Chemotherapy-Free Survival of CDK4/6 Inhibitor Combination Therapy or Endocrine Monotherapy as First-Line Treatment for HR+/HER2–Advanced Breast Cancer

Chemotherapy-Free Survival of CDK4/6 Inhibitor Combination Therapy or Endocrine Monotherapy as First-Line Treatment for HR+/HER2–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 Article Chemotherapy-Free Survival of CDK4/6 Inhibitor Combination Therapy or Endocrine Monotherapy as First-Line Treatment for HR+/HER2–Advanced Breast Cancer Sayaka Kuba, Michiko Haro, Yusuke Kajimoto, Takafumi Sangai, Eriko Tokunaga, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7266744/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 Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) significantly prolong progression-free survival (PFS) compared to endocrine monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer (ABC). However, research regarding chemotherapy-free survival (CFS) comparing CDK4/6i combination therapy and endocrine monotherapy in real-world settings is limited. This retrospective, multicenter observational study aimed to assess the noninferiority of CFS between CDK4/6i combination therapy and endocrine monotherapy as first-line treatments for patients with HR+/HER2– ABC. The primary endpoint was CFS (noninferiority margin for comparison: 1.2). Among 443 patients (monotherapy: 318; CDK4/6i: 125), no significant difference was observed in median CFS after adjusting for patient background using inverse probability of treatment weighting (monotherapy: 35 months; CDK4/6i: 30 months; hazard ratio: 0.93; 95% confidence interval, 0.70–1.23). In the favorable group (patients with a performance status of 0 and no liver metastasis), those with either de novo stage IV disease or a disease-free interval of ≥ 60 months had a median CFS of 48 months for endocrine monotherapy and 44 months for CDK4/6i combination therapy. In HR+/HER2– ABC, the endocrine monotherapy group did not show noninferiority in CFS compared with the CDK4/6i combination group, with a small difference. Biological sciences/Cancer Health sciences/Diseases Health sciences/Oncology advanced breast cancer CDK4/6 inhibitor endocrine monotherapy chemotherapy-free survival Figures Figure 1 Figure 2 Figure 3 Introduction Breast cancer is the most commonly diagnosed cancer and has the highest mortality rate in women [ 1 ]. In 2022, 2.3 million women were diagnosed with breast cancer worldwide, and 660,000 died of the disease [ 1 ]. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) breast cancer is the most common subtype, accounting for 70% of cases [ 2 ]. Compared with other subtypes, early-stage HR+/HER2– breast cancer generally has a better prognosis [ 2 ]. However, the 5-year relative survival rate for distant metastasis in HR+/HER2– breast cancer was 35% in 2017 [ 2 ]. In patients with HR+/HER2– advanced breast cancer (ABC), combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) nearly doubles the progression-free survival (PFS) compared with endocrine monotherapy in both first- and second-line settings [ 3 – 12 ]. CDK4/6i combination therapy consistently extended overall survival considerably in the second-line setting; however, in the first-line setting, the survival outcomes varied in different studies [ 10 , 13 – 18 ]. In addition, grade 3 or higher adverse events occurred more frequently with CDK4/6i combination therapy [ 3 – 12 ]. However, no substantial intergroup difference was observed in the overall quality of life (QoL) in the first-line setting [ 19 , 20 ]. Although the frequency of adverse events increases with CDK4/6 combination therapy, these adverse events can be effectively controlled, allowing for the maintenance of QoL while achieving high therapeutic efficacy. Nevertheless, high drug costs impose an increasing financial burden on patients. Therefore, long-term use of expensive drugs may not always be in the patient's best interest. In the SONIA trial, a randomized phase III trial in patients with HR+/HER2– ABC without prior treatment, where CDK4/6i was assigned as first- or second-line treatment, the duration from randomization to disease progression after second-line treatment showed no significant benefit between the two groups [ 21 ]. In contrast, first-line CDK4/6i use resulted in a longer treatment duration than second-line use, with a higher incidence of grade ≥ 3 adverse events [ 21 ]. Therefore, the authors concluded that these data challenge the perceived need for first-line CDK4/6i therapy in all patients. Furthermore, few single-center Japanese retrospective studies examining chemotherapy-free survival (CFS) in first- or second-line CDK4/6i therapy versus endocrine monotherapy found no significant difference in CFS [ 22 ]. This study aimed to assess the noninferiority of CFS between the CDK4/6i combination therapy and endocrine monotherapy groups as first-line treatments for patients with HR+/HER2– ABC. If endocrine monotherapy as the first-line treatment can demonstrate non-inferiority in CFS compared to CDK4/6is, it will become easier to select endocrine monotherapy based on the patient's circumstances and preferences. Results Participants Overall, 443 participants with ABC were included, with 318 receiving endocrine monotherapy and 125 receiving CDK4/6i combination therapy (Table 1 ). The mean (standard deviation) age was 61.2 (13.1) years in the endocrine monotherapy group and 57.9 (12.8) years in the CDK4/6i combination group. Ribociclib is not available in Japan; therefore, this study used palbociclib and abemaciclib in 57% and 43% of the patients, respectively, in the CDK4/6i combination group (Table 1 ). Moreover, 5.7% and 16.0% of patients, respectively, were still receiving their first-line endocrine treatment (Supplemental Table 1). The reasons for discontinuation of first-line endocrine therapy were disease progression (81.3% in the monotherapy group vs. 78.1% in the CDK4/6i group), adverse events (4.7% vs. 9.5%, respectively), and patient’s wish (9.7% vs. 2.9%, respectively; Supplemental Table 1). In the monotherapy group that received second-line treatment, 50.6% had received a CDK4/6i at some point by the time of analysis. Regarding second-line treatment, endocrine monotherapy (38.7%) was the most commonly selected option in the endocrine monotherapy group, followed by CDK4/6i (26.4%) and chemotherapy (14.8%). In contrast, in the CDK4/6i group, the most common second-line therapy was chemotherapy (23.2%), followed by endocrine monotherapy (21.6%), and a different CDK4/6i combination (18.4%, Table 2 ). The CDK4/6i combination group included a higher proportion of patients with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and those with organ metastasis (lung and/or liver), whereas the endocrine monotherapy group included more patients with bone-only metastases and those diagnosed in the earlier years of the study period. After adjustment using inverse probability of treatment weighting (IPTW), baseline characteristics between the groups were generally balanced, except for the time of diagnosis because CDK4/6i was approved in Japan in 2017. After IPTW, the median (range) follow-up was 45.5 (1.2–114.5) months in the endocrine monotherapy group and 36.2 (0.9–95.2) months in the CDK4/6i combination group. Table 1 Clinicodemographic characteristics of the study participants Unadjusted cohort Cohort after IPTW Monotherapy N = 318 CDK4/6i N = 125 Standardized difference Monotherapy N = 442 CDK4/6i N = 421 Standardized difference Year of diagnosis, n (%) 2015–2018 245 (77.0) 26 (20.8) 1.3374 346 (78.2) 85 (20.2) 1.4050 2019–2022 73 (23.0) 99 (79.2) –1.3374 96 (21.8) 336 (79.8) –1.4050 Age, years, n (%) Mean a 61.2 (13.1) 57.9 (12.8) 0.2558 ≤ 49 71 (22.3) 33 (26.4) –0.0978 102 (23.0) 93 (22.1) 0.0210 50–64 100 (31.4) 46 (36.8) –0.1153 145 (32.9) 147 (34.8) –0.0410 65–74 91 (28.6) 36 (28.8) –0.0041 129 (29.2) 131 (31.1) –0.0402 ≥ 75 56 (17.6) 10 (8.0) 0.2523 66 (14.9) 51 (12.0) 0.0807 Menopausal status, n (%) Postmenopausal 78 (24.5) 33 (26.4) 0.0323 110 (24.8) 106 (25.2) –0.0111 Premenopausal 236 (74.2) 91 (72.8) –0.0435 327 (73.9) 309 (73.4) 0.0117 Male 4 (1.3) 1 (0.8) 0.0411 6 (1.3) 6 (1.4) –0.0028 Disease stage before relapse, n (%) 0 1 (0.3) 0 (0.0) 0.0562 1 (0.3) 0 (0.0) 0.0545 1 31 (9.7) 16 (12.8) –0.1029 41 (9.3) 56 (13.2) –0.1362 2 102 (32.1) 40 (32.0) 0.0016 139 (31.4) 137 (32.6) –0.0257 3 74 (23.3) 24 (19.2) 0.0963 103 (23.2) 86 (20.5) 0.0654 4 104 (32.7) 45 (36.0) –0.0702 151 (34.1) 142 (33.7) 0.0084 Unknown 6 (1.9) 0 (0.0) 0.1387 8 (1.7) 0 (0.0) 0.1311 Type of origin of Stage Ⅳ, n (%) De novo 104 (32.7) 46 (36.8) –0.0873 151 (34.1) 144 (34.2) –0.0024 Non-de novo 214 (67.3) 79 (63.2) 0.0873 291 (65.9) 277 (65.8) 0.0024 Nuclear grade, n (%) 1 110 (34.6) 34 (27.2) 0.1554 152 (34.4) 124 (29.5) 0.1042 2 87 (27.4) 33 (26.4) 0.0215 118 (26.7) 106 (25.1) 0.0366 3 90 (28.3) 45 (36.0) –0.1709 129 (29.2) 139 (32.9) –0.0815 Unknown 31 (9.7) 13 (10.4) –0.0220 42 (9.6) 53 (12.5) –0.0971 DFI (excluding de novo Stage Ⅳ), months, n (%) Median b 50.0 (29.0–91.5) 56.0 (35.5–88.0) < 60 125 (39.3) 42 (33.6) 0.1169 167 (37.7) 157 (37.4) 0.0061 ≥ 60 89 (28.0) 37 (29.6) –0.0359 125 (28.3) 120 (28.4) –0.0041 ECOG-PS at diagnosis of metastasis, n (%) 0 237 (74.5) 107 (85.6) –0.2541 343 (77.5) 345 (81.9) –0.1049 1 52 (16.4) 16 (12.8) 0.0960 69 (15.5) 65 (15.5) –0.0017 2 14 (4.4) 2 (1.6) 0.1366 16 (3.6) 11 (2.6) 0.0564 3 5 (1.6) 0 (0.0) 0.1264 5 (1.1) 0 (0.0) 0.1069 Unknown 10 (3.1) 0 (0.0) 0.1802 10 (2.3) 0 (0.0) 0.1521 Symptomatic, n (%) 147 (46.2) 59 (47.2) –0.0195 206 (46.5) 193 (45.8) 0.0137 Organ metastasis c , n (%) 128 (40.3) 68 (54.4) –0.2885 194 (43.8) 195 (46.4) –0.0508 Liver metastasis, n (%) 48 (15.1) 37 (29.6) –0.4052 84 (19.0) 82 (19.4) –0.0109 Brain metastasis, n (%) 4 (1.3) 0 (0.0) 0.1129 6 (1.4) 0 (0.0) 0.1171 Only bone metastasis, n (%) 104 (32.7) 26 (20.8) 0.2538 130 (29.4) 123 (29.2) 0.0036 Number of metastases, n (%) 1 198 (62.3) 57 (45.6) 0.3438 254 (57.5) 232 (55.1) 0.0492 2 84 (26.4) 41 (32.8) –0.1448 126 (28.4) 128 (30.3) –0.0411 ≥ 3 34 (10.7) 27 (21.6) –0.3530 60 (13.6) 62 (14.7) –0.0300 Unknown 2 (0.6) 0 (0.0) 0.0796 2 (0.5) 0 (0.0) 0.0674 CDK4/6i in first-line treatment, n (%) Palbociclib - 71 (56.8) - - 250 (59.4) - Abemaciclib - 54 (43.2) - - 171 (40.6) - a y.o. (standard deviation), b month (interquartile range), c Organ metastasis is defined as a metastatic site in the liver and/or lung. CDK4/6i, CDK4/6 inhibitor; DFI, disease-free interval; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IPTW, inverse probability of treatment weighting. Table 2 Subsequent second-line anticancer treatments Monotherapy N = 318 CDK4/6i N = 125 First-line treatment only a 37 (11.6) 27 (21.6) Any second-line treatment 267 (84.0) 90 (72.0) CDK4/6i 84 (31.5) 23 (25.6) Endocrine Monotherapy Everolimus Chemotherapy Oral chemotherapy Intravenous chemotherapy Other systemic therapy 123 (46.1) 10 (3.7) 47 (17.6) 17 (6.4) 30 (11.2) 3 (1.1) 27 (30.0) 9 (10.0) 29 (32.2) 10 (11.1) 19 (21.1) 2 (2.2) Unknown 14 (4.4) 8 (6.4) a patients who continued treatment, died, or were censored in the first-line setting CFS in the Endocrine Monotherapy and CDK4/6i Combination Therapy Groups During a median follow-up of 46 and 36 months for the endocrine monotherapy and CDK4/6i combination therapy groups, respectively, 298 CFS events (67%) occurred in total. In the unadjusted analysis of the full cohort, the median CFS1 was 35 (95% confidence interval [CI]: 31–40) months in the endocrine monotherapy group and 29 (95% CI: 21–37) months in the CDK4/6i combination therapy group (Fig. 1 a). The hazard ratio (HR) of the endocrine monotherapy group to the CDK4/6i combination therapy group was 0.86 (95% CI: 0.66–1.12; Fig. 1 a). After IPTW adjustment, the median CFS1 was 35 (95% CI: 31–40) months in the endocrine monotherapy group and 30 (95% CI: 21–44) months in the CDK4/6i combination therapy group (Fig. 1 b). Correspondingly, the HR of the endocrine monotherapy group relative to the CDK4/6i combination group was 0.93 (95% CI: 0.70–1.23; Fig. 1 b). The upper limit of the 95% CI exceeded the prespecified noninferiority margin of 1.20; thus, noninferiority was not proved. The post-IPTW subgroup analysis for comparing the CDK4/6i combination therapy and endocrine monotherapy groups revealed no substantial intergroup differences in all parameters; however, premenopausal women showed a favorable trend in the CDK4/6i combination therapy group (Fig. 2 ). Similarly, no significant intergroup difference was detected in the CFS2 and after IPTW (Supplementary Fig. S1 ). Time to Treatment Failure (TTF) in the Endocrine Monotherapy and CDK4/6i Combination Therapy Groups In the unadjusted analysis of the full cohort, the median TTF1 was 12 months in both the endocrine monotherapy and CDK4/6i combination therapy groups (Supplementary Fig. S2). The HR of the endocrine monotherapy group compared with the CDK4/6i combination therapy group was 1.13 (95% CI: 0.90–1.41; Fig. 3 ). Similarly, after IPTW adjustment, median TTF1 was 12 months in both the endocrine monotherapy and CDK4/6i combination therapy groups (Supplementary Fig. S2). The HR of the endocrine monotherapy group compared with the CDK4/6i combination therapy group was 1.12 (95% CI: 0.91–1.47). However, regarding TTF2, which included patients who continued first-line treatment or received endocrine therapy in second-line treatment, the CDK4/6i combination group had a considerably longer treatment duration than the endocrine monotherapy group in both the unadjusted analysis and after the IPTW-adjusted cohort (Supplementary Fig. S3). Prognostic Factors for CFS and Comparison of CDK4/6i Combination Therapy Against Endocrine Monotherapy in the Favorable Prognosis Group We further divided the study cohort into two groups: participants with a CFS < 60 months (n = 257) and those with a CFS ≥ 60 months (n = 61). The CFS ≥ 60 months group had a considerably higher frequency of PS 0, without liver metastasis, compared with the group with CFS 5 years was approximately 10% higher than in the group with CFS < 60 months. We defined patients with ECOG-PS of 0 and no liver metastasis as the favorable group if they had either de novo stage IV disease or a DFI ≥ 60 months. In the favorable group (after IPTW adjustment), the median CFS was 48 (95% CI: 39–62) months in the endocrine monotherapy group and 44 (95% CI: 33–not available) months in the CDK4/6i combination therapy group (Fig. 3 ). The HR of the endocrine monotherapy group relative to the CDK4/6i combination therapy group was 0.97 (95% CI: 0.60–1.58; Fig. 3 ). Table 3 Prognostic factors of chemotherapy-free survival 1 CFS1 < 60 months (n = 257) CFS1 ≥ 60 month (n = 61) p-value Year of diagnosis, n (%) 2015–2018 185 (72.0) 60 (98.4) < 0.0001 2019–2022 72 (28.0) 1 (1.6) Age, years, n (%) Mean a 61.2 (12.8) 61.4 (14.2) 0.56 ≤ 49 57 (22.2) 14 (23.0) 50–64 85 (33.1) 15 (24.6) 65–74 70 (27.2) 21 (34.4) ≥ 75 45 (17.5) 11 (18.0) Menopausal status, n (%) Postmenopausal 63 (24.5) 15 (24.6) 1 Premenopausal 191 (74.3) 45 (73.8) Male 3 (1.2) 1 (1.6) Disease stage before relapse, n (%) 0 1 (0.4) 0 (0.0) 0.047 1 21 (8.2) 10 (16.4) 2 85 (33.1) 17 (27.9) 3 66 (25.7) 8 (13.1) 4 79 (30.7) 25 (41.0) Unknown 5 (1.9) 1 (1.6) Type of origin of stage Ⅳ, n (%) De novo 79 (30.7) 25 (41.0) 0.13 Non-de novo 178 (69.3) 36 (59.0) Nuclear grade, n (%) 1 87 (33.9) 23 (37.7) 0.17 2 66 (25.7) 21 (34.4) 3 78 (30.4) 12 (19.7) Unknown 26 (10.1) 5 (8.2) DFI (excluding de novo Stage Ⅳ), months, n (%) Median b 48.0 (27.3–85.8) 62.0 (40.0–121.0) 0.11 < 60 108 (42.0) 17 (27.9) 0.14 ≥ 60 70 (27.2) 19 (31.1) ECOG-PS at diagnosis of metastasis, n (%) 0 184 (74.5) 53 (86.9) 0.04 ≥ 1 63 (25.5) 8 (13.1) Symptomatic, n (%) 118 (45.9) 29 (47.5) 0.89 Organ metastasis c , n (%) 101 (39.3) 27 (44.3) 0.56 Liver metastasis, n (%) 44 (17.1) 4 (6.6) 0.045 Brain metastasis, n (%) 3 (1.2) 1 (1.6) 0.58 Only bone metastasis, n (%) 82 (31.9) 22 (36.1) 0.55 Number of metastases, n (%) 1 156 (60.7) 42 (68.9) 0.56 2 71 (27.6) 13 (21.3) ≥ 3 28 (10.9) 6 (9.8) Unknown 2 (0.8) 0 (0.0) a y.o. (standard deviation), b month (interquartile range), c Organ metastasis is defined as a metastatic site in the liver and/or lung. CDK4/6i, CDK4/6 inhibitor; DFI, disease-free interval; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IPTW, inverse probability of treatment weighting. Discussion This multicenter retrospective study compared the noninferiority of CFS in patients with HR+/HER2– ABC who were treated with either first-line endocrine monotherapy or CDK4/6i combination therapy. There was no substantial difference in the median CFS between the two treatment groups, both before and after IPTW adjustment. The primary analysis did not support the noninferiority of endocrine monotherapy, with a small difference in this real-world cohort. Regarding factors associated with CFS, ECOG-PS 0 and no liver metastasis were significantly favorable factors, while a longer DFI and de novo stage IV showed a trend toward significance. In the favorable group (ECOG-PS 0, no liver metastasis, and either de novo stage IV or DFI ≥ 60 months), the median CFS was 48 months in the endocrine monotherapy group. In the PALOMA2 trial, the median CFS was 40.4 months for the palbociclib group and 29.9 months for the placebo group (HR [95% CI]: 0.74 [0.59–0.92]) [ 23 ]. In particular, patients with DFS ≤ 12 months and organ metastasis showed a greater extension effect in the palbociclib group than the placebo group. Similarly, in the MONARCH 3 trial, the median CFS was reported as 46.7 months for the abemaciclib group and 30.6 months for the placebo group (HR [95% CI]: 0.69 [0.56–0.83]) [ 18 ]. Furthermore, in a real-world setting, the median time to chemotherapy was reported as 37.4 months for palbociclib plus an aromatase inhibitor (AI) and 29.2 months for AI alone for first-line treatment in the USA (HR [95% CI]: 0.77 [0.69–0.86]) [ 24 ]. A multicenter retrospective study from Japan, lacking a endocrine monotherapy control, showed that the CFS for cases treated with palbociclib was 36.7 months in the first-line setting and 23.8 months in the second-line setting [ 25 ]. In our study, the median CFS in the CDK4/6i group was approximately 6 months shorter than that previously reported in a real-world data study [ 24 ]. One possible explanation is that many patients in our cohort received CDK4/6i therapy early after its approval, when it was frequently used in the second-line or later settings. Even in the first-line setting, CDK4/6i was often selected for patients with poor endocrine sensitivity or rapidly progressing disease. These patients were more likely to require chemotherapy shortly after the initial treatment, resulting in shorter CFS durations. Although patient background was adjusted using the IPTW method, selection bias may have still have influenced the results. This is suggested by the fact that CDK4/6i combination therapy did not show a noticeable extension in TTF compared to endocrine monotherapy. Conversely, in TTF2, which includes both first- and second-line treatments, CDK4/6i combination therapy showed a considerable extension compared to endocrine monotherapy. The TTF2 analysis included patients who continued endocrine therapy in first-line treatment or had selected endocrine therapy as second-line treatment. Another contributing factor was that a higher proportion of patients in the CDK4/6i group were still receiving first-line treatment compared to those in the endocrine monotherapy group. Recently, with the development of new drugs, the prolonged duration of treatment has increased the financial burden on patients. “Financial toxicity” is an emerging problem wherein high out-of-pocket medical costs are associated with a decreased QoL, delayed or forgone care, or a combination of these, further increasing the risk of adverse health outcomes [ 26 , 27 ]. Japan has an excellent public health insurance system, and all citizens are eligible for enrollment. Patients’ co-payments are determined based on their age and income: 10%, 20%, or 30% of the full medical costs [ 28 ]. The maximum out-of-pocket costs range from JPY 8,000 to 252,600 per month, depending on income tiers. Despite the reduced copayment, patient costs exceed the limit for more than 3 months in a year, making CDK4/6i combination therapy considerably more expensive than tamoxifen and AIs. Recent reports have highlighted factors related to financial toxicity in metastatic breast cancer in Japan, emphasizing the need to reduce the financial burden on patients and provide personalized support tailored to individual needs [ 29 ]. The SONIA trial showed no statistically significant benefit of first-line CDK4/6i combination therapy over second-line treatment in terms of disease progression after initiating second-line treatment [ 21 ]. The SONIA trial demonstrated noninferiority in combined primary and secondary PFS when CDK4/6i combination therapy was used as second-line instead of first-line. Furthermore, first-line use of CDK4/6i combination therapy had considerably more grade 3 or higher adverse events compared with its second-line use. The results of the SONIA trial challenge the need for first-line use of a CDK4/6i combination therapy in all patients. Our study showed that in patients with a favorable prognosis, even without selecting CDK4/6i combination therapy as first-line treatment, long-term CFS can be achieved. In such cases, it may be reasonable to consider the patient's preferences when choosing the treatment. This study had some limitations. First, IPTW was used to adjust for baseline and clinical patient characteristics; however, this technique could not account for unobserved variables. Second, the follow-up period was not long enough to analyze CFS, and the median follow-up duration differed between the two groups (45.5 and 36.2 months in the endocrine monotherapy and CDK4/6i combination therapy groups, respectively), potentially affecting the comparison of outcomes. Third, as the study was conducted in a multicenter setting, variability in clinical practices across institutions might have influenced the treatment choices and patient management. Fourth, the sample size of this multicenter retrospective study was too small for noninferiority analysis. In conclusion, for HR+/HER2– ABC, the endocrine monotherapy group did not show noninferiority in CFS compared with the CDK4/6i combination group. However, our results suggest that endocrine monotherapy may not be ruled out as a viable first-line therapy, particularly in patients with favorable prognostic factors. The high cost of combination therapy and its potential impact on healthcare resources warrant further investigation into the cost-effectiveness of CDK4/6i combination therapy in various clinical settings. Methods Participant Selection and Characteristics This retrospective, multicenter observational study enrolled patients who were diagnosed with HR+/HER2– ABC between 2015 and 2020. Patients who received first-line treatment with either endocrine monotherapy or CDK4/6i combination therapy were eligible for this study. However, patients who received chemotherapy as first-line treatment were excluded. This study was approved by the Ethics Committee of Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval no. 23061906) on June 20, 2023. The study utilized an opt-out method to ascertain tacit informed consent, wherein a summary of the study was published online, and patients had the opportunity to refuse consent for study participation. All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. Endpoints The primary endpoint was to show non-inferiority of endocrine monotherapy compared with CDK4/6i combination therapy with CFS1, defined as the time from initiation of first-line ABC treatment to the commencement of chemotherapy or death. The secondary endpoints included CFS2, defined as the time from the initiation of first-line ABC treatment to the commencement of infusion chemotherapy or death; TTF1, defined as the duration from the initiation of first-line ABC treatment to the time when the treatment was discontinued for any reason; and TTF2, defined as the duration from the initiation of first-line to second-line endocrine therapy for ABC until the second-line treatment was discontinued for any reason. Patients who received chemotherapy as second-line treatment were excluded from the TTF2 analysis. Prognostic factors and CFS1 were identified in the favorable group based on the analyzed prognostic factors. Statistical Analysis To account for factors that influence the choice of endocrine therapy (CDK4/6i combination vs. monotherapy), propensity scores were generated using the following covariates: age, disease-free interval, which was defined as the interval between breast cancer diagnosis and ABC diagnosis; menopausal status; de novo/non-de novo stage 4; symptomatic or asymptomatic ABC; presence or absence of liver metastasis; presence or absence of lung metastasis; bone disease only; number of metastatic sites; and ECOG-PS score. Comparative analysis was performed using two methods: (1) an unadjusted analysis that did not account for baseline participant characteristics and (2) IPTW, which was used as the primary analysis to balance baseline characteristics between the treatment groups and control for confounders. In adjusting for participant characteristics, participants with missing values were excluded, and a complete case analysis was performed. Kaplan–Meier curves were generated to estimate the CFS. Statistical significance was determined using a two-sided alpha level of 5%. HRs for CFS were calculated using Cox regression models. Furthermore, the 95% CIs and p-values were calculated. Subgroup analyses were conducted to examine variations in the HRs across different categories. The noninferiority margin was set at 1.2. Declarations Acknowledgments The authors thank the Editage Group (https://www.editage.com/) for editing the draft of this manuscript Funding This work was supported by Project Mirai Cancer Research Grants. Author Contributions (CRediT) Sayaka Kuba developed the study design and concept. Yusuke Kajimoto and Ataru Igarashi performed the statistical analysis. Sayaka Kuba, Michiko Haro, Takafumi Sangai, Eriko Tokunaga, Tadahiko Shien, Kosho Yamanouchi, Hiroaki Inoue, Miki Yamaguchi, Kaori Terata, Hiroaki Shima, Goro Kutomi, Takaaki Fujii contributed to data acquisition and investigation. Sayaka Kuba wrote the first draft, and all authors participated in critical revision for important intellectual content. All authors approved the version of the manuscript. Data Availability Statement The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. Disclosure of Potential Conflicts of Interest SK received a research grant from Pfizer; and received lecture fees from Pfizer, Daiici-Sankyo, Kyowa-Kirin, and AstraZeneca. MH received lecture fees from AstraZeneca, Chugai, Eli Lilly, MSD, Pfizer, and Daiichi-Sankyo. YK is an employee of MSD, but this research is not related to MSD. TaSa received a research grant from Taiho; and received lecture fees from Chugai, Novartis, AstraZeneca, MSD, Taiho, Eli Lilly, Pfizer, Eisai, Daiichi-Sankyo, Maruho, PDRadiophama, Nippon-Kayaku, and Kyowa-Kirin. ET received lecture fees from Daiichi-Sankyo, AstraZeneca, Eli Lilly, Chugai, Eisai, MSD, Taiho, and EXACT SCIENCES. ToShi received lecture fees from AstraZeneca, Novartis, Eisai, Eli Lilly, MSD, Taiho, Gilead, Chugai, Daiichi-Sankyo, Takeda, Kyowa-Kirin and Pfizer. HS received lecture fees from Eli Lilly, AstraZeneca, Roche, Daiichi-Sankyo, Fuji Film, and Pfizer. KY received lecture fees from Chugai, and Merck. MY received lecture fees from Chugai, Taiho, Kyowa-Kirin, Lilly, AstraZeneca, Eisai, Pfizer, Daiichi-Sankyo, MSD, and EXACT SCIENCES. KT received lecture fees from Eli Lilly, Daiici-Sankyo, Pfizer, AstraZeneca. GK received lecture fees from AstraZeneca, Eli Lilly, MSD, and Pfizer. AI received lecture fees from AstraZeneca, Chugai, Eisai, Eli Lilly, Ono pharmaceutical, and Illumina. TF has received honoraria from Eli Lilly, Pfizer, AstraZeneca, Chugai, Eisai, Daiichi-Sankyo. HI has no conflict of interest. References Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74 , 229–263 (2024). Cancer Stat Facts. Female breast cancer subtypes. https://seer.cancer.gov/statfacts/html/breast-subtypes.html Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl. J. Med. 373 , 209–219 (2015). Cristofanilli, M. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 17 , 425–439 (2016). Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N Engl. J. Med. 375 , 1925–1936 (2016). Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl. J. Med. 375 , 1738–1748 (2016). Sledge, G. W. Jr. et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 35 , 2875–2884 (2017). Goetz, M. P. et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35 , 3638–3646 (2017). Hortobagyi, G. N. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann. Oncol. 29 , 1541–1547 (2018). Turner, N. C. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl. J. Med. 379 , 1926–1936 (2018). Rugo, H. S. et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res. Treat. 174 , 719–729 (2019). Johnston, S. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer . 5 10.1038/s41523-018-0097-z (2019). Cristofanilli, M. et al. Overall survival with palbociclib and fulvestrant in women with HR+/HER2- ABC: updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study. Clin. Cancer Res. 28 , 3433–3442 (2022). Slamon, D. J. et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl. J. Med. 382 , 514–524 (2020). Sledge, G. W. Jr. et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 6 , 116–124 (2020). Hortobagyi, G. N. et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl. J. Med. 386 , 942–950 (2022). Slamon, D. J. et al. Overall survival with palbociclib plus letrozole in advanced breast cancer. J. Clin. Oncol. 42 , 994–1000 (2024). Goetz, M. P. et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann. Oncol. 35 , 718–727 (2024). Rugo, H. S. et al. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann. Oncol. 29 , 888–894 (2018). Goetz, M. P. et al. Health-related quality of life in MONARCH 3: abemaciclib plus an aromatase inhibitor as initial therapy in HR+, HER2- advanced breast cancer. Oncologist 25 , e1346–e1354 (2020). Sonke, G. S. et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature 636 , 474–480 (2024). Endo, Y. et al. Time to chemotherapy for patients with estrogen receptor-positive breast cancer and cyclin-dependent kinase 4 and 6 inhibitor use. J. Breast Cancer . 25 , 296–306 (2022). Rugo, H. S. et al. Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: post hoc analyses from PALOMA-2 and PALOMA-3. Breast 66 , 324–331 (2022). Rugo, H. S. et al. Real-world treatment patterns for palbociclib plus an aromatase inhibitor, or an aromatase inhibitor alone, for patients with metastatic breast cancer in the Flatiron Database. Int. J. Cancer . 15 , 701–711 (2024). Yoshinami, T. et al. Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) 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 (2024). Zafar, S. Y. et al. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expense and the insured cancer patient’s experience. Oncologist 18 , 381–390 (2013). Richman, I. B. & Brodie, M. A national study of burdensome health care costs among non-elderly Americans. BMC Health Serv. Res. 14 , 435 (2014). Ministry of Health. Labour and Welfare. https://www.mhlw.go.jp/content/000333279.pdf Saeki, S. et al. Factors associated with financial toxicity in patients with breast cancer in Japan: a comparison of patient and physician perspectives. Breast Cancer . 30 , 820–830 (2023). Additional Declarations No competing interests reported. Supplementary Files Supplementalfiles.docx 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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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takaaki","middleName":"","lastName":"Fujii","suffix":""}],"badges":[],"createdAt":"2025-08-01 02:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7266744/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7266744/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90311161,"identity":"3b1ea867-1d67-437a-8b7a-afaa0d5b977f","added_by":"auto","created_at":"2025-09-01 09:48:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51659,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of chemotherapy-free survival 1, (a) unadjusted analysis; (b) after inverse probability of treatment weighting (IPTW)\u003c/p\u003e\n\u003cp\u003eCFS, chemotherapy-free survival; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; HR, hazard ratio\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7266744/v1/c7bf1856e297d76a7937db93.png"},{"id":90312472,"identity":"c59a6008-9ec1-4d91-82af-41747e3442ea","added_by":"auto","created_at":"2025-09-01 09:56:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100919,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of chemotherapy-free survival 1 stratified by subgroup after stabilized inverse probability of treatment weighting (IPTW)\u003c/p\u003e\n\u003cp\u003eECOG-PS, Eastern Cooperative Oncology Group Performance Status; CI, confidence interval\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7266744/v1/86a038ce56546971c4d0489b.png"},{"id":90311159,"identity":"e0b23aa0-0783-4e20-9eb5-5aba52e7e366","added_by":"auto","created_at":"2025-09-01 09:48:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":47828,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve of chemotherapy-free survival 1 in the favorable group\u003c/p\u003e\n\u003cp\u003eCFS, chemotherapy-free survival; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; HR, hazard ratio\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7266744/v1/f93605edd468096e8dff45e4.png"},{"id":90329236,"identity":"a1b82cdb-b8b0-4d61-8d30-97df03bead30","added_by":"auto","created_at":"2025-09-01 12:47:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1094256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7266744/v1/f37a88fd-6cdc-4c7b-8282-6feff022f8b0.pdf"},{"id":90311172,"identity":"956e78ea-7403-47e8-baf1-8aba1a27c05e","added_by":"auto","created_at":"2025-09-01 09:48:39","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":341562,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalfiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-7266744/v1/d235113db45057c758dd7cb5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eChemotherapy-Free Survival of CDK4/6 Inhibitor Combination Therapy or Endocrine Monotherapy as First-Line Treatment for HR+/HER2–Advanced Breast Cancer\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is the most commonly diagnosed cancer and has the highest mortality rate in women [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In 2022, 2.3\u0026nbsp;million women were diagnosed with breast cancer worldwide, and 660,000 died of the disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2\u0026ndash;) breast cancer is the most common subtype, accounting for 70% of cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Compared with other subtypes, early-stage HR+/HER2\u0026ndash; breast cancer generally has a better prognosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, the 5-year relative survival rate for distant metastasis in HR+/HER2\u0026ndash; breast cancer was 35% in 2017 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn patients with HR+/HER2\u0026ndash; advanced breast cancer (ABC), combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) nearly doubles the progression-free survival (PFS) compared with endocrine monotherapy in both first- and second-line settings [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. CDK4/6i combination therapy consistently extended overall survival considerably in the second-line setting; however, in the first-line setting, the survival outcomes varied in different studies [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, grade 3 or higher adverse events occurred more frequently with CDK4/6i combination therapy [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, no substantial intergroup difference was observed in the overall quality of life (QoL) in the first-line setting [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although the frequency of adverse events increases with CDK4/6 combination therapy, these adverse events can be effectively controlled, allowing for the maintenance of QoL while achieving high therapeutic efficacy. Nevertheless, high drug costs impose an increasing financial burden on patients. Therefore, long-term use of expensive drugs may not always be in the patient's best interest.\u003c/p\u003e\u003cp\u003eIn the SONIA trial, a randomized phase III trial in patients with HR+/HER2\u0026ndash; ABC without prior treatment, where CDK4/6i was assigned as first- or second-line treatment, the duration from randomization to disease progression after second-line treatment showed no significant benefit between the two groups [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In contrast, first-line CDK4/6i use resulted in a longer treatment duration than second-line use, with a higher incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, the authors concluded that these data challenge the perceived need for first-line CDK4/6i therapy in all patients. Furthermore, few single-center Japanese retrospective studies examining chemotherapy-free survival (CFS) in first- or second-line CDK4/6i therapy versus endocrine monotherapy found no significant difference in CFS [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study aimed to assess the noninferiority of CFS between the CDK4/6i combination therapy and endocrine monotherapy groups as first-line treatments for patients with HR+/HER2\u0026ndash; ABC. If endocrine monotherapy as the first-line treatment can demonstrate non-inferiority in CFS compared to CDK4/6is, it will become easier to select endocrine monotherapy based on the patient's circumstances and preferences.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eParticipants\u003c/em\u003e\u003c/p\u003e\u003cp\u003eOverall, 443 participants with ABC were included, with 318 receiving endocrine monotherapy and 125 receiving CDK4/6i combination therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean (standard deviation) age was 61.2 (13.1) years in the endocrine monotherapy group and 57.9 (12.8) years in the CDK4/6i combination group. Ribociclib is not available in Japan; therefore, this study used palbociclib and abemaciclib in 57% and 43% of the patients, respectively, in the CDK4/6i combination group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, 5.7% and 16.0% of patients, respectively, were still receiving their first-line endocrine treatment (Supplemental Table\u0026nbsp;1). The reasons for discontinuation of first-line endocrine therapy were disease progression (81.3% in the monotherapy group vs. 78.1% in the CDK4/6i group), adverse events (4.7% vs. 9.5%, respectively), and patient\u0026rsquo;s wish (9.7% vs. 2.9%, respectively; Supplemental Table\u0026nbsp;1). In the monotherapy group that received second-line treatment, 50.6% had received a CDK4/6i at some point by the time of analysis. Regarding second-line treatment, endocrine monotherapy (38.7%) was the most commonly selected option in the endocrine monotherapy group, followed by CDK4/6i (26.4%) and chemotherapy (14.8%). In contrast, in the CDK4/6i group, the most common second-line therapy was chemotherapy (23.2%), followed by endocrine monotherapy (21.6%), and a different CDK4/6i combination (18.4%, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The CDK4/6i combination group included a higher proportion of patients with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and those with organ metastasis (lung and/or liver), whereas the endocrine monotherapy group included more patients with bone-only metastases and those diagnosed in the earlier years of the study period. After adjustment using inverse probability of treatment weighting (IPTW), baseline characteristics between the groups were generally balanced, except for the time of diagnosis because CDK4/6i was approved in Japan in 2017. After IPTW, the median (range) follow-up was 45.5 (1.2\u0026ndash;114.5) months in the endocrine monotherapy group and 36.2 (0.9\u0026ndash;95.2) months in the CDK4/6i combination group.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinicodemographic characteristics of the study participants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eUnadjusted cohort\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eCohort after IPTW\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonotherapy\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;318\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCDK4/6i\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStandardized difference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMonotherapy\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;442\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCDK4/6i\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;421\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eStandardized difference\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eYear of diagnosis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2015\u0026ndash;2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e245 (77.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (20.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3374\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e346 (78.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e85 (20.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.4050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019\u0026ndash;2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73 (23.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99 (79.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;1.3374\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e96 (21.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e336 (79.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;1.4050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eAge, years, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.2 (13.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57.9 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2558\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71 (22.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0978\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e102 (23.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e93 (22.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0210\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e50\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100 (31.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 (36.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.1153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e145 (32.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e147 (34.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0410\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e65\u0026ndash;74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e91 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (28.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e129 (29.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e131 (31.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0402\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56 (17.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (8.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2523\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e66 (14.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e51 (12.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0807\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eMenopausal status, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostmenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78 (24.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0323\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e110 (24.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e106 (25.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0111\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePremenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e236 (74.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91 (72.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0435\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e327 (73.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e309 (73.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0117\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0411\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0028\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eDisease stage before relapse, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0562\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0545\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (9.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.1029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41 (9.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e56 (13.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.1362\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (32.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40 (32.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e139 (31.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e137 (32.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0257\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74 (23.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (19.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0963\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e103 (23.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e86 (20.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0654\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104 (32.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45 (36.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0702\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e151 (34.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e142 (33.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0084\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1387\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (1.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1311\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eType of origin of Stage Ⅳ, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104 (32.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 (36.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0873\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e151 (34.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e144 (34.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0024\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-de novo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e214 (67.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e79 (63.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0873\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e291 (65.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e277 (65.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0024\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eNuclear grade, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e110 (34.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34 (27.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1554\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e152 (34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e124 (29.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87 (27.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0215\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e118 (26.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e106 (25.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0366\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90 (28.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45 (36.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.1709\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e129 (29.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e139 (32.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0815\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (9.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 (9.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e53 (12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0971\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eDFI (excluding de novo Stage Ⅳ), months, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50.0 (29.0\u0026ndash;91.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.0 (35.5\u0026ndash;88.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e125 (39.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (33.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1169\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e167 (37.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e157 (37.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0061\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89 (28.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37 (29.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0359\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e125 (28.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e120 (28.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0041\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eECOG-PS at diagnosis of metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e237 (74.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e107 (85.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.2541\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e343 (77.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e345 (81.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.1049\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52 (16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0960\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e69 (15.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e65 (15.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0564\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1264\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1802\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1521\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSymptomatic, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e147 (46.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59 (47.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.0195\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e206 (46.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e193 (45.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0137\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrgan metastasis \u003csup\u003ec\u003c/sup\u003e, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e128 (40.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68 (54.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.2885\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e194 (43.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e195 (46.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0508\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48 (15.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37 (29.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.4052\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e84 (19.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e82 (19.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0109\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1171\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnly bone metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104 (32.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (20.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2538\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e130 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e123 (29.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0036\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eNumber of metastases, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e198 (62.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57 (45.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3438\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e254 (57.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e232 (55.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0492\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41 (32.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.1448\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e126 (28.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e128 (30.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0411\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (21.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.3530\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e60 (13.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e62 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;0.0300\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (0.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0796\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.0674\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eCDK4/6i in first-line treatment, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePalbociclib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71 (56.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e250 (59.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbemaciclib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54 (43.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e171 (40.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003e y.o. (standard deviation), \u003csup\u003eb\u003c/sup\u003e month (interquartile range), \u003csup\u003ec\u003c/sup\u003e Organ metastasis is defined as a metastatic site in the liver and/or lung.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eCDK4/6i, CDK4/6 inhibitor; DFI, disease-free interval; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IPTW, inverse probability of treatment weighting.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSubsequent second-line anticancer treatments\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMonotherapy\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;318\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCDK4/6i\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;125\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst-line treatment only\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37 (11.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (21.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny second-line treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e267 (84.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e90 (72.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDK4/6i\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e84 (31.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23 (25.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndocrine Monotherapy\u003c/p\u003e\u003cp\u003eEverolimus\u003c/p\u003e\u003cp\u003eChemotherapy\u003c/p\u003e\u003cp\u003eOral chemotherapy\u003c/p\u003e\u003cp\u003eIntravenous chemotherapy\u003c/p\u003e\u003cp\u003eOther systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e123 (46.1)\u003c/p\u003e\u003cp\u003e10 (3.7)\u003c/p\u003e\u003cp\u003e47 (17.6)\u003c/p\u003e\u003cp\u003e17 (6.4)\u003c/p\u003e\u003cp\u003e30 (11.2)\u003c/p\u003e\u003cp\u003e3 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (30.0)\u003c/p\u003e\u003cp\u003e9 (10.0)\u003c/p\u003e\u003cp\u003e29 (32.2)\u003c/p\u003e\u003cp\u003e10 (11.1)\u003c/p\u003e\u003cp\u003e19 (21.1)\u003c/p\u003e\u003cp\u003e2 (2.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8 (6.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003e patients who continued treatment, died, or were censored in the first-line setting\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eCFS in the Endocrine Monotherapy and CDK4/6i Combination Therapy Groups\u003c/em\u003e\u003c/p\u003e\u003cp\u003eDuring a median follow-up of 46 and 36 months for the endocrine monotherapy and CDK4/6i combination therapy groups, respectively, 298 CFS events (67%) occurred in total. In the unadjusted analysis of the full cohort, the median CFS1 was 35 (95% confidence interval [CI]: 31\u0026ndash;40) months in the endocrine monotherapy group and 29 (95% CI: 21\u0026ndash;37) months in the CDK4/6i combination therapy group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The hazard ratio (HR) of the endocrine monotherapy group to the CDK4/6i combination therapy group was 0.86 (95% CI: 0.66\u0026ndash;1.12; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). After IPTW adjustment, the median CFS1 was 35 (95% CI: 31\u0026ndash;40) months in the endocrine monotherapy group and 30 (95% CI: 21\u0026ndash;44) months in the CDK4/6i combination therapy group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Correspondingly, the HR of the endocrine monotherapy group relative to the CDK4/6i combination group was 0.93 (95% CI: 0.70\u0026ndash;1.23; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The upper limit of the 95% CI exceeded the prespecified noninferiority margin of 1.20; thus, noninferiority was not proved. The post-IPTW subgroup analysis for comparing the CDK4/6i combination therapy and endocrine monotherapy groups revealed no substantial intergroup differences in all parameters; however, premenopausal women showed a favorable trend in the CDK4/6i combination therapy group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similarly, no significant intergroup difference was detected in the CFS2 and after IPTW (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eTime to Treatment Failure (TTF) in the Endocrine Monotherapy and CDK4/6i Combination Therapy Groups\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn the unadjusted analysis of the full cohort, the median TTF1 was 12 months in both the endocrine monotherapy and CDK4/6i combination therapy groups (Supplementary Fig. S2). The HR of the endocrine monotherapy group compared with the CDK4/6i combination therapy group was 1.13 (95% CI: 0.90\u0026ndash;1.41; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Similarly, after IPTW adjustment, median TTF1 was 12 months in both the endocrine monotherapy and CDK4/6i combination therapy groups (Supplementary Fig. S2). The HR of the endocrine monotherapy group compared with the CDK4/6i combination therapy group was 1.12 (95% CI: 0.91\u0026ndash;1.47). However, regarding TTF2, which included patients who continued first-line treatment or received endocrine therapy in second-line treatment, the CDK4/6i combination group had a considerably longer treatment duration than the endocrine monotherapy group in both the unadjusted analysis and after the IPTW-adjusted cohort (Supplementary Fig. S3).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003ePrognostic Factors for CFS and Comparison of CDK4/6i Combination Therapy Against Endocrine Monotherapy in the Favorable Prognosis Group\u003c/em\u003e\u003c/p\u003e\u003cp\u003eWe further divided the study cohort into two groups: participants with a CFS\u0026thinsp;\u0026lt;\u0026thinsp;60 months (n\u0026thinsp;=\u0026thinsp;257) and those with a CFS\u0026thinsp;\u0026ge;\u0026thinsp;60 months (n\u0026thinsp;=\u0026thinsp;61). The CFS\u0026thinsp;\u0026ge;\u0026thinsp;60 months group had a considerably higher frequency of PS 0, without liver metastasis, compared with the group with CFS\u0026thinsp;\u0026lt;\u0026thinsp;60 months (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, in the group with CFS\u0026thinsp;\u0026ge;\u0026thinsp;60 months, the proportion of patients with de novo stage IV disease and a disease-free interval (DFI)\u0026thinsp;\u0026gt;\u0026thinsp;5 years was approximately 10% higher than in the group with CFS\u0026thinsp;\u0026lt;\u0026thinsp;60 months. We defined patients with ECOG-PS of 0 and no liver metastasis as the favorable group if they had either de novo stage IV disease or a DFI\u0026thinsp;\u0026ge;\u0026thinsp;60 months. In the favorable group (after IPTW adjustment), the median CFS was 48 (95% CI: 39\u0026ndash;62) months in the endocrine monotherapy group and 44 (95% CI: 33\u0026ndash;not available) months in the CDK4/6i combination therapy group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The HR of the endocrine monotherapy group relative to the CDK4/6i combination therapy group was 0.97 (95% CI: 0.60\u0026ndash;1.58; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrognostic factors of chemotherapy-free survival 1\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCFS1\u0026thinsp;\u0026lt;\u0026thinsp;60 months\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;257)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCFS1\u0026thinsp;\u0026ge;\u0026thinsp;60 month\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eYear of diagnosis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2015\u0026ndash;2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e185 (72.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60 (98.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019\u0026ndash;2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 (28.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eAge, years, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.2 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61.4 (14.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57 (22.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (23.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e50\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (33.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e65\u0026ndash;74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 (27.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (17.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (18.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eMenopausal status, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostmenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63 (24.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePremenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e191 (74.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45 (73.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eDisease stage before relapse, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (8.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (33.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (27.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66 (25.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (13.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e79 (30.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (41.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eType of origin of stage Ⅳ, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e79 (30.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (41.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-de novo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e178 (69.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (59.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eNuclear grade, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87 (33.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (37.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66 (25.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78 (30.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (19.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (8.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eDFI (excluding de novo Stage Ⅳ), months, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.0 (27.3\u0026ndash;85.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62.0 (40.0\u0026ndash;121.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e108 (42.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (27.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 (27.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19 (31.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eECOG-PS at diagnosis of metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e184 (74.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53 (86.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63 (25.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (13.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSymptomatic, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e118 (45.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29 (47.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrgan metastasis \u003csup\u003ec\u003c/sup\u003e, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e101 (39.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (44.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44 (17.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (6.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnly bone metastasis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82 (31.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (36.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eNumber of metastases, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e156 (60.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (68.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71 (27.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (21.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (10.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e y.o. (standard deviation), \u003csup\u003eb\u003c/sup\u003e month (interquartile range), \u003csup\u003ec\u003c/sup\u003e Organ metastasis is defined as a metastatic site in the liver and/or lung.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eCDK4/6i, CDK4/6 inhibitor; DFI, disease-free interval; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; IPTW, inverse probability of treatment weighting.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter retrospective study compared the noninferiority of CFS in patients with HR+/HER2\u0026ndash; ABC who were treated with either first-line endocrine monotherapy or CDK4/6i combination therapy. There was no substantial difference in the median CFS between the two treatment groups, both before and after IPTW adjustment. The primary analysis did not support the noninferiority of endocrine monotherapy, with a small difference in this real-world cohort. Regarding factors associated with CFS, ECOG-PS 0 and no liver metastasis were significantly favorable factors, while a longer DFI and de novo stage IV showed a trend toward significance. In the favorable group (ECOG-PS 0, no liver metastasis, and either de novo stage IV or DFI\u0026thinsp;\u0026ge;\u0026thinsp;60 months), the median CFS was 48 months in the endocrine monotherapy group.\u003c/p\u003e\u003cp\u003eIn the PALOMA2 trial, the median CFS was 40.4 months for the palbociclib group and 29.9 months for the placebo group (HR [95% CI]: 0.74 [0.59\u0026ndash;0.92]) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In particular, patients with DFS\u0026thinsp;\u0026le;\u0026thinsp;12 months and organ metastasis showed a greater extension effect in the palbociclib group than the placebo group. Similarly, in the MONARCH 3 trial, the median CFS was reported as 46.7 months for the abemaciclib group and 30.6 months for the placebo group (HR [95% CI]: 0.69 [0.56\u0026ndash;0.83]) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, in a real-world setting, the median time to chemotherapy was reported as 37.4 months for palbociclib plus an aromatase inhibitor (AI) and 29.2 months for AI alone for first-line treatment in the USA (HR [95% CI]: 0.77 [0.69\u0026ndash;0.86]) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. A multicenter retrospective study from Japan, lacking a endocrine monotherapy control, showed that the CFS for cases treated with palbociclib was 36.7 months in the first-line setting and 23.8 months in the second-line setting [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our study, the median CFS in the CDK4/6i group was approximately 6 months shorter than that previously reported in a real-world data study [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. One possible explanation is that many patients in our cohort received CDK4/6i therapy early after its approval, when it was frequently used in the second-line or later settings. Even in the first-line setting, CDK4/6i was often selected for patients with poor endocrine sensitivity or rapidly progressing disease. These patients were more likely to require chemotherapy shortly after the initial treatment, resulting in shorter CFS durations. Although patient background was adjusted using the IPTW method, selection bias may have still have influenced the results. This is suggested by the fact that CDK4/6i combination therapy did not show a noticeable extension in TTF compared to endocrine monotherapy. Conversely, in TTF2, which includes both first- and second-line treatments, CDK4/6i combination therapy showed a considerable extension compared to endocrine monotherapy. The TTF2 analysis included patients who continued endocrine therapy in first-line treatment or had selected endocrine therapy as second-line treatment. Another contributing factor was that a higher proportion of patients in the CDK4/6i group were still receiving first-line treatment compared to those in the endocrine monotherapy group.\u003c/p\u003e\u003cp\u003eRecently, with the development of new drugs, the prolonged duration of treatment has increased the financial burden on patients. \u0026ldquo;Financial toxicity\u0026rdquo; is an emerging problem wherein high out-of-pocket medical costs are associated with a decreased QoL, delayed or forgone care, or a combination of these, further increasing the risk of adverse health outcomes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Japan has an excellent public health insurance system, and all citizens are eligible for enrollment. Patients\u0026rsquo; co-payments are determined based on their age and income: 10%, 20%, or 30% of the full medical costs [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The maximum out-of-pocket costs range from JPY 8,000 to 252,600 per month, depending on income tiers. Despite the reduced copayment, patient costs exceed the limit for more than 3 months in a year, making CDK4/6i combination therapy considerably more expensive than tamoxifen and AIs. Recent reports have highlighted factors related to financial toxicity in metastatic breast cancer in Japan, emphasizing the need to reduce the financial burden on patients and provide personalized support tailored to individual needs [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The SONIA trial showed no statistically significant benefit of first-line CDK4/6i combination therapy over second-line treatment in terms of disease progression after initiating second-line treatment [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The SONIA trial demonstrated noninferiority in combined primary and secondary PFS when CDK4/6i combination therapy was used as second-line instead of first-line. Furthermore, first-line use of CDK4/6i combination therapy had considerably more grade 3 or higher adverse events compared with its second-line use. The results of the SONIA trial challenge the need for first-line use of a CDK4/6i combination therapy in all patients. Our study showed that in patients with a favorable prognosis, even without selecting CDK4/6i combination therapy as first-line treatment, long-term CFS can be achieved. In such cases, it may be reasonable to consider the patient's preferences when choosing the treatment.\u003c/p\u003e\u003cp\u003eThis study had some limitations. First, IPTW was used to adjust for baseline and clinical patient characteristics; however, this technique could not account for unobserved variables. Second, the follow-up period was not long enough to analyze CFS, and the median follow-up duration differed between the two groups (45.5 and 36.2 months in the endocrine monotherapy and CDK4/6i combination therapy groups, respectively), potentially affecting the comparison of outcomes. Third, as the study was conducted in a multicenter setting, variability in clinical practices across institutions might have influenced the treatment choices and patient management. Fourth, the sample size of this multicenter retrospective study was too small for noninferiority analysis.\u003c/p\u003e\u003cp\u003eIn conclusion, for HR+/HER2\u0026ndash; ABC, the endocrine monotherapy group did not show noninferiority in CFS compared with the CDK4/6i combination group. However, our results suggest that endocrine monotherapy may not be ruled out as a viable first-line therapy, particularly in patients with favorable prognostic factors. The high cost of combination therapy and its potential impact on healthcare resources warrant further investigation into the cost-effectiveness of CDK4/6i combination therapy in various clinical settings.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eParticipant Selection and Characteristics\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThis retrospective, multicenter observational study enrolled patients who were diagnosed with HR+/HER2\u0026ndash; ABC between 2015 and 2020. Patients who received first-line treatment with either endocrine monotherapy or CDK4/6i combination therapy were eligible for this study. However, patients who received chemotherapy as first-line treatment were excluded. This study was approved by the Ethics Committee of Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval no. 23061906) on June 20, 2023. The study utilized an opt-out method to ascertain tacit informed consent, wherein a summary of the study was published online, and patients had the opportunity to refuse consent for study participation. All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments.\u003c/p\u003e\u003cp\u003e\u003cem\u003eEndpoints\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe primary endpoint was to show non-inferiority of endocrine monotherapy compared with CDK4/6i combination therapy with CFS1, defined as the time from initiation of first-line ABC treatment to the commencement of chemotherapy or death. The secondary endpoints included CFS2, defined as the time from the initiation of first-line ABC treatment to the commencement of infusion chemotherapy or death; TTF1, defined as the duration from the initiation of first-line ABC treatment to the time when the treatment was discontinued for any reason; and TTF2, defined as the duration from the initiation of first-line to second-line endocrine therapy for ABC until the second-line treatment was discontinued for any reason. Patients who received chemotherapy as second-line treatment were excluded from the TTF2 analysis. Prognostic factors and CFS1 were identified in the favorable group based on the analyzed prognostic factors.\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eTo account for factors that influence the choice of endocrine therapy (CDK4/6i combination vs. monotherapy), propensity scores were generated using the following covariates: age, disease-free interval, which was defined as the interval between breast cancer diagnosis and ABC diagnosis; menopausal status; de novo/non-de novo stage 4; symptomatic or asymptomatic ABC; presence or absence of liver metastasis; presence or absence of lung metastasis; bone disease only; number of metastatic sites; and ECOG-PS score. Comparative analysis was performed using two methods: (1) an unadjusted analysis that did not account for baseline participant characteristics and (2) IPTW, which was used as the primary analysis to balance baseline characteristics between the treatment groups and control for confounders. In adjusting for participant characteristics, participants with missing values were excluded, and a complete case analysis was performed. Kaplan\u0026ndash;Meier curves were generated to estimate the CFS. Statistical significance was determined using a two-sided alpha level of 5%. HRs for CFS were calculated using Cox regression models. Furthermore, the 95% CIs and p-values were calculated. Subgroup analyses were conducted to examine variations in the HRs across different categories. The noninferiority margin was set at 1.2.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors thank the Editage Group (https://www.editage.com/) for editing the draft of this manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Project Mirai Cancer Research Grants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions (CRediT)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSayaka Kuba developed the study design and concept. Yusuke Kajimoto and Ataru Igarashi performed the statistical analysis. Sayaka Kuba, Michiko Haro, Takafumi Sangai, Eriko Tokunaga, Tadahiko Shien, Kosho Yamanouchi, Hiroaki Inoue, Miki Yamaguchi, Kaori Terata, Hiroaki Shima, Goro Kutomi, Takaaki Fujii contributed to data acquisition and investigation. Sayaka Kuba wrote the first draft, and all authors participated in critical revision for important intellectual content. All authors approved the version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Potential Conflicts of Interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSK received a research grant from Pfizer; and received lecture fees from Pfizer, Daiici-Sankyo, Kyowa-Kirin, and AstraZeneca. MH received lecture fees from AstraZeneca, Chugai, Eli Lilly, MSD, Pfizer, and Daiichi-Sankyo. YK is an employee of MSD, but this research is not related to MSD. TaSa received a research grant from Taiho; and received lecture fees from Chugai, Novartis, AstraZeneca, MSD, Taiho, Eli Lilly, Pfizer, Eisai, Daiichi-Sankyo, Maruho, PDRadiophama, Nippon-Kayaku, and Kyowa-Kirin. ET received lecture fees from Daiichi-Sankyo, AstraZeneca, Eli Lilly, Chugai, Eisai, MSD, Taiho, and EXACT SCIENCES. ToShi received lecture fees from AstraZeneca, Novartis, Eisai, Eli Lilly, MSD, Taiho, Gilead, Chugai, Daiichi-Sankyo, Takeda, Kyowa-Kirin and Pfizer. HS received lecture fees from Eli Lilly, AstraZeneca, Roche, Daiichi-Sankyo, Fuji Film, and Pfizer. KY received lecture fees from Chugai, and Merck. MY received lecture fees from Chugai, Taiho, Kyowa-Kirin, Lilly, AstraZeneca, Eisai, Pfizer, Daiichi-Sankyo, MSD, and EXACT SCIENCES. KT received lecture fees from Eli Lilly, Daiici-Sankyo, Pfizer, AstraZeneca. GK received lecture fees from AstraZeneca, Eli Lilly, MSD, and Pfizer. AI received lecture fees from AstraZeneca, Chugai, Eisai, Eli Lilly, Ono pharmaceutical, and Illumina. TF has received honoraria from Eli Lilly, Pfizer, AstraZeneca, Chugai, Eisai, Daiichi-Sankyo. HI has no conflict of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J. Clin.\u003c/em\u003e \u003cb\u003e74\u003c/b\u003e, 229\u0026ndash;263 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCancer Stat Facts. 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Factors associated with financial toxicity in patients with breast cancer in Japan: a comparison of patient and physician perspectives. \u003cem\u003eBreast Cancer\u003c/em\u003e. \u003cb\u003e30\u003c/b\u003e, 820\u0026ndash;830 (2023).\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":"advanced breast cancer, CDK4/6 inhibitor, endocrine monotherapy, chemotherapy-free survival","lastPublishedDoi":"10.21203/rs.3.rs-7266744/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7266744/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) significantly prolong progression-free survival (PFS) compared to endocrine monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2\u0026ndash;) advanced breast cancer (ABC). However, research regarding chemotherapy-free survival (CFS) comparing CDK4/6i combination therapy and endocrine monotherapy in real-world settings is limited. This retrospective, multicenter observational study aimed to assess the noninferiority of CFS between CDK4/6i combination therapy and endocrine monotherapy as first-line treatments for patients with HR+/HER2\u0026ndash; ABC. The primary endpoint was CFS (noninferiority margin for comparison: 1.2). Among 443 patients (monotherapy: 318; CDK4/6i: 125), no significant difference was observed in median CFS after adjusting for patient background using inverse probability of treatment weighting (monotherapy: 35 months; CDK4/6i: 30 months; hazard ratio: 0.93; 95% confidence interval, 0.70\u0026ndash;1.23). In the favorable group (patients with a performance status of 0 and no liver metastasis), those with either de novo stage IV disease or a disease-free interval of \u0026ge;\u0026thinsp;60 months had a median CFS of 48 months for endocrine monotherapy and 44 months for CDK4/6i combination therapy. In HR+/HER2\u0026ndash; ABC, the endocrine monotherapy group did not show noninferiority in CFS compared with the CDK4/6i combination group, with a small difference.\u003c/p\u003e","manuscriptTitle":"Chemotherapy-Free Survival of CDK4/6 Inhibitor Combination Therapy or Endocrine Monotherapy as First-Line Treatment for HR+/HER2–Advanced Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 09:48:34","doi":"10.21203/rs.3.rs-7266744/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":"32e21cc1-9aa7-4174-98fc-a548ecb6db43","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53901247,"name":"Biological sciences/Cancer"},{"id":53901248,"name":"Health sciences/Diseases"},{"id":53901249,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-11-08T15:53:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 09:48:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7266744","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7266744","identity":"rs-7266744","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}