Background
Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), HER2-negative ...(HER2−) advanced breast cancer (ABC). Though significant improvements of progression-free survival (PFS) for CDK4/6 inhibitors were demonstrated, however, the results of overall survival (OS) profile were not consistent. This study is conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+ /HER2− ABC, and explore the prefer population through subgroup analysis.
Method
We identified relevant randomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+ /HER2− ABC. We calculated the hazard ratios (HRs) for PFS and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with the random-effects model.
Result
Eight trials and 4580 patients were included in this meta-analysis. Compared to ET alone, CDK4/6 inhibitors plus ET not only produced a significantly longer PFS (HR = 0.55, 95% confidence interval CI 0.50–0.59,
p
< 0.00001), but also manifested an extension of OS (HR = 0.79, 95% CI 0.67–0.93,
p
= 0.004) for HR+ /HER2− ABC. Similarly, the benefit was also manifested in ORR (RR = 1.47, 95% CI 1.30–1.67,
p
< 0.00001) and CBR (RR = 1.20, 95% CI 1.12–1.30,
p
< 0.00001). The improvements of PFS were observed in the combined treatment group as both the first-line (HR = 0.56) and the second-line therapy (HR = 0.53), and irrespective of menopausal status, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more hematologic and gastrointestinal adverse events were observed with CDK4/6 inhibitors. The most common Grade 3–4 AEs is neutropenia (RR 31.95).
Conclusion
Significant advantages of PFS and OS were observed for CDK4/6 inhibitors in HR+/HER2− ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increased occurrence of AEs, most of which are reversible, manageable, and acceptable. Therefore, CDK4/6 inhibitors could be recommended as a preferred options for patients with HR+ /HER2− ABC.
Abstract Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive ...triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming.
Background Bilateral breast cancer (BBC), as well as ovarian cancer, are significantly associated with germline deleterious variants in BRCA1/2, while BRCA1/2 germline deleterious variants carriers ...can exquisitely benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. However, formal genetic testing could not be carried out for all patients due to extensive use of healthcare resources, which in turn results in high medical costs. To date, existing BRCA1/2 deleterious variants prediction models have been developed in women of European or other descent who are quite genetically different from Asian population. Therefore, there is an urgent clinical need for tools to predict the frequency of BRCA1/2 deleterious variants in Asian BBC patients balancing the increased demand for and cost of cancer genetics services. Methods The entire coding region of BRCA1/2 was screened for the presence of germline deleterious variants by the next generation sequencing in 123 Chinese BBC patients. Chi-square test, univariate and multivariate logistic regression were used to assess the relationship between BRCA1/2 germline deleterious variants and clinicopathological characteristics. The R software was utilized to develop artificial neural network (ANN) and nomogram modeling for BRCA1/2 germline deleterious variants prediction. Results Among 123 BBC patients, we identified a total of 20 deleterious variants in BRCA1 (8; 6.5%) and BRCA2 (12; 9.8%). c.5485del in BRCA1 is novel frameshift deleterious variant. Deleterious variants carriers were younger at first diagnosis (P = 0.0003), with longer interval between two tumors (P = 0.015), at least one medullary carcinoma (P = 0.001), and more likely to be hormone receptor negative (P = 0.006) and HER2 negative (P = 0.001). Area under the receiver operating characteristic curve was 0.903 in ANN and 0.828 in nomogram modeling individually (P = 0.02). Conclusion This study shows the spectrum of the BRCA1/2 germline deleterious variants in Chinese BBC patients and indicates that the ANN can accurately predict BRCA deleterious variants than conventional statistical linear approach, which confirms the BRCA1/2 deleterious variants carriers at the lowest costs without adding any additional examinations. Keywords: Bilateral breast cancer, BRCA1, BRCA2, Germline deleterious variant, Artificial neural network
Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, ...whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated.
The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan-Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models.
BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.43395%CI 1.038-1.978, P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.34095% CI 1.163-4.708, P = 0.017 and 5-year OS: aHR = 2.446 95% CI 1.218-4.913, P = 0.011).
For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.
Although breast-conserving therapy (BCT) promises at least a similar survival rate for patients with early breast cancer compared with mastectomy, its efficacy in patients with human epidermal growth ...factor receptor 2 (HER2)-positive tumors remains unclear. Therefore, we conducted this study to explore differential effects of BCT and mastectomy on survival outcomes of patients with early-stage HER2-positive breast cancer.
Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and basic characteristics of patients who received either BCT or mastectomy were balanced using propensity score matching (PSM). Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression were performed.
In total, 20,277 patients were diagnosed with T1-2N0-1M0 HER2-positive breast cancer between 2010 and 2015. After PSM, 6,185 pairs of patients were enrolled for further analysis. Compared with those undergoing mastectomy, patients receiving BCT had superior overall survival (OS) (hazard ratio HR, 0.63; 95% confidence interval CI: 0.55-0.73; p < 0.001) and breast cancer-specific survival (BCSS) (HR: 0.59; 95% CI: 0.48-0.71; p < 0.001). The subgroup analyses revealed that survival outcomes (OS and BCSS) of BCT were better than those of mastectomy among estrogen receptor (ER)+/progesterone receptor (PR)+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+ subtypes (p < 0.05 for all); however, patients with ER-/PR+/HER2+ subtypes who underwent BCT had similar OS and BCSS (p > 0.05 for both) to those treated with mastectomy.
Despite the aggressiveness of the disease, we found that BCT may confer better long-term survival than mastectomy for patients with T1-2N0-1M0 HER2-positive breast cancer, particularly for those with ER+/PR+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+ subtypes. In addition, our study provided insights into the clinical applications of BCT. However, this retrospective study has introduced several inevitable limitations, and further prospective research is warranted to verify these conclusions.
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Background: Male breast cancer (MBC) is a rare disease. Research on trends and survival outcomes in systemic treatment for MBC is limited. This study aims to describe trends and survival outcomes ...of different systemic treatments in hormone receptor-positive (HR+) early MBC and to assess the factors related to treatment selection. Methods: We identified stage I-III HR+ invasive MBC patients who have undergone surgery and systemic therapy diagnosed during 2004-2014 from the National Cancer Database (NCDB). Treatment groups include: endocrine therapy (ET), chemotherapy (ET), combination therapy (ET+CT), and None. Using Cochran-Armitage trend tests to describe the temporal trends of different treatments. Performing propensity score models to evaluate overall survival. Conducting a logistic regression to analyze factors associated with ET+CT. Results: Among 6217 patients included (median follow-up 50.1months), 1290 (20.7%) patients received no systemic therapy (None), 705 (11.3%) patients only received CT, 2358 (37.9%) patients only received ET, and 1864 (30.0%) patients received ET+CT. From 2004 to 2013, there was a significant increase in the use of ET ( P(trend) < .001), which was accompanied by a decrease in CT and no treatment (all P(trend) < .001). And the use of ET+CT showed no significant change. After using overlap weighting (OW) to control confounders, multivariable cox regression analysis showed that ET+CT was associated with improved survival compared with ET (hazard ratio HR, 0.46; P< .001). Sensitivity analyses (including the inverse probability of treatment weighting (IPTW) (HR,0.49; P < .001), IPTW with stabilized weight (HR,0.49; P< .001), propensity score matching (PSM) (HR,0.51; P < .001), PS regression adjustment (HR,0.47; P < .001), and PS stratification (HR 0.44; P < .001)) and exploratory subgroup analyses (except for well-differentiated, stage I, and breast conservation + radiotherapy subgroups) indicated similar outcome. Factors associated with receiving ET+CT include younger age, private insurance, Charlson Comorbidity Index was 0, poorer differentiation, higher stage, mastectomy and radiotherapy, estrogen receptor-positive and progesterone receptor-negative, and HER2-positive. Conclusions: ET+CT was associated with improved survival compared with ET in HR+ early MBC patients, except for some low-risk subgroups.
Abstract
Background Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), ...HER2-negative (HER2-) advanced breast cancer (ABC). Surprisingly, the overall survival (OS) advantage of ribociclib was reported in the MONALEESE-7 trial. This study was conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+/HER2- ABC. MethodWe searched PUBMUD, MEDLINE, EMBASE et al to identify relevant randomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+/HER2- ABC. We extracted the hazard ratios (HRs) for progression-free survival (PFS) and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with random-effects model. Heterogeneity was assessed by I2 statistic. Result Eight trials and 4,580 patients were included in this meta-analysis. Both PFS (HR=0.54, 95% confidence interval CI: 0.50-0.59, p<0.00001) and OS (HR=0.79, 95% CI: 0.67-0.93, p=0.004) were significantly improved with CDK4/6 inhibitors for HR+/HER2- ABC. Similarly, the benefit was also manifested in ORR (RR=1.47, 95%CI: 1.30-1.67, p<0.00001) and CBR (RR=1.20, 95%CI: 1.12-1.30, p<0.00001). The improvement of PFS were observed in the combined treatment group, as both first-line (HR=0.56) and second-line therapy (HR=0.53), and irrespective of menopausal statue, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more toxicity profiles were observed with CDK4/6 inhibitors. The most common Grade 3-4 AEs is neutropenia (RR 31.95). Conclusion Substantial advantages of PFS and OS was observed for CDK4/6 inhibitors in HR+/HER2- ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increasing occurrence of AEs, most of which are reversable, manageable and acceptable. Therefore, CDK4/6 inhibitors could be recommended as the preferred options for HR+/HER2- ABC.
Citation Format: Li Jing, Fu Fangmeng, Yu Liuwen, Huang Meng, Lin Yuxiang, Mei Qian, Lv Jinxing, Wang Chuan. The efficacy and safety of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC): A systematic review and meta-analysis abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-16.
To assess the predictive and prognostic value of a subtyping method based on immunohistochemistry in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC). ...This study included patients with TNBC treated with anthracycline- and taxane-based NAC and curative surgery. Immunohistochemical (IHC) subtyping was performed using core needle biopsy specimens before NAC (pre-NAC) and residual tumors after NAC (post-NAC). Logistic regression was performed to identify predictive biomarkers of pathological complete response (pCR). Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed using the log-rank test and Cox proportional hazards regression. A total of 230 patients were followed up for a median of 59 months. Clinical lymph node status and the pre-NAC subtype were independent predictors of pCR (P=0.006 and 0.005, respectively). The pre-NAC subtype was an independent prognostic factor for long-term survival (iDFS: P < 0.001, DDFS: P=0.010, and OS: P=0.044). Among patients with residual disease (RD) after NAC, approximately 45% of tumors changed their IHC subtype. Furthermore, the post-NAC subtype, but not the pre-NAC subtype, was strongly associated with the survival of patients with RD (iDFS: P < 0.001, DDFS: P=0.005, and OS: P=0.006). The IHC subtype predicted response to NAC and long-term survival in patients with early TNBC. In patients with RD, almost 45% of the tumors changed subtype after NAC. The IHC subtype should be considered when planning additional therapies pre- and post-NAC.
Purpose. Although trastuzumab is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)- positive early breast cancer (EBC), drug resistance and disease relapse occur. ...Therefore, we performed a meta-analysis to assess the efficacy and safety of trastuzumab-containing dual anti-HER2 therapy compared to trastuzumab alone. Methods. A systematic search was performed to identify eligible randomized controlled trials (RCTs). Main outcomes including event-free survival/invasive disease-free survival (EFS/iDFS), overall survival (OS), and safety were considered. Results. Ten RCTs were included (15,284 patients). Significant improvements were observed in both EFS/iDFS (HR 0.86, p=0.0003) and OS (HR 0.86, p=0.02) with trastuzumab-based dual anti-HER2 therapy, especially in adjuvant treatment, while in the neoadjuvant setting, dual-targeted therapy also achieved a substantial pathological complete response (pCR) benefit (HR 1.34, p=0.0002). Subgroup analysis revealed that the EFS/iDFS benefit was slightly higher with trastuzumab plus pertuzumab or plus neratinib than trastuzumab plus lapatinib, while OS benefit was significant with trastuzumab plus lapatinib, but there were no subgroup differences (interaction test, p=0.80 and 0.24, resp.). In addition, EFS/iDFS benefit was unrelated to hormone receptor status but pronounced in the lymph node-positive (LN+) subgroup, which should be interpreted cautiously for lacking interaction (p=0.18). Besides, patients receiving dual therapy, especially with the lapatinib-containing regimen, experienced more toxicity, but no increase in cardiotoxicity. Conclusions. Despite being associated with more toxicity, trastuzumab-containing dual anti-HER2 therapy is superior to trastuzumab single agent for HER2-positive EBC independent of hormone receptor status. The correlation between survival and LN status needs further verification. Trastuzumab plus pertuzumab or plus neratinib is the preferred regimen with substantial efficacy and lower toxicity.
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