Bevacizumab Plays a double-edged role in Neoadjuvant Therapy for Non-metastatic Breast Cancer: A Systemic Review and Meta-Analysis.
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SUBMITTER: Chen X
PROVIDER: S-EPMC8040714 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeResults from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting.MethodsA literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3.ResultsNine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18-1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17-1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90-3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09-1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78-2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand-foot syndrome.ConclusionsHigher proportions of patients achieved pCR when bevacizumab was added to NAC compared with when they received chemotherapy alone; acceptable toxicities were also found. Subgroup analysis demonstrated that patients with histologically confirmed HER2-negative and HR-negative breast cancer benefited the most.
| S-EPMC4699216 | biostudies-literature
Project description:BackgroundLocoregional therapy (LRT) in de novo metastatic disease is controversial with inconsistent results from randomized control trials (RCTs).MethodsRCTs comparing LRT and systemic therapy to standard therapy alone in de novo metastatic breast cancer were identified. Hazard ratios (HRs) and their associated 95% confidence intervals (CIs) were computed and pooled in a meta-analysis using generic inverse variance. Overall survival (OS) and time to locoregional progression data were extracted for the intention to treat (ITT) population. Data on OS for pre-specified subgroups defined by tumor subtype and by site of metastases were also extracted.ResultsAnalyses included 4 trials comprising 970 patients. LRT included standard surgery to the primary breast tumor in all studies, and adjuvant radiation per standard of care was required in 3 studies. Compared to standard treatment, LRT was not associated with improved OS in the ITT population (HR 0.97, 95% CI 0.72-1.29, p = 0.81). However, LRT was associated with improved time to locoregional progression (HR 0.36, 95% CI 0.14-0.95, p = 0.04). LRT was not associated with improved OS in any tumor subtypes, including hormone receptor positive (HR 0.96, 95% CI 0.65-1.43), triple negative (HR 1.4, 95% CI 0.50-3.91) and human epidermal growth factor receptor 2 positive disease (HR 0.93, 95% CI 0.68-1.28). Additionally, LRT did not improve OS in bone only disease (HR 0.97, 95% CI 0.58-1.62) and in visceral disease (HR = 1.02, 95% CI 0.77-1.35). Our critical appraisal has identified some methodological problems in the design and conduct of the studies included that could affect the meta-analysis result.ConclusionsLRT in de novo metastatic breast cancer is not associated with improved OS. Results are consistent among different breast cancer subgroups. However, this conclusion should be interpreted with caution in view of the limitations identified in meta-analysis.
| S-EPMC8481908 | biostudies-literature
Project description:BackgroundThis study aimed to assess the influence of disease- and patient-related factors on surgeons' decisions to refer patients with early-stage breast cancer (EBC) for neoadjuvant systemic therapy (NST).MethodsAn online survey of United States surgeons evaluated the influence of selected disease- and patient-related factors on surgeons' decisions, rated their influence (individually and in combination), and provided a relative ranking of jointly considered factors using best-worst scaling.ResultsThe participants in this study were 100 licensed surgeons. The surgeons referred approximately 25 % of EBC patients for NST to improve surgical management. Approximately 75 % of the surgeons agreed that NST is important for EBC, if only to improve surgical management. More than half were "very likely" to refer EBC patients for NST based on anatomicopathologic factors. Less than 50 % were "very likely" to do so when considering tumor phenotype factors. Tumor size and lymph node status were ranked highest in hypothetical patient scenarios. Regarding combinations of factors, the importance of any single factor varied according to the combinations presented. Less than half of the respondents were "very familiar," and half were "somewhat familiar" with NST guidelines for breast cancer. More than half of the respondents were unaware that findings have shown achievement of pathologic complete response (pCR) after NST to be associated with improved survival.ConclusionsSurgeons' decision to refer for NST is strongly driven by surgical management goals. Anatomicopathologic factors are more influential than tumor phenotype. However, no single disease or patient factor consistently drives the decision to refer for NST. Surgeons' awareness of the association between pCR achievement and longer survival could be improved.
| S-EPMC5009159 | biostudies-literature
Project description:Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.
| S-EPMC9433456 | biostudies-literature
Project description:Background: We aimed to explore whether the expression of serum miR-222-3p might contribute to early prediction of therapeutic response, clinical outcomes, and adverse events for HER2-positive breast cancer patients receiving neoadjuvant therapy (NAT). Methods: A total of 65 HER2-positive breast cancer patients receiving NAT were analyzed. The concentration of serum miR-222-3p was detected by quantitative real-time PCR. Logistic regression analysis was used to identify the association of serum miR-222-3p with pathological complete response (pCR). The relationship of serum miR-222-3p with disease-free survival (DFS) and overall survival (OS) was examined via log-rank test and Cox proportional hazards analysis. The ordered logistic regression was applied to evaluate the association between serum miR-222-3p and adverse events. Results: The miR-222-3p low group was more likely to achieve pCR [odds ratio (OR) = 0.258, P = 0.043]. The interaction between miR-222-3p and presenting Ki67 level was also detected for pCR (OR = 49.230, P interaction = 0.025). The miR-222-3p low group was correlated with superior DFS (P = 0.029) and OS (P = 0.0037). The expression of serum miR-222-3p was the independent protective factor for trastuzumab-induced cardiotoxicity (P < 0.05) and anemia (P = 0.013). Conclusions: Serum miR-222-3p is the potential factor to predict pCR, survival benefit and trastuzumab-induced cardiotoxicity for HER2-positive breast cancer patients receiving NAT.
| S-EPMC7212359 | biostudies-literature
Project description:BackgroundBevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.MethodsWe randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.ResultsThe addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis.ConclusionsThe addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).
| S-EPMC3401076 | biostudies-literature
Project description:Cadmium (Cd) contamination in soils poses great risks to both agricultural production and human health. Calcium (Ca) is an essential element playing a significant role in protecting plants against Cd toxicity. However, how Ca affects Cd uptake and translocation in rice is still not fully elucidated. In this study, the regulatory role of Ca in Cd uptake and upward translocation was investigated in rice at different growth stages. Our results showed that the supplement of 5 mM Ca significantly reduced Cd uptake by rice roots, because of their competition for Ca-permeable channels as an absorption site and Ca-induced downregulation of OsNRAMP1 and OsNRAMP5. However, Ca application facilitated the upward translocation of Cd by both upregulating OsHMA2 to induce xylem loading of Cd and downregulating OsHMA3 to reduce vacuolar sequestration of Cd. Such contrary results suggested a double-edged role of Ca in regulating root Cd uptake and root-to-shoot Cd translocation in rice. Although it increased Cd content in the aboveground vegetative tissues during the whole growth period, the addition of 5 mM Ca eventually decreased Cd content in rice grains at the ripening stage. All these results suggest that Ca-based amendments possess great potential for the production of low-Cd rice grains.
| S-EPMC7662230 | biostudies-literature
Project description:BackgroundThe use of neoadjuvant systemic therapy (nast) in the treatment of breast cancer is increasing, and the role of adjuvant radiation therapy (rt) in that setting is uncertain. We sought to review and report the use of nast, its trends over time, and its relationship with the prescribing patterns of locoregional rt in a provincial cancer system.MethodsPatients with stages i-iii breast cancer diagnosed during 2007-2012 were identified using a provincial database. Patient, tumour, and treatment characteristics were extracted. Multivariable logistic regression analyses were used to assess associations with the use of nast. Kaplan-Meier and Cox regression were used for survival analyses.ResultsOf the 11,658 patients who met the inclusion criteria, 602 (5%) had received nast. Use of nast was more frequent in stage iii patients (53%) than in stages i and ii patients (2%). In clinically lymph-node positive patients, a pathology assessment was made approximately 50% of the time. Higher clinical tumour stage and increasing clinical nodal stage predicted for increasing use of nast and of nodal rt after nast, but pathologic nodal status after nast was not associated with use of nodal rt. A statistically significant survival difference was observed between patients in the nast and no-nast groups, but that significance disappeared in a multivariable Cox regression analysis.ConclusionsThis population-based study demonstrated 5% use of nast for breast cancer. Most patients received nodal rt after nast, and nodal rt was not associated with pathologic stage after nast. Findings likely reflect the realities of clinical practice and show that reliance on clinical nodal staging results in outcomes similar to those reported in the literature.
| S-EPMC5659152 | biostudies-literature
Project description:PurposeTo investigate the value of performing mid-treatment axillary ultrasound (AUS) in triple-negative breast cancer (TNBC) patients who are undergoing neoadjuvant systemic therapy (NAST) by determining the optimal cutoff number of abnormal nodes associated with residual nodal disease on surgical pathology.Materials and methodsThis sub-study, an interim analysis of an ongoing single-institution clinical trial enrolling patients with stage I-III TNBC, included 106 patients. Number of abnormal nodes at mid-treatment was assessed and recorded by experienced breast radiologists, who empirically categorized lymph nodes using a binary approach of sonographically-normal versus abnormal. Pathologic lymph node positivity was defined as presence of macrometastasis or micrometastasis in ≥1 axillary node from sentinel lymph node biopsy and/or axillary lymph node dissection.ResultsOf 106 patients, 26 (25 %) had residual nodal disease and 80 (75 %) had no nodal disease at surgery. Median number of abnormal nodes at mid-treatment was 5 (standard deviation [SD], 5) for patients with residual nodal disease and 0 (SD, 2) for patients with no nodal disease at surgery (p < 0.0001). TNBC patients with >4 abnormal nodes at mid-treatment had a significantly higher chance of being node-positive at surgery (AUC = 0.908, p < 0.0001; PPV = 90 %).ConclusionOur data suggest that a cutoff of >4 abnormal nodes on mid-treatment AUS is associated with residual disease post-NAST. If our findings are substantiated by subsequent analyses, then mid-treatment AUS could be used to identify patients unlikely to achieve nodal pathologic complete response and who should be offered alternative therapy.
| S-EPMC7534548 | biostudies-literature
Project description:BackgroundChemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels.MethodsA phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods.ResultsIn both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime.ConclusionsTaken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy.Trial registrationNCT00773695 . Registered 15 October 2008.
| S-EPMC6262977 | biostudies-literature