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Scientific Reports Jan 2022Epidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in various malignancies. Lapatinib is a dual tyrosine kinase inhibitor that...
Epidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in various malignancies. Lapatinib is a dual tyrosine kinase inhibitor that inhibits both EGFR and HER2. Although a phase III trial failed to show the survival benefits of lapatinib treatment after first-line chemotherapy in patients with EGFR/HER2-positive metastatic urothelial carcinoma, the efficacy of lapatinib for untreated urothelial carcinoma is not well defined. Here, we describe the therapeutic efficacy of lapatinib as a first-line treatment in a canine model of muscle-invasive urothelial carcinoma. In this non-randomized clinical trial, we compared 44 dogs with naturally occurring urothelial carcinoma who received lapatinib and piroxicam, with 42 age-, sex-, and tumor stage-matched dogs that received piroxicam alone. Compared to the dogs treated with piroxicam alone, those administered the lapatinib/piroxicam treatment had a greater reduction in the size of the primary tumor and improved survival. Exploratory analyses showed that HER2 overexpression was associated with response and survival in dogs treated with lapatinib. Our study suggests that lapatinib showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use for untreated advanced urothelial carcinoma in dogs. The use of lapatinib as a first-line treatment may be investigated further in human patients with urothelial carcinoma.
Topics: Animals; Antineoplastic Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Lapatinib; Male; Muscles; Piroxicam; Protein Kinase Inhibitors; Receptor, ErbB-2; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 35027594
DOI: 10.1038/s41598-021-04229-0 -
Journal of Translational Medicine Oct 2022Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that...
BACKGROUND
Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that highly correlated with the prognosis of tumors. However, the prognostic value of pyroptosis in PAAD remains unclear.
METHODS
A total of 178 pancreatic cancer PAAD samples and 167 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The "DESeq2" R package was used to identify differntially expressed pyroptosis-related genes between normal pancreatic samples and PAAD samples. The prognostic model was established in TCGA cohort based on univariate Cox and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, which was validated in test set from Gene Expression Omnibus (GEO) cohort. Univariate independent prognostic analysis and multivariate independent prognostic analysis were used to determine whether the risk score can be used as an independent prognostic factor to predict the clinicopathological features of PAAD patients. A nomogram was used to predict the survival probability of PAAD patients, which could help in clinical decision-making. The R package "pRRophetic" was applied to calculate the drug sensitivity of each samples from high- and low-risk group. Tumor immune infiltration was investigated using an ESTIMATE algorithm. Finally, the pro-tumor phenotype of GSDMC was explored in PANC-1 and CFPAC-1 cells.
RESULT
On the basis of univariate Cox and LASSO regression analyses, we constructed a risk model with identified five pyroptosis-related genes (IL18, CASP4, NLRP1, GSDMC, and NLRP2), which was validated in the test set. The PAAD samples were divided into high-risk and low-risk groups on the basis of the risk score's median. According to Kaplan Meier curve analysis, samples from high-risk groups had worse outcomes than those from low-risk groups. The time-dependent receiver operating characteristics (ROC) analysis revealed that the risk model could predict the prognosis of PAAD accurately. A nomogram accompanied by calibration curves was presented for predicting 1-, 2-, and 3-year survival in PAAD patients. More importantly, 4 small molecular compounds (A.443654, PD.173074, Epothilone. B, Lapatinib) were identified, which might be potential drugs for the treatment of PAAD patients. Finally, the depletion of GSDMC inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells.
CONCLUSION
In this study, we developed a pyroptosis-related prognostic model based on IL18, CASP4, NLRP1, NLRP2, and GSDMC , which may be helpful for clinicians to make clinical decisions for PAAD patients and provide valuable insights for individualized treatment. Our result suggest that GSDMC may promote the proliferation and migration of PAAD cell lines. These findings may provide new insights into the roles of pyroptosis-related genes in PAAD, and offer new therapeutic targets for the treatment of PAAD.
Topics: Adenocarcinoma; Biomarkers, Tumor; DNA-Binding Proteins; Epothilones; Gene Expression Regulation, Neoplastic; Humans; Interleukin-18; Lapatinib; Pancreatic Neoplasms; Pore Forming Cytotoxic Proteins; Prognosis; Pyroptosis
PubMed: 36199146
DOI: 10.1186/s12967-022-03632-z -
Neuro-oncology Mar 2021No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its...
BACKGROUND
No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.
METHODS
Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected.
RESULTS
The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.
CONCLUSIONS
This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
Topics: Adolescent; Adult; Brain Neoplasms; Dacarbazine; Disease-Free Survival; Ependymoma; Humans; Lapatinib; Prospective Studies; Spinal Cord Neoplasms; Temozolomide
PubMed: 33085768
DOI: 10.1093/neuonc/noaa240 -
Journal of Clinical Oncology : Official... Sep 2020NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase... (Comparative Study)
Comparative Study Randomized Controlled Trial
Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.
PURPOSE
NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.
METHODS
Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).
RESULTS
A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% 29.2%; 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; .0004). The most common all-grade adverse events were diarrhea (N+C 83% L+C 66%) and nausea (53% 42%). Discontinuation rates and HRQoL were similar between groups.
CONCLUSION
N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Breast Neoplasms, Male; Capecitabine; Diarrhea; Female; Humans; Kaplan-Meier Estimate; Lapatinib; Male; Middle Aged; Nausea; Progression-Free Survival; Quality of Life; Quinolines; Receptor, ErbB-2; Retreatment; Survival Rate
PubMed: 32678716
DOI: 10.1200/JCO.20.00147 -
Clinical Cancer Research : An Official... Feb 2021Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC.
EXPERIMENTAL DESIGN
Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2 (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry-based protocols.
RESULTS
Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy ( = 0.03) and associated with trastuzumab response ( = 0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC , but it did not consistently correlate with HER2 expression in HER2 or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone.
CONCLUSIONS
TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.
Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Killer Cells, Natural; Lapatinib; MCF-7 Cells; Middle Aged; Neoadjuvant Therapy; Protein Kinase Inhibitors; RNA-Seq; Receptor, ErbB-2; Trastuzumab; Young Adult
PubMed: 33122343
DOI: 10.1158/1078-0432.CCR-20-2007 -
Annals of Oncology : Official Journal... Jun 2007Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in... (Review)
Review
Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in HER2-overexpressing breast cancers and, at present, is currently approved for patients whose tumours have this abnormality, in both the metastatic and the adjuvant setting. Several issues about its optimal use, however, are still unresolved. One of the reasons for these uncertainties lies in the absence of conclusive data about its mechanism of action and possible primary or acquired resistance mechanisms. Therefore, clinical questions such as how to optimize patient selection, how to prevent resistance to trastuzumab, or what is the optimal management of those patients whose tumours progress during treatment still await convincing answers. This review summarises the current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance and also briefly discusses their possible clinical implications.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Gefitinib; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Lapatinib; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab
PubMed: 17229773
DOI: 10.1093/annonc/mdl475 -
Bioengineered Jan 2022Lapatinib (LAP) is an important anti-cancer drug and is frequently alongside doxorubicin (DOX) as a combination therapy for better anti-cancer efficacy. However, many...
Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway.
Lapatinib (LAP) is an important anti-cancer drug and is frequently alongside doxorubicin (DOX) as a combination therapy for better anti-cancer efficacy. However, many studies have reported that LAP in combination with DOX may induce highly cardiotoxicity. Accordingly, we aimed to explore the potential mechanism involved in the synergistic effect of LAP in DOX-induced cardiotoxicity. Here, cell counting kit-8 was used to detect cell viability and lactate dehydrogenase measurement was performed to assess cell injury. Cell apoptosis was evaluated by TUNEL assay and western blot assay. Mitochondrial dysfunction was identified by JC-1 assay, adenosine triphosphate (ATP) and Cytochrome C. Moreover, the activity of ROS, SOD, CAT and GSH were measured to elucidate oxidative stress level. Ferroptosis was examined by levels of Fe, GPX4 and ASCL4. Expressions of PI3K/AKT signaling were identified by western blot assay. The results revealed that LAP inhibited the cell viability and exacerbated cell injury induced by Dox, as well as increased cell apoptosis. LAP aggravated DOX-induced mitochondria damage by changed mitochondrial membrane potential, decreased ATP and increased level of Cytochrome C. In addition, the combination of LAP and DOX induced oxidative stress and ferroptosis in H9c2 cells. The activation of PI3K/AKT signaling reversed the detrimental effects of LAP on DOX-induced H9c2 cells. The data in this study showed for the first time that LAP aggravated Dox-induced cardiotoxicity by promoting oxidative stress and ferroptosis in cardiomyocytes via PI3K/AKT-mediated mitochondrial dysfunction, suggesting that PI3K/AKT activation is a promising cardioprotective strategy for DOX /LAX combination therapies.
Topics: Animals; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Ferroptosis; Gene Expression Regulation; Lapatinib; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction
PubMed: 34898356
DOI: 10.1080/21655979.2021.2004980 -
JAMA Oncology Apr 2023Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR)... (Comparative Study)
Comparative Study Randomized Controlled Trial
Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials.
IMPORTANCE
Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known.
OBJECTIVE
To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022.
MAIN OUTCOMES AND MEASURES
Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses.
RESULTS
The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature-adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99).
CONCLUSIONS AND RELEVANCE
Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.
Topics: Adult; Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Immunoglobulin G; Lapatinib; Lymphocytes, Tumor-Infiltrating; Neoadjuvant Therapy; Prognosis; Receptor, ErbB-2; Transcriptome; Trastuzumab; Treatment Outcome; Gene Expression Profiling; Randomized Controlled Trials as Topic; Paclitaxel
PubMed: 36602784
DOI: 10.1001/jamaoncol.2022.6288 -
Systematic Reviews Dec 2022Trastuzumab, as the gold standard for HER2-positive BC treatment, was the first-line HER2 targeted drug. However, some studies reported patients benefited more from... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Trastuzumab, as the gold standard for HER2-positive BC treatment, was the first-line HER2 targeted drug. However, some studies reported patients benefited more from lapatinib and lapatinib plus trastuzumab therapy than standard trastuzumab therapy. This study presents an update of a systematic review and meta-analysis involving comparison of lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy.
AIM
We determined whether trastuzumab plus lapatinib or lapatinib therapy is not inferior to trastuzumab therapy in HER2-positive breast cancer patients.
METHODS
Relevant trials were searched in CNKI, Wanfang, VIP, Sinomed, PubMed, Embase, and Cochrane CENTRAL databases from inception until October 25, 2021. Primary outcomes were OS, DFS/EFS, and PFS while secondary outcomes were pCR (ypT0/is ypN0), pCR (ypT0/is ypN0/+), ORR, DCR, rate of BCS, RFS, cardiac toxicities, and other toxicities.
RESULTS
Thirteen randomized controlled trials were included in this study. Trastuzumab combined with lapatinib therapy was found to be superior to standard trastuzumab therapy alone with regard to overall survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0), pathologic complete response (ypT0/is ypN0/+), recurrence-free survival, higher incidences of diarrhea, and rash/skin toxicity. Lapatinib therapy was established to be inferior to trastuzumab therapy in overall survival, progression-free survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0) and pathologic complete response (ypT0/is ypN0/+), diarrhea, and rash/skin toxicity and had a low incidence of left ventricular ejection fraction decline.
CONCLUSIONS
The efficacy of trastuzumab combined with lapatinib therapy is superior to standard trastuzumab therapy alone; however, it has more non-cardiac grade III/IV toxicities. Moreover, the efficacy of lapatinib therapy is inferior to that of standard trastuzumab therapy alone.
Topics: Humans; Female; Trastuzumab; Lapatinib; Breast Neoplasms; Receptor, ErbB-2; Stroke Volume; Antineoplastic Combined Chemotherapy Protocols; Ventricular Function, Left; Randomized Controlled Trials as Topic
PubMed: 36496473
DOI: 10.1186/s13643-022-02134-9 -
BMJ Open Mar 2017The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour actively in... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour actively in models of HER2-positive breast cancer. However, the efficacy of trastuzumab in combination with lapatinib remains controversial. Therefore, we conducted this meta-analysis to compare combination treatment with lapatinib and trastuzumab to trastuzumab or lapatinib alone in the treatment of HER2-positive breast cancer.
METHODS
Randomised controlled trials (RCTs), published in PubMed, Embase and Web of Science, were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with breast cancer who were treated with lapatinib and trastuzumab. Outcomes included pathological complete response (pCR), event-free survival (EFS), overall survival (OS) and toxicities. Results were expressed as the risk ratio (RR) or HR with 95% CIs. Pooled estimates were calculated by using a fixed-effects model or a randomised-effects model.
RESULTS
A total of 7 RCTs involving 2084 patients met the inclusion criteria and were included in this meta-analysis. The combination of lapatinib and trastuzumab significantly improved pCR (RR=1.43, 95% CI 1.23 to 1.67; p<0.001), EFS (HR=0.75, 95% CI 0.60 to 0.93; p=0.009) and OS (HR=0.72, 95% CI 0.56 to 0.93; p=0.011) in the treatment of HER2-positive breast cancer compared with trastuzumab or lapatinib alone. The combination treatment also increased the pCR irrespective of hormone receptor status and tumour size. More frequent grade 3 or 4 adverse events, including diarrhoea, rash or erythema, neutropenia and hepatic adverse events, were found in the combination group than in the trastuzumab or lapatinib group.
CONCLUSIONS
On the basis of the current evidence, our results reveal that the addition of lapatinib to trastuzumab can significantly improve pCR, EFS and OS with a tolerated toxicity in patients with HER2-positive breast cancer. Further well-conducted, large-scale trials are needed to validate these findings.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Female; Humans; Lapatinib; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Receptor, ErbB-2; Trastuzumab
PubMed: 28289045
DOI: 10.1136/bmjopen-2016-013053