\u003e \u003cp\u003eProspective studies incorporating detailed geriatric assessments and evaluating different dosing strategies are warranted to further refine the therapeutic approach in this growing and vulnerable patient population.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions: Conceptualization, P.F. and M.L.; methodology F.F, ; software F.F, ; validation, V.C.; formal analysis, G.G-C.; investigation L.C, ; resources, L.C..; data curation F.F ,; writing\u0026mdash;original draft preparation F.G; writing\u0026mdash; review and editing, A.C.; visualization ; supervision, P.F.; and project administration, P.F.All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. \u003cem\u003eCA Cancer J. Clin.\u003c/em\u003e 2023, \u003cem\u003e73\u003c/em\u003e, 17\u0026ndash;48. https://doi.org/10.3322/caac.21763.\u003c/li\u003e\n\u003cli\u003eCardoso, F.; Kyriakides, S.; Ohno, S.; Penault-Llorca, F.; Poortmans, P.; Rubio, I.T.; Zackrisson, S.; Senkus, E. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. \u003cem\u003eAnn. Oncol.\u003c/em\u003e 2019, \u003cem\u003e30\u003c/em\u003e, 1674\u0026ndash;1705. https://doi.org/10.1093/annonc/mdz173.\u003c/li\u003e\n\u003cli\u003eHortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Petrakova, K.; Blackwell, K.L.; Perez, A.T.; et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e 2016, \u003cem\u003e375\u003c/em\u003e, 1738\u0026ndash;1748. https://doi.org/10.1056/NEJMoa1609709.\u003c/li\u003e\n\u003cli\u003eSlamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; De Laurentiis, M.; Im, S.A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Mart\u0026iacute;n, M.; et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e 2020, \u003cem\u003e382\u003c/em\u003e, 514\u0026ndash;524. https://doi.org/10.1056/NEJMoa1911149.\u003c/li\u003e\n\u003cli\u003eHortobagyi GN, Stemmer SM, Burris HA, et al: Overall survival with ribociclib plus letrozole in advanced breast cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e 386:942-950, 2022. https://doi.org/10.1056/NEJMoa2114663.\u003c/li\u003e\n\u003cli\u003eSledge, G.W.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Takahashi, M.; et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2\u0026minus; advanced breast cancer who had progressed while receiving endocrine therapy. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e 2017, \u003cem\u003e35\u003c/em\u003e, 2875\u0026ndash;2884. https://doi.org/10.1200/JCO.2017.73.7585.\u003c/li\u003e\n\u003cli\u003eFinn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.A.; Gelmon, K.; Harbeck, N.; Lipatov, O.; Winer, E.P.; Gauthier, E.; et al. Palbociclib and Letrozole in Advanced Breast Cancer. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e 2016, \u003cem\u003e375\u003c/em\u003e, 1925\u0026ndash;1936. https://doi.org/10.1056/NEJMoa1607303.\u003c/li\u003e\n\u003cli\u003eTurner, N.C.; Slamon, D.J.; Ro, J.; Bondarenko, I.; Im, S.A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S.; et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e 2018, \u003cem\u003e379\u003c/em\u003e, 1926\u0026ndash;1936. https://doi.org/10.1056/NEJMoa1810527.\u003c/li\u003e\n\u003cli\u003eBattisti, N.M.L.; Mislang, A.R.; Cooper, L.; O\u0026rsquo;Donovan, A.; Audisio, R.A.; Extermann, M.; Biganzoli, L.; Wildiers, H. Adapting breast cancer management for older patients: Recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 Working Group. \u003cem\u003eJ. Geriatr. Oncol.\u003c/em\u003e 2020, \u003cem\u003e11\u003c/em\u003e, 1190\u0026ndash;1198. https://doi.org/10.1016/j.jgo.2020.06.008.\u003c/li\u003e\n\u003cli\u003eDe Glas, N.A.; Kiderlen, M.; Bastiaannet, E.; de Craen, A.J.M.; van de Water, W.; van de Velde, C.J.H.; Liefers, G.J.; Siesling, S.; Portielje, J.E.A.; van der Velde, S.; et al. Validity of Adjuvant! Online program in older patients with breast cancer: A population-based study. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2014, \u003cem\u003e15\u003c/em\u003e, 722\u0026ndash;729. https://doi.org/10.1016/S1470-2045(14)70103-9.\u003c/li\u003e\n\u003cli\u003eExtermann, M.; Aapro, M.; Bernabei, R.; Cohen, H.J.; Droz, J.P.; Lichtman, S.; Mor, V.; Monfardini, S.; Repetto, L.; S\u0026oslash;rbye, L.; et al. Use of comprehensive geriatric assessment in older cancer patients: Recommendations from the Task Force on CGA of the International Society of Geriatric Oncology (SIOG). \u003cem\u003eCrit. Rev. Oncol. Hematol.\u003c/em\u003e 2005, \u003cem\u003e55\u003c/em\u003e, 241\u0026ndash;252. https://doi.org/10.1016/j.critrevonc.2005.06.003.\u003c/li\u003e\n\u003cli\u003eWildiers, H.; Mauer, M.; Pallis, A.; Hurria, A.; Extermann, M.; Lichtman, S.; Biganzoli, L.; Trimble, E.L.; Audisio, R.; Senior, J.; et al. End points and trial design in geriatric oncology research: A joint European Organisation for Research and Treatment of Cancer\u0026mdash;Alliance for Clinical Trials in Oncology\u0026mdash;International Society of Geriatric Oncology position article. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e 2013, \u003cem\u003e31\u003c/em\u003e, 3711\u0026ndash;3718. https://doi.org/10.1200/JCO.2013.49.6125.\u003c/li\u003e\n\u003cli\u003eWorld Population Prospects 2022: Summary of Results; United Nations Department of Economic and Social Affairs, Population Division: New York, NY, USA, 2022.\u003c/li\u003e\n\u003cli\u003eBiganzoli, L.; Wildiers, H.; Oakman, C.; Marotti, L.; Loibl, S.; Kunkler, I.; Reed, M.; Brain, E.; Cardoso, M.J.; Dilhuydy, J.M.; et al. Management of elderly patients with breast cancer: Updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). \u003cem\u003eLancet Oncol.\u003c/em\u003e 2012, \u003cem\u003e13\u003c/em\u003e, e148\u0026ndash;e160. https://doi.org/10.1016/S1470-2045(11)70383-7.\u003c/li\u003e\n\u003cli\u003eFedele P, Landriscina M, Moraca L, Cusmai A, Gnoni A, Licchetta A, Guarini C, Lanotte L, Pappagallo MN, Melaccio A, Giordano G, Maselli FM, Pinto A, Giuliani F, Chiuri V, Giotta F, Gadaleta-Caldarola G. Evaluating CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: A Retrospective Real-World Multicenter Study. Cancers (Basel). 2024 Oct 10;16(20):3442. doi: https://doi.org/10.3390/cancers16203442.\u003c/li\u003e\n\u003cli\u003eNational Institute of Health. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. NIH Publication (2017).\u003c/li\u003e\n\u003cli\u003eFedele P, Landriscina M, Moraca L, Gadaleta-Caldarola A, Cusmai A, Giuliani F, Chiuri V, Giotta F, Pinto A, Mirisola V, Gadaleta-Caldarola G. Standard Versus Reduced CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: An Observational Multicenter Study. J Clin Med. 2024 Dec 6;13(23):7441. doi: 10.3390/jcm13237441.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metastatic breast cancer, Elderly patients, HR+/HER2- breast cancer, CDK4/6 inhibitors, Real-world evidence, Geriatric oncology, Treatment tolerability","lastPublishedDoi":"10.21203/rs.3.rs-6594505/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6594505/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe management of metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer in elderly patients, particularly those aged 80 years and older, remains an area of significant clinical uncertainty due to limited representation in clinical trials. Given the anticipated rise in the oldest-old population, real-world data are urgently needed to inform therapeutic strategies in this setting. This study aimed to evaluate the effectiveness and safety of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) in patients aged ≥ 80 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective, multicenter analysis across seven Italian oncology centers. Eligible patients were aged 80 years or older and had initiated CDK4/6i therapy for HR+/HER2- metastatic breast cancer between January 2020 and May 2024. Data on demographics, comorbidities, frailty (G8 score), treatment regimens, and adverse events were collected. Primary endpoints included progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan–Meier method. Safety was assessed according to CTCAE v5.0 criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 39 patients were included. The median age was 83 years. Visceral metastases were present in 53.8% of cases, and 41.1% of patients were classified as frail (G8 ≤ 14). A reduced starting dose was adopted in 43.6% of patients. Median PFS was 13 months, and median OS was 15 months. Hematologic toxicities were the most frequent adverse events: neutropenia occurred in 62% of patients (grade ≥ 3 in 25%), and anemia in 13% (grade ≥ 3 in 6%). Non-hematologic toxicities included asthenia (16%), diarrhea (8%, mainly with abemaciclib), and elevated liver enzymes (24%). No cases of thrombocytopenia or QTc prolongation were observed. Temporary treatment interruptions were necessary in a substantial proportion of patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this real-world cohort of patients aged ≥ 80 years, CDK4/6 inhibitors combined with endocrine therapy demonstrated clinically meaningful outcomes with an acceptable safety profile. Individualized treatment approaches, including dose adjustments based on frailty and comorbidities, appear critical for optimizing outcomes. These findings support the feasibility of CDK4/6i-based therapy in the oldest-old population and highlight the need for prospective geriatric-focused studies.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-20 06:47:15","doi":"10.21203/rs.3.rs-6594505/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4049e9ee-228b-4bd9-b887-6861780a994c","owner":[],"postedDate":"May 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-18T19:23:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-20 06:47:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6594505","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6594505","identity":"rs-6594505","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}