{"paper_id":"3cbe19d9-3d64-437d-a959-cdf2c18ba7fe","body_text":"Germline BRCA Mutation Affect the Clinical Outcomes of Metastatic Breast Cancer Treated with CDK4/6 Inhibitor: A Real-world Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Germline BRCA Mutation Affect the Clinical Outcomes of Metastatic Breast Cancer Treated with CDK4/6 Inhibitor: A Real-world Study Yingbo Shao, Yaning He, Fangfang Guo, Zhifen Luo, Yang Yu, Chaojun Liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7072445/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 Few clinical studies pay attention to clinical outcomes of CDK4/6 inhibitor in metastatic breast cancer with germline BRCA mutation. The present study aimed to explore whether germline BRCA mutation will affect the clinical efficacy of CDK4/6 inhibitor for metastatic breast cancer. Patients with HR+/HER-2- metastatic breast cancer who were treated with CDK4/6 inhibitor from January 2019 to December 2022 were retrospectively analyzed. Genetic testing of BRCA mutation was performed on next generation sequencing (NGS) platform. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), and overall survival(OS). Of the 62 HR+/HER2- metastatic breast cancer patients receiving CDK4/6 inhibitor, gBRCA mutation were detected in 6 patients, 40 patients were gBRCA wt and 16 patients with unknown gBRCA status. Even though there was no statistical difference, the median PFS (9.2m vs. 18.5m vs. 14.1m) and ORR (0% vs. 35.0% vs. 43.8%) of patients with gBRCA mutation was inferior to patients with gBRCA wt and patients with unknown gBRCA status. And simultaneously, the DCR of patients with gBRCA mutation was worse than patients with gBRCA wt (33.3% vs. 75.0%, P=0.039) and patients with unknown gBRCA status (33.3% vs. 81.3%, P=0.032). No statistically significant differences were found in OS. Our study findings indicating that germline BRCA mutation may affect the clinical outcomes of metastatic breast cancer treated with CDK4/6 inhibitor. Additionally, the results support incorporating gBRCA mutation into systemic therapy decisions for patients with HR+/HER-2- metastatic breast cancer treated with CDK4/6 inhibitor. Breast cancer Endocrine therapy CDK4/6 inhibitor BRCA Genetic testing Figures Figure 1 Figure 2 Introduction The most prevalent molecular subtype of breast cancer is hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative[ 1 – 2 ]. Endocrine therapy (ET) mainly inhibits the growth of tumor cells by reducing and suppressing estrogen levels in breast cancer patients. The cornerstone of treatment for this subgroup metastatic breast cancer is endocrine therapy due to its convenient administration and accurate efficacy[ 3 – 4 ]. However, with the widespread use of endocrine therapy, the problem of drug resistance has gradually emerged[ 5 – 6 ]. With the continuous exploration and research on mechanisms of drug resistance, inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have garnered a lot of interest, changing the traditional model of endocrine therapy[ 7 ]. For HR+/HER-2 metastasized breast cancer, endocrine therapy in combination with a CDK4/6 inhibitor has become the accepted treatment approach[ 8 – 10 ]. As treatment paradigms become increasingly complex, there is an ongoing need to prospectively identify those who are most likely to gain most from CDK4/6 inhibitors and whose tumors may become intrinsically resistant to treatment. This approach would allow endocrine therapy to be used only for those likely to gain meaningful benefit and avoid those who are unlikely to improve survival outcomes with CDK4/6 inhibitors. There are several known mechanisms of primary resistance to CDK4/6 inhibitors, including: inactivating mutations and/or deletions of retinoblastoma susceptibility gene (RB1)[ 11 ]; amplification of aurora kinase A (AURKA); activation of cyclin E1 or CDK2[ 12 ]; activation of PI3K-Akt signaling pathway[ 13 ]; aberrant fibroblast growth factor receptor 1 (FGFR1) signaling[ 14 ], and etc. BRCA2, the gene that predisposes people to breast cancer, is found on chromosome 13, close to RB1[ 15 ]. Patients whose tumors have hereditary BRCA2 mutations frequently have deletion of both the neighboring RB1 allele and wild-type BRCA2, which renders the remaining wild-type RB1 allele susceptible to therapeutic mutations. Additionally, Cyclin D1 expression is generally higher in breast cancer patients with BRCA1/2 mutations than in patients without the mutation, according to data from clinical samples[ 16 ]. Furthermore, breast cancer cells that have an overexpression of Cyclin D1 become resistant to CDK4/6 inhibitors. Collectively, germline BRCA1/2 mutation may affect the clinical efficacy of CDK4/6 inhibitors. However, few clinical studies are conducted. The goal of the current study was to investigate the link between clinical outcomes of HR+/HER-2 metastasized breast cancer treated with a CDK4/6 inhibitor and germline BRCA mutation. Materials and methods Study population Patients diagnosed with HR+/HER2- metastatic breast cancer at Henan Provincial People's Hospital between January 2019 and December 2022 were screened. In this study, a retrospective collection of breast cancer patients receiving fulvestrant endocrine therapy or aromatase inhibitor (AI) plus CDK4/6 inhibitor was made. The following criteria were used to include patients in the analysis: 1) histopathologically verified metastatic breast cancer; 2) HR positive and HER-2 negative validated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC); 3) at least one measurable lesion based on RECIST v1.1; 4) having had fulvestrant or AI therapy plus CDK4/6 inhibitor. Individuals lacking follow-up data and those who got fulvestrant treatment or AI in addition to CDK4/6 inhibitor for fewer than two cycles were eliminated. Clinicopathological characteristics Clinical and pathological information, such as age, Eastern Cooperative Oncology Group performance status (ECOG PS), HR status, HER2, menopausal status, prior chemotherapy before metastasis, prior adjuvant endocrine therapy, disease status (initial diagnosis stage IV or recurrence and metastasis), metastatic site, number of metastatic sites, prior endocrine therapy after metastasis, treatment manner and treatment line were retrieved for all patients. IHC was used to detect the progesterone receptor (PR) and estrogen receptor (ER), with a cut-off value of ≥ 1%. ER or PR positive was the definition of HR positive. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) standards for HER2 testing were used to determine the HER2 negative. IHC 0 was the definition of HER2-zero, whereas IHC 1+, IHC 2 + and FISH negative was the definition of HER2-low. Genetic testing of BRCA mutation BRCA1 and BRCA2 testing were performed using AmoyDx Biotech(Xiamen, China) on next generation sequencing (NGS) platform. The detective specimens used were fresh peripheral venous blood. BRCA germline variants were interpreted in accordance with the criteria and standards for the interpretation of sequence variants, which were jointly recommended by the Association for Molecular Pathology (AMP) and the American College of Medical Genetics and Genomics (ACMG). The variants identified in germline BRCA mutation were described as pathogenic(P), likely pathogenic(LP), uncertain significance, likely benign and benign. We evaluated the frequency of pathogenic and likely pathogenic as germline BRCA mutation. Treatment and efficacy evaluation The patients were treated with fulvestrant or AI plus CDK4/6 inhibitor in this study until the patients' condition progressed, the toxicity was intolerable, or death. The initial scheme of palbociclib was administered orally at a dose of 125 mg once daily on days 1 to 21 throughout each 28-day cycle. 150 mg of abemaciclib were taken orally twice a day throughout each 28-day cycle. Concurrent administration of fulvestrant or anastrozole was used. Oral administration of 1 mg of anastrozole was done on every day. Intramuscular fulvestrant 500 mg was used on days 1 and 15 of cycle 1, and starting in cycle 2, it was given every four weeks. Gonadotropin-releasing hormone (GnRH) agonists were given to individuals with premenopausal breast cancer prior to endocrine therapy. Every 28 days, 3.6 mg of goserelin was subcutaneously administered. Every two cycles following treatment, imaging exams were conducted on each patient to assess clinical effectiveness. According to RECIST version 1.1, tumors were classified as complete response (CR), partial response (PR), stable disease (SD), or progressing disease (PD) based on computed tomography or magnetic resonance imaging assessments. The percentage of CR + PR was defined as the objective response rate (ORR), and the proportion of CR + PR and SD was defined as the disease control rate (DCR). Statistical Analysis The clinical features of the group were compared using descriptive statistics. Medians were used to describe continuous variables. Fisher's exact test or Pearson's chi-squared test were used to compare the differences between the groups. The deadline for a follow-up is December 31, 2023. The term progression free survival (PFS) refers to the time interval between the start of the CDK4/6 inhibitor medication and the onset of disease progression or death. From the start of CDK4/6 inhibitor medication until the patient's death or the last follow-up, overall survival (OS) was defined. The Kaplan-Meier method was used to estimate the patient survival curves, and the log-rank test was used to compare them. With SPSS 22.0 (SPSS Inc., IL, US), statistical descriptive analyses were carried out for all of them. P < 0.05 was considered significant. Results Features of the patient and the treatment We investigated 62 individuals with HR+/HER2-metastasized breast cancer for this analysis. Table 1 listed the characteristics of the patients and their treatments. Of the total patients, ECOG PS 0–1 and PS 2 were found in 72.6% and 27.4% of the population, respectively. 66.1% of the patients were premenopausal, while the remaining 33.9% patients were postmenopausal. Four patients (6.5%) had an initial diagnosis of stage IV, and 58 patients (93.5%) had metastases and recurrences of the disease. Furthermore, 75.8% of the study's patients had previously undergone adjuvant or neoadjuvant chemotherapy. All the patients in this study were HR positive, 87.1% patients had received previous adjuvant endocrine therapy with tamoxifen or AI. Table 1 Clinicopathological characteristics of population Characteristic Total (n = 62) n (%) gBRCA m (n = 6) n (%) gBRCA wt (n = 40) n (%) gBRCA unknown (n = 16) n (%) P Age(years, median) 50 42 50 50 ECOG 0.284 0–1 45(72.6%) 6(100.0%) 28(70.0%) 11(68.8%) 2 17(27.4%) 0(0%) 12(30.0%) 5(31.2%) Menopausal status 0.635 Premenopausal 41(66.1%) 5(83.3%) 26(65.0%) 10(62.5%) Postmenopausal 21(33.9%) 1(16.7%) 14(35.0%) 6(37.5%) Prior chemotherapy before metastasis 0.166 Neo-adjuvant/Adjuvant 47(75.8%) 3(50.0%) 33(82.5%) 11(68.8%) None 15(24.2%) 3(50.0%) 7(17.5%) 5(31.2%) Prior adjuvant endocrine therapy 0.221 Tamoxifen 31(50.0%) 5(83.3%) 20(50.0%) 6(37.5%) AI 27(43.5%) 0(0%) 19(47.5%) 8(50.0%) None 8(12.9%) 1(16.7%) 4(10.0%) 3(18.8%) Disease status 0.555 Initial diagnosis stage IV 4(6.5%) 1(16.7%) 2(5.0%) 1(6.2%) Recurrence and metastasis 58(93.5%) 5(83.3%) 38(95.0%) 15(93.8%) Metastatic site 0.895 Lymph node 27(43.5%) 2(33.3%) 20(50.0%) 5(31.2%) Chest wall 12(19.4%) 1(16.7%) 8(20.0%) 3(18.8%) Liver 16(25.8%) 1(16.7%) 8(20.0%) 7(43.8%) Lung 27(43.5%) 3(50.0%) 19(47.5%) 5(31.2%) Bone 38(61.3%) 3(50.0%) 24(60.0%) 11(68.8%) Brain 3(4.8%) 0(0%) 2(5.0%) 1(6.3%) Number of metastatic sites 0.597 1–2 37(59.7%) 4(66.7%) 22(55.0%) 11(68.8%) ≥ 3 25(40.3%) 2(33.3%) 18(45.0%) 5(31.2%) Metastatic sites type 0.850 Visceral 43(69.4%) 4(66.7%) 27(67.5%) 12(75.0%) Non-Visceral 19(30.6%) 2(33.3%) 13(32.5%) 4(25.0%) Prior endocrine therapy after metastasis 0.633 AI 32(51.6%) 4(66.7%) 20(50.0%) 8(50.0%) Fulvestrant 6(9.7%) 0(0%) 3(7.5%) 3(18.8%) None 30(48.4%) 2(33.3%) 20(50.0%) 8(50.0%) Treatment manner 0.740 CDK4/6 + AI 32(51.6%) 4(66.7%) 20(50.0%) 8(50.0%) CDK4/6 + Fulvestrant 30(48.4%) 2(33.3%) 20(50.0%) 8(50.0%) Treatment line 0.349 1 21(33.9%) 0(0%) 15(37.5%) 6(37.5%) 2 23(37.1%) 3(50.0%) 13(32.5%) 7(43.8%) ≥ 3 18(29.0%) 3(50.0%) 12(30.0%) 3(18.8%) ECOG, Eastern Cooperative Oncology Group; HR, hormone receptor; AI, aromatase inhibitor; CDK4/6, cyclin-dependent kinase 4 and 6. Of the patients in the metastatic disease stage, 19 patients (30.6%) had non-visceral metastasis, and 43 patients (69.4%) had visceral metastasis. Bone (61.3%), lymph nodes (43.5%), lungs (43.5%), and liver (25.8%) were the most often seen metastatic sites. One or two metastatic sites were present in 37 individuals (59.7%), while three or more metastatic sites were present in 25 patients (40.3%). 51.6% of the patients had undergone endocrine therapy, which included fulvestrant and AI. First line therapy with CDK4/6 inhibitor plus AI or fulvestrant was given to 21 (33.9%) patients, second line therapy with 23 (37.1%) patients, and third or above line therapy with 18 (29.0%) patients. Palbociclib was administered to 51 (82.3%) patients, while abemaciclib was administered to 11 (17.7%) patients. Thirty patients (48.4%) received CDK4/6 inhibitor plus fulvestrant, while thirty-two patients (51.6%) received CDK4/6 inhibitor plus anastrozole. Prevalence and characterization of BRCA mutation Of the 62 HR+/HER2- metastatic breast cancer patients, 46 patients were tested for gBRCA status. In these patients with known gBRCA status, gBRCA mutation were detected in 6 patients and the other 40 patients were gBRCA wt. Among the 6 patients with gBRCA mutation, 2 (33.3%) patients were gBRCA1m and 4 (66.7%) patients were gBRCA2m. The clinicopathological and treatment characteristics were compared among gBRCA mutation, gBRCA wt and gBRCA unknown. Patients with gBRCA mutation were younger than those with gBRCA wt or unknown gBRCA status. The median age was 42, 50 and 50 years for those with gBRCA mutation, gBRCA wt, and unknown gBRCA status, respectively. Other features of patients and treatment characteristics assessed were similar among the three groups. Efficacy evaluation based on gBRCA mutation status CR wasn't seen in this investigation. Out of the total number of patients, 21 patients had PR, 24 had SD, and 17 had PD. The overall ORR and DCR were 33.9% and 72.6%, respectively (Table 2 ). In patients with gBRCA mutation, 2 patients had SD and 4 patients had PD. In patients with gBRCA wt, 14 patients achieved PR, 16 patients had SD and 10 patients had PD. In patients with unknown gBRCA status, 7 patients achieved PR, 6 patients had SD and 3 patients had PD. Even though there was no statistical difference, the ORR of patients with gBRCA mutation was inferior to patients with gBRCA wt (0% vs. 35.0%, P = 0.097) and patients with unknown gBRCA status (0% vs. 43.8%, P = 0.050). And simultaneously, the DCR of patients with gBRCA mutation was worse than that of patients with gBRCA wt (33.3% vs. 75.0%, P = 0.039) and patients with unknown gBRCA status (33.3% vs. 81.3%, P = 0.032). Table 2 Efficacy of CDK4/6 inhibitor treatment in metastatic breast cancer Parameter Best response ORR P DCR P Median PFS (95%CI) P Median OS (95%CI) P CR PR SD PD Total 0 21 24 17 33.9% 72.6% 16.6(13.2–20.0) 39.6(37.1–42.1) BRCA status gBRCA m 0 0 2 4 0 33.3% 9.2(6.9–11.5) 29.6(19.4–39.8) gBRCA wt 0 14 16 10 35.0% 0.097 75.0% 0.039 18.5(14.6–22.4) 0.056 39.6(35.2–44.0) 0.195 gBRCA unknown 0 7 6 3 43.8% 0.050 81.3% 0.032 14.1(7.4–20.8) 0.296 39.0(34.0-44.1) 0.430 Metastatic sites type 0.800 0.172 0.616 0.196 Non-Visceral 0 6 10 3 31.6% 84.2% 19.6(13,2–26.0) 45.0 Visceral 0 15 14 14 34.9% 67.4% 16.5(12.2–20.8) 39.0(37.1–40.9) Treatment line 0.057 0.013 0.003 0.787 First-line 0 11 9 1 52.4% 95.2% 22.6(21.3–23.9) 41.0(37.1–44.9) Second-line 0 7 8 8 30.4% 65.2% 16.6(12.8–20.4) 38.0(36.5–39.5) Third-line or above 0 3 7 8 16.7% 55.6% 10.8(9.7–11.9) NR Treatment manner 0.652 0.205 0.250 0.214 CDK4/6 + AI 0 10 11 11 31.3% 65.6% 12.8(2.5–23.1) 39.0 CDK4/6 + Ful 0 11 13 6 36.7% 80.0% 16.9(12.9–20.9) 39.6(37.5–41.7) HER2 status 0.931 0.659 0.271 0.055 Zero 0 11 13 8 34.4% 75.0% 16.2(5.1–27.3) 37.6(28.1–47.1) Low 0 10 11 9 33.3% 70.0% 16.6(13.6–19.6) 41.0(38.4–43.6) The median PFS and OS for the total population were 16.6 (95%CI = 13.2–20.0) and 39.6 (95%CI = 37.1–42.1) months, respectively. Although there was no statistical difference, the median PFS of patients with gBRCA mutation was inferior to patients with gBRCA wt (9.2m vs. 18.5m, P = 0.056) and patients with unknown gBRCA status (9.2m vs. 14.1m, P = 0.296, Fig. 1 ). The median OS of patients with gBRCA mutation, gBRCA wt and unknown gBRCA status were 29.6, 39.6 and 39.0 months, respectively. Furthermore, no statistically significant variations existed across the three groups. In addition to gBRCA mutation status, the efficacy of CDK4/6 inhibitor was related to treatment line. The DCR (95.2% vs. 65.2% vs. 55.6%, P = 0.013) and median PFS (22.6m vs. 16.6m vs. 10.8m, P = 0.003) were significantly better in patients received CDK4/6 inhibitor as first-line therapy than those received CDK4/6 inhibitor as second or third line therapy. Additionally, there were no statistically significant changes in the median PFS and OS according to the kind of metastatic site (non-visceral vs. visceral), HER2 status (HER2-zero vs. HER2-low), or the way of treatment (CDK4/6 + AI vs. CDK4/6 + fulvestrant, Fig. 2 ). Discussion One of the primary features of HR positive breast cancer is the hyperactivity of CDK4/6, which also serves as the primary cause of resistance to endocrine therapy[ 17 – 18 ]. Patients with HR-positive metastatic breast cancer have demonstrated a significant improvement in PFS when combining CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib with endocrine therapy, as opposed to endocrine therapy alone. Regretfully, a significant number of patients will eventually become resistant to CDK4/6 inhibitors. About 20% of breast cancer patients did not respond to initial CDK4/6 inhibitor treatment[ 19 ]. Furthermore, within two years of starting treatment, almost 30% of the recruited patients in the PALOMA-2 study exhibited acquired resistance to palbociclib[ 20 ]. The Cyclin D1–CDK4/6–Rb pathway appears to be activated in all major resistance mechanisms that have been found to date[ 7 ]. Interestingly, primary resistance to CDK4/6 inhibitor is present in all tumors harboring Rb gene mutations. The Cyclin D1–CDK4/6–Rb pathway, activation of proliferation pathways, alterations in the tumor microenvironment, and the regulation of tumor metabolism are among the mechanisms of acquired resistance to CDK4/6 inhibitor[ 21 ]. It is worth noting that activation of the Cyclin D1–CDK4/6–Rb pathway maybe a critical inducer both in primary and acquired resistance to CDK4/6 inhibitor. The findings of this real-world investigation imply that individuals with gBRCA mutations may have worse clinical outcomes in metastatic breast cancer treated with CDK4/6 inhibitor. Even though there was no statistical difference, the median PFS (9.2m vs. 18.5m vs. 14.1m) and ORR (0% vs. 35.0% vs. 43.8%) of patients with gBRCA mutation was inferior to patients with gBRCA wt and patients with unknown gBRCA status. And simultaneously, the DCR of patients with gBRCA mutation was worse than patients with gBRCA wt and patients with unknown gBRCA status. These findings indicate that gBRCA mutation may be involved in the resistance to CDK4/6 inhibitor. Previous studies have shown that 60%~80% of breast cancer with BRCA1 mutation is triple negative breast cancer (TNBC), and more than 75% of breast cancer with BRCA2 mutation is Luminal type[ 22 ]. Among the 6 patients with gBRCA mutation in this study, 2 (33.3%) patients were gBRCA1m and 4 (66.7%) patients were gBRCA2m. Compared to BRCA1 mutations, BRCA2 mutations are more commonly linked to an HR-positive breast cancer phenotype. Clinical results of CDK4/6 inhibitor in metastatic breast cancer with germline BRCA mutation have not received much attention in clinical research to date. BRCA mutation was identified as a potential biomarker of ribociclib endocrinology by a pooled biomarker analysis of the MONALEESA-2, -3, -7 study, and patients with BRCA mutation had a better prognosis than BRCA wt patients[ 23 ]. Nonetheless, the majority of research indicates that individuals with BRCA mutations exhibit a subpar reaction to CDK4/6 inhibitor treatment. According to a review of the PADA-1 study, which used palbociclib in addition to AI as the first-line treatment for HR+/HER2-metastatic breast cancer, patients with gBRCA mutations often had a shorter PFS (14.3 vs. 26.7 m) than those with gBRCA wild type [ 24 ]. A real-world investigation that examined the clinical effectiveness of CDK4/6 inhibitors in patients with gBRCA mutations found that these patients' overall survival was significantly shorter[ 25 ]. Additionally, our current study showed that patients with gBRCA mutations had poorer PFS, DCR, and ORR. When taken together, these findings show that individuals with gBRCA mutations who have HR+/HER2-metastasized breast cancer may benefit less from CDK4/6 inhibitor plus endocrinology. It's still unclear exactly how BRCA contributes to breast cancer resistance to the CDK4/6 inhibitor. A few conceivable mechanisms are as follows. First, ribociclib was found to be considerably less beneficial for patients with RB1 mutations in circulating tumor DNA (ctDNA) compared to those with wild-type RB1 (median PFS: 3.8 vs. 18.9 m) in the analysis of samples from the MONALEESA trial cohort[ 23 ]. According to earlier research, individuals with gBRCA2 mutations may exhibit co-loss of RB1 and BRCA2, which are neighboring loci on chromosome 13q. Patients with gBRCA2 mutations may develop primary resistance to CDK4/6 inhibitor as a result of this aberrant alteration. Second, as demonstrated by clinical tumor samples, patients with wide-type BRCA do not usually express Cyclin D1 at higher levels than those with BRCA mutations[ 16 ]. Research using cell lines from breast cancer patients has verified that resistance to CDK4/6 inhibitors is caused by Cyclin D1 overexpression. Down-regulation of Cyclin D1 leads to breast cancer cell cycle arrest in the G1 phase and restores sensitivity to CDK4/6 inhibitor[ 26 ]. Collectively, gBRCA mutation may affect the sensitivity of CDK4/6 inhibitor treatment by participating in Cyclin D1–CDK4/6–Rb signal pathway. Phase III clinical research In metastatic gBRCA mutant breast cancer, OlympiAD and EMBRACA verified the survival benefits of olaparib and talazoparib, which are poly ADP ribose polymerase (PARP) inhibitors [ 27 – 30 ]. In HR+/HER2- metastatic breast cancer with BRCA mutation, no published clinical trial has examined treatment selection and sequencing of PARPi + ET, CDK4/6i + ET, or therapeutic synergy of PARPi + CDK4/6i + ET. The safety and effectiveness of palbociclib, olaparib, and ET in metastatic breast cancer were investigated in a phase I/II clinical trial; however, the possible side effects restrict the clinical use of this combination[ 31 ]. Another study confirmed that the combination of olaparib and palbociclib has synergistic effects against BRCA mutation TNBC both in vitro and in vivo[ 32 ]. There is still a significant unmet clinical need in HR+/HER2- metastatic breast cancer with BRCA mutation. Future prospective clinical trials are needed to explore the optimal use and sequencing of PARPi and CDK4/6i in HR+/HER2- metastatic breast cancer with BRCA mutation. The present study does have some limitations. First, not all patients received genetic testing of BRCA mutation. Secondly, the study is observational, based on a single center, and not many patients are included. Consequently, additional clinical trials are required to validate the findings of this investigation. However, our work offers important insights into CDK4/6 inhibitor in HR+/HER2- metastatic breast cancer in a real-world context involving a BRCA mutation. Conclusion In conclusion, our study findings indicate that germline BRCA mutation may impact the clinical results of CDK4/6 inhibitor-treated metastatic breast cancer. Additionally, the results support incorporating the gBRCA mutation into systemic therapy decisions for patients receiving CDK4/6 inhibitor treatment for HR+/HER-2-metastatic breast cancer. Declarations Clinical trial number : not applicable. Ethics approval and consent to participate This study was carried out in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committee of the Henan Provincial People’s Hospital. Written informed consent was obtained from all patients for the use of the medical records for research purposes. Consent for publication Not Applicable. Author contributions All authors contributed to the article and approved the submitted version. Yingbo Shao and Hui Liu designed the research, analyzed the data and drafted the paper. Yingbo Shao, Yaning He, Fangfang Guo, Zhifen Luo and Yang Yu were mainly responsible for data collection and analysis. Chaojun Liu, Qi Chen and Fangyuan Zhu were primarily responsible for statistical analysis. Funding This work was supported by Medical Science and Technique Foundation of Henan Province (No. LHGJ20240012) and Beijing Medical Award Foundation Project (No.YXJL-2020-0941-0748). Acknowledgements None. Competing interests The authors declare that no potential conflict of interest exist. Data availability The raw data of this article will be made available by contacting the corresponding author. References Pegram M, Pietras R, Dang CT, et al. 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Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925–36. Alvarez-Fernandez M, Malumbres M. Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition. Cancer Cell. 2020;37(4):514–29. Koh SJ, Ohsumi S, Takahashi M, et al. Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study. Breast Cancer. 2022;29(1):92–102. Andre F, Su F, Solovieff N, et al. Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials. Ann Oncol. 2023;34(11):1003–14. Frenel J, Dalenc F, Pistilli B, et al. 304P ESR1 mutations and outcomes in BRCA1/2 or PALB2 germline mutation carriers receiving frst line aromatase inhibitor + palbociclib (AI + P) for metastatic breast cancer (MBC) in the PADA-1 trial. Ann Oncol. 2020;31:364. Collins JM, Nordstrom BL, McLaurin KK, et al. A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status. Oncol Ther. 2021;9(2):575–89. Cai Z, Wang J, Li Y, et al. Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Sci China Life Sci. 2023;66(1):94–109. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523–33. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558–66. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018;379(8):753–63. Litton JK, Hurvitz SA, Mina LA, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol. 2020;31(11):1526–35. Torres A, Kokkonen C, Oladeji M, et al. Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer. Cancer Res. 2022;82:OT2–18. Zhu X, Chen L, Huang B, et al. Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer. J Exp Clin Cancer Res. 2021;40(1):122. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7072445\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":492631734,\"identity\":\"eb91c645-66b7-4e43-9d34-c036bd7e16a3\",\"order_by\":0,\"name\":\"Yingbo Shao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yingbo\",\"middleName\":\"\",\"lastName\":\"Shao\",\"suffix\":\"\"},{\"id\":492631735,\"identity\":\"807ce0d0-1059-47d4-a8ef-2452e219a552\",\"order_by\":1,\"name\":\"Yaning He\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yaning\",\"middleName\":\"\",\"lastName\":\"He\",\"suffix\":\"\"},{\"id\":492631736,\"identity\":\"d4a3d928-39c9-4010-9fdf-9e8517e53598\",\"order_by\":2,\"name\":\"Fangfang Guo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Fangfang\",\"middleName\":\"\",\"lastName\":\"Guo\",\"suffix\":\"\"},{\"id\":492631737,\"identity\":\"1d9abfe1-bc2a-4977-a500-7d032f2a8196\",\"order_by\":3,\"name\":\"Zhifen Luo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhifen\",\"middleName\":\"\",\"lastName\":\"Luo\",\"suffix\":\"\"},{\"id\":492631738,\"identity\":\"592611de-2cb1-453c-9ea7-9dd56a88ce29\",\"order_by\":4,\"name\":\"Yang Yu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yang\",\"middleName\":\"\",\"lastName\":\"Yu\",\"suffix\":\"\"},{\"id\":492631739,\"identity\":\"2312f18c-b040-47dd-9da3-b88d99703202\",\"order_by\":5,\"name\":\"Chaojun Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chaojun\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":492631740,\"identity\":\"7717036d-489b-4187-ac89-2fd48ceccddf\",\"order_by\":6,\"name\":\"Qi Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Qi\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":492631741,\"identity\":\"d1f946e0-453e-425f-9992-2d77160c73a2\",\"order_by\":7,\"name\":\"Fangyuan Zhu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Fangyuan\",\"middleName\":\"\",\"lastName\":\"Zhu\",\"suffix\":\"\"},{\"id\":492631743,\"identity\":\"fc6a83f4-a083-4043-b521-d48bd8977c81\",\"order_by\":8,\"name\":\"Hui Liu\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYFAC5oYDjA0MPPxQHjFaGCFaJBtI0QJCDAYHiNViPiOx8TDvjsMyxuePP5NgqLBObGA/ewCvFpkzBxsO8545zGN24ECaBMOZ9MQGnrwEvFok2BuBWtqAWg42HJNgbDuc2CDBY4BfCzMjRItxM2ObBOM/YrTAbDFgY2aTAGonQgvPwYaDc9vSeSTOsDFbJBxLN27jySGgRSL58Ie3bdb2/P3HH974UGMt289+Br8WVJAAxGwkqB8Fo2AUjIJRgAMAAODKQhYI/qciAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Hui\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-07-08 08:23:34\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7072445/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7072445/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":88000296,\"identity\":\"e477cc95-f2cf-4198-baa4-9f5f9385c639\",\"added_by\":\"auto\",\"created_at\":\"2025-07-31 10:19:28\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":727721,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan-Meier curve of PFS (A) in patients with different BRCA mutation status. Kaplan-Meier curve of OS (B) in patients with different BRCA mutation status.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7072445/v1/ce41f4b35893fb8685570a01.png\"},{\"id\":88000294,\"identity\":\"57e4b52c-6c22-4279-ba03-901c5625946c\",\"added_by\":\"auto\",\"created_at\":\"2025-07-31 10:19:28\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1287642,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan-Meier curve of PFS in patients with different treatment lines(A), different ET scheme(B), metastatic sites type(C) and HER2 status(D).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7072445/v1/1449e593b88c1baaedf24628.png\"},{\"id\":89244488,\"identity\":\"2a0b733b-85a6-4e1a-b09b-1fed6c8a5aad\",\"added_by\":\"auto\",\"created_at\":\"2025-08-18 00:31:25\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":3232671,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7072445/v1/fe2ff366-a05d-4710-9317-3703a8e2ccf7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Germline BRCA Mutation Affect the Clinical Outcomes of Metastatic Breast Cancer Treated with CDK4/6 Inhibitor: A Real-world Study\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eThe most prevalent molecular subtype of breast cancer is hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Endocrine therapy (ET) mainly inhibits the growth of tumor cells by reducing and suppressing estrogen levels in breast cancer patients. The cornerstone of treatment for this subgroup metastatic breast cancer is endocrine therapy due to its convenient administration and accurate efficacy[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. However, with the widespread use of endocrine therapy, the problem of drug resistance has gradually emerged[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. With the continuous exploration and research on mechanisms of drug resistance, inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have garnered a lot of interest, changing the traditional model of endocrine therapy[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. For HR+/HER-2 metastasized breast cancer, endocrine therapy in combination with a CDK4/6 inhibitor has become the accepted treatment approach[\\u003cspan additionalcitationids=\\\"CR9\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eAs treatment paradigms become increasingly complex, there is an ongoing need to prospectively identify those who are most likely to gain most from CDK4/6 inhibitors and whose tumors may become intrinsically resistant to treatment. This approach would allow endocrine therapy to be used only for those likely to gain meaningful benefit and avoid those who are unlikely to improve survival outcomes with CDK4/6 inhibitors. There are several known mechanisms of primary resistance to CDK4/6 inhibitors, including: inactivating mutations and/or deletions of retinoblastoma susceptibility gene (RB1)[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]; amplification of aurora kinase A (AURKA); activation of cyclin E1 or CDK2[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]; activation of PI3K-Akt signaling pathway[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]; aberrant fibroblast growth factor receptor 1 (FGFR1) signaling[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e], and etc.\\u003c/p\\u003e\\u003cp\\u003eBRCA2, the gene that predisposes people to breast cancer, is found on chromosome 13, close to RB1[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Patients whose tumors have hereditary BRCA2 mutations frequently have deletion of both the neighboring RB1 allele and wild-type BRCA2, which renders the remaining wild-type RB1 allele susceptible to therapeutic mutations. Additionally, Cyclin D1 expression is generally higher in breast cancer patients with BRCA1/2 mutations than in patients without the mutation, according to data from clinical samples[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Furthermore, breast cancer cells that have an overexpression of Cyclin D1 become resistant to CDK4/6 inhibitors. Collectively, germline BRCA1/2 mutation may affect the clinical efficacy of CDK4/6 inhibitors. However, few clinical studies are conducted. The goal of the current study was to investigate the link between clinical outcomes of HR+/HER-2 metastasized breast cancer treated with a CDK4/6 inhibitor and germline BRCA mutation.\\u003c/p\\u003e\"},{\"header\":\"Materials and methods\",\"content\":\"\\u003cp\\u003e\\u003cb\\u003eStudy population\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003ePatients diagnosed with HR+/HER2- metastatic breast cancer at Henan Provincial People's Hospital between January 2019 and December 2022 were screened. In this study, a retrospective collection of breast cancer patients receiving fulvestrant endocrine therapy or aromatase inhibitor (AI) plus CDK4/6 inhibitor was made. The following criteria were used to include patients in the analysis: 1) histopathologically verified metastatic breast cancer; 2) HR positive and HER-2 negative validated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC); 3) at least one measurable lesion based on RECIST v1.1; 4) having had fulvestrant or AI therapy plus CDK4/6 inhibitor. Individuals lacking follow-up data and those who got fulvestrant treatment or AI in addition to CDK4/6 inhibitor for fewer than two cycles were eliminated.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eClinicopathological characteristics\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eClinical and pathological information, such as age, Eastern Cooperative Oncology Group performance status (ECOG PS), HR status, HER2, menopausal status, prior chemotherapy before metastasis, prior adjuvant endocrine therapy, disease status (initial diagnosis stage IV or recurrence and metastasis), metastatic site, number of metastatic sites, prior endocrine therapy after metastasis, treatment manner and treatment line were retrieved for all patients. IHC was used to detect the progesterone receptor (PR) and estrogen receptor (ER), with a cut-off value of \\u0026ge;\\u0026thinsp;1%. ER or PR positive was the definition of HR positive. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) standards for HER2 testing were used to determine the HER2 negative. IHC 0 was the definition of HER2-zero, whereas IHC 1+, IHC 2\\u0026thinsp;+\\u0026thinsp;and FISH negative was the definition of HER2-low.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eGenetic testing of BRCA mutation\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eBRCA1 and BRCA2 testing were performed using AmoyDx Biotech(Xiamen, China) on next generation sequencing (NGS) platform. The detective specimens used were fresh peripheral venous blood. BRCA germline variants were interpreted in accordance with the criteria and standards for the interpretation of sequence variants, which were jointly recommended by the Association for Molecular Pathology (AMP) and the American College of Medical Genetics and Genomics (ACMG). The variants identified in germline BRCA mutation were described as pathogenic(P), likely pathogenic(LP), uncertain significance, likely benign and benign. We evaluated the frequency of pathogenic and likely pathogenic as germline BRCA mutation.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eTreatment and efficacy evaluation\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eThe patients were treated with fulvestrant or AI plus CDK4/6 inhibitor in this study until the patients' condition progressed, the toxicity was intolerable, or death. The initial scheme of palbociclib was administered orally at a dose of 125 mg once daily on days 1 to 21 throughout each 28-day cycle. 150 mg of abemaciclib were taken orally twice a day throughout each 28-day cycle. Concurrent administration of fulvestrant or anastrozole was used. Oral administration of 1 mg of anastrozole was done on every day. Intramuscular fulvestrant 500 mg was used on days 1 and 15 of cycle 1, and starting in cycle 2, it was given every four weeks. Gonadotropin-releasing hormone (GnRH) agonists were given to individuals with premenopausal breast cancer prior to endocrine therapy. Every 28 days, 3.6 mg of goserelin was subcutaneously administered. Every two cycles following treatment, imaging exams were conducted on each patient to assess clinical effectiveness. According to RECIST version 1.1, tumors were classified as complete response (CR), partial response (PR), stable disease (SD), or progressing disease (PD) based on computed tomography or magnetic resonance imaging assessments. The percentage of CR\\u0026thinsp;+\\u0026thinsp;PR was defined as the objective response rate (ORR), and the proportion of CR\\u0026thinsp;+\\u0026thinsp;PR and SD was defined as the disease control rate (DCR).\\u003c/p\\u003e\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStatistical Analysis\\u003c/h2\\u003e\\u003cp\\u003eThe clinical features of the group were compared using descriptive statistics. Medians were used to describe continuous variables. Fisher's exact test or Pearson's chi-squared test were used to compare the differences between the groups. The deadline for a follow-up is December 31, 2023. The term progression free survival (PFS) refers to the time interval between the start of the CDK4/6 inhibitor medication and the onset of disease progression or death. From the start of CDK4/6 inhibitor medication until the patient's death or the last follow-up, overall survival (OS) was defined. The Kaplan-Meier method was used to estimate the patient survival curves, and the log-rank test was used to compare them. With SPSS 22.0 (SPSS Inc., IL, US), statistical descriptive analyses were carried out for all of them. P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered significant.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cb\\u003eFeatures of the patient and the treatment\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eWe investigated 62 individuals with HR+/HER2-metastasized breast cancer for this analysis. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e listed the characteristics of the patients and their treatments. Of the total patients, ECOG PS 0\\u0026ndash;1 and PS 2 were found in 72.6% and 27.4% of the population, respectively. 66.1% of the patients were premenopausal, while the remaining 33.9% patients were postmenopausal. Four patients (6.5%) had an initial diagnosis of stage IV, and 58 patients (93.5%) had metastases and recurrences of the disease. Furthermore, 75.8% of the study's patients had previously undergone adjuvant or neoadjuvant chemotherapy. All the patients in this study were HR positive, 87.1% patients had received previous adjuvant endocrine therapy with tamoxifen or AI.\\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\\u003eClinicopathological characteristics of population\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"6\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCharacteristic\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eTotal (n\\u0026thinsp;=\\u0026thinsp;62)\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003egBRCA m (n\\u0026thinsp;=\\u0026thinsp;6)\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003egBRCA wt (n\\u0026thinsp;=\\u0026thinsp;40)\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003egBRCA unknown\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;16) n (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eAge(years, median)\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e50\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e42\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e50\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e50\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eECOG\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.284\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e0\\u0026ndash;1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e45(72.6%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e6(100.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e28(70.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e11(68.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e17(27.4%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0(0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12(30.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5(31.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eMenopausal status\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.635\\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\\u003e41(66.1%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e5(83.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e26(65.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e10(62.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003ePostmenopausal\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e21(33.9%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(16.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e14(35.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e6(37.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003ePrior chemotherapy before metastasis\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.166\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNeo-adjuvant/Adjuvant\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e47(75.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e33(82.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e11(68.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNone\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e15(24.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e7(17.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5(31.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003ePrior adjuvant endocrine therapy\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.221\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eTamoxifen\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e31(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e5(83.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e6(37.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAI\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e27(43.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0(0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e19(47.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNone\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8(12.9%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(16.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e4(10.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3(18.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eDisease status\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.555\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eInitial diagnosis stage IV\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e4(6.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(16.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e2(5.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1(6.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eRecurrence and metastasis\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e58(93.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e5(83.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e38(95.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e15(93.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eMetastatic site\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.895\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLymph node\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e27(43.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(33.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5(31.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eChest wall\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e12(19.4%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(16.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e8(20.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3(18.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLiver\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e16(25.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(16.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e8(20.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e7(43.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLung\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e27(43.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e19(47.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5(31.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eBone\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e38(61.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e24(60.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e11(68.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eBrain\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3(4.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0(0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e2(5.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1(6.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eNumber of metastatic sites\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.597\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1\\u0026ndash;2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e37(59.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(66.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e22(55.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e11(68.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u0026ge; 3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e25(40.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(33.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e18(45.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e5(31.2%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eMetastatic sites type\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.850\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVisceral\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e43(69.4%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(66.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e27(67.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e12(75.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNon-Visceral\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e19(30.6%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(33.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e13(32.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e4(25.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003ePrior endocrine therapy after metastasis\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.633\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAI\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e32(51.6%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(66.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eFulvestrant\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e6(9.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0(0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e3(7.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3(18.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNone\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e30(48.4%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(33.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eTreatment manner\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.740\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCDK4/6\\u0026thinsp;+\\u0026thinsp;AI\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e32(51.6%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(66.7%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCDK4/6\\u0026thinsp;+\\u0026thinsp;Fulvestrant\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e30(48.4%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(33.3%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e20(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eTreatment line\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.349\\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(33.9%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0(0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e15(37.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e6(37.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e23(37.1%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e13(32.5%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e7(43.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u0026ge; 3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e18(29.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(50.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12(30.0%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3(18.8%)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003eECOG, Eastern Cooperative Oncology Group; HR, hormone receptor; AI, aromatase inhibitor; CDK4/6, cyclin-dependent kinase 4 and 6.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eOf the patients in the metastatic disease stage, 19 patients (30.6%) had non-visceral metastasis, and 43 patients (69.4%) had visceral metastasis. Bone (61.3%), lymph nodes (43.5%), lungs (43.5%), and liver (25.8%) were the most often seen metastatic sites. One or two metastatic sites were present in 37 individuals (59.7%), while three or more metastatic sites were present in 25 patients (40.3%). 51.6% of the patients had undergone endocrine therapy, which included fulvestrant and AI. First line therapy with CDK4/6 inhibitor plus AI or fulvestrant was given to 21 (33.9%) patients, second line therapy with 23 (37.1%) patients, and third or above line therapy with 18 (29.0%) patients. Palbociclib was administered to 51 (82.3%) patients, while abemaciclib was administered to 11 (17.7%) patients. Thirty patients (48.4%) received CDK4/6 inhibitor plus fulvestrant, while thirty-two patients (51.6%) received CDK4/6 inhibitor plus anastrozole.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003ePrevalence and characterization of BRCA mutation\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eOf the 62 HR+/HER2- metastatic breast cancer patients, 46 patients were tested for gBRCA status. In these patients with known gBRCA status, gBRCA mutation were detected in 6 patients and the other 40 patients were gBRCA wt. Among the 6 patients with gBRCA mutation, 2 (33.3%) patients were gBRCA1m and 4 (66.7%) patients were gBRCA2m. The clinicopathological and treatment characteristics were compared among gBRCA mutation, gBRCA wt and gBRCA unknown. Patients with gBRCA mutation were younger than those with gBRCA wt or unknown gBRCA status. The median age was 42, 50 and 50 years for those with gBRCA mutation, gBRCA wt, and unknown gBRCA status, respectively. Other features of patients and treatment characteristics assessed were similar among the three groups.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eEfficacy evaluation based on gBRCA mutation status\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eCR wasn't seen in this investigation. Out of the total number of patients, 21 patients had PR, 24 had SD, and 17 had PD. The overall ORR and DCR were 33.9% and 72.6%, respectively (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). In patients with gBRCA mutation, 2 patients had SD and 4 patients had PD. In patients with gBRCA wt, 14 patients achieved PR, 16 patients had SD and 10 patients had PD. In patients with unknown gBRCA status, 7 patients achieved PR, 6 patients had SD and 3 patients had PD. Even though there was no statistical difference, the ORR of patients with gBRCA mutation was inferior to patients with gBRCA wt (0% vs. 35.0%, P\\u0026thinsp;=\\u0026thinsp;0.097) and patients with unknown gBRCA status (0% vs. 43.8%, P\\u0026thinsp;=\\u0026thinsp;0.050). And simultaneously, the DCR of patients with gBRCA mutation was worse than that of patients with gBRCA wt (33.3% vs. 75.0%, P\\u0026thinsp;=\\u0026thinsp;0.039) and patients with unknown gBRCA status (33.3% vs. 81.3%, P\\u0026thinsp;=\\u0026thinsp;0.032).\\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\\u003eEfficacy of CDK4/6 inhibitor treatment in metastatic breast cancer\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"13\\\"\\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\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" 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=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c12\\\" colnum=\\\"12\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c13\\\" colnum=\\\"13\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e\\u003cp\\u003eParameter\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c5\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003eBest response\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eORR\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eDCR\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003eMedian PFS (95%CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003eMedian OS (95%CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eCR\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ePR\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eSD\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ePD\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eTotal\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e21\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e24\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e17\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e33.9%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e72.6%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e16.6(13.2\\u0026ndash;20.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e39.6(37.1\\u0026ndash;42.1)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eBRCA status\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003egBRCA m\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e33.3%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e9.2(6.9\\u0026ndash;11.5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e29.6(19.4\\u0026ndash;39.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003egBRCA wt\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e14\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e16\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e35.0%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.097\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e75.0%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.039\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e18.5(14.6\\u0026ndash;22.4)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e0.056\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e39.6(35.2\\u0026ndash;44.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c13\\\"\\u003e\\u003cp\\u003e0.195\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003egBRCA unknown\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e43.8%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.050\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e81.3%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.032\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e14.1(7.4\\u0026ndash;20.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e0.296\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e39.0(34.0-44.1)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c13\\\"\\u003e\\u003cp\\u003e0.430\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eMetastatic sites type\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.800\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.172\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e0.616\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" 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colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCDK4/6\\u0026thinsp;+\\u0026thinsp;Ful\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e13\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e36.7%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e80.0%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e16.9(12.9\\u0026ndash;20.9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e39.6(37.5\\u0026ndash;41.7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eHER2 status\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\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=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.931\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.659\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e0.271\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c13\\\"\\u003e\\u003cp\\u003e0.055\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eZero\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e13\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e34.4%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e75.0%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e16.2(5.1\\u0026ndash;27.3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e37.6(28.1\\u0026ndash;47.1)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLow\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e33.3%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e70.0%\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e16.6(13.6\\u0026ndash;19.6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c12\\\"\\u003e\\u003cp\\u003e41.0(38.4\\u0026ndash;43.6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c13\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eThe median PFS and OS for the total population were 16.6 (95%CI\\u0026thinsp;=\\u0026thinsp;13.2\\u0026ndash;20.0) and 39.6 (95%CI\\u0026thinsp;=\\u0026thinsp;37.1\\u0026ndash;42.1) months, respectively. Although there was no statistical difference, the median PFS of patients with gBRCA mutation was inferior to patients with gBRCA wt (9.2m vs. 18.5m, P\\u0026thinsp;=\\u0026thinsp;0.056) and patients with unknown gBRCA status (9.2m vs. 14.1m, P\\u0026thinsp;=\\u0026thinsp;0.296, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The median OS of patients with gBRCA mutation, gBRCA wt and unknown gBRCA status were 29.6, 39.6 and 39.0 months, respectively. Furthermore, no statistically significant variations existed across the three groups.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eIn addition to gBRCA mutation status, the efficacy of CDK4/6 inhibitor was related to treatment line. The DCR (95.2% vs. 65.2% vs. 55.6%, P\\u0026thinsp;=\\u0026thinsp;0.013) and median PFS (22.6m vs. 16.6m vs. 10.8m, P\\u0026thinsp;=\\u0026thinsp;0.003) were significantly better in patients received CDK4/6 inhibitor as first-line therapy than those received CDK4/6 inhibitor as second or third line therapy. Additionally, there were no statistically significant changes in the median PFS and OS according to the kind of metastatic site (non-visceral vs. visceral), HER2 status (HER2-zero vs. HER2-low), or the way of treatment (CDK4/6\\u0026thinsp;+\\u0026thinsp;AI vs. CDK4/6\\u0026thinsp;+\\u0026thinsp;fulvestrant, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eOne of the primary features of HR positive breast cancer is the hyperactivity of CDK4/6, which also serves as the primary cause of resistance to endocrine therapy[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. Patients with HR-positive metastatic breast cancer have demonstrated a significant improvement in PFS when combining CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib with endocrine therapy, as opposed to endocrine therapy alone. Regretfully, a significant number of patients will eventually become resistant to CDK4/6 inhibitors. About 20% of breast cancer patients did not respond to initial CDK4/6 inhibitor treatment[\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. Furthermore, within two years of starting treatment, almost 30% of the recruited patients in the PALOMA-2 study exhibited acquired resistance to palbociclib[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. The Cyclin D1\\u0026ndash;CDK4/6\\u0026ndash;Rb pathway appears to be activated in all major resistance mechanisms that have been found to date[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Interestingly, primary resistance to CDK4/6 inhibitor is present in all tumors harboring Rb gene mutations. The Cyclin D1\\u0026ndash;CDK4/6\\u0026ndash;Rb pathway, activation of proliferation pathways, alterations in the tumor microenvironment, and the regulation of tumor metabolism are among the mechanisms of acquired resistance to CDK4/6 inhibitor[\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. It is worth noting that activation of the Cyclin D1\\u0026ndash;CDK4/6\\u0026ndash;Rb pathway maybe a critical inducer both in primary and acquired resistance to CDK4/6 inhibitor.\\u003c/p\\u003e\\u003cp\\u003eThe findings of this real-world investigation imply that individuals with gBRCA mutations may have worse clinical outcomes in metastatic breast cancer treated with CDK4/6 inhibitor. Even though there was no statistical difference, the median PFS (9.2m vs. 18.5m vs. 14.1m) and ORR (0% vs. 35.0% vs. 43.8%) of patients with gBRCA mutation was inferior to patients with gBRCA wt and patients with unknown gBRCA status. And simultaneously, the DCR of patients with gBRCA mutation was worse than patients with gBRCA wt and patients with unknown gBRCA status. These findings indicate that gBRCA mutation may be involved in the resistance to CDK4/6 inhibitor. Previous studies have shown that 60%~80% of breast cancer with BRCA1 mutation is triple negative breast cancer (TNBC), and more than 75% of breast cancer with BRCA2 mutation is Luminal type[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. Among the 6 patients with gBRCA mutation in this study, 2 (33.3%) patients were gBRCA1m and 4 (66.7%) patients were gBRCA2m. Compared to BRCA1 mutations, BRCA2 mutations are more commonly linked to an HR-positive breast cancer phenotype.\\u003c/p\\u003e\\u003cp\\u003eClinical results of CDK4/6 inhibitor in metastatic breast cancer with germline BRCA mutation have not received much attention in clinical research to date. BRCA mutation was identified as a potential biomarker of ribociclib endocrinology by a pooled biomarker analysis of the MONALEESA-2, -3, -7 study, and patients with BRCA mutation had a better prognosis than BRCA wt patients[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Nonetheless, the majority of research indicates that individuals with BRCA mutations exhibit a subpar reaction to CDK4/6 inhibitor treatment. According to a review of the PADA-1 study, which used palbociclib in addition to AI as the first-line treatment for HR+/HER2-metastatic breast cancer, patients with gBRCA mutations often had a shorter PFS (14.3 vs. 26.7 m) than those with gBRCA wild type [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. A real-world investigation that examined the clinical effectiveness of CDK4/6 inhibitors in patients with gBRCA mutations found that these patients' overall survival was significantly shorter[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. Additionally, our current study showed that patients with gBRCA mutations had poorer PFS, DCR, and ORR. When taken together, these findings show that individuals with gBRCA mutations who have HR+/HER2-metastasized breast cancer may benefit less from CDK4/6 inhibitor plus endocrinology.\\u003c/p\\u003e\\u003cp\\u003eIt's still unclear exactly how BRCA contributes to breast cancer resistance to the CDK4/6 inhibitor. A few conceivable mechanisms are as follows. First, ribociclib was found to be considerably less beneficial for patients with RB1 mutations in circulating tumor DNA (ctDNA) compared to those with wild-type RB1 (median PFS: 3.8 vs. 18.9 m) in the analysis of samples from the MONALEESA trial cohort[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. According to earlier research, individuals with gBRCA2 mutations may exhibit co-loss of RB1 and BRCA2, which are neighboring loci on chromosome 13q. Patients with gBRCA2 mutations may develop primary resistance to CDK4/6 inhibitor as a result of this aberrant alteration. Second, as demonstrated by clinical tumor samples, patients with wide-type BRCA do not usually express Cyclin D1 at higher levels than those with BRCA mutations[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Research using cell lines from breast cancer patients has verified that resistance to CDK4/6 inhibitors is caused by Cyclin D1 overexpression. Down-regulation of Cyclin D1 leads to breast cancer cell cycle arrest in the G1 phase and restores sensitivity to CDK4/6 inhibitor[\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Collectively, gBRCA mutation may affect the sensitivity of CDK4/6 inhibitor treatment by participating in Cyclin D1\\u0026ndash;CDK4/6\\u0026ndash;Rb signal pathway.\\u003c/p\\u003e\\u003cp\\u003ePhase III clinical research In metastatic gBRCA mutant breast cancer, OlympiAD and EMBRACA verified the survival benefits of olaparib and talazoparib, which are poly ADP ribose polymerase (PARP) inhibitors [\\u003cspan additionalcitationids=\\\"CR28 CR29\\\" citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. In HR+/HER2- metastatic breast cancer with BRCA mutation, no published clinical trial has examined treatment selection and sequencing of PARPi\\u0026thinsp;+\\u0026thinsp;ET, CDK4/6i\\u0026thinsp;+\\u0026thinsp;ET, or therapeutic synergy of PARPi\\u0026thinsp;+\\u0026thinsp;CDK4/6i\\u0026thinsp;+\\u0026thinsp;ET. The safety and effectiveness of palbociclib, olaparib, and ET in metastatic breast cancer were investigated in a phase I/II clinical trial; however, the possible side effects restrict the clinical use of this combination[\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. Another study confirmed that the combination of olaparib and palbociclib has synergistic effects against BRCA mutation TNBC both in vitro and in vivo[\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. There is still a significant unmet clinical need in HR+/HER2- metastatic breast cancer with BRCA mutation. Future prospective clinical trials are needed to explore the optimal use and sequencing of PARPi and CDK4/6i in HR+/HER2- metastatic breast cancer with BRCA mutation.\\u003c/p\\u003e\\u003cp\\u003eThe present study does have some limitations. First, not all patients received genetic testing of BRCA mutation. Secondly, the study is observational, based on a single center, and not many patients are included. Consequently, additional clinical trials are required to validate the findings of this investigation. However, our work offers important insights into CDK4/6 inhibitor in HR+/HER2- metastatic breast cancer in a real-world context involving a BRCA mutation.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eIn conclusion, our study findings indicate that germline BRCA mutation may impact the clinical results of CDK4/6 inhibitor-treated metastatic breast cancer. Additionally, the results support incorporating the gBRCA mutation into systemic therapy decisions for patients receiving CDK4/6 inhibitor treatment for HR+/HER-2-metastatic breast cancer.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eClinical trial number\\u003c/strong\\u003e:\\u0026nbsp;not applicable.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was carried out in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committee of the Henan Provincial People’s Hospital. Written informed consent was obtained from all patients for the use of the medical records for research purposes.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot Applicable.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors contributed to the article and approved the submitted version. Yingbo Shao and Hui Liu designed the research, analyzed the data and drafted the paper. Yingbo Shao, Yaning He, Fangfang Guo, Zhifen Luo and Yang Yu were mainly responsible for data collection and analysis. Chaojun Liu, Qi Chen and Fangyuan Zhu were primarily responsible for statistical analysis.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis work was supported by Medical Science and Technique Foundation of Henan Province (No. LHGJ20240012) and Beijing Medical Award Foundation Project (No.YXJL-2020-0941-0748).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNone. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that no potential conflict of interest exist.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData availability\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe raw data of this article will be made available by contacting the corresponding author. \\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003ePegram M, Pietras R, Dang CT, et al. Evolving perspectives on the treatment of HR+/HER2\\u0026thinsp;+\\u0026thinsp;metastatic breast cancer. Ther Adv Med Oncol. 2023;15:17588359231187201.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eHuppert LA, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023;73(5):480\\u0026ndash;515.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eRobertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997\\u0026ndash;3005.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eDe Placido S, Gallo C, De Laurentiis M, et al. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):474\\u0026ndash;85.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eHerzog SK, Fuqua SAW. ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges. Br J Cancer. 2022;126(2):174\\u0026ndash;86.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSaatci O, Huynh-Dam KT, Sahin O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J Mol Med (Berl). 2021;99(12):1691\\u0026ndash;710.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMorrison L, Loibl S, Turner NC. The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nat Rev Clin Oncol. 2024;21(2):89\\u0026ndash;105.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSlamon DJ, Neven P, Chia S, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465\\u0026ndash;72.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSledge GW Jr., Toi M, Neven P, 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. 2017;35(25):2875\\u0026ndash;84.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCristofanilli M, Turner NC, Bondarenko I, 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. 2016;17(4):425\\u0026ndash;39.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eDean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle. 2012;11(14):2756\\u0026ndash;61.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eGuarducci C, Bonechi M, Benelli M, et al. Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer. 2018;4:38.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eVilgelm AE, Saleh N, Shattuck-Brandt R, et al. 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Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol. 2020;31(11):1526\\u0026ndash;35.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTorres A, Kokkonen C, Oladeji M, et al. Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer. Cancer Res. 2022;82:OT2\\u0026ndash;18.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eZhu X, Chen L, Huang B, et al. Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer. J Exp Clin Cancer Res. 2021;40(1):122.\\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\":\"info@researchsquare.com\",\"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\":\"Breast cancer, Endocrine therapy, CDK4/6 inhibitor, BRCA, Genetic testing\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7072445/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7072445/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eFew clinical studies pay attention to clinical outcomes of CDK4/6 inhibitor in metastatic breast cancer with germline BRCA mutation. The present study aimed to explore whether germline BRCA mutation will affect the clinical efficacy of CDK4/6 inhibitor for metastatic breast cancer. Patients with HR+/HER-2- metastatic breast cancer who were treated with CDK4/6 inhibitor from January 2019 to December 2022 were retrospectively analyzed. Genetic testing of BRCA mutation was performed on next generation sequencing (NGS) platform. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), and overall survival(OS). Of the 62 HR+/HER2- metastatic breast cancer patients receiving CDK4/6 inhibitor, gBRCA mutation were detected in 6 patients, 40 patients were gBRCA wt and 16 patients with unknown gBRCA status. Even though there was no statistical difference, the median PFS (9.2m vs. 18.5m vs. 14.1m) and ORR (0% vs. 35.0% vs. 43.8%) of patients with gBRCA mutation was inferior to patients with gBRCA wt and patients with unknown gBRCA status. And simultaneously, the DCR of patients with gBRCA mutation was worse than patients with gBRCA wt (33.3% vs. 75.0%, P=0.039) and patients with unknown gBRCA status (33.3% vs. 81.3%, P=0.032). No statistically significant differences were found in OS.\\u003cstrong\\u003e \\u003c/strong\\u003eOur study findings indicating that germline BRCA mutation may affect the clinical outcomes of metastatic breast cancer treated with CDK4/6 inhibitor. Additionally, the results support incorporating gBRCA mutation into systemic therapy decisions for patients with HR+/HER-2- metastatic breast cancer treated with CDK4/6 inhibitor.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Germline BRCA Mutation Affect the Clinical Outcomes of Metastatic Breast Cancer Treated with CDK4/6 Inhibitor: A Real-world Study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-31 10:19:24\",\"doi\":\"10.21203/rs.3.rs-7072445/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"7aff5924-0cf7-4c58-b79a-8a380b7032ed\",\"owner\":[],\"postedDate\":\"July 31st, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-08-18T00:23:11+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-07-31 10:19:24\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7072445\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7072445\",\"identity\":\"rs-7072445\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}