The impact of body mass index on the progression free survival of CDK 4/6 inhibitors in metastatic breast cancer patients

The impact of body mass index on the progression free survival of CDK 4/6 inhibitors in metastatic breast cancer patients | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The impact of body mass index on the progression free survival of CDK 4/6 inhibitors in metastatic breast cancer patients Dilek Çağlayan, Mehmet Zahid Koçak, Çağlayan Geredeli, Muhammed Mustafa Atcı, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4144594/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 Endocrine therapy (ET) plus cyclin-dependent kinase (CDK) 4/6 inhibitors is a standard therapy for patients with hormone receptor (HR)-positive HER-2-negative metastatic breast cancer (MBC). We aimed to investigate the effect of body mass index (BMI) on the progression-free survival (PFS) in hormone receptor (HR)-positive MBC patients who received ET plus CDK4/6 inhibitor in second- and later-line therapy. Methods Patients with metastatic HR-positive breast cancer receiving CDK 4/6 inhibitors from three institutions were enrolled in the study. A total of 116 patients admitted between January 2019 and December 2021 were retrospectively evaluated. The patients were divided into three groups according to BMI level as follows: normal weight (group 1) as 18.5–24.9 kg/m 2 , overweight (group 2) as 25-29.9 kg/m 2 , and obese (group 3): ≥ 30 kg/m 2 . Median duration of follow-up was 10.83 months. Comparisons of PFS and BMI categories were performed with Kaplan-Meier curve and log-rank test. Results The PFS was 9.3 (5.3–13.4) month in normal-weight patients, 11.1 (9.7-12.56) month in obese patients, and could not be reached in overweight patients. This difference was statistically significant (p = 0.02). The best response to CDK 4/6 inhibitor treatment in all BMI groups was partial response (group 1: 48.3%, group 2: 69%, and group 3: 46.7%; p = 0.06). Cardiac, hematological and gastrointestinal side effects were similar in all BMI groups (p > 0.05). Conclusion It was shown that while a normal weight had a negative prognostic effect on survival in patients with metastatic breast cancer, the progression-free survival of overweight patients was found to be longer. metastatic breast cancer CDK4/6 inhibitors endocrine therapy body mass index progression free survival Figures Figure 1 Introduction Obesity is one of the determined risk factors for development of breast cancer, especially during postmenopausal period. Moreover, obesity and weight gain are potential prognostic and predictive factors for the effectiveness and toxicity of the treatment for breast cancer, with an increasing interest on this issue [ 1 , 2 ]. Trials conducted on early-stage breast cancer have shown that weight gain in pre- and postmenopausal patients is associated with a higher recurrence rate and worse survival compared to those of normal-weight patients. This negative prognostic effect in early-stage breast cancer has been supported by several meta-analyses and is more pronounced in estrogen receptor-positive (ER-positive) breast cancer [ 3 – 5 ]. Recent studies in metastatic breast cancer patients have shown that obesity is a potential protective factor in metastatic disease, which differs from early stage breast cancer (1). This obesity paradox has also been demonstrated in patients with advanced colorectal cancer [ 6 ]. In a study including advanced stage metastatic breast cancer patients treated with aromatase inhibitors, it was shown that centrally obese metastatic breast cancer patients with high serum leptin level (≥ 19400 pg/ml) survived longer [ 7 ]. Cyclin-dependent kinase inhibitors (CDK 4/6 inhibitors) are drugs used together with endocrine therapy (fulvestrant and aromatase inhibitors) in the treatment of hormone receptor-positive human epidermal growth factor receptor-2 (HER-2)-negative metastatic breast cancer [ 8 – 10 ]. Ribociclib and palbociclib, selective CDK4/6 inhibitors, are administered orally. They suppress DNA synthesis by inhibiting the transition of the cell cycle from G1 phase to S phase [ 11 ]. Cyclin-dependent kinases (CDK 4/6) regulate the cell cycle by taking part in cell cycle signaling and proliferation. They also manage important metabolic processes such as lipid synthesis, glycolysis and mitochondrial functions [ 12 – 14 ]. CDK 4 activity is required for adipogenesis. CDK 4 participates in the clonal expansion phase of adipocyte differentiation. CDK 4 has also a positive, cell cycle-independent role in terminal differentiation and function of adipocytes [ 15 ]. Obesity-related peripheral effects of CDK 4/6 inhibitors are minimal, and it was shown that there is no effect of abemaciclib on obesity in the absence of type 4 melanocortin receptor in a mouse study [ 16 ]. Studies have shown that increased body mass index is associated with good prognosis, especially in male cancer patients, while increased body mass index is associated with neither good nor worse prognosis in female patients. No significant relationship has been found between body mass index and survival in breast cancer patients [ 17 ]. The effect of body mass index on survival in patients with metastatic breast cancer treated with CDK 4/6 inhibitors is poorly understood. In this study, we aimed to evaluate the effect of body mass index (BMI) on progression-free survival in patients with hormone receptor-positive HER-2-negative metastatic breast cancer treated with CDK 4/6 inhibitor and hormonal therapy. Method A hundred and sixteen patients diagnosed with hormone receptor-positive HER-2-negative metastatic breast cancer were included in this study. All patients were female. Patients received CDK 4/6 inhibitor (ribociclib or palbociclib) and endocrine therapy (letrozole or fulvestrant) as second- or subsequent-line therapy for the treatment of metastatic breast cancer. This study was conducted in three centers between January 2019 and December 2021. Ethics committee approval was received (Ethics committee approval number:2021/3340,2024/4748). Laboratory and clinical data of the patients were obtained retrospectively by scanning the hospital registry system. Body mass indexes of the patients were calculated by measuring their height and weight before starting CDK 4/6 inhibitor and endocrine therapy. The patients were divided into 3 groups according to their body mass index: group 1: 18.5–24.9 kg/m2, group 2: 25-29.9 kg/m2 and group 3: ≥ 30 kg/m2. Progression-free survival time, treatment response, and side effects of CDK4/6 inhibitors were compared between these groups. Progression-free survival was defined as the time from the beginning of treatment to disease progression detected by radiological and laboratory tests. Statistical analysis Data were analyzed with SPSS software (SPSS 15.0; IBM Inc., Chicago, IL, USA). Chi-square test was used to compare categorical variables between the groups. The distribution of study parameters was examined with the Kolmogorov-Smirnov test. Comparison of homogeneously distributed parameters was performed with the independent sample t test, whereas comparison of non-homogeneous parameters was performed with the Mann-Whitney U test. Survival curve analysis was obtained by the Kaplan Meier method and evaluated by the log-rank test. Cox-regression model was used to identify risk factors for PFS in patient groups. The significance level was considered to be a p < 0.05. Results Twenty-nine patients (25%) had a body mass index of 18.5–24.9 kg/m2, 42 patients (36.2%) 25-29.9 kg/m2, and 45 patients (38.8%) ≥ 30 kg/m2. Median duration of follow-up was 10.83 months. There was no difference between group 1, group 2 and group 3 in terms of age, ECOG-PS, hypertension, diabetes mellitus, hyperlipidemia, menopause status and metastasis at the time of diagnosis (p > 0.05 for all) (Table 1 ). Toxicity profile, dose reduction and response to CDK 4/6 inhibitors according to body mass index are similar ,in all groups(Table 2 ). No difference was detected between BMI groups in terms of palbociclib and ribociclib use (p = 0.15). There was no difference in the use of letrozole and fulvestrant in combination with CDK 4/6 inhibitors (p = 0.75). Response to CDK 4/6 inhibitors, dose reduction in CDK 4/6 inhibitors, and rates of grade 3–4 side effects of CDK 4/6 inhibitors were found to be similar between the groups (p > 0.05 for all). mPFS of Group 1 was 9.3 (5.3–13.4) months. While the mPFS of group 3 was 11.1 (9.7-12.56) months, the mPFS of group 2 could not be reached. This difference between the three groups was statistically significant (p = 0.02) (Fig. 1 ). When the patients were divided into two groups as patients receiving palbociclib and endocrine therapy and those receiving ribociclib and endocrine therapy, group 2 had better PFS than group 1 and group 3 (Fig. 1 ). The best response to CDK 4/6 inhibitor treatment in all BMI groups was partial response (group 1: 48.3%, group 2: 69%, and group 3: 46.7%; p = 0.06). Cardiac, hematological and gastrointestinal side effects were similar in all BMI groups (p > 0.05). Table 1 Characteristics of the study population according to body mass index Study population Group 1 Group 2 Group 3 p (BMI = 18-24.5 kg/m 2 ) (BMI = 25-29.5kg/m 2 ) (BMI ≥ 30 kg/m 2 ) Age (years) < 65 20 (69%) 30 (71.4%) 33 (73.3%) 0.92 ≥ 65 9 (31%) 12 (28.6%) 12 (26.7%) ECOG-PS (n) 0 20 (69%) 33 (78.6%) 29 (64.4%) 0.54 1 9 (31%) 9 (21.4%) 16 (35.6%) Hypertension (n) Yes 5 (17.2%) 11 (26.2%) 16 (35.6%) 0.22 No 24 (82.8%) 31 (73.8%) 29 (64.4%) Diabetes mellitus (n) Yes 3 (10.3%) 7 (16.7%) 11 (24.4%) 0.29 No 26 (89.7%) 35 (83.3%) 34 (75.6%) Hyperlipidemia (n) Yes 1 (3.4%) 3 (7.1%) 4 (8.9%) 0.66 No 28 (96.6%) 39 (92.9%) 41 (91.1%) Menopause status (n) Premenopausal 15 (51.7%) 19 (45.2%) 20 (44.4%) 0.81 Postmenopausal 14 (48.3%) 23 (54.8%) 25 (55.6%) Metastatic at diagnosis (n) Yes 8 (27.6%) 12 (28.6%) 16 (35.6%) 0.7 No 21 (72.4%) 30 (71.4%) 29 (64.4%) CDK 4/6 inhibitors (n) Ribociclib 12 (41.4%) 12 (28.6%) 22 (48.9%) 0.15 Palbociclib 17 (58.6%) 30 (71.4%) 23 (51.1%) Combination with CDK 4/6 inhibitors (n) Letrozole 14 (48.3%) 21 (50%) 19 (42.2%) 0.75 Fulvestrant 15 (51.7%) 21 (50%) 26 (57.8%) Table 2 Toxicity profile, dose reduction and response to CDK 4/6 inhibitors according to body mass index Group 1 Group 2 Group 3 p (BMI = 18-24.5 kg/m 2 ) (BMI = 25-29.5kg/m 2 ) (BMI ≥ 30 kg/m 2 ) Dose reduction in CDK 4/6 inhibitors (n) No 11 (37.9%) 27 (64.3%) 25 (55.6%) 0.21 Reduced 13 (44.8%) 11 (26.2%) 12 (36.7%) Interrupted 5 (17.2%) 4 (9.5%) 8 (17.8%) Response to CDK 4/6 inhibitors (n) Stable 6 (20.7%) 10 (23.8%) 16 (35.6%) 0.07 Partial 14 (48.3%) 29 (69%) 21 (46.7%) Complete 1 (3.4%) 1 (2.4%) 0 (0%) Progression 8 (27.6%) 2 (4.8%) 8 (17.8%) Grade 3–4 toxicity in CDK 4/6 inhibitors (n) Yes 15 (51.7%) 15 (35.7%) 15 (33.3%) 0.25 No 14 (48.3%) 27 (64.3%) 30 (66.7%) Discussion To our knowledge, our study is the first study evaluating the effect of BMI on progression-free survival and treatment response in patients with metastatic breast cancer receiving CDK 4/6 inhibitors (ribociclib and palbociclib) and endocrine therapy. In our study, overweight patients (BMI: 25-29.9 kg/m2) were found to have statistically better progression-free survival and response rate compared to normal-weight and obese patients. In a study evaluating the baseline body composition of patients with metastatic breast cancer receiving CDK 4/6 inhibitors and endocrine therapy, and investigating the effect of baseline body composition on PFS, sarcopenia was detected in approximately 40% of the patients at baseline and was shown to be associated with poor PFS. In the same study, it was shown that patients with higher visceral fat index and visceral fat density had better PFS. In this study, the body compositions of the patients were evaluated with computed tomography [ 18 ]. In our study, BMI, which is an easier and more cost-effective method, was used and its effect on patient survival was demonstrated. In a study in which abemaciclib was used as a CDK 4/6 inhibitor, when patients were divided into two arms as those with normal-weight BMI < 25 kg/m2 and overweight BMI ≥ 25 kg/m2, no statistically significant difference in PFS was found between both arms [ 19 ]. Ribociclib and palbociclib were used with hormonal therapy concurrently with CDK 4/6 inhibitors in our study, and the patients were divided into three arms according to BMI. PFS of obese patients with a BMI of > 30 kg/m2 was also evaluated. In a study in which palbociclib was used as a CDK 4/6 inhibitor, patients with a BMI of < 25 were associated with significantly worse PFS compared with patients with a BMI of ≥ 25 (HR 2.32, 95%CI 1.09–4.95; log-rank p = 0.0360) [ 20 ]. In a study evaluating 5668 early stage breast cancer patients who underwent curative surgery, a BMI of ≥ 25 kg/m2 was found to be a negative factor for overall survival. When the patients were divided into subgroups according to their molecular intrinsic characteristics, both OS and PFS were found to be longer in the BMI 25 kg/m2 group in the hormone receptor-positive, HER-2-negative subgroup (3). Obesity was associated with an increased risk of breast cancer recurrence among postmenopausal patients with hormone receptor-positive, early-stage breast cancer treated with aromatase inhibitors [ 21 ]. In similar studies, the cut-off value for body mass index was assumed to be 25 kg/m2 and they were divided into two arms: normal-weight patients and overweight-obese patients. In our study, when the patients were divided into three arms and overweight patients with a BMI of 25-29.9 kg/m2 were evaluated as a separate subgroup, mPFS was found to be better in this group compared to the other arms. In our previous study consisting of 179 patients, when patients receiving endocrine therapy with CDK 4/6 inhibitors were divided into 3 groups according to their body mass index, overweight patients were found to have better PFS. This difference in PFS did not show statistical significance. The median duration of follow-up in the study was 10.94 months. In this study, patients received CDK 4/6 inhibitor treatment in the first and subsequent lines [ 22 ]. The limitations of our study are low number of patients and that all patients received this therapy in the second and subsequent lines. Median duration of follow-up is not enough to calculate the overall survival. In hormone receptor-positive HER-2-negative breast cancer, peripheral estrogen production by the enzyme aromatase may explain the decreased survival in obese patients; furthermore, insufficient muscle mass and fat tissue in sarcopenic and lean patients may affect the distribution of drugs across the body and increase rate of toxicity. There was no difference in term of adverse event between all groups. Conclusion It was shown that low body mass index had a negative prognostic effect on survival in patients with metastatic breast cancer, and the progression-free survival of overweight patients was found to be longer. Moreover, obese patients had better PFS than normal-weight patients. The results of this study will be further clarified with a clear understanding of the effects of CDK 4/6 inhibitors on metabolic processes. Declarations Ethics Committee Approval: This research was conducted ethically in accordance with the World Medical Association Helsinki Declaration. All patients had to give informed consent before participating in our sensitive study. Ethics approval was obtained from Necmettin Erbakan University Medical Faculty, Konya, Turkey (Ethics Committee No: Informed Consent: Written informed consent was obtained from the patients who participated in this study. Conflict of Interest: The authors have no conflict of interest to declare. Author Contributions: Concept – D.Ç., M.A..; Design –D.Ç., M.A.; Supervision –All authors; Data Collection and/or Processing –All authors.; Analysis and/or Interpretation –M.Z.K, M.A..; Literature Search – D.Ç.; Writing –D.Ç., M.Z.K, M.A, Critical Reviews – All authors. Funding: No funding was received for conducting this study. Data availability: None References Trestini I, Carbognin L, Monteverdi S. et al (2018) Clinical implication of changes in body composition and weight in patients with early-stage and metastatic breast cancer. Crit Rev Oncol Hematol 129:54–66 Ligibel JA, Alfano CM, Courneya KS. et al (2014) American Society of Clinical Oncology Position Statement on Obesity and Cancer. J Clin Oncol 32:3568–3574 Cho WK, Choi DH, Park W. et al (2018) Effect of Body Mass Index on Survival in Breast Cancer Patients According to Subtype, Metabolic Syndrome, and Treatment. Clinical Breast Cancer 18:e1141–e1147 Chan DSM, Vieira AR, Aune D. et al (2014) Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25:1901–1914 Yerushalmi R, Dong B, Chapman JW. et al (2017) Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 28:1560–1568 Charette N, Vandeputte C, Ameye L. et al (2019) Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials. BMC Cancer 19:134 Artac M., Bozcuk H., Kıyıcı A. et al (2013). Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs). Breast Cancer , 20 , 174-180. Goetz MP, Toi M, Campone M. et al (2017) MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 35:3638–3646 Hortobagyi GN, Stemmer SM, Burris HA. et al (2018) Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 29:1541–1547 Rugo HS, Finn RS, Diéras V. et al (2019) 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 174:719–729 Spring LM, Wander SA, Andre F. et al (2020) Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395:817– 827. Aguilar V, Fajas L (2010) Cycling through metabolism. EMBO Mol Med 2:338–348 Lagarrigue S, Lopez-Mejia IC, Denechaud P-D. et al (2015) CDK4 is an essential insulin effector in adipocytes. Journal of Clinical Investigation 126:335–348 Fajas L (2013) Re-thinking cell cycle regulators: the cross-talk with metabolism. Frontiers in Oncology 3:1–6 Abella A, Dubus P, Malumbres M. et al.(2005) Cdk4 promotes adipogenesis through PPARgamma activation. Cell Metab . 2005;2(4):239-249. doi:10.1016/j.cmet.2005.09.003 Iqbal NJ, Schwartz GJ, Zhao H. et al (2021) Cyclin-dependent kinase 4/6 inhibitors require an arcuate-to-paraventricular hypothalamus melanocortin circuit to treat diet-induced obesity. Am J Physiol Endocrinol Metab. 2021;320(3):E467-E474. doi:10.1152/ajpendo.00386.2020 Greenlee H, Unger JM, LeBlanc M. et al (2017) Association between Body Mass Index and Cancer Survival in a Pooled Analysis of 22 Clinical Trials. Cancer Epidemiol Biomarkers Prev 26:21–29 Franzoi M.A, Vandeputte C, Eiger D. et.al(2020) Computed tomography-based analyses of baseline body composition parameters and changes in breast cancer patients under treatment with CDK 4/6 inhibitors, Breast Cancer Research and Treatment volume 181, pages199–209 Franzoi M.A.,Eiger D., Ameve L. et. al.(2020) Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy, J Natl Cancer Inst. 2021 Apr; 113(4): 462–470. doi: 10.1093/jnci/djaa116 Roncato R, Peruzzi E, Gerratana L. et al.(2023) "Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure." Biomedicine & Pharmacotherapy 164 (2023): 114906. Harborg S, Cronin-Fenton D, Jensen MR. et al (2023) Obesity and Risk of Recurrence in Patients With Breast Cancer Treated With Aromatase Inhibitors. JAMA Netw Open . 2023;6(10):e2337780. Published. doi:10.1001/jamanetworkopen.2023.37780 Çağlayan D., Koçak M.Z., Geredeli Ç. et.al (2022) The effect of BMI on the outcomes of CDK 4/6 inhibitor therapy in HR-positive metastatic breast cancer patients. Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) e13010-e13010. DOI: 10.1200/JCO.2022.40.16_suppl.e13010 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About In Review Editorial Policies 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-4144594","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":282648897,"identity":"55dc2cab-3b56-4049-a96e-8ffd25d4d380","order_by":0,"name":"Dilek Çağlayan","email":"data:image/png;base64,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","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Dilek","middleName":"","lastName":"Çağlayan","suffix":""},{"id":282648898,"identity":"3c611630-8627-42e4-85ce-d8febba18027","order_by":1,"name":"Mehmet Zahid Koçak","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"Zahid","lastName":"Koçak","suffix":""},{"id":282648899,"identity":"7ec4225d-75a7-4f04-8703-7fa6b1dc4c2e","order_by":2,"name":"Çağlayan Geredeli","email":"","orcid":"","institution":"Okmeydanı Training and Research Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Çağlayan","middleName":"","lastName":"Geredeli","suffix":""},{"id":282648900,"identity":"5d4b9d9b-c021-43fc-bdba-a80b82d38588","order_by":3,"name":"Muhammed Mustafa Atcı","email":"","orcid":"","institution":"Prof. Dr. Cemil Tasçıoğlu City Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"Mustafa","lastName":"Atcı","suffix":""},{"id":282648901,"identity":"4e545ac2-873d-44e2-8a63-dfcc83779859","order_by":4,"name":"Ali Murat Tatlı","email":"","orcid":"","institution":"Akdeniz University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ali","middleName":"Murat","lastName":"Tatlı","suffix":""},{"id":282648902,"identity":"f99ae5b4-6379-40e6-add4-4ac2c7eb71c4","order_by":5,"name":"Sema Sezgin Göksu","email":"","orcid":"","institution":"Akdeniz University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sema","middleName":"Sezgin","lastName":"Göksu","suffix":""},{"id":282648903,"identity":"aa7f35e1-13a3-4a7f-acb6-ee9062ef471c","order_by":6,"name":"Melek Karakurt Eryılmaz","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Melek","middleName":"Karakurt","lastName":"Eryılmaz","suffix":""},{"id":282648904,"identity":"364ebdc4-cbd5-4a55-83b9-c1a3f56e3754","order_by":7,"name":"Murat Araz","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Murat","middleName":"","lastName":"Araz","suffix":""},{"id":282648905,"identity":"026487f7-f038-4840-87d0-076aef129651","order_by":8,"name":"Mehmet Artaç","email":"","orcid":"","institution":"Necmettin Erbakan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"","lastName":"Artaç","suffix":""}],"badges":[],"createdAt":"2024-03-21 15:32:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4144594/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4144594/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53580949,"identity":"5663ba1f-4f38-4ab2-847a-18fb7da75e06","added_by":"auto","created_at":"2024-03-27 17:30:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":321908,"visible":true,"origin":"","legend":"\u003cp\u003eThe progression free survival according to body mass index groups (Ribociclib group: log-rank p=0.23; Palbociclib group: log-rank p=0.058; Study group log-rank p=0.02)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4144594/v1/439d596e7fe55ed18b0ccfd3.png"},{"id":53658586,"identity":"90a36d1f-9e1f-45be-82c3-9651884600cb","added_by":"auto","created_at":"2024-03-28 15:59:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":408346,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4144594/v1/4cc37d2d-56c4-4028-a6c1-de87a998516b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of body mass index on the progression free survival of CDK 4/6 inhibitors in metastatic breast cancer patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eObesity is one of the determined risk factors for development of breast cancer, especially during postmenopausal period. Moreover, obesity and weight gain are potential prognostic and predictive factors for the effectiveness and toxicity of the treatment for breast cancer, with an increasing interest on this issue [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTrials conducted on early-stage breast cancer have shown that weight gain in pre- and postmenopausal patients is associated with a higher recurrence rate and worse survival compared to those of normal-weight patients. This negative prognostic effect in early-stage breast cancer has been supported by several meta-analyses and is more pronounced in estrogen receptor-positive (ER-positive) breast cancer [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies in metastatic breast cancer patients have shown that obesity is a potential protective factor in metastatic disease, which differs from early stage breast cancer (1). This obesity paradox has also been demonstrated in patients with advanced colorectal cancer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a study including advanced stage metastatic breast cancer patients treated with aromatase inhibitors, it was shown that centrally obese metastatic breast cancer patients with high serum leptin level (\u0026ge;\u0026thinsp;19400 pg/ml) survived longer [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCyclin-dependent kinase inhibitors (CDK 4/6 inhibitors) are drugs used together with endocrine therapy (fulvestrant and aromatase inhibitors) in the treatment of hormone receptor-positive human epidermal growth factor receptor-2 (HER-2)-negative metastatic breast cancer [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRibociclib and palbociclib, selective CDK4/6 inhibitors, are administered orally. They suppress DNA synthesis by inhibiting the transition of the cell cycle from G1 phase to S phase [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCyclin-dependent kinases (CDK 4/6) regulate the cell cycle by taking part in cell cycle signaling and proliferation. They also manage important metabolic processes such as lipid synthesis, glycolysis and mitochondrial functions [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. CDK 4 activity is required for adipogenesis. CDK 4 participates in the clonal expansion phase of adipocyte differentiation. CDK 4 has also a positive, cell cycle-independent role in terminal differentiation and function of adipocytes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eObesity-related peripheral effects of CDK 4/6 inhibitors are minimal, and it was shown that there is no effect of abemaciclib on obesity in the absence of type 4 melanocortin receptor in a mouse study [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have shown that increased body mass index is associated with good prognosis, especially in male cancer patients, while increased body mass index is associated with neither good nor worse prognosis in female patients. No significant relationship has been found between body mass index and survival in breast cancer patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe effect of body mass index on survival in patients with metastatic breast cancer treated with CDK 4/6 inhibitors is poorly understood. In this study, we aimed to evaluate the effect of body mass index (BMI) on progression-free survival in patients with hormone receptor-positive HER-2-negative metastatic breast cancer treated with CDK 4/6 inhibitor and hormonal therapy.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eA hundred and sixteen patients diagnosed with hormone receptor-positive HER-2-negative metastatic breast cancer were included in this study. All patients were female. Patients received CDK 4/6 inhibitor (ribociclib or palbociclib) and endocrine therapy (letrozole or fulvestrant) as second- or subsequent-line therapy for the treatment of metastatic breast cancer. This study was conducted in three centers between January 2019 and December 2021. Ethics committee approval was received (Ethics committee approval number:2021/3340,2024/4748). Laboratory and clinical data of the patients were obtained retrospectively by scanning the hospital registry system. Body mass indexes of the patients were calculated by measuring their height and weight before starting CDK 4/6 inhibitor and endocrine therapy. The patients were divided into 3 groups according to their body mass index: group 1: 18.5\u0026ndash;24.9 kg/m2, group 2: 25-29.9 kg/m2 and group 3: \u0026ge; 30 kg/m2. Progression-free survival time, treatment response, and side effects of CDK4/6 inhibitors were compared between these groups. Progression-free survival was defined as the time from the beginning of treatment to disease progression detected by radiological and laboratory tests.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were analyzed with SPSS software (SPSS 15.0; IBM Inc., Chicago, IL, USA). Chi-square test was used to compare categorical variables between the groups. The distribution of study parameters was examined with the Kolmogorov-Smirnov test. Comparison of homogeneously distributed parameters was performed with the independent sample t test, whereas comparison of non-homogeneous parameters was performed with the Mann-Whitney U test. Survival curve analysis was obtained by the Kaplan Meier method and evaluated by the log-rank test. Cox-regression model was used to identify risk factors for PFS in patient groups. The significance level was considered to be a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty-nine patients (25%) had a body mass index of 18.5\u0026ndash;24.9 kg/m2, 42 patients (36.2%) 25-29.9 kg/m2, and 45 patients (38.8%)\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m2. Median duration of follow-up was 10.83 months. There was no difference between group 1, group 2 and group 3 in terms of age, ECOG-PS, hypertension, diabetes mellitus, hyperlipidemia, menopause status and metastasis at the time of diagnosis (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Toxicity profile, dose reduction and response to CDK 4/6 inhibitors according to body mass index are similar ,in all groups(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No difference was detected between BMI groups in terms of palbociclib and ribociclib use (p\u0026thinsp;=\u0026thinsp;0.15). There was no difference in the use of letrozole and fulvestrant in combination with CDK 4/6 inhibitors (p\u0026thinsp;=\u0026thinsp;0.75). Response to CDK 4/6 inhibitors, dose reduction in CDK 4/6 inhibitors, and rates of grade 3\u0026ndash;4 side effects of CDK 4/6 inhibitors were found to be similar between the groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all). mPFS of Group 1 was 9.3 (5.3\u0026ndash;13.4) months. While the mPFS of group 3 was 11.1 (9.7-12.56) months, the mPFS of group 2 could not be reached. This difference between the three groups was statistically significant (p\u0026thinsp;=\u0026thinsp;0.02) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). When the patients were divided into two groups as patients receiving palbociclib and endocrine therapy and those receiving ribociclib and endocrine therapy, group 2 had better PFS than group 1 and group 3 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The best response to CDK 4/6 inhibitor treatment in all BMI groups was partial response (group 1: 48.3%, group 2: 69%, and group 3: 46.7%; p\u0026thinsp;=\u0026thinsp;0.06). Cardiac, hematological and gastrointestinal side effects were similar in all BMI groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population according to body mass index\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eStudy population\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(BMI\u0026thinsp;=\u0026thinsp;18-24.5 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(BMI\u0026thinsp;=\u0026thinsp;25-29.5kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (71.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (26.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eECOG-PS (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (78.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (64.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (35.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHypertension (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (17.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (35.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (82.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (73.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (64.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDiabetes mellitus (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (24.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (89.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34 (75.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHyperlipidemia (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (96.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (92.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41 (91.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMenopause status (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (48.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (54.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMetastatic at diagnosis (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (35.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (72.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (71.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (64.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCDK 4/6 inhibitors (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRibociclib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (41.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 (48.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePalbociclib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (71.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (51.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCombination with CDK 4/6 inhibitors (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLetrozole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (48.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (42.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFulvestrant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (57.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eToxicity profile, dose reduction and response to CDK 4/6 inhibitors according to body mass index\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(BMI\u0026thinsp;=\u0026thinsp;18-24.5 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(BMI\u0026thinsp;=\u0026thinsp;25-29.5kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eDose reduction in CDK 4/6 inhibitors (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (37.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReduced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (44.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (36.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInterrupted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (17.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (17.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eResponse to CDK 4/6 inhibitors (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (20.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (35.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePartial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (48.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (46.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProgression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (4.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (17.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGrade 3\u0026ndash;4 toxicity in CDK 4/6 inhibitors (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (48.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, our study is the first study evaluating the effect of BMI on progression-free survival and treatment response in patients with metastatic breast cancer receiving CDK 4/6 inhibitors (ribociclib and palbociclib) and endocrine therapy. In our study, overweight patients (BMI: 25-29.9 kg/m2) were found to have statistically better progression-free survival and response rate compared to normal-weight and obese patients.\u003c/p\u003e \u003cp\u003eIn a study evaluating the baseline body composition of patients with metastatic breast cancer receiving CDK 4/6 inhibitors and endocrine therapy, and investigating the effect of baseline body composition on PFS, sarcopenia was detected in approximately 40% of the patients at baseline and was shown to be associated with poor PFS. In the same study, it was shown that patients with higher visceral fat index and visceral fat density had better PFS. In this study, the body compositions of the patients were evaluated with computed tomography [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, BMI, which is an easier and more cost-effective method, was used and its effect on patient survival was demonstrated.\u003c/p\u003e \u003cp\u003eIn a study in which abemaciclib was used as a CDK 4/6 inhibitor, when patients were divided into two arms as those with normal-weight BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m2 and overweight BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m2, no statistically significant difference in PFS was found between both arms [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRibociclib and palbociclib were used with hormonal therapy concurrently with CDK 4/6 inhibitors in our study, and the patients were divided into three arms according to BMI. PFS of obese patients with a BMI of \u0026gt;\u0026thinsp;30 kg/m2 was also evaluated. In a study in which palbociclib was used as a CDK 4/6 inhibitor, patients with a BMI of \u0026lt;\u0026thinsp;25 were associated with significantly worse PFS compared with patients with a BMI of \u0026ge;\u0026thinsp;25 (HR 2.32, 95%CI 1.09\u0026ndash;4.95; log-rank p\u0026thinsp;=\u0026thinsp;0.0360) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a study evaluating 5668 early stage breast cancer patients who underwent curative surgery, a BMI of \u0026ge;\u0026thinsp;25 kg/m2 was found to be a negative factor for overall survival. When the patients were divided into subgroups according to their molecular intrinsic characteristics, both OS and PFS were found to be longer in the BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m2 group compared to those of the BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m2 group in the hormone receptor-positive, HER-2-negative subgroup (3). Obesity was associated with an increased risk of breast cancer recurrence among postmenopausal patients with hormone receptor-positive, early-stage breast cancer treated with aromatase inhibitors [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn similar studies, the cut-off value for body mass index was assumed to be 25 kg/m2 and they were divided into two arms: normal-weight patients and overweight-obese patients. In our study, when the patients were divided into three arms and overweight patients with a BMI of 25-29.9 kg/m2 were evaluated as a separate subgroup, mPFS was found to be better in this group compared to the other arms.\u003c/p\u003e \u003cp\u003eIn our previous study consisting of 179 patients, when patients receiving endocrine therapy with CDK 4/6 inhibitors were divided into 3 groups according to their body mass index, overweight patients were found to have better PFS. This difference in PFS did not show statistical significance. The median duration of follow-up in the study was 10.94 months. In this study, patients received CDK 4/6 inhibitor treatment in the first and subsequent lines [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe limitations of our study are low number of patients and that all patients received this therapy in the second and subsequent lines. Median duration of follow-up is not enough to calculate the overall survival.\u003c/p\u003e \u003cp\u003eIn hormone receptor-positive HER-2-negative breast cancer, peripheral estrogen production by the enzyme aromatase may explain the decreased survival in obese patients; furthermore, insufficient muscle mass and fat tissue in sarcopenic and lean patients may affect the distribution of drugs across the body and increase rate of toxicity. There was no difference in term of adverse event between all groups.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIt was shown that low body mass index had a negative prognostic effect on survival in patients with metastatic breast cancer, and the progression-free survival of overweight patients was found to be longer. Moreover, obese patients had better PFS than normal-weight patients.\u003c/p\u003e \u003cp\u003eThe results of this study will be further clarified with a clear understanding of the effects of CDK 4/6 inhibitors on metabolic processes.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cstrong\u003eEthics Committee Approval:\u003c/strong\u003e This research was conducted ethically in accordance with the World Medical Association Helsinki Declaration. \u0026nbsp;All patients had to give informed consent before participating in our sensitive study. Ethics approval was obtained from Necmettin Erbakan University Medical Faculty, Konya, Turkey (Ethics Committee No:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent:\u003c/strong\u003e Written informed consent was obtained from the patients who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e The authors have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Concept \u0026ndash; D.\u0026Ccedil;., M.A..; Design \u0026ndash;D.\u0026Ccedil;., M.A.; Supervision \u0026ndash;All authors; Data Collection and/or Processing \u0026ndash;All authors.; Analysis and/or Interpretation \u0026ndash;M.Z.K, M.A..; Literature Search \u0026ndash; D.\u0026Ccedil;.; Writing \u0026ndash;D.\u0026Ccedil;., M.Z.K, M.A, Critical Reviews \u0026ndash; All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTrestini I, Carbognin L, Monteverdi S. et al (2018) Clinical implication of changes in body composition and weight in patients with early-stage and metastatic breast cancer. Crit Rev Oncol Hematol 129:54\u0026ndash;66\u003c/li\u003e\n\u003cli\u003eLigibel JA, Alfano CM, Courneya KS. et al (2014) American Society of Clinical Oncology Position Statement on Obesity and Cancer. J Clin Oncol 32:3568\u0026ndash;3574\u003c/li\u003e\n\u003cli\u003eCho WK, Choi DH, Park W. et al (2018) Effect of Body Mass Index on Survival in Breast Cancer Patients According to Subtype, Metabolic Syndrome, and Treatment. Clinical Breast Cancer 18:e1141\u0026ndash;e1147\u003c/li\u003e\n\u003cli\u003eChan DSM, Vieira AR, Aune D. et al (2014) Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25:1901\u0026ndash;1914\u003c/li\u003e\n\u003cli\u003eYerushalmi R, Dong B, Chapman JW. et al (2017) Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 28:1560\u0026ndash;1568\u003c/li\u003e\n\u003cli\u003eCharette N, Vandeputte C, Ameye L. et al (2019) Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials. BMC Cancer 19:134\u003c/li\u003e\n\u003cli\u003eArtac M., Bozcuk H., Kıyıcı A. et al (2013). Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs). \u003cem\u003eBreast Cancer\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e, 174-180.\u003c/li\u003e\n\u003cli\u003eGoetz MP, Toi M, Campone M. et al (2017) MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 35:3638\u0026ndash;3646\u003c/li\u003e\n\u003cli\u003eHortobagyi GN, Stemmer SM, Burris HA. et al (2018) Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 29:1541\u0026ndash;1547\u003c/li\u003e\n\u003cli\u003eRugo HS, Finn RS, Di\u0026eacute;ras V. et al (2019) 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 174:719\u0026ndash;729\u003c/li\u003e\n\u003cli\u003eSpring LM, Wander SA, Andre F. et al (2020) Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395:817\u0026ndash; 827.\u003c/li\u003e\n\u003cli\u003eAguilar V, Fajas L (2010) Cycling through metabolism. EMBO Mol Med 2:338\u0026ndash;348\u003c/li\u003e\n\u003cli\u003eLagarrigue S, Lopez-Mejia IC, Denechaud P-D. et al (2015) CDK4 is an essential insulin effector in adipocytes. Journal of Clinical Investigation 126:335\u0026ndash;348\u003c/li\u003e\n\u003cli\u003eFajas L (2013) Re-thinking cell cycle regulators: the cross-talk with metabolism. Frontiers in Oncology 3:1\u0026ndash;6\u003c/li\u003e\n\u003cli\u003eAbella A, Dubus P, Malumbres M. et al.(2005) Cdk4 promotes adipogenesis through PPARgamma activation. \u003cem\u003eCell Metab\u003c/em\u003e. 2005;2(4):239-249. doi:10.1016/j.cmet.2005.09.003\u003c/li\u003e\n\u003cli\u003eIqbal NJ, Schwartz GJ, Zhao H. et al (2021) Cyclin-dependent kinase 4/6 inhibitors require an arcuate-to-paraventricular hypothalamus melanocortin circuit to treat diet-induced obesity. Am J Physiol Endocrinol Metab. 2021;320(3):E467-E474. doi:10.1152/ajpendo.00386.2020\u003cstrong\u003e \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003eGreenlee H, Unger JM, LeBlanc M. et al (2017) Association between Body Mass Index and Cancer Survival in a Pooled Analysis of 22 Clinical Trials. Cancer Epidemiol Biomarkers Prev 26:21\u0026ndash;29\u003c/li\u003e\n\u003cli\u003eFranzoi M.A, Vandeputte C, Eiger D. et.al(2020) Computed tomography-based analyses of baseline body composition parameters and changes in breast cancer patients under treatment with CDK 4/6 inhibitors, \u003cem\u003eBreast Cancer Research and Treatment\u003c/em\u003e volume 181, pages199\u0026ndash;209 \u003c/li\u003e\n\u003cli\u003eFranzoi M.A.,Eiger D., Ameve L. et. al.(2020) Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy, J Natl Cancer Inst. 2021 Apr; 113(4): 462\u0026ndash;470. doi: 10.1093/jnci/djaa116\u003c/li\u003e\n\u003cli\u003eRoncato R, Peruzzi E, Gerratana L. et al.(2023) \u0026quot;Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure.\u0026quot; Biomedicine \u0026amp; Pharmacotherapy 164 (2023): 114906.\u003c/li\u003e\n\u003cli\u003eHarborg S, Cronin-Fenton D, Jensen MR. et al (2023) Obesity and Risk of Recurrence in Patients With Breast Cancer Treated With Aromatase Inhibitors. \u003cem\u003eJAMA Netw Open\u003c/em\u003e. 2023;6(10):e2337780. Published. doi:10.1001/jamanetworkopen.2023.37780\u003c/li\u003e\n\u003cli\u003e\u0026Ccedil;ağlayan D., Ko\u0026ccedil;ak M.Z., Geredeli \u0026Ccedil;. et.al (2022) The effect of BMI on the outcomes of CDK 4/6 inhibitor therapy in HR-positive metastatic breast cancer patients. \u003ccite\u003eJournal of Clinical Oncology\u003c/cite\u003e\u003cem\u003e 40,\u003c/em\u003e no. 16_suppl (June 01, 2022) e13010-e13010. DOI: 10.1200/JCO.2022.40.16_suppl.e13010\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, CDK4/6 inhibitors, endocrine therapy, body mass index, progression free survival","lastPublishedDoi":"10.21203/rs.3.rs-4144594/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4144594/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eEndocrine therapy (ET) plus cyclin-dependent kinase (CDK) 4/6 inhibitors is a standard therapy for patients with hormone receptor (HR)-positive HER-2-negative metastatic breast cancer (MBC). We aimed to investigate the effect of body mass index (BMI) on the progression-free survival (PFS) in hormone receptor (HR)-positive MBC patients who received ET plus CDK4/6 inhibitor in second- and later-line therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with metastatic HR-positive breast cancer receiving CDK 4/6 inhibitors from three institutions were enrolled in the study. A total of 116 patients admitted between January 2019 and December 2021 were retrospectively evaluated. The patients were divided into three groups according to BMI level as follows: normal weight (group 1) as 18.5\u0026ndash;24.9 kg/m\u003csup\u003e2\u003c/sup\u003e, overweight (group 2) as 25-29.9 kg/m\u003csup\u003e2\u003c/sup\u003e, and obese (group 3): \u0026ge; 30 kg/m\u003csup\u003e2\u003c/sup\u003e. Median duration of follow-up was 10.83 months. Comparisons of PFS and BMI categories were performed with Kaplan-Meier curve and log-rank test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe PFS was 9.3 (5.3\u0026ndash;13.4) month in normal-weight patients, 11.1 (9.7-12.56) month in obese patients, and could not be reached in overweight patients. This difference was statistically significant (p\u0026thinsp;=\u0026thinsp;0.02). The best response to CDK 4/6 inhibitor treatment in all BMI groups was partial response (group 1: 48.3%, group 2: 69%, and group 3: 46.7%; p\u0026thinsp;=\u0026thinsp;0.06). Cardiac, hematological and gastrointestinal side effects were similar in all BMI groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIt was shown that while a normal weight had a negative prognostic effect on survival in patients with metastatic breast cancer, the progression-free survival of overweight patients was found to be longer.\u003c/p\u003e","manuscriptTitle":"The impact of body mass index on the progression free survival of CDK 4/6 inhibitors in metastatic breast cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-27 17:30:54","doi":"10.21203/rs.3.rs-4144594/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":"fd73ad01-b28b-4a6b-ba6a-84ad7c4da0be","owner":[],"postedDate":"March 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-03T02:44:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-27 17:30:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4144594","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4144594","identity":"rs-4144594","version":["v1"]},"buildId":"pf3fE39SIOqb-0xH_OWvX","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}