Alopecia induced by CDK 4/6 Inhibitors and its Impact on the Quality of Life of Patients with advanced Breast cancer

Alopecia induced by CDK 4/6 Inhibitors and its Impact on the Quality of Life of Patients with advanced Breast cancer | 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 Alopecia induced by CDK 4/6 Inhibitors and its Impact on the Quality of Life of Patients with advanced Breast cancer Wissam Khalil, Nahed Damaj, Rami Mohanna, Fadi El Karak, Joseph Kattan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7690740/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 Background Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the management of hormone receptor-positive (HR+) advanced and metastatic breast cancer. However, CDK4/6 inhibitor-induced alopecia, a distinct and often underestimated adverse effect, can significantly impact patients' quality of life. This study aims to identify and quantify the severity of alopecia caused by CDK4/6 inhibitors and its effect on quality of life using validated assessment tools. Methods This cross-sectional, single-center study included 51 female breast cancer patients treated with CDK4/6 inhibitors for at least three months, as first line for metastatic disease. Alopecia severity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading scale, while the impact on quality of life was assessed through the Hair-Specific Skindex-29 questionnaire. Statistical analysis included t-tests, ANOVA, Chi-square tests, and linear regression to identify predictors of quality-of-life impairment. Results Nearly half of the participants (49%) developed alopecia, with 26% graded as CTCAE grade I and 23% as grade II. Higher CTCAE grades were associated with significantly worse Hair-Specific Skindex-29 scores in the emotions, symptoms, and functional capacity subsections (p < 0.05). Regression analysis showed that both the CTCAE grade and the specific CDK4/6 inhibitor used were significant predictors of overall quality-of-life impairment. Conclusion This study is the first to quantify the impact of CDK4/6 inhibitor-induced alopecia on quality of life in the MENA (Middle East and North Africa) region, showing that greater alopecia severity leads to more symptoms, and worse emotional and functional well-being. CDK4/6inhibitors hormone positive metastatic breast cancer alopecia quality of life CTCAE grade 1-Introduction Approximately 1 in 8 women in the US (13.1%) will be diagnosed with invasive breast cancer, and 1 in 43 (2.3%) will die from the disease. In 2024, an estimated 310,720 new invasive breast cancers will be diagnosed among women in the US, and an additional 2,790 cases will be diagnosed in men. Approximately 42,250 women and 530 men are expected to die from breast cancer in 2024. Breast cancer incidence increased during the most recent decade by 1% annually overall, with a steeper increase among women younger than 50 years (1.4% per year) than in those 50 or older (0.7% per year) ( 1 ). By 2040, due to population growth and aging, breast cancer cases are projected to surpass 3 million annually, with deaths reaching 1 million each year ( 2 ). The development of CDK 4/6 inhibitors has transformed the therapeutic landscape of metastatic breast cancer management. The FDA has initially approved three highly selective, orally active, and reversible CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, for use in combination with specific endocrine therapies in the treatment of hormone receptor-positive (HR+) advanced or metastatic breast cancer. However, CDK 4/6 inhibitors are not avoiding adverse events. It was found that the addition of CDK4/6 inhibitors resulted in a significant increase of leucopenia, neutropenia, anemia, nausea, diarrhea, constipation, fatigue, pyrexia, venous thromboembolism abdominal pain, cough, and even alopecia ( 3 ). Alopecia is a significant adverse event, affecting 55% of breast cancer patients and causing considerable psychological distress ( 4 ). It ranks as the third most common adverse event of breast cancer treatment, following nausea and vomiting ( 5 , 6 ). Alopecia induced by CDK 4/6 inhibitors is almost underestimated, distinct from other forms due to its distribution and early onset. Although few studies have examined the impact of alopecia on patients undergoing breast cancer treatment, no study, to our knowledge, has specifically quantified the impact of CDK 4/6 inhibitor-induced alopecia on quality of life. Therefore, this study aims to identify and quantify the severity of alopecia caused by CDK 4/6 inhibitors, graded using the CTCAE grading scale, and its impact on quality of life, as assessed through the Hair-Specific Skindex-29 questionnaire. 2-Material and Methods 2.1 Study Design: This is a cross-sectional single center study assessing the impact of alopecia on patients being currently treated for breast cancer with a CDK4/6 inhibitor. All patients signed an informed consent form and procedures were conducted according to the Declaration of Helsinki. The institutional ethical committee approved the study under the code number CEHDF2302. Inclusion criteria consisted of female patients having a diagnosis of metastatic or high-risk localized breast cancer, being treated with a CDK4/6 inhibitor for a minimal duration of 3 months in association with aromatase inhibitors or estrogen receptor modulators and being able to independently respond to the administered questionnaire. Exclusion criteria consisted of patients being admitted to the hospital at the time of questionnaires administration because it may impact their response to the questionnaire, patients presenting with alopecia that is not induced by the CDK4/6 inhibitors, and patients with incomplete data. 2.2 Included Variables Measurements: Patients are selected from the outpatient clinics of the physicians practicing at Hotel Dieu De France Hospital. For the patients to be included, they should complete CTCAE grading scale for alopecia where a grade I is assigned to a hair loss of 50% compared to baseline ( 7 ). In addition, patients should fill out the Hair-Specific Skindex-29 questionnaire(HSS-29)( 8 ). (Table 1 ). The HSS-29 designed to assess quality of life in patients with alopecia. It contains 29 items distributed across three domains: Symptoms: 7 items (covering physical sensations such as itching, irritation, burning, or sensitivity of the scalp) Functioning: 12 items (impact on daily activities, social interactions, work, and self-perception) Emotions: 10 items (feelings of embarrassment, frustration, worry, depression, or diminished confidence due to hair loss) In the HSS-29, the degree of quality-of-life impairment can be categorized into four levels based on total and domain scores (scaled 0–100). As shown in Table 1 , very little impairment is reflected by scores < 5 in the emotions domain, < 3 in symptoms, < 3 in functional capacity, and < 5 in total score, meaning hair loss has minimal impact. Mild impairment is defined by scores of 6–24 for emotions, 4–10 for symptoms, 4–10 for functioning, and 6–17 in the total score, indicating occasional but limited interference in daily life. Moderate impairment corresponds to scores of 25–49 in emotions, 11–25 in symptoms, 11–32 in functioning, and 18–36 overall, showing more frequent bother and a noticeable effect on psychosocial well-being. Severe impairment is reached at ≥ 50 in emotions, 26–49 in symptoms, ≥ 33 in functioning, and ≥ 37 overall, demonstrating substantial and persistent impact with social and emotional consequences. Finally, extremely severe impairment is specifically defined for the symptoms domain at ≥ 50, representing the highest level of distress, where scalp sensations and hair concerns dominate daily life. This stratification helps clinicians and researchers interpret HSS-29 scores consistently, compare groups, and correlate disease severity with quality-of-life burden. 2.3 Statistical Analysis: The data have been analyzed using the SPSS 26.0 software (SPSS Inc., Chicago, IL, USA). The raw Hair-Specific Skindex-29 questionnaire scores were converted to a 0-100 scale to categorize them according to Nijsten et al. ( 8 ) The Kolmogorov–Smirnov test was used to assess the normal distribution of the data. Continuous data was expressed with means ± standard deviation while categorical data was expressed with %. To determine a potential existing relation between categorical variables a Chi-square test was used. Independent samples t-test, and ANOVA were used to compare quantitative variables between the groups. Finally, linear regression was used to determine possible independent risk factors for skindex-29 questionnaire scores. p = 0.05 was considered for statistical significance threshold. 3-Results Fifty-one (n = 51) female patients with breast cancer being treated with CDK4/6 inhibitors were included in this study with a mean age of 55.4 (S D = 10.4 years). Of these patients, 31 (61%) were treated with Palbociclib, 11 (21%) with Abemaciclib, and 9 (18%) with Ribociclib. All the patients are metastatic and are treated with CDK4/6inhibitors with aromatase inhibitors. All patients have metastatic disease and are receiving treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor. Among the 51 patients, 26 (51%) had a CTCAE grade 0 alopecia, followed by 13 patients (26%) having a grade I, and 12 patients (23%) with a grade II (Table 2 ). Regarding the Hair-Specific Skindex-29 questionnaire categories, in the emotions domain, 33 patients (65%) were classified as very little , 13 (25%) as mild , 4 (8%) as moderate , and 1 (3%) as severe . In the symptoms domain, 27 patients (53%) fell into the very little category, 14 (27%) into mild , 7 (14%) into moderate , and 3 (6%) into severe . For functional capacity, 32 patients (63%) reported very little impact, 7 (13%) mild , 10 (20%) moderate , and 2 (4%) severe . Considering the overall total score, 27 patients (53%) were categorized as very little , 13 (25%) as mild , 7 (14%) as moderate , and 4 (8%) as severe (Table 2 ). When comparing the age of patients across the 3 different categories of CTCAE, there was no difference between the groups. Furthermore, there was no significant difference among the three CDK4/6 inhibitors across the CTCAE grade groups (Table 3 ). However, when looking at Hair-Specific Skindex-29 questionnaire, the score became worse across all the subsections of this questionnaire when the CTCAE grade was higher (Table 3 ). Finally, a linear regression involving age, treatment, and the CTCAE grade, was done to help find the independent variables affecting the category in each subsection of the Hair-Specific Skindex-29 questionnaire. Both the CTCAE grade and treatment drug were shown to be a significant variable affecting the category of the Hair-Specific Skindex-29 questionnaire in the emotions, and functional capacity subsections as well as the total. However, for the symptoms subsection, only the CTCAE grade was shown to be a significant predictor (Table 4 ). 4-Discussion CDK4/6 inhibitors are shown to be effective in managing hormone receptor-positive breast cancer, However, these drugs are not void of side effects. One of their rare side effects consists of alopecia (18–33% with palbociclib and ribociclib, 12%with abemaciclib) which impact on patients’quality of life is often underestimated. In our study, we showed that alopecia occurred in almost half of the patients (25 patients out of 51) being treated with CDK 4/6. Furthermore, the presence and severity of the alopecia was associated with worsening of the quality of life which was measured using the Hair-Specific Skindex-29 questionnaire. The estrogen receptor (ER)-cyclin D-CDK4/6 pathway is upregulated in ER-positive breast cancer when the ER signaling pathway is activated. The cyclin-CDKs pathway is essential for controlling the cell cycle ( 9 ). The transcription factor E2F is released when CDK4/6 phosphorylates the retinoblastoma protein (Rb) after being bound and activated by cyclin D. Cells move from the G1 phase to the S phase as a result of this, which stimulates the transcription of cell cycle-related genes ( 10 , 11 , 12 , 13 ). In ER-positive advanced breast cancer, dual inhibition of CDK4/6 and ER has shown significant therapeutic efficacy and may also help explain the emergence of certain toxicities, including alopecia ( 14 ). This is because CDK4/6 inhibitors not only block proliferation in tumor cells but also affect rapidly dividing normal cells, such as hair follicle matrix cells, disrupting the normal hair cycle. In addition, aromatase inhibitors reduce estrogen levels, which can shift hair follicles from the anagen (growth) phase to the telogen (resting) phase, further contributing to hair thinning. The combined inhibition of both pathways therefore impacts hair follicle proliferation and maintenance, providing a mechanistic basis for the alopecia observed in patients receiving this therapy. The safety profile of CDK4/6 inhibitors has attracted a lot of interest. In fact, an umbrella review of randomized controlled trials meta-analyses has shown that among other adverse events, CDK4/6 were shown to increase the risk of alopecia ( 3 ). They also showed that among CDK 4/6 inhibitors, alopecia was mostly associated with Ribociclib ( 3 ). However, in our study, there was no difference in alopecia incidence between the three CDK4/6 inhibitors. Chemotherapy-induced alopecia (CIA) is a significant adverse event to consider, causing substantial psychological distress in almost 55% of breast cancer patients ( 4 ). CIA-related distress has been closely linked to depression, poorer body image, and reduced health and psychological well-being. It is one of the three most common adverse effects of breast cancer treatment, following nausea and vomiting, and has been reported as the most emotionally upsetting side effect experienced by women undergoing chemotherapy ( 5 , 6 ). CIA also affects how cancer patients are perceived, making their illness more visible, while negatively impacting their sexuality and social interactions ( 15 ). Although hair regrowth typically occurs within six months after completing chemotherapy, CIA can rarely persist and become permanent ( 16 ). In patients receiving CDK4/6 inhibitors, while alopecia is frequent as shown in our study, it presents uniquely with baldness occurring on the vertex scalp and appearing earlier than the alopecia pattern observed with aromatase inhibitors and estrogen receptor modulators ( 17 ). Additionally, alopecia in patients undergoing both endocrine therapy and CDK4/6 inhibitors may respond less effectively to prescription hair loss treatments ( 17 ). Alopecia has a significant detrimental effect on the quality of life of breast cancer patients and survivors, as shown in our study. Qualitative research has linked alopecia to a loss of privacy, as it visibly signals chemotherapy treatment to those around the patient. Many women described alopecia as an obvious sign of cancer, leading to anxiety about returning to work and negatively impacting their social interactions and activities ( 18 , 19 ). Additionally, alopecia contributed to a decline in sensuality, sexuality, self-esteem, and self-perception. A qualitative meta-synthesis by Kocan et al. identified two key themes regarding breast cancer patients' experiences with CIA: "I am not comfortable in this body" and "Who am I?” ( 20 ), highlighting its deep effect on self-identity and body image, as well as fears of losing both their partners and them. Another study interviewing breast cancer patients undergoing chemotherapy found that alopecia was the primary factor influencing their changes in self-image ( 21 ). Moreover, alopecia can even deter some patients from undergoing treatment, with up to 14% declining chemotherapy due to fear of hair loss, making it one of the most feared side effects of cancer treatment ( 22 ). Additionally, 8.3% of patients reported that baldness was the sole reason they discontinued breast cancer treatment ( 23 ). Abena Minta et al. conducted a retrospective study evaluating alopecia in 28 breast cancer patients treated with either endocrine therapy alone or in combination with CDK4/6 inhibitors. They found that CDK4/6 inhibitor–associated alopecia (CDKiA) closely resembled androgenetic alopecia, with significantly more vertex involvement in patients receiving combination therapy (70% vs. 36.4%). Although 80% of CDKiA patients showed moderate to significant improvement after 4–6 months of minoxidil treatment, the response was less favorable compared to those with endocrine-induced alopecia (94.4%), suggesting a need for alternative or adjunctive therapies such as topical antiandrogens ( 24 ). In the literature review, there are only two articles that studied the impact of alopecia caused by CDK4/6 inhibitors and QOL. Donald Shan et al. conducted a retrospective study to evaluate alopecia induced by CDK4/6 inhibitors combined with aromatase inhibitors (CDKIA) in breast cancer patients, focusing on its clinical features, quality of life (QoL) impact, and response to dermatologic treatment. Among 39 female patients (median age 62), CDKIA presented in all cases with features resembling androgenetic alopecia and was most linked to the combination of a CDK4/6 inhibitor and letrozole. Compared to endocrine-induced alopecia (EIA), CDKIA appeared earlier, was more severe, showed more diffuse hair loss, and had a greater presence of vellus hairs. QoL, assessed via the Hairdex questionnaire, was significantly worse in CDKIA patients, especially in the emotional domain. Treatment with topical minoxidil led to moderate significant improvement in 85% of patients treated, suggesting it may be an effective option for managing CDKIA ( 25 ). The second study was conducted by Benlong Yang et al. as a large multicenter cross-sectional survey in China involving 1,254 patients with HR+/HER2- advanced breast cancer receiving CDK4/6 inhibitors. Authors found that alopecia, reported by 14.02% of patients, was more frequent with palbociclib (16.40%) and abemaciclib (19.82%) than with dalpiciclib (8.81%), and was significantly associated with worse quality-of-life domains, including body image, systemic therapy side effects, breast symptoms, arm symptoms, and emotional distress from hair loss (all P < 0.001), highlighting that even low-grade alopecia can meaningfully affect patients’ emotional well-being and overall QoL ( 26 ). This study has several limitations. Firstly, this study is cross-sectional, making it susceptible to the biases associated with the nature of this study. Secondly, the sample was small. However, significant results were found despite the small sample size. Lastly, confounding variables such as the usage of aromatase inhibitors, and duration of treatment among others may have affected the results, limiting its generalizability. Nevertheless, this study remained the only study in the MENA regions to assess the occurrence and the impact of CDK4/6 inhibitors induced alopecia on quality of life. 5-Conclusion Alopecia induced by CDK4/6 inhibitors is a frequent and underestimated toxicity in patients treated for hormone-positive advanced breast cancer. To our knowledge, this is the only study in the MENA region to assess the impact of CDK4/6 inhibitor-induced alopecia on patients' quality of life. We found that nearly half of the patients receiving these treatments developed alopecia, which negatively affected their quality of life. Moreover, more severe alopecia was associated with greater quality-of-life impairment. Future studies with larger cohorts are needed to confirm our findings and explore strategies to mitigate alopecia occurrence. Declarations Author Contribution W.K. and N.D. contributed equally as first authors.W.K: data collection, drafting the manuscript, and preparing the revised versions.N.D.: data collection, drafting the manuscript, preparing the revised versions and handled the submission process. R. M.: contributed to data collection. F.E.,J.K.: provided supervision, critical revision, and validation of the manuscript. References Islami F, Marlow EC, Thomson B, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019. CA Cancer J Clin. Published online July 11, 2024. doi: 10.3322/caac.21858 Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast . 2022;66:15–23. doi: 10.1016/j.breast.2022.08.010 Pu D, Wu Y, Xu D, et al. The adverse events of CDK4/6 inhibitors for HR+/ HER2- breast cancer: an umbrella review of meta-analyses of randomized controlled trials. 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CDK4/6 plus aromatase inhibitor-induced alopecia in breast cancer patients. Journal of Clinical Oncology . Published May 26, 2019. © 2019 Wolters Kluwer Health. Yang B, Sun Z, Ouyang Q, Tong Z, Wang S, Li H, Niu Z, Chen Y, Ma LX, Wang H, Tang M, Hu Z, Gao X, Wang X, Xie F, Cheng Q, Shen Y, Geng C, Wang H, Wu J. Safety and quality of life of CDK4/6 inhibitors therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: a multicenter cross-sectional survey in China. BMC Cancer. 2025;25(1):951. doi: 10.1186/s12885-025-14223-8 . PMID: 40426093; PMCID: PMC12117832. 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. 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05:20:48","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91427,"visible":true,"origin":"","legend":"","description":"","filename":"4e847fae60c44d10878c68c9d40ccc9f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7690740/v1/641fbb054d59675b1d1e45f4.xml"},{"id":96044550,"identity":"88dad20a-003e-4db7-8f33-eda6ddec4452","added_by":"auto","created_at":"2025-11-17 05:20:48","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99011,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7690740/v1/ebefd34b5dd2ff101790e146.html"},{"id":98625652,"identity":"c242c2ab-7961-475e-aee4-d00a5487fc85","added_by":"auto","created_at":"2025-12-19 17:09:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":376634,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7690740/v1/fc5cd742-978f-4886-a2d0-77e9eaa5d838.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Alopecia induced by CDK 4/6 Inhibitors and its Impact on the Quality of Life of Patients with advanced Breast cancer","fulltext":[{"header":"1-Introduction","content":"\u003cp\u003eApproximately 1 in 8 women in the US (13.1%) will be diagnosed with invasive breast cancer, and 1 in 43 (2.3%) will die from the disease. In 2024, an estimated 310,720 new invasive breast cancers will be diagnosed among women in the US, and an additional 2,790 cases will be diagnosed in men. Approximately 42,250 women and 530 men are expected to die from breast cancer in 2024. Breast cancer incidence increased during the most recent decade by 1% annually overall, with a steeper increase among women younger than 50 years (1.4% per year) than in those 50 or older (0.7% per year) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). By 2040, due to population growth and aging, breast cancer cases are projected to surpass 3\u0026nbsp;million annually, with deaths reaching 1\u0026nbsp;million each year (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe development of CDK 4/6 inhibitors has transformed the therapeutic landscape of metastatic breast cancer management. The FDA has initially approved three highly selective, orally active, and reversible CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, for use in combination with specific endocrine therapies in the treatment of hormone receptor-positive (HR+) advanced or metastatic breast cancer. However, CDK 4/6 inhibitors are not avoiding adverse events. It was found that the addition of CDK4/6 inhibitors resulted in a significant increase of leucopenia, neutropenia, anemia, nausea, diarrhea, constipation, fatigue, pyrexia, venous thromboembolism abdominal pain, cough, and even alopecia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlopecia is a significant adverse event, affecting 55% of breast cancer patients and causing considerable psychological distress (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It ranks as the third most common adverse event of breast cancer treatment, following nausea and vomiting (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Alopecia induced by CDK 4/6 inhibitors is almost underestimated, distinct from other forms due to its distribution and early onset. Although few studies have examined the impact of alopecia on patients undergoing breast cancer treatment, no study, to our knowledge, has specifically quantified the impact of CDK 4/6 inhibitor-induced alopecia on quality of life. Therefore, this study aims to identify and quantify the severity of alopecia caused by CDK 4/6 inhibitors, graded using the CTCAE grading scale, and its impact on quality of life, as assessed through the Hair-Specific Skindex-29 questionnaire.\u003c/p\u003e"},{"header":"2-Material and Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study Design:\u003c/h2\u003e\u003cp\u003eThis is a cross-sectional single center study assessing the impact of alopecia on patients being currently treated for breast cancer with a CDK4/6 inhibitor. All patients signed an informed consent form and procedures were conducted according to the Declaration of Helsinki. The institutional ethical committee approved the study under the code number CEHDF2302. Inclusion criteria consisted of female patients having a diagnosis of metastatic or high-risk localized breast cancer, being treated with a CDK4/6 inhibitor for a minimal duration of 3 months in association with aromatase inhibitors or estrogen receptor modulators and being able to independently respond to the administered questionnaire. Exclusion criteria consisted of patients being admitted to the hospital at the time of questionnaires administration because it may impact their response to the questionnaire, patients presenting with alopecia that is not induced by the CDK4/6 inhibitors, and patients with incomplete data.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Included Variables Measurements:\u003c/h2\u003e\u003cp\u003ePatients are selected from the outpatient clinics of the physicians practicing at Hotel Dieu De France Hospital. For the patients to be included, they should complete CTCAE grading scale for alopecia where a grade I is assigned to a hair loss of \u0026lt;\u0026thinsp;50% compared to baseline, and visible only upon close inspection and a grade II is assigned to a hair loss\u0026thinsp;\u0026gt;\u0026thinsp;50% compared to baseline (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In addition, patients should fill out the Hair-Specific Skindex-29 questionnaire(HSS-29)(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The HSS-29 designed to assess quality of life in patients with alopecia. It contains 29 items distributed across three domains:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSymptoms: 7 items (covering physical sensations such as itching, irritation, burning, or sensitivity of the scalp)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFunctioning: 12 items (impact on daily activities, social interactions, work, and self-perception)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eEmotions: 10 items (feelings of embarrassment, frustration, worry, depression, or diminished confidence due to hair loss)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eIn the HSS-29, the degree of quality-of-life impairment can be categorized into four levels based on total and domain scores (scaled 0\u0026ndash;100). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, very little impairment is reflected by scores\u0026thinsp;\u0026lt;\u0026thinsp;5 in the emotions domain, \u0026lt;\u0026thinsp;3 in symptoms, \u0026lt;\u0026thinsp;3 in functional capacity, and \u0026lt;\u0026thinsp;5 in total score, meaning hair loss has minimal impact. Mild impairment is defined by scores of 6\u0026ndash;24 for emotions, 4\u0026ndash;10 for symptoms, 4\u0026ndash;10 for functioning, and 6\u0026ndash;17 in the total score, indicating occasional but limited interference in daily life. Moderate impairment corresponds to scores of 25\u0026ndash;49 in emotions, 11\u0026ndash;25 in symptoms, 11\u0026ndash;32 in functioning, and 18\u0026ndash;36 overall, showing more frequent bother and a noticeable effect on psychosocial well-being. Severe impairment is reached at \u0026ge;\u0026thinsp;50 in emotions, 26\u0026ndash;49 in symptoms, \u0026ge;\u0026thinsp;33 in functioning, and \u0026ge;\u0026thinsp;37 overall, demonstrating substantial and persistent impact with social and emotional consequences. Finally, extremely severe impairment is specifically defined for the symptoms domain at \u0026ge;\u0026thinsp;50, representing the highest level of distress, where scalp sensations and hair concerns dominate daily life. This stratification helps clinicians and researchers interpret HSS-29 scores consistently, compare groups, and correlate disease severity with quality-of-life burden.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical Analysis:\u003c/h2\u003e\u003cp\u003eThe data have been analyzed using the SPSS 26.0 software (SPSS Inc., Chicago, IL, USA). The raw Hair-Specific Skindex-29 questionnaire scores were converted to a 0-100 scale to categorize them according to Nijsten et al. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) The Kolmogorov\u0026ndash;Smirnov test was used to assess the normal distribution of the data. Continuous data was expressed with means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation while categorical data was expressed with %. To determine a potential existing relation between categorical variables a Chi-square test was used. Independent samples t-test, and ANOVA were used to compare quantitative variables between the groups. Finally, linear regression was used to determine possible independent risk factors for skindex-29 questionnaire scores. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05 was considered for statistical significance threshold.\u003c/p\u003e\u003c/div\u003e"},{"header":"3-Results","content":"\u003cp\u003eFifty-one (n\u0026thinsp;=\u0026thinsp;51) female patients with breast cancer being treated with CDK4/6 inhibitors were included in this study with a mean age of 55.4 (S D\u0026thinsp;=\u0026thinsp;10.4 years). Of these patients, 31 (61%) were treated with Palbociclib, 11 (21%) with Abemaciclib, and 9 (18%) with Ribociclib. All the patients are metastatic and are treated with CDK4/6inhibitors with aromatase inhibitors. All patients have metastatic disease and are receiving treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor.\u003c/p\u003e\u003cp\u003eAmong the 51 patients, 26 (51%) had a CTCAE grade 0 alopecia, followed by 13 patients (26%) having a grade I, and 12 patients (23%) with a grade II (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eRegarding the Hair-Specific Skindex-29 questionnaire categories, in the emotions domain, 33 patients (65%) were classified as \u003cem\u003every little\u003c/em\u003e, 13 (25%) as \u003cem\u003emild\u003c/em\u003e, 4 (8%) as \u003cem\u003emoderate\u003c/em\u003e, and 1 (3%) as \u003cem\u003esevere\u003c/em\u003e. In the symptoms domain, 27 patients (53%) fell into the \u003cem\u003every little\u003c/em\u003e category, 14 (27%) into \u003cem\u003emild\u003c/em\u003e, 7 (14%) into \u003cem\u003emoderate\u003c/em\u003e, and 3 (6%) into \u003cem\u003esevere\u003c/em\u003e. For functional capacity, 32 patients (63%) reported \u003cem\u003every little\u003c/em\u003e impact, 7 (13%) \u003cem\u003emild\u003c/em\u003e, 10 (20%) \u003cem\u003emoderate\u003c/em\u003e, and 2 (4%) \u003cem\u003esevere\u003c/em\u003e. Considering the overall total score, 27 patients (53%) were categorized as \u003cem\u003every little\u003c/em\u003e, 13 (25%) as \u003cem\u003emild\u003c/em\u003e, 7 (14%) as \u003cem\u003emoderate\u003c/em\u003e, and 4 (8%) as \u003cem\u003esevere\u003c/em\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhen comparing the age of patients across the 3 different categories of CTCAE, there was no difference between the groups. Furthermore, there was no significant difference among the three CDK4/6 inhibitors across the CTCAE grade groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, when looking at Hair-Specific Skindex-29 questionnaire, the score became worse across all the subsections of this questionnaire when the CTCAE grade was higher (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFinally, a linear regression involving age, treatment, and the CTCAE grade, was done to help find the independent variables affecting the category in each subsection of the Hair-Specific Skindex-29 questionnaire. Both the CTCAE grade and treatment drug were shown to be a significant variable affecting the category of the Hair-Specific Skindex-29 questionnaire in the emotions, and functional capacity subsections as well as the total. However, for the symptoms subsection, only the CTCAE grade was shown to be a significant predictor (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e"},{"header":"4-Discussion","content":"\u003cp\u003eCDK4/6 inhibitors are shown to be effective in managing hormone receptor-positive breast cancer, However, these drugs are not void of side effects. One of their rare side effects consists of alopecia (18\u0026ndash;33% with palbociclib and ribociclib, 12%with abemaciclib) which impact on patients\u0026rsquo;quality of life is often underestimated. In our study, we showed that alopecia occurred in almost half of the patients (25 patients out of 51) being treated with CDK 4/6. Furthermore, the presence and severity of the alopecia was associated with worsening of the quality of life which was measured using the Hair-Specific Skindex-29 questionnaire.\u003c/p\u003e\u003cp\u003eThe estrogen receptor (ER)-cyclin D-CDK4/6 pathway is upregulated in ER-positive breast cancer when the ER signaling pathway is activated. The cyclin-CDKs pathway is essential for controlling the cell cycle (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The transcription factor E2F is released when CDK4/6 phosphorylates the retinoblastoma protein (Rb) after being bound and activated by cyclin D. Cells move from the G1 phase to the S phase as a result of this, which stimulates the transcription of cell cycle-related genes (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In ER-positive advanced breast cancer, dual inhibition of CDK4/6 and ER has shown significant therapeutic efficacy and may also help explain the emergence of certain toxicities, including alopecia (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). This is because CDK4/6 inhibitors not only block proliferation in tumor cells but also affect rapidly dividing normal cells, such as hair follicle matrix cells, disrupting the normal hair cycle. In addition, aromatase inhibitors reduce estrogen levels, which can shift hair follicles from the anagen (growth) phase to the telogen (resting) phase, further contributing to hair thinning. The combined inhibition of both pathways therefore impacts hair follicle proliferation and maintenance, providing a mechanistic basis for the alopecia observed in patients receiving this therapy.\u003c/p\u003e\u003cp\u003eThe safety profile of CDK4/6 inhibitors has attracted a lot of interest. In fact, an umbrella review of randomized controlled trials meta-analyses has shown that among other adverse events, CDK4/6 were shown to increase the risk of alopecia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). They also showed that among CDK 4/6 inhibitors, alopecia was mostly associated with Ribociclib (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). However, in our study, there was no difference in alopecia incidence between the three CDK4/6 inhibitors.\u003c/p\u003e\u003cp\u003eChemotherapy-induced alopecia (CIA) is a significant adverse event to consider, causing substantial psychological distress in almost 55% of breast cancer patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). CIA-related distress has been closely linked to depression, poorer body image, and reduced health and psychological well-being. It is one of the three most common adverse effects of breast cancer treatment, following nausea and vomiting, and has been reported as the most emotionally upsetting side effect experienced by women undergoing chemotherapy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). CIA also affects how cancer patients are perceived, making their illness more visible, while negatively impacting their sexuality and social interactions (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Although hair regrowth typically occurs within six months after completing chemotherapy, CIA can rarely persist and become permanent (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn patients receiving CDK4/6 inhibitors, while alopecia is frequent as shown in our study, it presents uniquely with baldness occurring on the vertex scalp and appearing earlier than the alopecia pattern observed with aromatase inhibitors and estrogen receptor modulators (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Additionally, alopecia in patients undergoing both endocrine therapy and CDK4/6 inhibitors may respond less effectively to prescription hair loss treatments (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlopecia has a significant detrimental effect on the quality of life of breast cancer patients and survivors, as shown in our study. Qualitative research has linked alopecia to a loss of privacy, as it visibly signals chemotherapy treatment to those around the patient. Many women described alopecia as an obvious sign of cancer, leading to anxiety about returning to work and negatively impacting their social interactions and activities (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Additionally, alopecia contributed to a decline in sensuality, sexuality, self-esteem, and self-perception. A qualitative meta-synthesis by Kocan et al. identified two key themes regarding breast cancer patients' experiences with CIA: \"I am not comfortable in this body\" and \"Who am I?\u0026rdquo; (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), highlighting its deep effect on self-identity and body image, as well as fears of losing both their partners and them. Another study interviewing breast cancer patients undergoing chemotherapy found that alopecia was the primary factor influencing their changes in self-image (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Moreover, alopecia can even deter some patients from undergoing treatment, with up to 14% declining chemotherapy due to fear of hair loss, making it one of the most feared side effects of cancer treatment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Additionally, 8.3% of patients reported that baldness was the sole reason they discontinued breast cancer treatment (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAbena Minta et al. conducted a retrospective study evaluating alopecia in 28 breast cancer patients treated with either endocrine therapy alone or in combination with CDK4/6 inhibitors. They found that CDK4/6 inhibitor\u0026ndash;associated alopecia (CDKiA) closely resembled androgenetic alopecia, with significantly more vertex involvement in patients receiving combination therapy (70% vs. 36.4%). Although 80% of CDKiA patients showed moderate to significant improvement after 4\u0026ndash;6 months of minoxidil treatment, the response was less favorable compared to those with endocrine-induced alopecia (94.4%), suggesting a need for alternative or adjunctive therapies such as topical antiandrogens (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the literature review, there are only two articles that studied the impact of alopecia caused by CDK4/6 inhibitors and QOL. Donald Shan et al. conducted a retrospective study to evaluate alopecia induced by CDK4/6 inhibitors combined with aromatase inhibitors (CDKIA) in breast cancer patients, focusing on its clinical features, quality of life (QoL) impact, and response to dermatologic treatment. Among 39 female patients (median age 62), CDKIA presented in all cases with features resembling androgenetic alopecia and was most linked to the combination of a CDK4/6 inhibitor and letrozole. Compared to endocrine-induced alopecia (EIA), CDKIA appeared earlier, was more severe, showed more diffuse hair loss, and had a greater presence of vellus hairs. QoL, assessed via the Hairdex questionnaire, was significantly worse in CDKIA patients, especially in the emotional domain. Treatment with topical minoxidil led to moderate significant improvement in 85% of patients treated, suggesting it may be an effective option for managing CDKIA (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe second study was conducted by Benlong Yang et al. as a large multicenter cross-sectional survey in China involving 1,254 patients with HR+/HER2- advanced breast cancer receiving CDK4/6 inhibitors. Authors found that alopecia, reported by 14.02% of patients, was more frequent with palbociclib (16.40%) and abemaciclib (19.82%) than with dalpiciclib (8.81%), and was significantly associated with worse quality-of-life domains, including body image, systemic therapy side effects, breast symptoms, arm symptoms, and emotional distress from hair loss (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), highlighting that even low-grade alopecia can meaningfully affect patients\u0026rsquo; emotional well-being and overall QoL (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study has several limitations. Firstly, this study is cross-sectional, making it susceptible to the biases associated with the nature of this study. Secondly, the sample was small. However, significant results were found despite the small sample size. Lastly, confounding variables such as the usage of aromatase inhibitors, and duration of treatment among others may have affected the results, limiting its generalizability. Nevertheless, this study remained the only study in the MENA regions to assess the occurrence and the impact of CDK4/6 inhibitors induced alopecia on quality of life.\u003c/p\u003e"},{"header":"5-Conclusion","content":"\u003cp\u003eAlopecia induced by CDK4/6 inhibitors is a frequent and underestimated toxicity in patients treated for hormone-positive advanced breast cancer. To our knowledge, this is the only study in the MENA region to assess the impact of CDK4/6 inhibitor-induced alopecia on patients' quality of life. We found that nearly half of the patients receiving these treatments developed alopecia, which negatively affected their quality of life. Moreover, more severe alopecia was associated with greater quality-of-life impairment. Future studies with larger cohorts are needed to confirm our findings and explore strategies to mitigate alopecia occurrence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eW.K. and N.D. contributed equally as first authors.W.K: data collection, drafting the manuscript, and preparing the revised versions.N.D.: data collection, drafting the manuscript, preparing the revised versions and handled the submission process. R. M.: contributed to data collection. F.E.,J.K.: provided supervision, critical revision, and validation of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIslami F, Marlow EC, Thomson B, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019. CA Cancer J Clin. 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PMID: 40426093; PMCID: PMC12117832.\u003c/span\u003e\u003c/li\u003e\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":"CDK4/6inhibitors, hormone positive metastatic breast cancer, alopecia, quality of life, CTCAE grade","lastPublishedDoi":"10.21203/rs.3.rs-7690740/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7690740/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the management of hormone receptor-positive (HR+) advanced and metastatic breast cancer. However, CDK4/6 inhibitor-induced alopecia, a distinct and often underestimated adverse effect, can significantly impact patients' quality of life. This study aims to identify and quantify the severity of alopecia caused by CDK4/6 inhibitors and its effect on quality of life using validated assessment tools.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis cross-sectional, single-center study included 51 female breast cancer patients treated with CDK4/6 inhibitors for at least three months, as first line for metastatic disease. Alopecia severity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading scale, while the impact on quality of life was assessed through the Hair-Specific Skindex-29 questionnaire. Statistical analysis included t-tests, ANOVA, Chi-square tests, and linear regression to identify predictors of quality-of-life impairment.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eNearly half of the participants (49%) developed alopecia, with 26% graded as CTCAE grade I and 23% as grade II. Higher CTCAE grades were associated with significantly worse Hair-Specific Skindex-29 scores in the emotions, symptoms, and functional capacity subsections (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Regression analysis showed that both the CTCAE grade and the specific CDK4/6 inhibitor used were significant predictors of overall quality-of-life impairment.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study is the first to quantify the impact of CDK4/6 inhibitor-induced alopecia on quality of life in the MENA (Middle East and North Africa) region, showing that greater alopecia severity leads to more symptoms, and worse emotional and functional well-being.\u003c/p\u003e","manuscriptTitle":"Alopecia induced by CDK 4/6 Inhibitors and its Impact on the Quality of Life of Patients with advanced Breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 05:20:43","doi":"10.21203/rs.3.rs-7690740/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":"5e22cbc1-9878-4ee0-8f03-46d781e6f1d2","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-18T15:24:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 05:20:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7690740","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7690740","identity":"rs-7690740","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}