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Cancers Nov 2022Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of... (Review)
Review
AIM
Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM.
METHODS
A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool.
RESULTS
Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43-85%, I 0%) in a heavily pretreated population with asymptomatic BM (3 studies, = 96).
CONCLUSIONS
Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients.
PubMed: 36428705
DOI: 10.3390/cancers14225612 -
Frontiers in Oncology 2022Although dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab, has shown promising results in patients with HER2-positive breast cancer (BC), it is still unclear...
Pertuzumab combined with trastuzumab compared to trastuzumab in the treatment of HER2-positive breast cancer: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
Although dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab, has shown promising results in patients with HER2-positive breast cancer (BC), it is still unclear whether dual therapy will increase adverse effects (AEs) while ensuring the efficacy compared with trastuzumab monotherapy. We conducted a systematic review and meta-analysis to compare the efficacy and safety of combined therapy with monotherapy.
METHODS
A systematic search was performed to identify eligible randomized controlled trials (RCTs) that evaluated the administration of dual anti-HER2 therapy [pertuzumab plus trastuzumab or trastuzumab emtansine (T-DM1)] versus monotherapy (trastuzumab or T-DM1). The primary endpoints were overall survival (OS) and progression-free survival (PFS).
RESULTS
Fourteen RCTs (8,378 patients) were identified. Compared to monotherapy, dual therapy significantly improved the OS (HR = 0.77, 95% CI: 0.59-0.99) and PFS (HR = 0.74, 95% CI: 0.63-0.86) in advanced BC. In neoadjuvant therapy, dual blockade has a higher ORR rate than monotherapy. Grade 3 or higher febrile neutropenia, diarrhea, and anemia as well as heart failure were more frequently reported in dual therapy compared to monotherapy. No significant difference in serious AEs was observed between the two groups. In the subgroup analysis, compared to single-target therapy, dual-target therapy has higher OS and PFS rates in Asian patients with advanced therapy; however, total grade ≥3 AEs and serious AEs were significantly higher in the dual group in Asian patients.
CONCLUSIONS
Our study confirms that the combination of pertuzumab and trastuzumab therapy could substantially improve the outcome of patients with HER2-positive breast cancer and was well tolerated compared to trastuzumab monotherapy.
PubMed: 36249045
DOI: 10.3389/fonc.2022.894861 -
Cancers Sep 2022An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different... (Review)
Review
An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in breast cancer and to identify its correlation with the efficacy of different treatment regimens. A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted to identify studies exploring the association between HER2 ECD level and clinical outcomes among patients with breast cancer. Using the random effects models, pooled hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CI), were calculated for progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the objective response rate (ORR). Heterogeneity was further evaluated by subgroup and sensitivity analysis. Overall, 40 studies comprising 12,229 patients were included in this systematic review and meta-analysis. Elevated HER2 ECD levels were associated with worse PFS (HR 1.74, 95% CI 1.40−2.17; p < 0.001), and this effect was observed in patients treated with chemotherapy (HR 1.81, 95% CI 1.37−2.39; p < 0.001), endocrine therapy (HR 1.91, 95% CI 1.57−2.32; p < 0.001), and trastuzumab (HR 1.74, 95% CI 1.31−2.30; p < 0.001). However, this association was not present in patients treated with tyrosine kinase inhibitors (TKIs) (HR 1.44, 95% CI 0.85−2.43, p = 0.17). The HRs/ORs for an elevated HER2 ECD level for DFS, OS, and ORR were 2.73 (95% CI 2.17−3.42; p < 0.001), 2.13 (95% CI 1.77−2.57; p < 0.001), and 0.80 (95% CI 0.49−1.31; p = 0.381), respectively. An elevated sHER2 ECD was an unfavorable prognostic factor in breast cancer but did not affect the efficacy of tyrosine kinase inhibitors such as lapatinib. Detection of sHER2 ECD may be helpful for clinicians selecting the appropriate anti-HER2 therapy for patients with HER2-positive breast cancer.
PubMed: 36230471
DOI: 10.3390/cancers14194551 -
Cancer Treatment Reviews Dec 2022Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic... (Review)
Review
Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).
Topics: Humans; Triple Negative Breast Neoplasms; Bevacizumab; Poly(ADP-ribose) Polymerase Inhibitors; Network Meta-Analysis; B7-H1 Antigen; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Paclitaxel; Algorithms
PubMed: 36202026
DOI: 10.1016/j.ctrv.2022.102468 -
Journal of Cancer Research and... 2022Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently... (Meta-Analysis)
Meta-Analysis
Effectiveness and cost-effectiveness of trastuzumab emtansine in women with HER2-positive locally advanced or metastatic breast cancer: A systematic review and meta-analysis.
BACKGROUND
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently linked to DM1, a small molecule cytotoxin.
METHODS
We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. In addition, we systematically reviewed existing economic evaluations of T-DM1. An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Randomized controlled trials that compared T-DM1 with other active treatment agents were eligible for inclusion. In addition, studies that involved T-DM1 as one of the treatment comparators in an economic evaluation were included. Four trials with a total of 2462 participants were included in this meta-analysis.
RESULTS
Pooled results showed T-DM1 substantially improved overall survival (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.85; I = 0%) and progression-free survival (HR, 0.67; 95% CI, 0.52-0.85; I = 75%). In addition, T-DM1 showed greater association with severe thrombocytopenia and liver dysfunction than other regimens, but a lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and the overall quality was high.
CONCLUSIONS
T-DM1 is effective for the treatment of patients with HER2-positive metastatic breast cancer, and it demonstrates a tolerable safety profile compared with other active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cost-Benefit Analysis; Cytotoxins; Disease-Free Survival; Female; Humans; Immunoconjugates; Maytansine; Receptor, ErbB-2; Trastuzumab
PubMed: 36149162
DOI: 10.4103/jcrt.jcrt_1095_21 -
Medicine Aug 2022This systematic review and meta-analysis aimed to assess the efficacy of trastuzumab combined with chemotherapy for the treatment in HER2-positive advanced gastric... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and meta-analysis aimed to assess the efficacy of trastuzumab combined with chemotherapy for the treatment in HER2-positive advanced gastric cancer (HER2-PAGC).
METHODS
This systematic review and meta-analysis was designed using randomized controlled trials that compared trastuzumab in combination with chemotherapy and chemotherapy alone. A comprehensive search was conducted in the following databases from their inception onwards: PubMed, EMBASE, Cochrane Library, WANGFANG, and CNKI. We also searched other literature sources to avoid missing relevant studies. Two reviewers independently performed all record selection, data collection, and methodological assessments. Any confusion was resolved by discussion or referral to a third reviewer. If there were ample data from eligible studies, we performed a fixed-effects meta-analysis. Whenever this was not possible, we conducted a narrative synthesis.
RESULTS
Meta-analysis results showed that trastuzumab in combination with chemotherapy achieved better outcomes on response rate (trastuzumab plus CFC vs CFC: odds ratio [OR] = 1.56, 95% confidence interval [CI] [1.17-2.09], I2 = 0%, P < .003; trastuzumab plus OT vs OT: OR = 2.97, 95% CI [1.74-5.09], I2 = 0%, P < .0001; and trastuzumab plus CC vs CC: OR = 2.62, 95% CI [1.84-3.73], I2 = 0%, P < .0001), and disease control rate (trastuzumab plus CFC vs CFC: OR = 1.61, 95% CI [1.17-2.21], I2 = 0%, P = .004; trastuzumab plus OT vs OT: OR = 4.29, 95% CI [2.33-7.90], I2 = 0%, P < .0001; and trastuzumab plus CC vs CC: OR = 2.99, 95% CI [1.99-4.48], I2 = 0%, P < .0001). However, there were no significant differences in the adverse events.
CONCLUSIONS
The results of this study revealed that the efficacy of trastuzumab combined with chemotherapy was superior to that of chemotherapy alone for the treatment of HER2-PAGC. The 2 modalities showed similar safety profiles.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab
PubMed: 36042610
DOI: 10.1097/MD.0000000000029992 -
Biomedicines Aug 2022Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated... (Review)
Review
Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated by the epidermal growth factor. Intravenous and subcutaneous administration of trastuzumab have comparable clinical and pharmacological characteristics, but trastuzumab biosimilars are currently only available in intravenous form. Trastuzumab biosimilars are ultimately preferred by a proportion of patients, especially in cases where co-administration of other chemotherapeutic agents, such as trastuzumab and tucatinib, a small molecule of tyrosine kinase inhibitor, is required in patients with HER-positive metastatic breast cancer. Oncologists should be well-aware of the advantages of intravenously administered trastuzumab biosimilars over subcutaneous administration, certainly also taking into account the patient's preferences. Further cost-effectiveness analyses will be very important, along with expectations regarding successful concomitant subcutaneous administration of trastuzumab with other anticancer drugs, such as pertuzumab. This systematic review describes and analyzes the so-far published studies concerning the use of the available trastuzumab biosimilars in HER-positive early and metastatic breast cancer in terms of efficacy, safety, and cost-benefit ratio. An attempt was also made to draw some conclusions and to comment on future needs and perspectives.
PubMed: 36009592
DOI: 10.3390/biomedicines10082045 -
PharmacoEconomics - Open Jan 2023The introduction of human epidermal growth factor receptor 2 (HER2)-targeted treatment options, including dual HER2 blockade, has improved the prognosis for patients...
BACKGROUND
The introduction of human epidermal growth factor receptor 2 (HER2)-targeted treatment options, including dual HER2 blockade, has improved the prognosis for patients with HER2-positive breast cancer (BC) substantially. However, most of these treatments are administered via the intravenous (IV) route, which can present many challenges, such as long infusion and observation times, issues associated with repeated IV access, and increased strain on time and resources of medical centers and healthcare professionals. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO, F. Hoffmann-La Roche Ltd, Basel, Switzerland; PH FDC SC)) has been approved for use alongside chemotherapy for early-stage and metastatic HER2-positive BC.
OBJECTIVES
This systematic literature review was performed to identify evidence relating to time/resource use and resulting cost differences between SC and IV administration of oncology biologics in a hospital setting, and, ultimately, to inform economic modeling and associated health technology assessment of PH FDC SC.
METHODS
Electronic databases (Embase, MEDLINE, and EconLit) were searched on 9 April 2020. Additional hand searches were performed to identify publications not captured in the electronic database search. Publication screening and data extraction (study characteristics, participants, interventions, costs, and time/resource use) were carried out per the standard Cochrane review methodology. The quality of economic evidence of cost analyses was assessed using the 36-item checklist of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for submission of evidence (January 2015).
RESULTS
The database search identified 2,740 records, of which 237 underwent full text screening. Full text screening, prioritization of publications about patients with a cancer diagnosis, and the addition of four citations identified during the hand search resulted in 72 final included publications, relating to 71 unique studies. This included 40 publications that described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of HER2-positive BC, and 28 publications that described time/resource use and/or costs associated with rituximab SC versus IV administration for the treatment of non-Hodgkin's lymphoma/follicular lymphoma and diffuse large B-cell lymphoma. The majority of publications showed substantial time savings for preparation and administration of SC versus IV therapy, and cost savings associated with reductions in healthcare professional time and resource use for SC administration.
LIMITATIONS
There was a lack of consensus between publications regarding time and cost measurements. In addition, the search was limited to publications related to anticancer drugs; the majority of the studies included were performed in European countries.
CONCLUSIONS AND IMPLICATIONS
This review indicated a substantial body of evidence showing time/resource and cost savings of SC versus IV administration of oncology biologics in a hospital setting, which can be used to inform economic evaluations of PH FDC SC.
PubMed: 35996066
DOI: 10.1007/s41669-022-00361-3 -
Frontiers in Immunology 2022The optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear.
METHODS
We searched Web of Science, PubMed, and the Cochrane Central Register of Controlled Trials systematically to find out randomized controlled studies, up to January 2022, that compared different anti-HER2 regimens in the (neo)adjuvant setting. The primary endpoint was disease-free survival (DFS). We used a Bayesian statistical model to combine direct and indirect comparisons and used odds ratios (ORs) to pool effect sizes and performed the surface under the cumulative ranking area (SUCRA) curves to estimate the ranking probabilities of various regimens. For survival outcomes, we performed two parallel analyses, one based on data from both neoadjuvant and adjuvant studies and the other specific to adjuvant studies. All statistics were two-sided.
RESULTS
Fifteen studies were finally enrolled. Regarding DFS, the overall analysis indicated that the top two regimens for HER2-positive breast cancer were chemotherapy plus trastuzumab with lapatinib, and chemotherapy plus trastuzumab with pertuzumab (SUCAR of 81% and 79%, respectively), with the OR of 0.99 [95% confidence interval (CI), 0.59 to 1.54]; the parallel analysis specific to adjuvant trials indicated that the top two regimens were chemotherapy plus trastuzumab with sequential neratinib, and chemotherapy plus trastuzumab with pertuzumab (SUCRA of 80% and 76%, respectively), with the OR of 1.04 (95% CI, 0.63 to 1.73). The dual-target therapy that combines trastuzumab and pertuzumab showed the highest risk of inducing cardiac events, with an SUCRA of 92%.
CONCLUSIONS
Chemotherapy plus trastuzumab and pertuzumab might be the optimal regimen for HER2-positive breast cancer in improving the survival rate. However, the cardiotoxicity of this dual-target therapy should be taken care of.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Breast Neoplasms; Female; Humans; Network Meta-Analysis; Receptor, ErbB-2; Trastuzumab
PubMed: 35844533
DOI: 10.3389/fimmu.2022.919369 -
Metabolism: Clinical and Experimental Sep 2022Several anticancer agents have been associated with cardiac toxic effects. The currently proposed mechanisms to explain cardiotoxicity differ among anticancer agents,... (Review)
Review
Several anticancer agents have been associated with cardiac toxic effects. The currently proposed mechanisms to explain cardiotoxicity differ among anticancer agents, but in fact, the specific modulation is not completely elucidated. Thus, this systematic review aims to provide an integrative perspective of the molecular mechanisms underlying the toxicity of anticancer agents on heart muscle while using a high-throughput technology, mass spectrometry (MS)-based proteomics. A literature search using PubMed database led to the selection of 27 studies, of which 13 reported results exclusively on animal models, 13 on cardiomyocyte-derived cell lines and only one included both animal and a cardiomyocyte line. The reported anticancer agents were the proteasome inhibitor carfilzomib, the anthracyclines daunorubicin, doxorubicin, epirubicin and idarubicin, the antimicrotubule agent docetaxel, the alkylating agent melphalan, the anthracenedione mitoxantrone, the tyrosine kinase inhibitors (TKIs) erlotinib, lapatinib, sorafenib and sunitinib, and the monoclonal antibody trastuzumab. Regarding the MS-based proteomic approaches, electrophoretic separation using two-dimensional (2D) gels coupled with tandem MS (MS/MS) and liquid chromatography-MS/MS (LC-MS/MS) were the most common. Overall, the studies highlighted 1826 differentially expressed proteins across 116 biological processes. Most of them were grouped in larger processes and critically analyzed in the present review. The selection of studies using proteomics on heart muscle allowed to obtain information about the anticancer therapy-induced modulation of numerous proteins in this tissue and to establish connections that have been disregarded in other studies. This systematic review provides interesting points for a comprehensive understanding of the cellular cardiotoxicity mechanisms of different anticancer drugs.
Topics: Animals; Antineoplastic Agents; Cardiotoxicity; Chromatography, Liquid; Proteomics; Tandem Mass Spectrometry
PubMed: 35809654
DOI: 10.1016/j.metabol.2022.155250