Clinical benefit and safety profile of cross-line therapy with CDK4/6 inhibitors:a retrospective study of HR+/HER2–advanced breast cancer

Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.

LA-D-B1,a novel Abemaciclib derivative,exerts anti-breast cancer effects through CDK4/6

Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.

MiR-450b-5p enhances the radiosensitivity of HR^(+) and HER2^(−) breast cancer by targeting CDK6

Background:The sensitivity of breast cancer cells to radiation is a key cause of locoregional recurrence after postoperative radiotherapy.Several studies have reported that microRNAs(miRNAs)are involved in the radiosensitivity of human breast cancer cells.One miRNA microarray study showed that miR-450b-5p was overexpressed 13.3-fold in patients with estrogen receptor–positive(ER^(+))and human epidermal growth factor receptor 2–negative(HER2−)breast cancer and no local relapse compared with local relapse patients.However,its underlying mechanism of action remains unknown.Methods:The predicted target mRNAs of miR-450b-5p were screened using the TargetScan,miRDB,and miRWalk databases.Western blotting,quantitative polymerase chain reaction,and dual-luciferase reporter assays explored the association between cyclindependent kinase 6(CDK6)and miR-450b-5p.The cell counting kit-8 assay and flow cytometry detected the proliferation of transfected MCF7 cells.Colony formation and xenograft tumors detected the radiosensitivity of the transfected MCF7 cells.Results:Bioinformatics analysis,Western blotting,quantitative polymerase chain reaction,and dual-luciferase reporter assays demonstrated that CDK6 was the target gene of miR-450b-5p.Furthermore,in vitro and in vivo experiments showed that miR-450b-5p inhibited MCF7 cell proliferation and cell cycle progression,increased the sensitizer enhancement ratio,and decreased the volume of xenograft tumors after irradiation by regulating CDK6.Conclusions:This study demonstrates that miR-450b-5p enhances the radiosensitivity of hormone receptor–positive(HR^(+))and HER2−breast cancer cells and elucidates its mechanism.miR-450b-5p may be considered a therapeutic target in HR^(+)and HER2−breast cancer treated with radiotherapy.

Unveiling the therapeutic potential:KBU2046 halts triple-negative breast cancer cell migration by constricting TGF-β1 activation in vitro

Background:Triple-negative breast cancer(TNBC)is a heterogeneous,recurring cancer characterized by a high rate of metastasis,poor prognosis,and lack of efficient therapies.KBU2046,a small molecule inhibitor,can inhibit cell motility in malignant tumors,including breast cancer.However,the specific targets and the corresponding mechanism of its function remain unclear.Methods:In this study,we employed(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium)(MTS)assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells in vitro.RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC.Finally,confirmed the predicted important signaling pathways through RT-qPCR and western blotting.Results:In this study,we found that KBU2046 functioned as a novel transforming growth factor-β(TGF-β1)inhibitor,effectively suppressing tumor cell motility in vitro.Mechanistically,it directly down-regulated leucine-rich repeat-containing 8 family,member E(LRRC8E),latent TGFβ-binding protein 3(LTBP3),dynein light chain 1(DNAL1),and MAF family of bZIP transcription factors(MAFF)genes,along with reduced protein expression of the integrin family.Additionally,KBU2046 decreased phosphorylation levels of Raf and ERK.This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis.Conclusions:In summary,these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC.Furthermore,our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.

BMP-6 inhibits microRNA-21 expression in breast cancer through repressing 6EF1 and AP-1

MicroRNAs （miRNAs）, which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene （miR-21） has been reported to be highly expressed in various solid tumors, including breast cancer. Bone morphogenetic protein-6 （BMP-6） has been identified as an inhibitor of breast cancer epithelial-mesenchymal transition （EMT） through rescuing E-cadherin expression. We initiated experi- ments to identify the relationships between miR-21 and BMP-6 in breast cancer progression. Real-time PCR analysis showed that miR-21 expression was very high in MDA-MB-231 cells that expressed little BMP-6. A reverse correla- tion between BMP-6 and miR-21 was also determined in breast cancer tissue samples. Moreover, BMP-6 inhibited miR-21 transcription in MDA-MB-231 cells. In order to investigate how BMP-6 inhibited the miR-21 promoter （miPPR-21）, we constructed a series of miPPR-21 reporters. Luciferase assay results indicated that BMP-6 inhibited miPPR-21 activity through the E2-box and AP-l-binding sites. We also demonstrated that both δEF1 and TPA in- duced miR-21 expression. Using site-directed mutation and CHIP assay, we found that δEF1 induced miPPR-21 ac- tivity by binding to the E2-box on miPPR-21. Moreover, TPA triggered miPPR-21 activity through the AP-I binding sites. BMP-6 treatment significantly reduced the binding of these factors to miPPR-21 by decreasing the expression of δEF1 and c-Fos/c-Jun. We also demonstrated that BMP-6-induced downregulation of miR-21 modified the activ- ity of PDCD4 3＇UTR and inhibited MDA-MB-231 cell invasion. δEF1 overexpression and TPA induction blocked this inhibitory effect of BMP-6. In conclusion, BMP-6-induced inhibition of miR-21 suggests that BMP-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of miR-21 in breast cancer.

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450(CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning(null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, par-ticularly in terms of response to tamoxifen therapy and breast cancer outcome.

mRNA expression of DOK1-6 in human breast cancer

AIM:To examine the expression of downstream of tyrosine kinase(DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinicopathological and prognostic factors.METHODS:DOK1-6 m RNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples(n = 112) and normal background breast tissue(n = 31). Tissues were collected between 1991 and 1996 at two centres and all patients underwent mastectomy and ipsilateral axillary node dissection. All tissues were randomly numbered and the details were only made known after all analyses were completed. Transcript levels of expression were determined using real-time polymerase chain reaction and analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period.RESULTS:DOK-2 and DOK-6 expression decreased with increasing TNM stage. DOK-6 expression decreased with increasing Nottingham Prognostic Index(NPI) [NPI-1 vs NPI-3(mean copy number 15.4 vs 0.22, 95%CI:2.7-27.6, P = 0.018) and NPI-2 vs NPI-3(mean copy number 7.6 vs 0.22, 95%CI:0.1-14.6, P = 0.048)]. After a median follow up period of 10 years, higherlevels of DOK-2 expression were found among patients who remained disease-free compared to those who developed local or distant recurrence(mean copy number 3.94 vs 0.0000096, 95%CI:1.0-6.85, P = 0.0091), and distant recurrence(mean copy number 3.94 vs 0.0025, 95%CI:1.0-6.84, P = 0.0092). Patients who remained disease-free had higher levels of DOK-6 expression compared to those who died from breast cancer.CONCLUSION:Decreasing expression levels of DOK-2 and DOK-6 with increased breast tumour progression supports the notion that DOK-2 and DOK-6 behave as tumour suppressors in human breast cancer.

DDHD2 is involved in the malignant progression of early luminal A breast cancer by changing cell membrane proteins and immune responses functionality

Background:Luminal A breast cancer has the best prognosis of all malignant breast cancer types.In clinical practice,some patients with luminal A breast cancer present with small tumors(usually<20 mm)but with lymph node metastases or even distant organ metastasis.Owing to their insensitivity to chemotherapy and the lack of conclusive clinical evidence,there is a significant gap in research on luminal A breast cancer with high invasiveness.This study aimed to identify genes that drive the invasiveness of luminal A breast cancer and explore the underlying mechanisms.Methods:In this study,we first utilized bioinformatics techniques to analyze differentially expressed mRNAs and enrich common functional pathways to identify the target gene DDHD domain containing 2(DDHD2).We then evaluated the association between DDHD2 expression and patient prognosis,genetic material changes,and transcriptional,translational,and immune responses in luminal A breast cancer.We also conducted experiments at the molecular and cellular levels to validate these biochemical mechanisms.Results:The expression of DDHD2 varied between patients with low-grade luminal A breast cancer with and without lymph node metastases.Our findings demonstrated that DDHD2 exerted carcinogenic effects through various pathways by altering cell adhesion and migration,regulating cell proliferation and apoptosis cycles,and suppressing immune responses.Moreover,a pathway through which DDHD2 inhibited immunity was preliminarily verified.Conclusions:The results revealed a novel role for DDHD2 in promoting the malignant transformation and invasiveness of luminal A breast cancer.Considering its effects on the tumor microenvironment and tumor-infiltrating immune cells in the epithelial-mesenchymal transition,DDHD2 is proposed as a reliable direction for future immunotherapy and a potential target in luminal A breast cancer immune resistance.

The detection of micrometastases in the peripheral blood of patients with breast cancer for hSBEM mRNA and CD44V6 mRNA

Objective： Successful treatment of breast cancer greatly depends on the early detection of its metastasis, therefore a sensitive and specific biomarker for detecting dissemination of the cancer cells will help to achieve this goal. This study was to evaluate the prognostic significance of human small breast epithelial mucin （hSBEM） and CD44V6 in breast cancer. Methods： The expressions of hSBEM mRNA and CD44V6 mRNA were detected with nested reverse transcription polymerase chain reaction （nested RT-PCR） in 67 samples of breast cancer and adjacent normal breast tissue, 16 samples of breast benign lesions tissue, and 67 specimens of peripheral blood from patients with breast cancer, 16 specimens of benign breast lesions, 20 specimens of healthy volunteers, and 25 （each five cases） other carcinomas tissue samples, including those of gastric carcinoma, colorectal carcinoma, esophageal carcinoma, lung carcinoma, and ovary carcinoma, were analyzed for hSBEM mRNA expression by nested RT-PCR. Results： hSBEM mRNA expression was observed in 62/67 （92.54%） of breast cancer, 14/16 （87.50%） of breast benign lesions and 59/67 （88.05%） of normal breast tissue, with no significant differences between them （P 〉 0.05）. None of the samples from other cancer tissues were positive. In peripheral blood the expression of hSBEM mRNA was detected in 34/67 （50.75%） from patients with breast cancer, with significant increasing （P 〈 0.05） in the cases of metastatic disease （stage Ⅳ） and those with lymph node metastasis compared with localized disease （stage Ⅰ, Ⅱ and Ⅲ） and without lymph node metastasis, but its expression was not found in peripheral blood of patients with benign breast lesions or healthy volunteers. Although CD44V6 mRNA was significantly higher in breast cancer than in benign breast lesions tissue and normal breast tissue, its expression in peripheral blood show no significant difference （P 〉 0.05） in the patients with breast cancer （82.09%）, benign breast lesion （75.00%）, or healthy volunteers （70.00%）. The expressions of hSBEM mRNA and CD44V6 mRNA had no correlation with the age of the patients, size of primary tumor, histological type and estrogen or progestin receptor status （P 〉 0.05）. Conclusion： hSBEM mRNA, as assessed by nested RT-PCR, shows a mammary-specific and mammary-sensitive expression, and is a sensitive indicator of hematogeneous spread of breast cancer cell, while CD44V6 shows low sensitivity and specificity in detecting dissemination of breast cancer cell in peripheral blood, hSBEM mRNA is a promising molecular biomarker for detecting breast cancer micrometastases.

Serum Y-Box Binding Protein 1 (YBX-1) and Interleukin 6 (IL-6) Are Associated with Metastasis in Breast Cancer Patients

Objectives: The aim of this study was to assess the levels of Y-box binding protein 1 (YBX-1) and interleukin 6 (IL-6) in the sera of metastatic and non-metastatic breast cancer patients (BC), investigate their clinicopathological significance and to analyze their potential use as biomarkers of breast cancer metastasis. Methods: The study included ninety subjects sub-grouped equally into metastatic BC, non-metastatic BC and healthy volunteers. Serum YBX-1 and IL-6 were quantified using ELISA technique while CA 15-3 was quantified using IRMA kit. Clinical data were collected from patients’ records. Results: YBX-1 (p < 0.001), IL-6 (p < 0.001) and CA15-3 (p = 0.017, 0.001) were significantly elevated in metastatic and non-metastatic BC patients compared to healthy controls, however, only YBX-1 (p 0.001) showed a significant difference with cancer metastasis. Generally, YBX-1 and IL-6 were correlated with worse histological grade and late clinical stage in breast cancer patients and they were also associated with axillary lymph nodes involvement and positive vascular invasion in metastatic BC patients. Serum YBX-1 and IL-6 levels were positively correlated to each other (rs = 0.615, p < 0.001) and they showed high sensitivity and specificity compared to CA 15-3 (p < 0.001 and p = 0.004 for YBX-1 and IL-6 respectively) for predicting cancer metastasis. Conclusions: Serum YBX-1 and IL-6 are potential biomarkers of breast cancer patients with significant correlation with bad clinicopathological characteristics. Serum YBX-1 and IL-6 have superior sensitivity and specificity compared to CA15-3 and can serve as potential follow up and prognostic markers.

Downregulation of MTDH using short hairpin RNA inhibited EMT in breast cancer cells

Objective： Metadherin （MTDH） could regulate epithelial-mesenchymal transition （EMT）, and is involved in tumor metastasis.This study was designed to observe the effect of MTDH-short hairpin RNA （shRNA） on EMT, and the role of MTDH in breast tumor metastasis. Methods： RNA interference plasmid that can express shRNA targeting MTDH or shRNA-nega- tive plasmid that does not match any known human coding mRNA was designed, constructed and named MTDH-shRNA and MTDH-shRNA-neg, which were transiently transfected into MDA-MB-231 cells using LipofectamineTM2000. After 48 h, the levels of MTDH, E-cadherin and a-SMA expression were determined by reverse transcription-polymerase chain reactin （RT- PCR）, Western blot. The invasion and immigration potential was examined by Transwell chamber invasion or migration assay. Results： Compared with MDA-MB-231, the MTDH mRNA level was down-regulated by 41.2%, the MTDH protein level was down-regulated by 40.3%. The invasion and immigration potential of MDA-MB-231 cells was decreased after transfection of MTDH-shRNA. Compared with MDA-MB-231 or MTDH-shRNA-neg, the mRNA and protein level of a-SMA was reduced and E-candherin were increased in MTDH-shRNA, with statisticat significance. Conclusion： Downregulation of MTDH increase E-candherin expression and reduced a-SMA expression, which inhibit EMT in MDA-MB-231 cells. This knockdown significantly suppresse migration and invasion in MDA-MB-231 cells.

Abemaciclib, a Recent Novel FDA-Approved Small Molecule Inhibiting Cyclin-Dependant Kinase 4/6 for the Treatment of Metastatic Breast Cancer: A Mini-Review

Abemaciclib (Verzerio®) is a cell cycle inhibitor of both CDK4 and CDK6. In 2017, abemaciclib was approved by the Food and Drug Administration (FDA) and, in 2018 by the European Medicines Agency (EMA) for the treatment of postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer. In this mini-review, we provide a series of information for respectively their targets and its selectivity, results on preclinical trial, clinical phase I, II and III trials, and some perspectives. We also describe the batch and flow steps used for the synthesis of this cancer drug.

Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer

BACKGROUND There are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P4502D6(CYP2D6)polymorphisms.AIM To evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes.METHODS Eighty-two women were recruited.Seventy-eight completed CYP2D6 genotyping and were categorized into poor,intermediate(IM)and extensive or ultra metabolizer phenotypes.Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent.RESULTS More than 70%of the women had an IM phenotype,32%an extensive or ultra metabolizer phenotype,and 0%had a poor metabolizer phenotype.Regardless of genotype,more women opted for aromatase inhibitors.Overall,80%of women completed 5 years of hormonal therapy.Five women developed recurrence,3 contralateral breast cancer,5 died,and 1 was diagnosed with a second primary cancer.Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype,though not statistically significant[P=0.743,hazard ratio(HR):1.441,95%confidence interval(CI):0.191 to 10.17 and P=0.798,HR:1.327,95%CI:0.172 to 9.915,respectively].Women receiving aromatase inhibitors also appeared to have a better,but also nonsignificant,5-year recurrence-free and overall survival(P=0.253,HR:0.368,95%CI:0.031 to 0.258 and P=0.292,HR:0.252,95%CI:0.005 to 4.951,respectively).CONCLUSION The IM phenotype was highly prevalent but was not associated with clinical outcome.

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response(pCR) is rare in hormone receptor-positive(HR+)HER2-negative breast cancer(BC) treated with either endocrine therapy(ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures.The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced p CR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a p CR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified asendocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.

Expression of ATP synthase 6 in breast cancer cell line, T47D cells, induced by heregulin β1

目的 :探讨 Heregulinβ1诱导乳腺癌细胞 T47D相关基因的表达。方法 :应用差减杂交和斑点杂交技术检测乳腺癌细胞在 Heregulinβ1 ( 30 μg· L-1)作用 1 8h后 ,相关基因的表达情况。结果 :线粒体 ATP合成酶 6m RNA的表达在 1～ 6h明显增高。结论 :乳腺癌细胞 T47D在 Here-gulinβ1刺激后 ,细胞 ATP酶

CDK4/6 inhibitors in the treatment of hormone receptor-positive, HER2-negative advanced breast cancer

Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no response to ET due to primary or acquired ET resistance.In this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)inhibitors.The prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 inhibitors.In this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with ET.We also summarized several molecular features that would predict response or resistance to CDK4/6 inhibitors.In addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.

Impact of Drug-Drug Interaction between CDK4/6 Inhibitors and Proton Pump Inhibitors on Survival Outcomes in the Treatment of Metastatic Breast Cancer—Real World Data from a Portuguese Center

Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.

Insights into the Use of CDK 4/6 Inhibitors in Patients with HR-positive Advanced or Metastatic Breast Cancer

Hormone receptor(HR)-positive breast cancer(BC)is the most common subtype of BC and some patients with such tumors experience recurrences.Endocrine-based therapy(ET)(e.g.,tamoxifen,aromatase inhibitors(AIs),and fulvestrant)that has improved outcomes in such patients represents the initial therapy for women with HR-positive/human epidermal growth factor receptor 2(HER2)-negative BC(considering no evidence of visceral crisis).However,the resistance to ET can occur in almost 50%of HR-positive BCs.In order to improve outcomes of patients with HR-positive metastatic BC,new treatment strategies are required.One such therapy is the new class of medications,cyclin-dependent kinase(CDK)4/6 inhibitors,that have improved the outcomes in such patients(both endocrine-sensitive and endocrine-resistant).This article presents evidence from the main clinical trials,which led to the approval of palbociclib,ribociclib,and abemaciclib.These three CDK 4/6 inhibitors have shown a significant improvement of the progression-free survival(PFS)in patients with HR-positive/HER2-negative metastatic BC when used in combination with selected ETs.In addition,some important patient management considerations,when choosing a particular CDK 4/6 inhibitor for an individual patient are presented.Furthermore,a need to find biomarkers for CDK 4/6 inhibitor sensitivity,efficacy,and resistance,to be able to precisely select the best patientcandidates for this treatment is highlighted.

Effect of ultrasound-guided pleural paravertebral block combined with general anesthesia on serum monocyte chemokinin-1, interleukin-6 and interleukin-10 levels in patients with early breast cancer after modified radical mastectomy

Objective: To investigate the effect of ultrasound-guided pleural paravertebral block combined with general anesthesia on serum monocyte chemokinin-1 (McP-1), interleukin-6 (il-1) and il-10 levels in patients with early breast cancer after modified radical mastectomy. Methods: A total of 76 patients with early breast cancer from October 2015 to July 2018 were selected from our hospital and divided into study group (n=38) and control group (n=38). The control group received general anesthesia, and the study group received ultrasound-guided paravertebral block combined with general anesthesia. Data of two groups of perioperative situation (PCIA press the number, volume of intraoperative sufentanil and PACU time), preoperative and postoperative 12 h, 24 h serum factor (MCP-1, IL-6, IL-10) level, after 2 h, 4 h, 8 h, 12 h, 24 h when pain (VAS) score, preoperative (T1), 15 min after the anesthesia (T2), 5 min after surgery (T3) hemodynamic state [heart rate (HR), mean arterial pressure (MAP)], the incidence of adverse reactions were counted. Results: (1) Perioperative status: PCIA presses, intraoperative dose of sufentanil and PACU duration in the study group were less than those in the control group. (2) Serum factors: there was no significant difference in serum McP-1, il-6 and il-10 levels between the two groups before operation. The serum levels of McP-1, il-6 and il-10 in the two groups 12 h after operation were higher than those before operation. The serum levels of McP-1, il-6 and il-10 in the two groups at 24 h after surgery were significantly lower than those at 12 h after surgery, and the serum levels of McP-1, il-6 and il-10 in the group at 12 h and 24 h after surgery were lower than those of the control group. (3) Pain degree: the VAS score of the study group at 2 h, 4 h, 8 h, 12 h and 24 h after surgery was lower than that of the control group. (4) Hemodynamics: there was no significant difference in HR and MAP between the two groups during T1, HR and MAP in T2 were lower than those in T1, but the level of each indicator in the study group was higher than that in the control group. (5) Adverse Reactions: the incidence of adverse reactions was lower in the study group (10.53%) than in the control group (28.95%). Conclusion: The application of ultrasound guided early breast cancer modified radical block complex general anesthesia thoracic vertebra, can reduce the dosage of anesthetic drugs, shorten the PACU, residence time, reduce postoperative pain, maintain stable hemodynamic state, inhibiting inflammatory reaction caused by surgical trauma degree, and can reduce the incidence of adverse reactions, and has safety.

Mechanism of Ginsenoside Rh1 in Regulating Breast Cancer Cell Extravasation Based on CCL20- CCR6

Objective:To explore the regulatory mechanism of ginsenoside Rh1 on breast cancer cell extravasation based on CCL20-CCR6.Methods:In 2021,a total of 34 patients with breast cancer were treated in Baoding First Central Hospital.During hospitalization,pathological examinations were performed,and all the patients were diagnosed with invasive ductal carcinoma.Out of the 34 cases,16 cases were found to have CCR6 expression in breast cancer tissues,in which they were recorded as the CCR6 expression group,whereas 18 cases did not have CCR6 expression;these cases were recorded as the CCR6 non-expression group.During the same period,21 normal patients were selected as the control group.The peripheral blood CCL20 level and the expression of CCR6 on the surface of CD3+T lymphocytes were analyzed.The extracts of cancer cells were collected,purified,and cultured,and the effect of ginsenoside Rh1 on the invasion and metastasis of breast cancer cells was analyzed.Results:The peripheral blood CCL20 level in the CCR6 expression group was significantly higher than that in the CCR6 non-expression group and the control group,in which p<0.05,indicating that the difference was statistically significant;at 12,24,and 48 hours,the cell survival rate of each dose group was significantly higher than that of the blank control group and the dimethyl sulfoxide(DMSO)group(p<0.05).At 48 hours,comparing the low-dose group with the high-dose group,the cell survival rate significantly decreased(p<0.05).Compared with the blank control group and DMSO group,the invasion ability of breast cancer cells could be reduced in both,high-and medium-dose groups,where p<0.05,indicating that the difference was statistically significant.Conclusion:CCL20 may play a role in the pathogenesis of certain breast cancers,and ginsenoside Rh1 can effectively regulate the invasion and migration of breast cancer cells.