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Frontiers in Oncology 2020Intracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+...
BACKGROUND
Intracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+ BC). Stereotactic radiosurgery (SRS) has been increasingly used as the local therapy for brain metastases in breast cancer patients. Increased objective response rate was observed for lapatinib plus whole brain radiotherapy (WBRT) is such patients with high toxicity.
OBJECTIVE
We seek to obtain clinical evidence of synergistic efficacy of lapatinib in combination with radiation therapy, in particular, SRS.
MATERIALS AND METHODS
We carried out a comprehensive research using the following databases: PubMed; Medline; EMBASE; Cochrane library. These databases were searched until 10 June 2020. PRISMA guidelines were followed step by step for carrying out this systematic review and meta-analysis. Review Manager v 5.4 software was used for statistical evaluation of data.
RESULTS
Overall 6 studies with 843 HER-2 positive breast cancer patients (442 HER-2 amplified disease, 399 luminal B disease) were included in this systematic review and meta-analysis. A total 279 patients had received lapatinib in addition to HER-2 antibody (trastuzumab) plus/minus chemoradiotherapy, while 610 patients had received trastuzumab-based management or only chemoradiotherapy. Lapatinib-based management of BM was associated with significant increase in overall survival (HR 0.63 [0.52, 0.77], p < 0.00001). Combination of the two (trastuzumab plus lapatinib) was associated with increased survival advantage compared to each agent alone (0.55 [0.32, 0.92], p = 0.02). SRS in combination with lapatinib was associated with increased local control (HR 0.47 [0.33, 0.66], p = 0.0001). Ever use of lapatinib with SRS was associated an increased survival as reported in two studies (Shireen et al.: 27.3 vs. 19.5 months, p = 0.03; Kim et al.: 33.3 vs. 23.6 months, p = 0.009). Kim et al. also revealed significant increase in intracranial activity with concurrent lapatinib reporting 57% complete response compared to 38% (p < 0.001) and lower progressive disease rate of 11 vs. 19% (p < 0.001). Risk of radiation necrosis was decreased with lapatinib use.
CONCLUSIONS
Lapatinib has shown intracranial activity and yielded better survival for HER-2+ BC patients with BMs. SRS in combination with ever use of lapatinib had better local control and were associated with better survival. Radiation necrosis risk was reduced with the use of lapatinib.
PubMed: 33240815
DOI: 10.3389/fonc.2020.576926 -
Breast (Edinburgh, Scotland) Dec 2020One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be... (Meta-Analysis)
Meta-Analysis
One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be associated with reduced costs and side effects. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant trastuzumab are not consistent and have not been systematically reviewed using a non-inferiority meta-analysis approach. We conducted a systematic review and meta-analysis of randomized trials to assess whether a shorter duration of adjuvant trastuzumab was non-inferior to one year of treatment or not. The non-inferiority margin for the meta-analysis was pre-defined as the median of the margins of all the trials included. Data of 11,376 patients from 5 trials were analyzed. Non-inferiority margins in included studies varied from 1.15 to 1.53 with median of 1.29 for HR of DFS. A shorter duration of trastuzumab was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03-1.24) but inconclusive for OS (HR 1.14, 95%CI 1.00-1.30). In a subgroup analysis for DFS outcome, shorter therapy was non-inferior in patients with ER positive disease (HR 1.10, 95%CI 0.95-1.28) and those with sequential therapy (HR 0.97, 95%CI 0.75-1.27) and when the duration of treatment was 6 months (HR 1.09, 95%CI 0.98-1.22). Although a shorter duration of adjuvant trastuzumab was non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer based on our HR margin of 1.29, any benefit of a shorter duration comes at a loss of efficacy with an increase in absolute risk up to 3.9% for 5 year DFS. Whether the potential increased risk is clinically acceptable for the benefits of a shorter duration remains debatable.
Topics: Adult; Aged; Antineoplastic Agents, Immunological; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Equivalence Trials as Topic; Female; Humans; Middle Aged; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Time Factors; Trastuzumab; Treatment Outcome
PubMed: 33130486
DOI: 10.1016/j.breast.2020.10.003 -
Strahlentherapie Und Onkologie : Organ... Jan 2021Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk...
PURPOSE
Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk settings. We reviewed the evidence for sequencing of postoperative radiation and chemotherapy, with a focus on a capecitabine and trastuzumab emtansine (T-DM1)-based regimen.
METHODS
A systematic literature search using the PubMed/MEDLINE/Web of Science database was performed. We included prospective and retrospective reports published since 2015 and provided clinical data on toxicity and effectiveness.
RESULTS
Six studies were included, five of which investigated capecitabine-containing regimens. Of these, four were prospective investigations and one a retrospective matched comparative analysis. One randomized prospective trial was found for T‑DM1 and radiotherapy. In the majority of these reports, radiation-associated toxicities were not specifically addressed.
CONCLUSION
Regarding oncologic outcome, the influence of sequencing radiation therapy with maintenance capecitabine chemotherapy in the post-neoadjuvant setting is unclear. Synchronous administration of capecitabine is feasible, but reports on possible excess toxicities are partially conflicting. Dose reduction of capecitabine should be considered, especially if normofractionated radiotherapy is used. In terms of tolerance, hypofractionated schedules seem to be superior in terms of toxicity in concurrent settings. T‑DM1 can safely be administered concurrently with radiotherapy.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cardiomyopathies; Clinical Trials as Topic; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Multicenter Studies as Topic; Neoadjuvant Therapy; Prospective Studies; Retrospective Studies; Triple Negative Breast Neoplasms
PubMed: 32737515
DOI: 10.1007/s00066-020-01667-z -
Translational Cancer Research Aug 2020ERBB2 aberrations are oncogenic alterations in lung cancer. However, the reported therapeutic efficacy of ado-trastuzumab emtansine (T-DM1) varied. We therefore...
BACKGROUND
ERBB2 aberrations are oncogenic alterations in lung cancer. However, the reported therapeutic efficacy of ado-trastuzumab emtansine (T-DM1) varied. We therefore evaluated the efficacy and safety of T-DM1 in treating different types of ERBB2 aberrations.
METHODS
We conducted a systematic search for original articles and meeting abstracts about ERBB2-aberrant lung cancer treating with T-DM1 in PubMed and EMBASE databases from inception to June, 2020. Statistical analysis was carried out in R software.
RESULTS
A total of 120 patients with various ERBB2 aberrations were identified in five studies. ERBB2 upregulation (gene amplification and/or protein overexpression) was more common in smokers with adenocarcinoma, whereas mutations were more common in female non-smokers with adenocarcinoma. The overall objective response rate (ORR) for ERBB2 aberrations was 29% [95% confidence interval (CI): 15-56%]. Subgroup analysis showed an ORR of 41% (95% CI: 11-70%) for ERBB2 gene mutation, 66% (95% CI: 11-100%) for ERBB2 gene amplification, and 3% (95% CI: 0-9%) for ERBB2 protein overexpression. Notably, the ORR was 44% (95% CI: 25-63%) upon concomitant ERBB2 upregulation and mutation. Furthermore, the ORR was 26% (95% CI: 0-54%) for protein overexpression plus gene mutation but up to 80% (95% CI: 50-100%) for triple aberrations: gene amplification plus protein overexpression and gene mutation.
CONCLUSIONS
Collectively, T-DM1 might be a critical agent targeting ERBB2 mutated or/and amplified lung cancers.
PubMed: 35117816
DOI: 10.21037/tcr-19-2759 -
Therapeutic Advances in Drug Safety 2020Trastuzumab emtansine (T-DM1) is an anti-HER2 antibody-drug conjugate indicated for the treatment of HER2-positive breast cancer. One of the most severe adverse events...
BACKGROUND
Trastuzumab emtansine (T-DM1) is an anti-HER2 antibody-drug conjugate indicated for the treatment of HER2-positive breast cancer. One of the most severe adverse events reported with T-DM1 is hepatotoxicity. The objective of our meta-analysis is to investigate the risk of hepatic adverse events in patients with breast cancer receiving T-DM1 compared with controls.
METHODS
We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing T-DM1 with a control treatment in patients with HER2-positive breast cancer. Phase II/III RCTs with available event number or event rate of hepatic toxicity with an assessable sample size were included. Relative risk (RR) and corresponding 95% confidence intervals (CI) for all grade and high-grade (grade 3/4) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were calculated.
RESULTS
Seven RCTs were deemed eligible and were included in the meta-analysis. The RR for all-grade AST and ALT elevations were 3.24 (95% CI 2.16-4.86; < 0.00001) and 2.90 (95% CI 1.98-4.23; < 0.00001), respectively. The RR for high-grade AST and ALT elevations were 2.73 (95% CI 1.07-6.93; = 0.03) and 2.17 (95% CI 1.34-3.50; = 0.002), respectively.
CONCLUSIONS
Our meta-analysis demonstrates that T-DM1-based therapy is associated with an increased risk of AST and ALT elevations.
PubMed: 32341779
DOI: 10.1177/2042098620915058 -
Annals of Translational Medicine Mar 2020Although trastuzumab has been shown to be beneficial for treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, information...
BACKGROUND
Although trastuzumab has been shown to be beneficial for treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, information regarding its benefits is limited to very low-risk cases with tumours ≤1 cm and without lymphatic metastases (pT1abN0). The present meta-analysis integrates information from literature and determines the benefit of trastuzumab in pT1abN0, HER2-positive breast cancer patients.
METHODS
PubMed, MEDLINE, and EMBASE databases were searched for studies published before Sep 30, 2019. Our primary endpoint was tumor recurrence, whether provided as overall or distant recurrences.
RESULTS
Seven studies involving 1,181 patients with pT1abN0, HER2-positive breast cancer were included in the systemic review. The median follow-up periods ranged from 37 to 78 months. The patients in the trastuzumab arm had generally inferior profiles such as higher rate of T1b, grade 3, and hormone negative cases, among available studies. Concomitant chemotherapy was more commonly applied in the trastuzumab arm (75-100% 0-42%), and the hormone therapy application was similar in both arms (20-66%). In a pooled analysis of seven available studies, patients treated with trastuzumab had less overall recurrence relative to controls, with an odds ratio of 0.201 [95% confidence interval (CI): 0.100-0.404, P<0.001]. Five studies were available for a pooled analysis of distant recurrence. Although the results were not significant (P=0.115), distant recurrence did not occur in 237 patients treated with trastuzumab, but did occur in 16 out of 436 control patients. The odds ratio for distant recurrence was 0.328 (95% CI: 0.082-1.311).
CONCLUSIONS
The adjuvant treatment including trastuzumab was shown to reduce overall recurrence. Distant recurrence may also be reduced, as it did not occur among the 237 patients who underwent trastuzumab treatment.
PubMed: 32309334
DOI: 10.21037/atm.2020.01.81 -
Frontiers in Oncology 2020Both 12 and 6 months of trastuzumab in combination with chemotherapy are effective for HER2+ early-stage breast cancer. This meta-analysis was performed to assess the...
Both 12 and 6 months of trastuzumab in combination with chemotherapy are effective for HER2+ early-stage breast cancer. This meta-analysis was performed to assess the effectiveness and the toxicity of the two durations. We acquired relevant randomized controlled trials (RCTs) from PubMed, the Cochrane Library, ScienceDirect, EMBASE, Ovid MEDLINE, Web of Science, Scopus, and Google Scholar. Our endpoints included disease-free survival (DFS), overall survival (OS), number of recurrences, mortality and early stopping of trastuzumab, and adverse events (AEs). We included five good-quality studies. Both durations of trastuzumab were effective among women with HER2+ early-stage breast cancer, but 12 months of trastuzumab appeared to have better DFS [hazard ratio (HR) = 1.10, 95% confidence interval (CI): 0.99-1.23, = 0.09] and better OS than 6 months of trastuzumab (HR = 1.14, 95% CI: 0.99-1.32, = 0.07). However, the 12 month group had more AEs, especially cardiac events [risk ratio (RR) = 0.66, 95% CI: 0.56-0.77, < 0.00001]. In our sub-analyses, the 12 months duration had better DFS among patients using trastuzumab concurrently than the 6 months duration (HR = 1.23, 95% CI: 1.06-1.44, = 0.006). Additionally, the 12 months duration had superior OS in women with ER-negative breast cancer (HR = 1.51, 95% CI: 1.10-2.08, = 0.01) and patients treated with trastuzumab concurrently than the 6 months duration (HR = 1.61, 95% CI: 1.13-2.29, = 0.008). Twelve months was the standard duration of adjuvant trastuzumab among patients with HER2+ early-stage breast cancer, with a tendency toward superior survival. However, patients in the 12 month group had more significant cardiac toxicity than those in the 6 month group.
PubMed: 32266131
DOI: 10.3389/fonc.2020.00288 -
Journal of Oncology 2020Although trastuzumab is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)- positive early breast cancer (EBC), drug resistance and...
Dual HER2 Blockade versus a Single Agent in Trastuzumab-Containing Regimens for HER2-Positive Early Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
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, =0.0003) and OS (HR 0.86, =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, =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, =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 (=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.
PubMed: 32256583
DOI: 10.1155/2020/5169278 -
Breast Cancer Research and Treatment Apr 2020In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously... (Meta-Analysis)
Meta-Analysis
Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.
PURPOSE
In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC).
METHODS
Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints.
RESULTS
The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators.
CONCLUSIONS
The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Molecular Targeted Therapy; Network Meta-Analysis; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome
PubMed: 32100144
DOI: 10.1007/s10549-020-05577-7 -
ESMO Open Feb 2020Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question.
MATERIALS AND METHODS
A meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting.
RESULTS
Clinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias.
CONCLUSIONS
Compared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.
Topics: Antineoplastic Agents, Immunological; Cardiotoxicity; Clinical Trials as Topic; Humans; Time Factors; Trastuzumab
PubMed: 32079624
DOI: 10.1136/esmoopen-2019-000659