Clinical significance on Switching CDK4/6 inhibitors among 13,284 patients with metastatic breast cancer

Clinical significance on Switching CDK4/6 inhibitors among 13,284 patients with metastatic 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 Clinical significance on Switching CDK4/6 inhibitors among 13,284 patients with metastatic breast cancer Takuya Nishina, Maki Tanioka, Kenji Takada, Takahiro Tsukioki, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6616110/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 Recent clinical trials have shown that switching to a combination therapy of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) prolongs progression-free survival (PFS) compared with ET monotherapy. Reports indicate that abemaciclib provides benefits regardless of the PIK3CA mutation status; however, its clinical benefits remain insufficient. This study aimed to evaluate the clinical significance of switching CDK4/6i + ET in a large real-world cohort. Using a medical database, we identified 13,284 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer who received CDK4/6i + ET between 2008 and 2022. Patients were categorized into six groups based on their first- and second-line therapy patterns. We compared the median time to discontinuation (TTD) among the groups. In patients who switched from one CDK4/6i + ET to another CDK4/6i + ET, the second-line TTD and total TTD of first- and second-line therapies (n = 542) were significantly longer than those in patients who switched from CDK4/6i + ET to ET monotherapy (n = 490) (the second-line TTD: 11.2 vs. 4.9 months, p < 0.01; total TTD: 25.1 vs. 20.5 months, p < 0.01). The order of palbociclib and abemaciclib administration did not significantly affect the second-line or total TTD in patients who switched from one CDK4/6i + ET to another CDK4/6i + ET. Switching from one CDK4/6i + ET to another CDK4/6i + ET resulted in a significantly longer TTD than switching to ET monotherapy. Considering the phase III clinical trial results of capivasertib, switching to CDK4/6i + ET is a viable therapeutic option regardless of the PIK3CA mutation status. Cyclin-dependent kinase 4/6 inhibitors endocrine therapy HR-positive/HER2-negative advanced breast cancer progression-free survival time to discontinuation Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION According to the Hortobagyi algorithm, treatment for hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer (ABC) involves the selection of endocrine therapy (ET) in the absence of severe organ dysfunction or rapid disease progression (visceral crisis), whereas chemotherapy (CT) is chosen in cases of visceral crisis [ 1 ]. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) regulate the cell cycle by inducing cell cycle arrest in the G1 phase [ 2 ]. The three available CDK4/6is are palbociclib, abemaciclib, and ribociclib. CDK4/6is have been shown to improve progression-free survival (PFS) in patients with HR-positive/HER2-negative ABC when used in combination with ET as a first- or second-line therapy [ 3 – 9 ]. Combination therapy using a CDK4/6i and ET is the standard of care for HR-positive/HER2-negative ABC [ 1 ]. However, the development of resistance to hormone therapy is a major challenge in the treatment of HR-positive/HER2-negative ABC. According to the results from various clinical trials, ET monotherapy in the second-line setting after first-line CDK4/6i + ET has a PFS of only 2.8–4.6 months [ 10 – 15 ]. Additionally, PIK3CA/AKT1/PTEN mutations has been recognized as one of the causes of resistance to hormone therapy [ 16 ]. In the CAPItello-291 trial, capivasertib (AKT inhibitor) significantly prolonged PFS in patients with HR-positive/HER2-negative ABC with PIK3CA/AKT1/PTEN mutations; however, the absolute PFS benefit was modest, and the clinical significance remained limited (7.3 months vs. 3.1 months; hazard ratio [HR], 0.50; p < 0.001) [ 10 ]. Given these suboptimal treatment options, currently, physicians choose to switch CDK4/6is (from one CDK4/6i + ET to another CDK4/6i + ET), extend CDK4/6is with a different ET (from one CDK4/6i + ET to the same CDK4/6i + another ET), or transition to ET monotherapy, CT, or PI3K/AKT inhibitors depending on the patient’s condition. In recent years, clinical trials have been conducted on switching or extending CDK4/6i + ET. Extension of CDK4/6i therapy has been investigated in the PACE and PALMIRA trials. In these trials, extending palbociclib from first- to second-line therapy while changing the ET combination failed to prolong PFS in second-line therapy [ 11 , 12 ]. Switching to a CDK4/6i was investigated in the MAINTAIN, post-MONARCH, and EMBER-3 trials. In the MAINTAIN trial, switching from palbociclib + ET to ribociclib + ET significantly prolonged the second-line PFS compared with changing to ET monotherapy [ 13 ]. In the post-MONARCH trial, switching from palbociclib + aromatase inhibitor (AI) or from ribociclib + AI to abemaciclib + fulvestrant (FUL) significantly prolonged the second-line PFS compared with switching to FUL monotherapy [ 14 ]. In the EMBER-3 trial, switching from CDK4/6i + AI to abemaciclib + imlunestrant significantly prolonged the second-line PFS compared with changing to imlunestrant monotherapy [ 15 ]. However, these studies included a small number of patients. To overcome this, this study utilized a large real-world clinical database comprising 13,284 patients to evaluate the significance of switching to another CDK4/6i after the use of a CDK4/6i in the first-line therapy for HR-positive/HER2 − negative ABC. METHODS Data source This study utilized retrospective observational data from the Medical Data Vision Co., Ltd. (MDV) database. The MDV database is a de-identified database comprising discharge summaries and medical insurance billing data obtained from inpatient and outpatient visits at Japanese hospitals using the Diagnosis Procedure Combination (DPC) system [ 17 ]. The DPC system includes hospitals providing acute care and other services, incorporating many of Japan’s major medical and cancer centers. As of January 2021, the MDV database includes the data of approximately 34.84 million individuals [ 18 ]. This study was conducted in accordance with the guidelines of the Declaration of Helsinki and Good Pharmacoepidemiology Practices. According to Japan’s Ethical Guidelines for Medical and Health Research Involving Human Subjects [ 19 ], this noninterventional retrospective study using anonymized patient data did not require informed consent. Study design This study was designed as follows: (1) The follow-up period was set from April 2008 to December 2022, which was the maximum period for which the data were available. (2) Prescription records of palbociclib or abemaciclib as well as those of ET (FUL, letrozole [LET], anastrozole [ANA], exemestane [EXE], tamoxifen [TAM], and toremifene [TOR]) were confirmed. (3) The absence of prescriptions for anti-HER2 therapies (trastuzumab and pertuzumab) was confirmed. (5) The age at the time of CDK4/6i prescription was ≥ 20 years. (6) For patients prescribed CDK4/6is, information on CT (paclitaxel [PTX], bevacizumab + paclitaxel [Bev + PTX], doxorubicin + cyclophosphamide [AC], epirubicin + cyclophosphamide [EC], eribulin [Eri], vinorelbine [VNR], capecitabine [Cape], and tegafur/gimeracil/oteracil [TS1]) administered during the follow-up period was also investigated. Patients Patients who were prescribed CDK4/6is before the surgery date as well as those who were administered Bev + PTX, Eri, VNR, Cape, or TS1 before the surgery date were classified as having de novo stage IV disease. Patients who were prescribed a CDK4/6i after the surgery date were classified as having postoperative recurrence. If PTX, AC, or EC was administered in two regimens or within 6 months immediately before the surgery date, it was classified as neoadjuvant chemotherapy (NAC). If no chemotherapy was administered before the surgery date and PTX, AC, or EC was administered in two regimens or within 6 months immediately after the surgery date, it was classified as adjuvant chemotherapy. The prescription of LET, ANA, EXE, or TAM immediately after the surgery date was classified as postoperative adjuvant ET. If the postoperative adjuvant ET was switched between LET, ANA, EXE, or TAM, it was considered a continuation of postoperative adjuvant ET. The date of the first denosumab administration was defined as the date of the onset of bone metastases. The diagnosis date of postoperative recurrence was defined as the earliest date on which Bev + PTX, Eri, VNR, Cape, TS1, CDK4/6i, or denosumab was administered after the surgery date or the earliest date on which PTX, AC, or EC was administered at least 6 months after the surgery date. Endpoints The primary endpoint was to compare the time to discontinuation (TTD) of second-line therapy between two groups of patients with HR-positive/HER2-negative ABC diagnosed with de novo stage IV disease or recurrence: those who received CDK4/6i + ET as first-line therapy and switched to another CDK4/6i + ET in the second-line therapy and those who switched to ET monotherapy. The secondary endpoint was to investigate the therapy patterns, details of ET combined with a CDK4/6i, and the total TTD from the start of first-line therapy to the end of second-line therapy. TTD Only the first and last prescription dates are recorded in the DPC system. Therefore, there were no data regarding the exact date of drug discontinuation or the reasons for discontinuation. Therefore, the date of the first prescription of a drug was defined as the start date of drug administration, and the date of the last prescription was defined as the end date of drug administration. In some cases, patients appeared to have overlapping prescriptions, even when there was no actual concurrent administration. Patients with overlapping prescriptions for three or more drugs during the same period were excluded owing to data inaccuracies. If there was an overlap in the administration periods of two drugs, the drug with the shortest administration period during the overlap was considered the administered drug for that period. The total TTD of the first- and second-line therapies was defined as the period from the start of first-line therapy to the end of second-line therapy. Line of therapy The lines of therapy included ET and CT. When a CDK4/6i was added to ET monotherapy, it was considered the same therapy line, with the start of the line defined as the initiation of ET. Abemaciclib was approved in Japan in November 2018, and palbociclib was approved in September 2017. Patients who had been using ET for an extended period before October 2018 and those who received abemaciclib were excluded, as this did not provide accurate data for the combination therapy of CDK4/6i + ET. Similarly, patients who had been using ET for an extended period before August 2017 and then received palbociclib were excluded. If ET combined with a CDK4/6i was changed but the CDK4/6i remained unchanged, it was considered the same therapy line. Even if CDK4/6i administration was discontinued for any reason and if ET combined with CDK4/6i was continued, it was considered to be the same therapy line. Patients with a gap of 60 days or more between the end of first-line therapy and the start of second-line therapy (owing to adverse event [AE] management, radiation therapy, etc.) were excluded. Patients with an overlap of 7 days or more between the end of first-line therapy and the start of second-line therapy were excluded. Patients with unknown ET combined with CDK4/6i are excluded. Abemaciclib was approved in Japan in November 2018, and palbociclib was approved in September 2017. Patients who had been using ET for an extended period before October 2018 and those who received abemaciclib were excluded, as this did not provide accurate data for the combination therapy of CDK4/6i + ET. Similarly, patients who had been using ET for an extended period before August 2017 and then received palbociclib were excluded. Statistical analysis Patients with a final prescription date of December 2022 were considered to have ongoing drug administration and were considered as censored cases. HRs and 95% confidence intervals (CIs) between the two groups were examined using a Cox proportional hazards model for regression analysis. The Kaplan–Meier method was used to estimate the median and 95% CIs for the TTD. Differences between the groups were evaluated using the log-rank test. No adjustments were made for biases or confounding factors, and missing data were not imputed. Data were processed using SQLite 3.33.0 and Python 3.12.2. RESULTS Patient selection Figure 1 illustrates the recruitment process of the study cohort. A total of 13,284 patients with a history of CDK4/6i administration were identified in the database. Among these, 5,153 patients had a history of abemaciclib administration only, 6,126 had a history of palbociclib administration only, and 2,005 patients had a history of both abemaciclib and palbociclib administration. Thus, the 13,284 patients were classified into the following six groups: Group A: patients who switched from one CDK4/6i + ET to another CDK4/6i + ET. (N = 542) Group B: patients who switched from CDK4/6i + ET to ET monotherapy. (N = 490) Group C: patients who switched from CDK4/6i + ET to CT. (N = 608) Group D: patients who switched from ET monotherapy to CDK4/6i + ET. (N = 1,486) Group E: patients who switched from CT to CDK4/6i + ET. (422) Group F: patients who received CDK4/6i + ET as the first-line therapy without any changes in the regimen. (N = 3,271) Characteristics of patients Patient characteristics are summarized in Table 1 . The median age of all patients was 64 years (range, 21–100 years), and most of the patients were female (99.5%). Groups A, B, C, and F had a history of CDK4/6i use in the first-line setting. Among these groups, ET combined with a CDK4/6i as the first-line therapy was evenly split between FUL (50.0%) and AI (50.0%). Groups A, D, and E had a history of CDK4/6i use in the second-line setting. In these groups, FUL was the predominant ET combined with a CDK4/6i in the second-line therapy (FUL, 66.2%; AI, 33.8%). In all groups, patients with de novo stage IV disease outnumbered those with postoperative recurrence. Regimen patterns Figure 2 shows the patterns of regimens from first-line to second-line therapy for all patients. A total of 4,911 patients were prescribed a CDK4/6i in the first-line setting. Of these, 3,271 (66.6%) did not switch to any other antitumor drug until the end of the follow-up period. A total of 1,908 patients were prescribed a CDK4/6i for the first time in the second-line setting. The majority (46.4%) of patients received AI as first-line therapy (Table S1 ). Among patients who switched to another CDK4/6i, 35.8% switched by changing the combined ET, whereas 64.2% switched without changing the combined ET. In the first-line setting, FUL was more commonly combined with a CDK4/6i than AI (AI, 42.5%; FUL, 57.5%). In the second-line setting, FUL remained to be the more commonly combined drug with a CDK4/6i than AI (AI, 25.9%; FUL, 74.1%) (Fig. S1 ). Analysis of TTD The TTD for each group was determined using the Kaplan–Meier method and is presented as a bar graph (Fig. 3 ). The median TTD of groups A and B was compared. Group A showed a significantly longer second-line TTD of 11.20 months compared with group B at 4.93 months (HR, 0.54; 95% CI, 0.47–0.63; p < 0.01) (Fig. 4 a). Group A showed a significantly longer the total TTD of first- and second-line therapies (total TTD) of 25.16 months compared with group B at 20.50 months (HR, 0.72; 95% CI, 0.62–0.83; p < 0.01) (Fig. S2). The impact of the order of palbociclib and abemaciclib administration on the TTD was examined in group A. There was no significant difference in the second-line TTD between patients who switched from palbociclib to abemaciclib at 11.00 months and those who switched from abemaciclib to palbociclib at 11.33 months (HR, 1.04; 95% CI, 0.83–1.32; p = 0.67) (Fig. S3a). There was no significant difference in the total TTD between patients who switched from palbociclib to abemaciclib at 25.66 months and those who switched from abemaciclib to palbociclib at 23.10 months (HR, 0.89; 95% CI, 0.71–1.32; p = 0.34) (Fig. S3b). In group A, statistical significance was tested for the median TTD across variables such as age (< 65 years vs. ≥65 years), path of onset (recurrence vs. de novo stage IV disease), presence of bone metastasis, history of NAC among patients with recurrence, and time from the first surgery to recurrence (≥ 1 year vs. <1 year). Although not statistically significant, patients younger than 65 years, those with postoperative recurrence, those with bone metastasis, and those with recurrence without NAC showed a longer TTD. Patients who showed recurrence within 1 year after surgery had a significantly higher total TTD than those who showed recurrence after 1 year (HR, 1.99; 95% CI, 1.13–3.52; p = 0.01) (Table 2). The median TTD of groups A and C was compared. Group A showed a significantly longer second-line TTD of 11.20 months than group C at 5.16 months (HR, 0.47; 95% CI, 0.41–0.55; p < 0.01) (Fig. 4 b). Similarly, group A showed a significantly longer total TTD of 25.16 months than group C at 16.49 months (HR, 0.58; 95% CI, 0.51–0.67; p < 0.01) (Fig. S4). The median TTD of groups A and D was compared. Group A showed a significantly longer total TTD of 25.16 months than group D at 40.37 months (HR, 1.98; 95% CI, 1.74–2.25; p < 0.01) (Fig. 4 c). The median TTD of groups A and E was compared. There was no significant difference in the total TTD between group A at 25.16 months and group E at 21.29 months (HR, 0.91; 95% CI, 0.78–1.07; p = 0.26) (Fig. 4 d). DISCUSSION In this study, we used a large-scale MDV database of 13,284 patients with HR-positive/HER2-negative ABC to evaluate the clinical significance of switching CDK4/6i + ET. Regarding the AEs of CDK4/6is, a large-scale study with more than 100,000 patients was conducted using VigiBase and the Food and Drug Administration Adverse Event Reporting System [ 20 ]. Regarding therapy patterns and treatment duration after switching to CDK4/6i + ET, a study was conducted using the MDV database; however, the sample size of 1,170 patients was insufficient [ 21 ]. Other studies on the effectiveness of switching to a CDK4/6i have also been conducted; however, none have involved more than 10,000 patients. To the best of our knowledge, this is the largest retrospective study that investigated the effectiveness of CDK4/6is, including therapy patterns and treatment duration. Blumenthal et al. demonstrated a correlation between TTD and survival endpoints, suggesting that TTD is an important indicator for evaluating therapeutic effectiveness and tolerability [ 22 ]. We found that switching to another CDK4/6i in the second-line setting after using CDK4/6i + ET in the first-line setting for HR-positive/HER2-negative ABC resulted in a significantly longer TTD than switching to ET monotherapy. Furthermore, the TTD did not change according to the order of palbociclib and abemaciclib administration in the first- and second-line settings. Between groups A and B, switching from one CDK4/6i to another CDK4/6i (11.20 months) resulted in a significantly longer second-line TTD than switching to ET monotherapy (4.93 months). In the MAINTAIN trial, switching from palbociclib + ET (84%) or ribociclib + ET (11%) to ribociclib + FUL or EXE significantly prolonged the PFS in the second-line setting compared with switching to FUL or EXE monotherapy (5.3 vs. 2.8 months; HR, 0.57; 95% CI, 0.39–0.85; p < 0.01) [ 12 ]. In the post-MONARCH trial, switching from palbociclib + AI (59%) or ribociclib + AI (34%) to abemaciclib + FUL significantly prolonged the PFS in the second-line setting compared with switching to ET monotherapy (5.6 vs. 3.9 months; HR, 0.66; 95% CI, 0.48–0.91; p < 0.01) [ 13 ]. In the EMBER-3 trial, switching from palbociclib + AI (61%), ribociclib + AI (29%), or abemaciclib + AI (10%) to abemaciclib + imlunestrant significantly prolonged the PFS in the second-line setting compared with switching to imlunestrant monotherapy (9.1 vs. 3.7 months; HR, 0.51; 95% CI, 0.38–0.61) [ 14 ]. However, the EMBER-3 trial included patients who experienced disease progression while receiving AI (administered alone or with a CDK4/6i) as a neoadjuvant or adjuvant treatment within 12 months after completing adjuvant treatment or while receiving first-line treatment for ABC. We analyzed a larger, real-world cohort with more patients than those included in the clinical trials, and our findings were consistent with the results reported in these trials. A direct comparison was not possible; however, our TTD outcomes were superior to the PFS outcomes observed in these clinical trials. As clinical trials are strictly controlled by rigorous protocols, RECIST assessments are performed more frequently. By contrast, in real-world clinical practice, the frequency of RECIST assessments is relatively low and depends on the patient’s condition owing to factors such as the cost and radiation exposure. Consequently, the detection of disease progression (PD) may be delayed, which could be one of the reasons why our outcomes were superior. Additionally, the difference between the outcomes of this study and those of clinical trials is that group A showed a longer second-line TTD (11.20 months) compared with first-line TTD (8.06 months). At the Memorial Sloan Kettering Cancer Center in the United States, a retrospective comparative study was conducted on CDK4/6i switching, focusing on the TTD, to compare patients who discontinued first-line CDK4/6i therapy due to AEs with those who discontinued owing to PD. This study reported that the occurrence of AEs significantly shortened the TTD of first-line therapy. Furthermore, patients who discontinued first-line therapy due to AEs had a significantly longer TTD for second-line CDK4/6i therapy than those who discontinued treatment due to PD (patients who discontinued due to AEs: first-line TTD, 3.0 months; second-line TTD, 10.1 months and patients who discontinued due to PD: first-line TTD, 10.0 months; second-line TTD, 4.7 months). This suggests that a certain number of patients may have discontinued first-line CDK4/6i therapy due to AEs in our study. This could be one of the reasons why the second-line TTD was longer than the first-line TTD in group A. Next, between groups A and C, switching from one CDK4/6i to another CDK4/6i (11.20 months) resulted in a significantly longer second-line TTD than switching to CT (5.16 months). Some clinical trials have compared CDK4/6i therapy with CT. In the PEARL trial, palbociclib + ET failed to show PFS superiority over capecitabine in the second-line setting for patients with HR-positive/HER2-negative ABC (7.5 months vs. 10.0 months; HR, 1.13; 95% CI, 0.85–1.50) [ 23 ]. By contrast, in the Young-PEARL trial, palbociclib + EXE with ovarian function suppression for premenopausal patients with HR-positive/HER2-negative ABC significantly prolonged PFS compared with capecitabine therapy (19.5 months vs. 14.0 months; HR, 0.75; 95% CI, 0.57–0.98; p = 0.04) [ 24 ]. Similarly, in the RIGHT-Choice trial, ribociclib + ET with ovarian function suppression for premenopausal patients with HR-positive/HER2-negative ABC significantly prolonged PFS compared with CT (21.8 months vs. 12.8 months; HR, 0.61; 95% CI, 0.43–0.87; p = 0.03) [ 25 ]. The large cohort included in the present study also demonstrated the superiority of CDK4/6i therapy over CT, which is consistent with these findings. Therefore, switching to another CDK4/6i instead of CT in the second-line setting may remain a viable therapeutic option after first-line CDK4/6i therapy. The background characteristics of patients did not match in this study; therefore, further analyses using prospective data are required. Between groups B and D, in the transition from first-line to second-line therapy, switching from ET to a CDK4/6i (40.37 months) resulted in a significantly longer total TTD of first- and second-line therapy than switching from a CDK4/6i to ET (20.50 months). A similar comparison was made in the SONIA trial, where the use of a CDK4/6i in the first-line setting did not show a significantly different PFS following the first- and second-line therapies compared with CDK4/6i therapy in the second-line setting for patients with HR-positive/HER2-negative ABC (31.0 months vs. 26.8 months; HR, 0.87; 95% CI, 0.74–1.03; p = 0.10) [ 26 ]. Rather, the median CDK4/6i therapy duration was 16.5 months longer in patients who received a CDK4/6i in the first-line setting (24.6 months) than in those who received a CDK4/6i in the second-line setting (8.1 months). Additionally, the first-line CDK4/6i group had grade 3 or higher AEs, and the per-patient drug costs were $ 200,000 higher. Based on these findings, the SONIA trial concluded that starting the therapy with ET monotherapy in the first-line setting instead of combining it with a CDK4/6i could effectively reduce drug toxicity and make the therapy more accessible to cost-restricted patients. In our study, the total TTD of first- and second-line therapies was longer in group D (the second-line CDK4/6i group), which differs from the findings of the SONIA trial. The primary reason group D showed a significantly longer TTD than group B can be attributed to differences in patient characteristics. Between groups A and E, in the transition from first-line to second-line therapy, there was no significant difference in the total TTD of first- and second-line therapies between switching from one CDK4/6i to another CDK4/6i (25.16 months) and switching from CT to a CDK4/6i (21.29 months). Patients in group E received CT as the initial therapy; therefore, it was likely that many patients with a visceral crisis were included. It remains unclear which group of patients should be selected for CDK4/6is instead of CT; however, this suggests that, even in cases of visceral crisis, some patients may be able to receive a CDK4/6i as first-line therapy instead of CT. Developing resistance to hormone therapy is a major challenge in the treatment of HR-positive and HER2-negative ABC. The activation of the PI3K/AKT pathway has been recognized as a cause of hormone therapy resistance [ 27 ]. Several phase III trials (MONARCH-2, post-MONARCH, and EMBER-3) have investigated PIK3CA/AKT1/PTEN -mutated subgroups, and all have demonstrated the additional efficacy of abemaciclib, regardless of the PIK3CA/AKT1/PTEN mutations status [ 12 – 14 ]. Currently, targeted inhibitors of the PI3K/AKT pathway are available for HR-positive/HER2-negative ABC with PIK3CA/AKT1/PTEN mutations [ 16 ]. In the CAPItello-291 trial, capivasertib + FUL significantly prolonged PFS compared with FUL monotherapy in patients with HR-positive/HER2-negative ABC with AKT1 mutations, but the clinical benefit remained insufficient (median PFS, 7.3 months vs. 3.1 months; HR, 0.60; 95% CI, 0.51–0.71; p < 0.001) [ 15 ]. In the SOLAR-1 trial, alpelisib + FUL significantly prolonged PFS compared with FUL monotherapy in patients with HR-positive/HER2-negative ABC with PIK3CA mutations (median PFS, 11.0 months vs. 5.7 months; HR, 0.65; 95% CI, 0.50–0.85; p < 0.001) [ 28 ]. Therefore, both agents have the potential to become key drugs for HR-positive/HER2-negative ABC. Although a direct comparison could not be made, our findings were comparable to those of CAPItello-291 and SOLAR-1 trials. We propose that CDK4/6i switching is an effective therapeutic option for HR-positive/HER2-negative ABC with PIK3CA/AKT1/PTEN mutations. Limitations This retrospective study utilized real-world data, which leads to several limitations. The database does not allow patient tracking across multiple institutions, if a patient receives therapy at multiple facilities, there is the possibility of an overlapping or missing therapy history. Since the reasons for therapy discontinuation were unknown, we could not determine whether patients discontinued therapy because of disease progression, adverse events, or other reasons. Finally, we could not obtain important clinical information essential for therapeutic decision–making in clinical practice, such as the cancer stage, metastatic organs, number of metastases, and performance status. And we could not assess common efficacy endpoints, such as overall survival, PFS, or tumor response. The MDV database does not include data on therapeutic efficacy. However, there are studies in which the TTD has been used as a surrogate to evaluate the therapeutic effectiveness of CDK4/6is [ 29 , 30 ]. It has been suggested that the TTD is an important indicator for assessing both therapeutic effectiveness and tolerability [ 22 ]; therefore, examining the TTD holds significant value. CONCLUSION This study demonstrates the therapeutic outcomes of CDK4/6i switching in patients with HR-positive/HER2-negative ABC in real-world clinical practice. Going forward, CDK4/6i switching will continue to be considered a viable therapeutic option for this patient population. These findings may contribute to future therapeutic strategies, including the optimization of therapy sequencing. Declarations Funding: None Competing interests : Takuya Nishina, Maki Tanioka, Kenji Takada, Takahiro Tsukioki, Yuko Takahashi, Tadahiko Shien, and Shinichi Toyooka have no conflicts of interest that are directly relevant to the content of this article. Author contributions : All authors reviewed and edited the manuscript. Kenji Takada provided valuable technical support and Maki Tanioka provided essential data for this study. Data availability : The data that support the findings of this study are available from Medical Data Vision Co., Ltd. but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Medical Data Vision Co., Ltd. Ethics approval : Not applicable. Consent to participate : As this noninterventional retrospective study used anonymized patient data, this study did not require informed consent from patients. Consent to publish : Not applicable References Harold. J. B., Mark. R. S., Debra. L. B., et al. Endocrine Therapy and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. (2021) ;39(35):3959–3977 Hafner M, Mills CE, Subramanian K et al (2019) Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem Biol 26:1067–1080e8 Finn RS, Martin M, Rugo HS et al (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925–1936 Cristofanilli M, Turner NC, Bondarenko I et al (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for therapy of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425–439 Hortobagyi GN, Stemmer SM, Burris HA et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738–1748 Slamon DJ, Neven P, Chia S et al (2018) Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 36:2465–2472 Im SA, Lu YS, Bardia A et al (2019) Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med 381:307–316 Sledge GW Jr, Toi M, Neven P et al (2017) MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35:2875–2884 Goetz MP, Toi M, Huober J et al (2017) MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 35:3638–3646 Mayer EL, Ren Y, Wagle N et al (2024) PACE: A randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer. J Clin Oncol 42:2050–2060 Llombart-Cussac A, Harper-Wynne C, Perello A et al (2023) Second-line endocrine therapy with or without palbociclib maintenance in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMIRA trial. J Clin Oncol 41(16_suppl): Abstract 1001 Kalinsky K, Accordino MK, Chiuzan C et al (2023) Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol 41:4004–4013 Kalinsky K, Layman RM, Kaufman PA et al (2024) postMONARCH: A phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4/6 inhibitor and endocrine therapy. J Clin Oncol 42:2050–2060 Jhaveri KL, Neven P, Lis Casalnuovo M et al (2024) Imlunestrant with or without abemaciclib in advanced breast cancer: EMBER-3 trial. N Engl J Med Oliveira M, Rugo HS, Howell SJ et al (2024) Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 25:1231–1244 McCartney A, Migliaccio I, Bonechi M et al (2019) Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice. Front Oncol 9:666. 10.3389/fonc.2019.00666 Nakamura M (2016) Jpn J Pharmacoepidemiol 21(1):23–25. https://doi.org/10.3820/jjpe.21.23 . Utilization of MDV data and data quality control Medical Data Vision Co., Ltd (2022) Available from: https://en.mdv.co.jp/about-mdv-database/ . Accessed 30 Jul 2024 Sone S (2015) Ethical guidelines for clinical trials in medical research involving human subjects. Gan Kagaku Ryoho 42(8):893–902 Takeda T, Sugimoto S, Matsumoto J (2024) A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases. Int J Clin Pharm 46(2):536–541. 10.1007/s11096-023-01687-6 Yoshinami T, Nagai SE, Hattori M (2024) Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study. Breast Cancer 31:621–632 Blumenthal GM, Gong Y, Kehl K et al (2019) Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer. Ann Oncol 30(5):830–838 Martin M, Zielinski C, Ruiz-Borrego M et al (2021) Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor receptor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial (PEARL). Ann Oncol 32(4):488–499. 10.1016/j.annonc.2020.12.007 Park YH, Kim TY, Kim GM et al (2019) Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 20(12):1750–1759. 10.1016/S1470-2045(19)30565-0 Lu YS, Im SA, Bin Mohd Mahidin EI, Azim H et al (2024) Final results of RIGHT Choice: Ribociclib plus endocrine therapy versus combination chemotherapy in premenopausal women with clinically aggressive hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. J Clin Oncol 42(15):830–838. 10.1200/JCO.24.00144 Sonke GS, Van Ommen-Nijhof A, Wortelboer N et al (2023) Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive, HER2-negative advanced breast cancer. J Clin Oncol. ;41(suppl 16): LBA1000. 10.1200/JCO.2023.41.16_suppl.LBA1000 Corti C, Batra-Sharma H, Kelsten M et al (2024) Systemic therapy in breast cancer. Am Soc Clin Oncol Educ Book 44(3):e432442. 10.1200/EDBK_432442 André F, Ciruelos E, Rubovszky G et al (2019) Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 380(20):1929–1940. 10.1056/NEJMoa1813904 Kawai M, Takada M, Nakayama T et al (2023) Patient characteristics, treatment patterns, and outcomes of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer patients prescribed cyclin-dependent kinase 4 and 6 inhibitors: large-scale data analysis using a Japanese claims database. Breast Cancer Res Treat 196(1):85–95. 10.1007/s10549-022-06816-9 Mai N, dos Anjos CH, Razavi P et al (2024) Predictors of response to CDK4/6 inhibitor retrial after prior CDK4/6 inhibitor failure in ER-positive metastatic breast cancer. npj Breast Cancer 10:92. 10.1038/s41523-024-00699-3 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6616110","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457272492,"identity":"d7cc1f96-7948-4986-a2aa-eaa703c03de5","order_by":0,"name":"Takuya Nishina","email":"data:image/png;base64,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","orcid":"","institution":"Okayama University","correspondingAuthor":true,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Nishina","suffix":""},{"id":457272493,"identity":"9f5c617f-9167-41de-b55e-d1264209cb16","order_by":1,"name":"Maki Tanioka","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Tanioka","suffix":""},{"id":457272494,"identity":"eaaa3a21-35f2-48c7-b2ac-11db9da97b43","order_by":2,"name":"Kenji Takada","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Takada","suffix":""},{"id":457272495,"identity":"c16c8acd-a1a5-474e-b2ba-c883ddebb19e","order_by":3,"name":"Takahiro Tsukioki","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Tsukioki","suffix":""},{"id":457272496,"identity":"8e1b7388-fae4-47e2-9219-b5cd3c5ce3c6","order_by":4,"name":"Yuko Takahashi","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Takahashi","suffix":""},{"id":457272497,"identity":"90cb50ff-e239-416e-96c9-51ea07d8a21e","order_by":5,"name":"Tadahiko Shien","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Tadahiko","middleName":"","lastName":"Shien","suffix":""},{"id":457272498,"identity":"e7477519-ba27-4bd6-a828-5d9e48aefd7e","order_by":6,"name":"Shinichi Toyooka","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Toyooka","suffix":""}],"badges":[],"createdAt":"2025-05-08 03:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6616110/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6616110/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83108369,"identity":"1bfefa60-6ddd-4e34-8073-71b5c37a78d9","added_by":"auto","created_at":"2025-05-20 06:47:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87297,"visible":true,"origin":"","legend":"\u003cp\u003eThis Consort diagram presents patient selection. A total of 13,284 patients, aged 20 years or older, received combination therapy with CDK4/6i and ET between April 2008 and December 2022, without receiving anti-HER2 therapy. After excluding ineligible cases, 13,284 patients were classified into six groups based on their therapy patterns from first-line to second-line therapy. Patients with a history of abemaciclib administration only or palbociclib administration only were classified into groups B, C, D, E, or F. Most patients who received both CDK4/6i drugs were classified into group A. However, 27 patients who received CDK4/6i in the first-line setting, switched to ET in the second-line setting, and then received another CDK4/6i from the third line onward were classified into group B. 32 patients who received CDK4/6i in the first-line setting, switched to CT in the second-line setting, and then received another CDK4/6i from the third line onward were classified into group C. 249 patients who received ET in the first-line setting, received their first CDK4/6i in the second-line setting, and then received another CDK4/6i from the third line onward were classified into group D. 56 patients who received CT in the first-line setting, received their first CDK4/6i in the second-line setting, and then received another CDK4/6i from the third line onward were classified into group E.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/e9a5f4c9a7274d445c311d87.png"},{"id":83108372,"identity":"6526d311-074c-48fa-8460-47801d4a53fe","added_by":"auto","created_at":"2025-05-20 06:47:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":275860,"visible":true,"origin":"","legend":"\u003cp\u003eThis Sankey diagram presents the patterns of regimens from first-line to second-line therapy. The left side of the diagram shows the first-line regimens, while the right side displays the second-line regimens, along with the number of patients for each regimen. CDK4/6is are distinguished as abemaciclib (ABE) and palbociclib (PAL). Chemotherapy (CT) details include paclitaxel (PTX), bevacizumab+paclitaxel (Bev+PTX), doxorubicin+cyclophosphamide (AC), epirubicin+cyclophosphamide (EC), eribulin (Eri), vinorelbine (VNR), capecitabine (Cape), and tegafur/gimeracil/oteracil (TS1). aromatase inhibitors (AI) include letrozole (LET), anastrozole (ANA), and exemestane (EXE). Selective Estrogen Receptor Modulators (SERM) include tamoxifen (TAM) and toremifene (TOR). Fulvestrant (FUL) is classified as a selective estrogen receptor degrader (SERD).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/99f3bf933d1e006cd6afb259.png"},{"id":83109271,"identity":"d3d4772b-0226-4791-96d7-6299b06056cb","added_by":"auto","created_at":"2025-05-20 06:55:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":65811,"visible":true,"origin":"","legend":"\u003cp\u003eThe therapy regimens and median TTD values for each group are presented as bar graphs. Figure 3a shows the first-line TTD, Figure 3b shows the second-line TTD, and Figure 3c shows the total TTD of first- and second-line therapies (the total TTD). Since group F consists of patients who received only CDK4/6i+ET therapy during the observation period, they do not have a second-line TTD. Therefore, the first-line TTD and the total TTD for group F are the same. Furthermore, the total TTD is defined as the period from the start of first-line therapy to the end of second-line therapy. As a result, the sum of the first-line TTD and the second-line TTD does not necessarily match the total TTD. This is due to the use of the median in the TTD analysis. We compared the TTD between groups A and B, groups A and C, groups B and D, and groups A and E. For groups B and D and groups A and E, only the total TTD were compared owing to differences in the therapy line where a CDK4/6i was used.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/04dfd4c74178f33eed9235d7.png"},{"id":83108378,"identity":"260bb35f-cdac-417c-8392-ef1fef339cdf","added_by":"auto","created_at":"2025-05-20 06:47:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":274873,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of Time to Discontinuation (TTD) are shown in Figure 4a for groups A and B (second-line TTD), Figure 4b for groups A and C (second-line TTD), Figure 4c for groups B and D (total TTD of first- and second-line), and Figure 4d for groups A and E (total TTD of first- and second-line).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/5504e6a4f9ec4efa6cc911bf.png"},{"id":83794191,"identity":"3fc20345-7be3-4dca-bfbb-180c64321d31","added_by":"auto","created_at":"2025-06-02 22:01:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1226520,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/1477b3c3-1d55-40b0-ac98-562867290fbc.pdf"},{"id":83109612,"identity":"98172685-aa06-4777-a370-848ca9d3591f","added_by":"auto","created_at":"2025-05-20 07:03:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":519716,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/49fa7bc9ff799cd94ee598ca.docx"},{"id":83109269,"identity":"ce03da5e-1be8-4d12-8193-4c617a07312e","added_by":"auto","created_at":"2025-05-20 06:55:32","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":87080,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6616110/v1/afd7b6b4f2f2143ba307c216.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical significance on Switching CDK4/6 inhibitors among 13,284 patients with metastatic breast cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAccording to the Hortobagyi algorithm, treatment for hormone receptor (HR)\u0026ndash;positive, human epidermal growth factor receptor 2 (HER2)\u0026ndash;negative advanced breast cancer (ABC) involves the selection of endocrine therapy (ET) in the absence of severe organ dysfunction or rapid disease progression (visceral crisis), whereas chemotherapy (CT) is chosen in cases of visceral crisis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) regulate the cell cycle by inducing cell cycle arrest in the G1 phase [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The three available CDK4/6is are palbociclib, abemaciclib, and ribociclib. CDK4/6is have been shown to improve progression-free survival (PFS) in patients with HR-positive/HER2-negative ABC when used in combination with ET as a first- or second-line therapy [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Combination therapy using a CDK4/6i and ET is the standard of care for HR-positive/HER2-negative ABC [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, the development of resistance to hormone therapy is a major challenge in the treatment of HR-positive/HER2-negative ABC. According to the results from various clinical trials, ET monotherapy in the second-line setting after first-line CDK4/6i\u0026thinsp;+\u0026thinsp;ET has a PFS of only 2.8\u0026ndash;4.6 months [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e mutations has been recognized as one of the causes of resistance to hormone therapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the CAPItello-291 trial, capivasertib (AKT inhibitor) significantly prolonged PFS in patients with HR-positive/HER2-negative ABC with \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e mutations; however, the absolute PFS benefit was modest, and the clinical significance remained limited (7.3 months vs. 3.1 months; hazard ratio [HR], 0.50; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given these suboptimal treatment options, currently, physicians choose to switch CDK4/6is (from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET), extend CDK4/6is with a different ET (from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to the same CDK4/6i\u0026thinsp;+\u0026thinsp;another ET), or transition to ET monotherapy, CT, or PI3K/AKT inhibitors depending on the patient\u0026rsquo;s condition. In recent years, clinical trials have been conducted on switching or extending CDK4/6i\u0026thinsp;+\u0026thinsp;ET. Extension of CDK4/6i therapy has been investigated in the PACE and PALMIRA trials. In these trials, extending palbociclib from first- to second-line therapy while changing the ET combination failed to prolong PFS in second-line therapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Switching to a CDK4/6i was investigated in the MAINTAIN, post-MONARCH, and EMBER-3 trials. In the MAINTAIN trial, switching from palbociclib\u0026thinsp;+\u0026thinsp;ET to ribociclib\u0026thinsp;+\u0026thinsp;ET significantly prolonged the second-line PFS compared with changing to ET monotherapy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In the post-MONARCH trial, switching from palbociclib\u0026thinsp;+\u0026thinsp;aromatase inhibitor (AI) or from ribociclib\u0026thinsp;+\u0026thinsp;AI to abemaciclib\u0026thinsp;+\u0026thinsp;fulvestrant (FUL) significantly prolonged the second-line PFS compared with switching to FUL monotherapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the EMBER-3 trial, switching from CDK4/6i\u0026thinsp;+\u0026thinsp;AI to abemaciclib\u0026thinsp;+\u0026thinsp;imlunestrant significantly prolonged the second-line PFS compared with changing to imlunestrant monotherapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, these studies included a small number of patients. To overcome this, this study utilized a large real-world clinical database comprising 13,284 patients to evaluate the significance of switching to another CDK4/6i after the use of a CDK4/6i in the first-line therapy for HR-positive/HER2\u0026thinsp;\u0026minus;\u0026thinsp;negative ABC.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eThis study utilized retrospective observational data from the Medical Data Vision Co., Ltd. (MDV) database. The MDV database is a de-identified database comprising discharge summaries and medical insurance billing data obtained from inpatient and outpatient visits at Japanese hospitals using the Diagnosis Procedure Combination (DPC) system [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The DPC system includes hospitals providing acute care and other services, incorporating many of Japan\u0026rsquo;s major medical and cancer centers. As of January 2021, the MDV database includes the data of approximately 34.84\u0026nbsp;million individuals [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This study was conducted in accordance with the guidelines of the Declaration of Helsinki and Good Pharmacoepidemiology Practices. According to Japan\u0026rsquo;s Ethical Guidelines for Medical and Health Research Involving Human Subjects [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], this noninterventional retrospective study using anonymized patient data did not require informed consent.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis study was designed as follows:\u003c/p\u003e \u003cp\u003e(1) The follow-up period was set from April 2008 to December 2022, which was the maximum period for which the data were available. (2) Prescription records of palbociclib or abemaciclib as well as those of ET (FUL, letrozole [LET], anastrozole [ANA], exemestane [EXE], tamoxifen [TAM], and toremifene [TOR]) were confirmed. (3) The absence of prescriptions for anti-HER2 therapies (trastuzumab and pertuzumab) was confirmed. (5) The age at the time of CDK4/6i prescription was \u0026ge;\u0026thinsp;20 years. (6) For patients prescribed CDK4/6is, information on CT (paclitaxel [PTX], bevacizumab\u0026thinsp;+\u0026thinsp;paclitaxel [Bev\u0026thinsp;+\u0026thinsp;PTX], doxorubicin\u0026thinsp;+\u0026thinsp;cyclophosphamide [AC], epirubicin\u0026thinsp;+\u0026thinsp;cyclophosphamide [EC], eribulin [Eri], vinorelbine [VNR], capecitabine [Cape], and tegafur/gimeracil/oteracil [TS1]) administered during the follow-up period was also investigated.\u003c/p\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003ePatients who were prescribed CDK4/6is before the surgery date as well as those who were administered Bev\u0026thinsp;+\u0026thinsp;PTX, Eri, VNR, Cape, or TS1 before the surgery date were classified as having de novo stage IV disease. Patients who were prescribed a CDK4/6i after the surgery date were classified as having postoperative recurrence. If PTX, AC, or EC was administered in two regimens or within 6 months immediately before the surgery date, it was classified as neoadjuvant chemotherapy (NAC).\u003c/p\u003e \u003cp\u003eIf no chemotherapy was administered before the surgery date and PTX, AC, or EC was administered in two regimens or within 6 months immediately after the surgery date, it was classified as adjuvant chemotherapy. The prescription of LET, ANA, EXE, or TAM immediately after the surgery date was classified as postoperative adjuvant ET. If the postoperative adjuvant ET was switched between LET, ANA, EXE, or TAM, it was considered a continuation of postoperative adjuvant ET. The date of the first denosumab administration was defined as the date of the onset of bone metastases. The diagnosis date of postoperative recurrence was defined as the earliest date on which Bev\u0026thinsp;+\u0026thinsp;PTX, Eri, VNR, Cape, TS1, CDK4/6i, or denosumab was administered after the surgery date or the earliest date on which PTX, AC, or EC was administered at least 6 months after the surgery date.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was to compare the time to discontinuation (TTD) of second-line therapy between two groups of patients with HR-positive/HER2-negative ABC diagnosed with de novo stage IV disease or recurrence: those who received CDK4/6i\u0026thinsp;+\u0026thinsp;ET as first-line therapy and switched to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET in the second-line therapy and those who switched to ET monotherapy. The secondary endpoint was to investigate the therapy patterns, details of ET combined with a CDK4/6i, and the total TTD from the start of first-line therapy to the end of second-line therapy.\u003c/p\u003e\n\u003ch3\u003eTTD\u003c/h3\u003e\n\u003cp\u003eOnly the first and last prescription dates are recorded in the DPC system. Therefore, there were no data regarding the exact date of drug discontinuation or the reasons for discontinuation. Therefore, the date of the first prescription of a drug was defined as the start date of drug administration, and the date of the last prescription was defined as the end date of drug administration. In some cases, patients appeared to have overlapping prescriptions, even when there was no actual concurrent administration. Patients with overlapping prescriptions for three or more drugs during the same period were excluded owing to data inaccuracies. If there was an overlap in the administration periods of two drugs, the drug with the shortest administration period during the overlap was considered the administered drug for that period. The total TTD of the first- and second-line therapies was defined as the period from the start of first-line therapy to the end of second-line therapy.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLine of therapy\u003c/h2\u003e \u003cp\u003eThe lines of therapy included ET and CT. When a CDK4/6i was added to ET monotherapy, it was considered the same therapy line, with the start of the line defined as the initiation of ET. Abemaciclib was approved in Japan in November 2018, and palbociclib was approved in September 2017. Patients who had been using ET for an extended period before October 2018 and those who received abemaciclib were excluded, as this did not provide accurate data for the combination therapy of CDK4/6i\u0026thinsp;+\u0026thinsp;ET. Similarly, patients who had been using ET for an extended period before August 2017 and then received palbociclib were excluded. If ET combined with a CDK4/6i was changed but the CDK4/6i remained unchanged, it was considered the same therapy line. Even if CDK4/6i administration was discontinued for any reason and if ET combined with CDK4/6i was continued, it was considered to be the same therapy line.\u003c/p\u003e \u003cp\u003ePatients with a gap of 60 days or more between the end of first-line therapy and the start of second-line therapy (owing to adverse event [AE] management, radiation therapy, etc.) were excluded. Patients with an overlap of 7 days or more between the end of first-line therapy and the start of second-line therapy were excluded. Patients with unknown ET combined with CDK4/6i are excluded. Abemaciclib was approved in Japan in November 2018, and palbociclib was approved in September 2017. Patients who had been using ET for an extended period before October 2018 and those who received abemaciclib were excluded, as this did not provide accurate data for the combination therapy of CDK4/6i\u0026thinsp;+\u0026thinsp;ET. Similarly, patients who had been using ET for an extended period before August 2017 and then received palbociclib were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatients with a final prescription date of December 2022 were considered to have ongoing drug administration and were considered as censored cases. HRs and 95% confidence intervals (CIs) between the two groups were examined using a Cox proportional hazards model for regression analysis. The Kaplan\u0026ndash;Meier method was used to estimate the median and 95% CIs for the TTD. Differences between the groups were evaluated using the log-rank test. No adjustments were made for biases or confounding factors, and missing data were not imputed. Data were processed using SQLite 3.33.0 and Python 3.12.2.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the recruitment process of the study cohort. A total of 13,284 patients with a history of CDK4/6i administration were identified in the database. Among these, 5,153 patients had a history of abemaciclib administration only, 6,126 had a history of palbociclib administration only, and 2,005 patients had a history of both abemaciclib and palbociclib administration. Thus, the 13,284 patients were classified into the following six groups:\u003c/p\u003e \u003cp\u003eGroup A: patients who switched from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET. (N\u0026thinsp;=\u0026thinsp;542)\u003c/p\u003e \u003cp\u003eGroup B: patients who switched from CDK4/6i\u0026thinsp;+\u0026thinsp;ET to ET monotherapy. (N\u0026thinsp;=\u0026thinsp;490)\u003c/p\u003e \u003cp\u003eGroup C: patients who switched from CDK4/6i\u0026thinsp;+\u0026thinsp;ET to CT. (N\u0026thinsp;=\u0026thinsp;608)\u003c/p\u003e \u003cp\u003eGroup D: patients who switched from ET monotherapy to CDK4/6i\u0026thinsp;+\u0026thinsp;ET. (N\u0026thinsp;=\u0026thinsp;1,486)\u003c/p\u003e \u003cp\u003eGroup E: patients who switched from CT to CDK4/6i\u0026thinsp;+\u0026thinsp;ET. (422)\u003c/p\u003e \u003cp\u003eGroup F: patients who received CDK4/6i\u0026thinsp;+\u0026thinsp;ET as the first-line therapy without any changes in the regimen. (N\u0026thinsp;=\u0026thinsp;3,271)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of patients\u003c/h2\u003e \u003cp\u003ePatient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age of all patients was 64 years (range, 21\u0026ndash;100 years), and most of the patients were female (99.5%). Groups A, B, C, and F had a history of CDK4/6i use in the first-line setting. Among these groups, ET combined with a CDK4/6i as the first-line therapy was evenly split between FUL (50.0%) and AI (50.0%). Groups A, D, and E had a history of CDK4/6i use in the second-line setting. In these groups, FUL was the predominant ET combined with a CDK4/6i in the second-line therapy (FUL, 66.2%; AI, 33.8%). In all groups, patients with de novo stage IV disease outnumbered those with postoperative recurrence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRegimen patterns\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the patterns of regimens from first-line to second-line therapy for all patients. A total of 4,911 patients were prescribed a CDK4/6i in the first-line setting. Of these, 3,271 (66.6%) did not switch to any other antitumor drug until the end of the follow-up period. A total of 1,908 patients were prescribed a CDK4/6i for the first time in the second-line setting. The majority (46.4%) of patients received AI as first-line therapy (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Among patients who switched to another CDK4/6i, 35.8% switched by changing the combined ET, whereas 64.2% switched without changing the combined ET. In the first-line setting, FUL was more commonly combined with a CDK4/6i than AI (AI, 42.5%; FUL, 57.5%). In the second-line setting, FUL remained to be the more commonly combined drug with a CDK4/6i than AI (AI, 25.9%; FUL, 74.1%) (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of TTD\u003c/h2\u003e \u003cp\u003eThe TTD for each group was determined using the Kaplan\u0026ndash;Meier method and is presented as a bar graph (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The median TTD of groups A and B was compared. Group A showed a significantly longer second-line TTD of 11.20 months compared with group B at 4.93 months (HR, 0.54; 95% CI, 0.47\u0026ndash;0.63; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Group A showed a significantly longer the total TTD of first- and second-line therapies (total TTD) of 25.16 months compared with group B at 20.50 months (HR, 0.72; 95% CI, 0.62\u0026ndash;0.83; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig. S2). The impact of the order of palbociclib and abemaciclib administration on the TTD was examined in group A. There was no significant difference in the second-line TTD between patients who switched from palbociclib to abemaciclib at 11.00 months and those who switched from abemaciclib to palbociclib at 11.33 months (HR, 1.04; 95% CI, 0.83\u0026ndash;1.32; p\u0026thinsp;=\u0026thinsp;0.67) (Fig. S3a). There was no significant difference in the total TTD between patients who switched from palbociclib to abemaciclib at 25.66 months and those who switched from abemaciclib to palbociclib at 23.10 months (HR, 0.89; 95% CI, 0.71\u0026ndash;1.32; p\u0026thinsp;=\u0026thinsp;0.34) (Fig. S3b). In group A, statistical significance was tested for the median TTD across variables such as age (\u0026lt;\u0026thinsp;65 years vs. \u0026ge;65 years), path of onset (recurrence vs. de novo stage IV disease), presence of bone metastasis, history of NAC among patients with recurrence, and time from the first surgery to recurrence (\u0026ge;\u0026thinsp;1 year vs. \u0026lt;1 year). Although not statistically significant, patients younger than 65 years, those with postoperative recurrence, those with bone metastasis, and those with recurrence without NAC showed a longer TTD. Patients who showed recurrence within 1 year after surgery had a significantly higher total TTD than those who showed recurrence after 1 year (HR, 1.99; 95% CI, 1.13\u0026ndash;3.52; p\u0026thinsp;=\u0026thinsp;0.01) (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eThe median TTD of groups A and C was compared. Group A showed a significantly longer second-line TTD of 11.20 months than group C at 5.16 months (HR, 0.47; 95% CI, 0.41\u0026ndash;0.55; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). Similarly, group A showed a significantly longer total TTD of 25.16 months than group C at 16.49 months (HR, 0.58; 95% CI, 0.51\u0026ndash;0.67; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig. S4).\u003c/p\u003e \u003cp\u003eThe median TTD of groups A and D was compared. Group A showed a significantly longer total TTD of 25.16 months than group D at 40.37 months (HR, 1.98; 95% CI, 1.74\u0026ndash;2.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eThe median TTD of groups A and E was compared. There was no significant difference in the total TTD between group A at 25.16 months and group E at 21.29 months (HR, 0.91; 95% CI, 0.78\u0026ndash;1.07; p\u0026thinsp;=\u0026thinsp;0.26) (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e4\u003c/span\u003ed).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we used a large-scale MDV database of 13,284 patients with HR-positive/HER2-negative ABC to evaluate the clinical significance of switching CDK4/6i\u0026thinsp;+\u0026thinsp;ET. Regarding the AEs of CDK4/6is, a large-scale study with more than 100,000 patients was conducted using VigiBase and the Food and Drug Administration Adverse Event Reporting System [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Regarding therapy patterns and treatment duration after switching to CDK4/6i\u0026thinsp;+\u0026thinsp;ET, a study was conducted using the MDV database; however, the sample size of 1,170 patients was insufficient [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Other studies on the effectiveness of switching to a CDK4/6i have also been conducted; however, none have involved more than 10,000 patients. To the best of our knowledge, this is the largest retrospective study that investigated the effectiveness of CDK4/6is, including therapy patterns and treatment duration. Blumenthal et al. demonstrated a correlation between TTD and survival endpoints, suggesting that TTD is an important indicator for evaluating therapeutic effectiveness and tolerability [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We found that switching to another CDK4/6i in the second-line setting after using CDK4/6i\u0026thinsp;+\u0026thinsp;ET in the first-line setting for HR-positive/HER2-negative ABC resulted in a significantly longer TTD than switching to ET monotherapy. Furthermore, the TTD did not change according to the order of palbociclib and abemaciclib administration in the first- and second-line settings.\u003c/p\u003e \u003cp\u003eBetween groups A and B, switching from one CDK4/6i to another CDK4/6i (11.20 months) resulted in a significantly longer second-line TTD than switching to ET monotherapy (4.93 months). In the MAINTAIN trial, switching from palbociclib\u0026thinsp;+\u0026thinsp;ET (84%) or ribociclib\u0026thinsp;+\u0026thinsp;ET (11%) to ribociclib\u0026thinsp;+\u0026thinsp;FUL or EXE significantly prolonged the PFS in the second-line setting compared with switching to FUL or EXE monotherapy (5.3 vs. 2.8 months; HR, 0.57; 95% CI, 0.39\u0026ndash;0.85; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the post-MONARCH trial, switching from palbociclib\u0026thinsp;+\u0026thinsp;AI (59%) or ribociclib\u0026thinsp;+\u0026thinsp;AI (34%) to abemaciclib\u0026thinsp;+\u0026thinsp;FUL significantly prolonged the PFS in the second-line setting compared with switching to ET monotherapy (5.6 vs. 3.9 months; HR, 0.66; 95% CI, 0.48\u0026ndash;0.91; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In the EMBER-3 trial, switching from palbociclib\u0026thinsp;+\u0026thinsp;AI (61%), ribociclib\u0026thinsp;+\u0026thinsp;AI (29%), or abemaciclib\u0026thinsp;+\u0026thinsp;AI (10%) to abemaciclib\u0026thinsp;+\u0026thinsp;imlunestrant significantly prolonged the PFS in the second-line setting compared with switching to imlunestrant monotherapy (9.1 vs. 3.7 months; HR, 0.51; 95% CI, 0.38\u0026ndash;0.61) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the EMBER-3 trial included patients who experienced disease progression while receiving AI (administered alone or with a CDK4/6i) as a neoadjuvant or adjuvant treatment within 12 months after completing adjuvant treatment or while receiving first-line treatment for ABC. We analyzed a larger, real-world cohort with more patients than those included in the clinical trials, and our findings were consistent with the results reported in these trials. A direct comparison was not possible; however, our TTD outcomes were superior to the PFS outcomes observed in these clinical trials. As clinical trials are strictly controlled by rigorous protocols, RECIST assessments are performed more frequently. By contrast, in real-world clinical practice, the frequency of RECIST assessments is relatively low and depends on the patient\u0026rsquo;s condition owing to factors such as the cost and radiation exposure. Consequently, the detection of disease progression (PD) may be delayed, which could be one of the reasons why our outcomes were superior. Additionally, the difference between the outcomes of this study and those of clinical trials is that group A showed a longer second-line TTD (11.20 months) compared with first-line TTD (8.06 months). At the Memorial Sloan Kettering Cancer Center in the United States, a retrospective comparative study was conducted on CDK4/6i switching, focusing on the TTD, to compare patients who discontinued first-line CDK4/6i therapy due to AEs with those who discontinued owing to PD. This study reported that the occurrence of AEs significantly shortened the TTD of first-line therapy. Furthermore, patients who discontinued first-line therapy due to AEs had a significantly longer TTD for second-line CDK4/6i therapy than those who discontinued treatment due to PD (patients who discontinued due to AEs: first-line TTD, 3.0 months; second-line TTD, 10.1 months and patients who discontinued due to PD: first-line TTD, 10.0 months; second-line TTD, 4.7 months). This suggests that a certain number of patients may have discontinued first-line CDK4/6i therapy due to AEs in our study. This could be one of the reasons why the second-line TTD was longer than the first-line TTD in group A.\u003c/p\u003e \u003cp\u003eNext, between groups A and C, switching from one CDK4/6i to another CDK4/6i (11.20 months) resulted in a significantly longer second-line TTD than switching to CT (5.16 months). Some clinical trials have compared CDK4/6i therapy with CT. In the PEARL trial, palbociclib\u0026thinsp;+\u0026thinsp;ET failed to show PFS superiority over capecitabine in the second-line setting for patients with HR-positive/HER2-negative ABC (7.5 months vs. 10.0 months; HR, 1.13; 95% CI, 0.85\u0026ndash;1.50) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. By contrast, in the Young-PEARL trial, palbociclib\u0026thinsp;+\u0026thinsp;EXE with ovarian function suppression for premenopausal patients with HR-positive/HER2-negative ABC significantly prolonged PFS compared with capecitabine therapy (19.5 months vs. 14.0 months; HR, 0.75; 95% CI, 0.57\u0026ndash;0.98; p\u0026thinsp;=\u0026thinsp;0.04) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, in the RIGHT-Choice trial, ribociclib\u0026thinsp;+\u0026thinsp;ET with ovarian function suppression for premenopausal patients with HR-positive/HER2-negative ABC significantly prolonged PFS compared with CT (21.8 months vs. 12.8 months; HR, 0.61; 95% CI, 0.43\u0026ndash;0.87; p\u0026thinsp;=\u0026thinsp;0.03) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The large cohort included in the present study also demonstrated the superiority of CDK4/6i therapy over CT, which is consistent with these findings. Therefore, switching to another CDK4/6i instead of CT in the second-line setting may remain a viable therapeutic option after first-line CDK4/6i therapy. The background characteristics of patients did not match in this study; therefore, further analyses using prospective data are required.\u003c/p\u003e \u003cp\u003eBetween groups B and D, in the transition from first-line to second-line therapy, switching from ET to a CDK4/6i (40.37 months) resulted in a significantly longer total TTD of first- and second-line therapy than switching from a CDK4/6i to ET (20.50 months). A similar comparison was made in the SONIA trial, where the use of a CDK4/6i in the first-line setting did not show a significantly different PFS following the first- and second-line therapies compared with CDK4/6i therapy in the second-line setting for patients with HR-positive/HER2-negative ABC (31.0 months vs. 26.8 months; HR, 0.87; 95% CI, 0.74\u0026ndash;1.03; p\u0026thinsp;=\u0026thinsp;0.10) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Rather, the median CDK4/6i therapy duration was 16.5 months longer in patients who received a CDK4/6i in the first-line setting (24.6 months) than in those who received a CDK4/6i in the second-line setting (8.1 months). Additionally, the first-line CDK4/6i group had grade 3 or higher AEs, and the per-patient drug costs were \u003cspan\u003e$\u003c/span\u003e200,000 higher. Based on these findings, the SONIA trial concluded that starting the therapy with ET monotherapy in the first-line setting instead of combining it with a CDK4/6i could effectively reduce drug toxicity and make the therapy more accessible to cost-restricted patients. In our study, the total TTD of first- and second-line therapies was longer in group D (the second-line CDK4/6i group), which differs from the findings of the SONIA trial. The primary reason group D showed a significantly longer TTD than group B can be attributed to differences in patient characteristics.\u003c/p\u003e \u003cp\u003eBetween groups A and E, in the transition from first-line to second-line therapy, there was no significant difference in the total TTD of first- and second-line therapies between switching from one CDK4/6i to another CDK4/6i (25.16 months) and switching from CT to a CDK4/6i (21.29 months). Patients in group E received CT as the initial therapy; therefore, it was likely that many patients with a visceral crisis were included. It remains unclear which group of patients should be selected for CDK4/6is instead of CT; however, this suggests that, even in cases of visceral crisis, some patients may be able to receive a CDK4/6i as first-line therapy instead of CT.\u003c/p\u003e \u003cp\u003eDeveloping resistance to hormone therapy is a major challenge in the treatment of HR-positive and HER2-negative ABC. The activation of the PI3K/AKT pathway has been recognized as a cause of hormone therapy resistance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Several phase III trials (MONARCH-2, post-MONARCH, and EMBER-3) have investigated \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e-mutated subgroups, and all have demonstrated the additional efficacy of abemaciclib, regardless of the \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e mutations status [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Currently, targeted inhibitors of the PI3K/AKT pathway are available for HR-positive/HER2-negative ABC with \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e mutations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the CAPItello-291 trial, capivasertib\u0026thinsp;+\u0026thinsp;FUL significantly prolonged PFS compared with FUL monotherapy in patients with HR-positive/HER2-negative ABC with \u003cem\u003eAKT1\u003c/em\u003e mutations, but the clinical benefit remained insufficient (median PFS, 7.3 months vs. 3.1 months; HR, 0.60; 95% CI, 0.51\u0026ndash;0.71; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the SOLAR-1 trial, alpelisib\u0026thinsp;+\u0026thinsp;FUL significantly prolonged PFS compared with FUL monotherapy in patients with HR-positive/HER2-negative ABC with \u003cem\u003ePIK3CA\u003c/em\u003e mutations (median PFS, 11.0 months vs. 5.7 months; HR, 0.65; 95% CI, 0.50\u0026ndash;0.85; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, both agents have the potential to become key drugs for HR-positive/HER2-negative ABC. Although a direct comparison could not be made, our findings were comparable to those of CAPItello-291 and SOLAR-1 trials. We propose that CDK4/6i switching is an effective therapeutic option for HR-positive/HER2-negative ABC with \u003cem\u003ePIK3CA/AKT1/PTEN\u003c/em\u003e mutations.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis retrospective study utilized real-world data, which leads to several limitations. The database does not allow patient tracking across multiple institutions, if a patient receives therapy at multiple facilities, there is the possibility of an overlapping or missing therapy history. Since the reasons for therapy discontinuation were unknown, we could not determine whether patients discontinued therapy because of disease progression, adverse events, or other reasons. Finally, we could not obtain important clinical information essential for therapeutic decision\u0026ndash;making in clinical practice, such as the cancer stage, metastatic organs, number of metastases, and performance status. And we could not assess common efficacy endpoints, such as overall survival, PFS, or tumor response. The MDV database does not include data on therapeutic efficacy. However, there are studies in which the TTD has been used as a surrogate to evaluate the therapeutic effectiveness of CDK4/6is [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It has been suggested that the TTD is an important indicator for assessing both therapeutic effectiveness and tolerability [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; therefore, examining the TTD holds significant value.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis study demonstrates the therapeutic outcomes of CDK4/6i switching in patients with HR-positive/HER2-negative ABC in real-world clinical practice. Going forward, CDK4/6i switching will continue to be considered a viable therapeutic option for this patient population. These findings may contribute to future therapeutic strategies, including the optimization of therapy sequencing.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: Takuya Nishina, Maki Tanioka, Kenji Takada, Takahiro Tsukioki, Yuko Takahashi, Tadahiko Shien, and Shinichi Toyooka have no conflicts of interest that are directly relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: All authors reviewed and edited the manuscript. Kenji Takada provided valuable technical support and Maki Tanioka provided essential data for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e: The data that support the findings of this study are available from Medical Data Vision Co., Ltd. but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Medical Data Vision Co., Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: As\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ethis noninterventional retrospective study used anonymized patient data, this study did not require informed consent from patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHarold. J. B., Mark. R. S., Debra. L. B., et al. Endocrine Therapy and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 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Breast Cancer Res Treat 196(1):85\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10549-022-06816-9\u003c/span\u003e\u003cspan address=\"10.1007/s10549-022-06816-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMai N, dos Anjos CH, Razavi P et al (2024) Predictors of response to CDK4/6 inhibitor retrial after prior CDK4/6 inhibitor failure in ER-positive metastatic breast cancer. npj Breast Cancer 10:92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41523-024-00699-3\u003c/span\u003e\u003cspan address=\"10.1038/s41523-024-00699-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\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":"Cyclin-dependent kinase 4/6 inhibitors, endocrine therapy, HR-positive/HER2-negative advanced breast cancer, progression-free survival, time to discontinuation","lastPublishedDoi":"10.21203/rs.3.rs-6616110/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6616110/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRecent clinical trials have shown that switching to a combination therapy of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) prolongs progression-free survival (PFS) compared with ET monotherapy. Reports indicate that abemaciclib provides benefits regardless of the \u003cem\u003ePIK3CA\u003c/em\u003e mutation status; however, its clinical benefits remain insufficient. This study aimed to evaluate the clinical significance of switching CDK4/6i\u0026thinsp;+\u0026thinsp;ET in a large real-world cohort. Using a medical database, we identified 13,284 patients with hormone receptor\u0026ndash;positive/human epidermal growth factor receptor 2\u0026ndash;negative advanced breast cancer who received CDK4/6i\u0026thinsp;+\u0026thinsp;ET between 2008 and 2022. Patients were categorized into six groups based on their first- and second-line therapy patterns. We compared the median time to discontinuation (TTD) among the groups. In patients who switched from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET, the second-line TTD and total TTD of first- and second-line therapies (n\u0026thinsp;=\u0026thinsp;542) were significantly longer than those in patients who switched from CDK4/6i\u0026thinsp;+\u0026thinsp;ET to ET monotherapy (n\u0026thinsp;=\u0026thinsp;490) (the second-line TTD: 11.2 vs. 4.9 months, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; total TTD: 25.1 vs. 20.5 months, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The order of palbociclib and abemaciclib administration did not significantly affect the second-line or total TTD in patients who switched from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET. Switching from one CDK4/6i\u0026thinsp;+\u0026thinsp;ET to another CDK4/6i\u0026thinsp;+\u0026thinsp;ET resulted in a significantly longer TTD than switching to ET monotherapy. Considering the phase III clinical trial results of capivasertib, switching to CDK4/6i\u0026thinsp;+\u0026thinsp;ET is a viable therapeutic option regardless of the \u003cem\u003ePIK3CA\u003c/em\u003e mutation status.\u003c/p\u003e","manuscriptTitle":"Clinical significance on Switching CDK4/6 inhibitors among 13,284 patients with metastatic breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-20 06:47:27","doi":"10.21203/rs.3.rs-6616110/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":"cde7368c-6df2-4042-bf54-c91cfccfd400","owner":[],"postedDate":"May 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T21:53:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-20 06:47:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6616110","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6616110","identity":"rs-6616110","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}