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REVIEW ARTICLE
Incidence of central nervous system metastases in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with trastuzumab: A meta-analysis
Xue Bai
Corresponding author
baixue_pla@163.com

Corresponding author.
, Xue Lin, Jin Song, Jia-han Chang, Li-li Han, Cibo Fan
Medical Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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    "titulo" => "Incidence of central nervous system metastases in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with trastuzumab&#58; A meta-analysis"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Forest graph showing the results of the meta-analysis of the incidence rate of CNS metastases in patients with HER2-positive MBC treated with and without trastuzumab&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Breast cancer is the second leading cause of cancer-related deaths in women&#44; with a mortality rate of 2&#46;6&#37; in female patients &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; It accounts for 15&#46;3&#37; of all new cancer cases and 7&#37; of all cancer mortalities&#46; It is estimated that approximately 13&#37; of women will be diagnosed with breast cancer during their lifetime &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; Although the prognosis of breast cancer has improved&#44; it is also associated with an increased risk of metastases in the central nervous system &#40;CNS&#41;&#44; especially in the brain&#46; Among women with metastatic breast cancer &#40;MBC&#41;&#44; 15&#37; to 30&#37; develop CNS metastases&#44; which are associated with poor survival and neurological impairment &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Generally&#44; CNS metastases develop late in the disease course&#44; usually after the appearance of systemic metastases&#44; and many cases remain underdiagnosed&#46; Studies have shown that up to 30&#37; of patients with breast cancer have undiagnosed CNS diseases &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">The risk factors for the development of brain metastases include young age&#44; high-grade tumors&#44; negative hormone receptor status&#44; more than four lymph node metastases&#44; and human epidermal growth factor receptor-2 &#40;HER2&#41; positivity &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Progression to the CNS is also frequent in MBC patients with <span class="elsevierStyleItalic">BRCA</span> mutations&#44; especially <span class="elsevierStyleItalic">BRCA2</span> mutations &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#46; Approximately 20&#37; of women with breast cancer have a HER2-positive status&#44; which is associated with a poor prognosis &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Patients with overexpressing HER2 breast cancer have an increased risk of developing CNS metastases &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">The management of breast cancer usually involves multidisciplinary treatments&#44; including surgical interventions&#44; radiotherapy&#44; radiosurgery&#44; and systemic treatments&#46; The use of combination drugs and development of novel delivery systems have also improved in recent years &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46; Systemic therapies with cytotoxic and hormonal agents and biologically targeted therapies are the core treatment options for patients with MBC &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; Immunotherapies also have a promising role in the treatment of MBC&#44; especially in triple-negative and HER2-positive tumors &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">Trastuzumab is a HER2-targeted humanized monoclonal antibody&#46; It has been found to be efficacious for HER2-positive MBC and to be beneficial even after the progression of cancer &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46; Trastuzumab was approved for the treatment of HER2-positive MBC in 1998 in the United States and in 2000 in Europe&#46; Later&#44; it was also approved for use as an adjuvant therapy in 2006 and as a neoadjuvant therapy in 2011 &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46; Trastuzumab emtansine is formed by the combination of trastuzumab linked with a cytotoxic component comprising a maytansine-derivative microtubule inhibitory agent called mertansine or DM1 &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Although trastuzumab treatment improves the survival outcomes of patients with breast cancer&#44; it has been found to be associated with an increased risk of CNS metastases&#46; Many studies have reported the incidence of CNS metastases in patients with MBC during trastuzumab treatment&#59; however&#44; the magnitude of the incidence substantially varies across the studies&#46; Therefore&#44; we performed a systematic review to identify studies reporting the incidence of CNS metastases in patients with HER2-positive MBC treated with trastuzumab and conducted meta-analyses of CNS metastasis incidence and survival rates to obtain refined estimates&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Ethics</span><p id="para60" class="elsevierStylePara elsevierViewall">All analyses were based on previously published studies&#59; thus&#44; no ethical approval or patient consent was required&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Inclusion and exclusion criteria</span><p id="para70" class="elsevierStylePara elsevierViewall">The inclusion criteria for the studies were as follows&#58; &#40;a&#41; evaluating the outcomes of trastuzumab therapy either alone or with other therapies in HER2-positive MBC patient cohorts&#44; &#40;b&#41; reporting the incidence of CNS metastases in trastuzumab-treated patients&#44; &#40;c&#41; comparing the incidence of CNS metastases between trastuzumab-treated patients and patients treated with non-trastuzumab regimens&#44; and &#40;d&#41; reporting the survival outcomes of patients with HER2-positive MBC treated with trastuzumab&#46; The exclusion criteria were as follows&#58; &#40;a&#41; recruiting all patients with CNS metastases at baseline&#44; &#40;b&#41; reporting the CNS metastasis incidence in patients with MBC treated with more than one regimen without differentiating the outcomes of each treatment&#44; &#40;c&#41; reporting baseline CNS metastases but not the incidence during the study&#44; and &#40;d&#41; case reports&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Literature search</span><p id="para80" class="elsevierStylePara elsevierViewall">A literature search was conducted in electronic databases &#40;Google Scholar&#44; Ovid&#44; PubMed&#44; and Science Direct&#41;&#46; The key terms used were &#8220;breast cancer&#44;&#8221; &#8220;carcinoma&#44;&#8221; &#8220;metastatic&#44;&#8221; &#8220;metastasis&#44;&#8221; &#8220;trastuzumab&#44;&#8221; &#8220;brain metastases&#44;&#8221; &#8220;central nervous system metastases&#44;&#8221; &#8220;incidence&#44;&#8221; &#8220;progressive&#44;&#8221; &#8220;progression&#44;&#8221; &#8220;recurrence&#44;&#8221; &#8220;response&#44;&#8221; &#8220;survival&#44;&#8221; and &#8220;efficacy&#46;&#8221; The bibliographies of important research and review articles were also screened&#46; The literature search encompassed original research articles published in English before October 2020&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">Data extraction&#44; synthesis&#44; and statistical analysis</span><p id="para90" class="elsevierStylePara elsevierViewall">Demographic data&#44; study design&#44; molecular characteristics&#44; treatment and control regimens&#44; follow-up duration&#44; treatment duration&#44; prior therapies&#44; cancer stage&#44; performance status&#44; baseline CNS metastases&#44; CNS metastasis incidence&#44; treatment response&#44; and survival data were extracted from the included studies&#46; Publication bias was assessed with Begg&#39;s test using Kendall&#39;s rank correlation coefficients between the effect estimates and their variances&#46;</p><p id="para100" class="elsevierStylePara elsevierViewall">To estimate the incidence of CNS metastases&#44; a meta-analysis of proportions was performed with Stata software &#40;Stata Corporation&#44; College Station&#44; TX&#44; USA&#41; using binomial data reported by the individual studies&#46; For variance stabilization&#44; the Freeman-Tukey double arcsine transformation of proportions was incorporated using the exact binomial method&#46; The median overall survival times of trastuzumab-treated and control patients were pooled using a random-effects model by deriving the variance from the study sample sizes&#46; Follow-up periods and trastuzumab treatment periods were also pooled to achieve overall estimates&#44; which were the inverse variance weighted averages of individual study estimates&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">To determine the significance of a difference between trastuzumab and control regimens in the incidence of CNS metastases&#44; meta-analyses of odds ratios were performed&#46; To estimate the difference in survival between trastuzumab-treated patients with and without CNS metastases&#44; a meta-analysis of mean differences was performed&#46; Both meta-analyses were performed with the Cochrane Review Manager software &#40;version 5&#46;3&#59; Nordic Cochrane Center&#44; Copenhagen&#44; Denmark&#41;&#46; Statistical heterogeneity &#40;inconsistency of outcomes between studies&#41; was estimated using the I<span class="elsevierStyleSup">2</span> index&#46;</p></span></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">RESULTS</span><p id="para120" class="elsevierStylePara elsevierViewall">Thirty studies &#40;<a class="elsevierStyleCrossRefs" href="#bib13">13-42</a>&#41; were included &#40;Appendix <a class="elsevierStyleCrossRef" href="#fig5">Figure S1</a>&#41;&#46; In these studies&#44; 8121 patients with HER2-positive MBC were treated with trastuzumab with or without chemotherapy&#44; and 3972 control patients received treatments without trastuzumab&#46; Of the included studies&#44; 7 were randomized controlled trials&#44; 1 was a randomized prospective study&#44; 1 was a prospective non-randomized study&#44; and 21 were retrospective studies&#46; According to Begg&#39;s test for publication bias assessment&#44; there was no significant publication bias &#40;adjusted Kendall&#39;s score&#58; 83&#44; standard deviation&#58; 56&#59; <span class="elsevierStyleItalic">p</span>&#61;0&#46;139&#59; Appendix <a class="elsevierStyleCrossRef" href="#fig6">Figure S2</a>&#41;&#46; The important characteristics of the included studies are listed in Appendix <a class="elsevierStyleCrossRef" href="#tbl1">Table S1</a>&#46;</p><elsevierMultimedia ident="fig5"></elsevierMultimedia><elsevierMultimedia ident="fig6"></elsevierMultimedia><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para130" class="elsevierStylePara elsevierViewall">The percentage of patients with stage IV cancer was 32&#37; &#40;95&#37; confidence interval &#91;CI&#93;&#58; 13&#44; 55&#41;&#46; The percentage of estrogen receptor-positive patients was 47&#37; &#40;95&#37; CI&#58; 43&#44; 51&#41; and that of progesterone receptor-positive patients was 38&#37; &#40;95&#37; CI&#58; 32&#44; 43&#41;&#46; The percentage of estrogen- and progesterone receptor-positive patients was 43&#37; &#40;95&#37; CI&#58; 31&#44; 55&#41;&#46; Trastuzumab was used as first-line therapy in 61&#37; &#40;95&#37; CI&#58; 10&#44; 99&#41; of the patients&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">The follow-up duration of this population was 18&#46;9 months &#40;95&#37; CI&#58; 13&#46;8&#44; 24&#46;1&#41;&#44; and the duration of trastuzumab treatment was 9&#46;0 months &#40;95&#37; CI&#58; 7&#46;0&#44; 11&#46;0&#41;&#46; The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12&#46;2 months &#40;95&#37; CI&#58; 9&#46;5&#44; 14&#46;7&#41;&#46; The incidence of CNS metastasis in patients with HER2-positive MBC during trastuzumab therapy was 22&#37; &#40;95&#37; CI&#58; 16&#44; 27&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46; The incidence of CNS metastases was significantly higher in patients treated with trastuzumab-based regimens than in patients not treated with trastuzumab &#40;odds ratio&#58; 1&#46;39 &#91;95&#37; CI&#58; 1&#46;06&#44; 1&#46;82&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;02&#59; <a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><elsevierMultimedia ident="fig2"></elsevierMultimedia><p id="para150" class="elsevierStylePara elsevierViewall">The median survival time from the start of trastuzumab therapy in patients with MBC treated with trastuzumab was 23&#46;4 months &#40;95&#37; CI&#58; 19&#46;7&#44; 27&#46;1&#41;&#44; whereas the survival time after treatment with control regimens was 18&#46;4 months &#40;95&#37; CI&#58; 12&#46;7&#44; 24&#46;1&#41;&#46; The survival time after the development of CNS metastases in trastuzumab-treated patients was 19&#46;2 months &#40;95&#37; CI&#58; 15&#46;6&#44; 25&#46;9&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3</a>&#41;&#46; The survival time from the start of trastuzumab therapy was significantly shorter in patients with CNS metastases than in patients who did not develop CNS metastasis &#40;mean difference&#58; 10&#46;9 months &#91;95&#37; CI&#58; 8&#46;4&#44; 13&#46;3&#93;&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#59; Appendix <a class="elsevierStyleCrossRef" href="#fig7">Figure S3</a>&#41;&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia><elsevierMultimedia ident="fig7"></elsevierMultimedia><p id="para160" class="elsevierStylePara elsevierViewall">In meta-regression analyses&#44; the incidence rate of CNS metastases was not statistically significantly associated with study duration &#40;meta-regression coefficient &#91;MC&#93;&#58; 0&#46;005 &#91;95&#37; CI&#58;&#8722;0&#46;003&#44; 0&#46;013&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;194&#41;&#44; trastuzumab treatment duration &#40;MC&#58;&#8722;0&#46;0004 &#91;95&#37; CI&#58;&#8722;0&#46;010&#44; 0&#46;009&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;922&#41;&#44; age &#40;&#8722;0&#46;002 &#91;95&#37; CI&#58;&#8722;0&#46;012&#44; 0&#46;008&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;672&#41;&#44; baseline CNS metastases &#40;MC&#58;&#8722;0&#46;0004 &#91;95&#37; CI&#58;&#8722;0&#46;001&#44; 0&#46;0002&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;256&#41;&#44; estrogen receptor positivity &#40;MC&#58; &#8722;0&#46;006 &#91;95&#37; CI&#58;&#8722;0&#46;022&#44; 0&#46;010&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;438&#41;&#44; progesterone receptor positivity &#40;MC&#58; 0&#46;002 &#91;95&#37; CI&#58;&#8722;0&#46;012&#44; 0&#46;016&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;774&#41;&#44; or study publication year &#40;MC&#58;&#8722;0&#46;00005 &#91;95&#37; CI&#58;&#8722;0&#46;0002&#44; 0&#46;0001&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;367&#41;&#46; However&#44; the incidence rate of CNS metastases was significantly inversely associated with the study sample size &#40;MC&#58;&#8722;0&#46;0001 &#91;95&#37; CI&#58;&#8722;0&#46;0002&#44; &#8722;0&#46;00002&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;013&#41; independently &#40;<a class="elsevierStyleCrossRef" href="#fig4">Figure 4</a>&#41; and in multivariate analyses with all of the above explanatory variables&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">DISCUSSION</span><p id="para170" class="elsevierStylePara elsevierViewall">In this meta-analysis&#44; we found that approximately 22&#37; of patients treated with trastuzumab&#44; either alone or in combination with chemotherapy&#44; developed CNS metastases approximately 1 year after the start of trastuzumab therapy&#46; The duration of trastuzumab therapy was approximately 9 months&#46; The incidence of CNS metastases was significantly higher in trastuzumab-treated patients than in control patients&#46; The survival time from the start of trastuzumab and control therapies was approximately 23 and 18 months&#44; respectively&#46; The survival time after the development of CNS metastases in trastuzumab-treated patients was approximately 19 months&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">In a multicenter&#44; prospective&#44; observational cohort study of about 1000 patients with HER2-positive MBC with trastuzumab as the predominant treatment agent&#44; 9&#37; of the patients had CNS metastases at MBC diagnosis and 22&#37; additional patients developed CNS metastases after a median follow-up of 28 months &#40;<a class="elsevierStyleCrossRef" href="#bib43">43</a>&#41;&#46; These outcomes provide further support to the findings of the present study&#46; However&#44; a considerable variability was observed in the incidence of CNS metastases &#40;range&#58; 2&#37;-50&#37;&#41; in the included studies&#44; and a significant inverse relationship was found between the study sample size and CNS incidence&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">Krop et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41; found a similar incidence of CNS metastases in the trastuzumab and capecitabine groups and noted that the absolute risk of CNS progression was higher in patients with baseline metastases &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&#46; Moreover&#44; because the survival of patients with CNS metastases at baseline remains shorter than those without baseline CNS metastases &#40;<a class="elsevierStyleCrossRef" href="#bib33">33</a>&#41;&#44; the number of patients with baseline metastases can influence the incidence rate of CNS metastases in a study&#46; Young age and an estrogen receptor-negative status are also considered risk factors for CNS metastases &#40;<a class="elsevierStyleCrossRef" href="#bib44">44</a>&#44;<a class="elsevierStyleCrossRef" href="#bib45">45</a>&#41;&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">Although we found a statistically significantly higher incidence of CNS metastases in patients with HER2-positive MBC treated with trastuzumab than in those treated with control regimens&#44; this meta-analysis needs to be elaborated&#46; Seven of the 10 included studies in this meta-analysis did not find a statistically significant difference in the CNS metastasis incidence between the trastuzumab and control regimens&#46; Two studies found a higher incidence of CNS metastases with the control regimen than with the trastuzumab regimen&#46; In this meta-analysis&#44; the overall incidence of CNS metastases was 14&#37; &#40;95&#37; CI&#58; 7&#44; 22&#41; in the trastuzumab group and 12&#37; &#40;95&#37; CI&#58; 4&#44; 22&#41; in the control group&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">Metro et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#41; reviewed 69 patients with MBC treated with trastuzumab&#44; of whom 22 developed CNS metastases during the treatment&#46; Of the patients who developed CNS metastases&#44; 10 continued trastuzumab and 10 discontinued trastuzumab to receive second-line chemotherapy and radiotherapy&#46; The median time to progression in patients who continued trastuzumab was 10 months &#40;95&#37; CI&#58; 1&#44; 21&#41;&#59; however&#44; it was 7 months &#40;95&#37; CI&#58; 1&#44; 15&#41; in patients who stopped trastuzumab &#40;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#41;&#46; Swain et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib40">40</a>&#41; found a longer time to the development of CNS metastases in pertuzumab-trastuzumab-docetaxel-treated patients than in trastuzumab-docetaxel-treated patients&#46; Such observations support the growing evidence of the effectiveness of trastuzumab in preventing or delaying progression to the CNS&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">We found that the survival time of patients &#40;with or without CNS metastases&#41; treated with trastuzumab was approximately 2 years&#44; whereas the approximate survival time of patients treated with non-trastuzumab therapies was 18 months&#46; In trastuzumab-treated patients&#44; the survival time after the diagnosis of CNS metastasis was approximately 19 months&#46; A difference in the survival time after CNS metastasis of as much as 14 months has been observed between patients with and without trastuzumab treatment &#40;<a class="elsevierStyleCrossRef" href="#bib46">46</a>&#41;&#46; This shows that trastuzumab offers an overall benefit to patients with HER2-positive MBC despite conferring a marginally increased risk of CNS metastases&#46; This appears to have practical implications&#44; as evident from the continued use of trastuzumab therapy even after cancer progression in several trials &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">This study had some limitations&#46; The detection of a high statistical heterogeneity in some analyses is an important consideration&#46; The wide range of CNS metastasis incidence and confounders such as age&#44; estrogen&#47;progesterone receptor status&#44; and follow-up durations may have affected the outcomes&#46; We could not perform a quality assessment of the included studies because of the varying study designs&#46; For some variables&#44; such as performance status&#44; cancer stage&#44; and progression-free survival&#44; fewer data were available&#46; In addition&#44; insufficient information was available for performing subgroup analyses with respect to the combinations used in trastuzumab regimens&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">CONCLUSIONS</span><p id="para240" class="elsevierStylePara elsevierViewall">Approximately 22&#37; of patients with HER2-positive MBC developed CNS metastases during trastuzumab treatment&#44; although the range was rather wide and the incidence of CNS metastases increased with decreasing study population size&#44; indicating that the actual incidence may be lower than that estimated in the present study&#46; However&#44; trastuzumab-treated patients had a longer survival than patients treated with non-trastuzumab therapies&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">AUTHOR CONTRIBUTIONS</span><p id="para250" class="elsevierStylePara elsevierViewall">Bai X wrote the manuscript&#46; Lin X and Song J collected the data&#46; Chang JH&#44; Han LL and Fan C analyzed the data&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xpalclavsec1577263"
          "titulo" => "KEYWORDS"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Ethics"
            ]
            1 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "Inclusion and exclusion criteria"
            ]
            2 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "Literature search"
            ]
            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Data extraction&#44; synthesis&#44; and statistical analysis"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec70"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec80"
          "titulo" => "DISCUSSION"
        ]
        5 => array:2 [
          "identificador" => "cesec90"
          "titulo" => "CONCLUSIONS"
        ]
        6 => array:2 [
          "identificador" => "cesec100"
          "titulo" => "AUTHOR CONTRIBUTIONS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-12-07"
    "fechaAceptado" => "2021-02-03"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1577263"
          "palabras" => array:5 [
            0 => "Metastatic Breast Cancer"
            1 => "Central Nervous System"
            2 => "Brain"
            3 => "Metastases"
            4 => "Trastuzumab"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:1 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara50" class="elsevierStyleSimplePara elsevierViewall">This study aimed to estimate the incidence of central nervous system &#40;CNS&#41; metastases in patients with human epidermal growth factor receptor 2 &#40;HER2&#41;-positive metastatic breast cancer &#40;MBC&#41; treated with trastuzumab&#46;</p><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Studies were identified through a literature search of electronic databases&#46; Random-effects meta-analyses were performed to estimate the incidence rate of CNS metastases&#44; trastuzumab therapy duration&#44; and time from trastuzumab therapy to CNS metastasis diagnosis&#46; A meta-analysis of odds ratios was performed to evaluate the significance of a difference in CNS metastasis incidence between patients with and without trastuzumab treatment&#46;</p><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Thirty studies &#40;8121 trastuzumab-treated and 3972 control patients&#41; were included&#46; The follow-up duration was 18&#46;9 months &#40;95&#37; confidence interval &#91;CI&#93;&#58; 13&#46;8&#44; 24&#46;1&#41;&#46; The trastuzumab treatment duration was 9&#46;0 months &#40;95&#37; CI&#58; 7&#46;0&#44; 11&#46;0&#41;&#46; The median interval between the start of trastuzumab therapy and CNS metastasis diagnosis was 12&#46;2 months &#40;95&#37; CI&#58; 9&#46;5&#44; 14&#46;7&#41;&#46; The incidence of CNS metastasis after the start of trastuzumab therapy was 22&#37; &#40;95&#37; CI&#58; 16&#44; 27&#41;&#46; The incidence of CNS metastases was significantly higher in trastuzumab-treated than in non-trastuzumab-treated patients &#40;odds ratio&#58; 1&#46;39 &#91;95&#37; CI&#58; 1&#46;06&#44; 1&#46;82&#93;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;02&#41;&#46; The survival time from the start of the study was 23&#46;4 months &#40;95&#37; CI&#58; 19&#46;7&#44; 27&#46;1&#41; in trastuzumab-treated patients and 18&#46;4 months &#40;95&#37; CI&#58; 12&#46;7&#44; 24&#46;1&#41; in patients treated with control regimens&#46; The survival time after the development of CNS metastases in trastuzumab-treated patients was 19&#46;2 months &#40;95&#37; CI&#58; 15&#46;6&#44; 25&#46;9&#41;&#46;</p><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Approximately 22&#37; of patients with HER2-positive MBC who were treated with trastuzumab developed CNS metastases&#46; However&#44; trastuzumab-treated patients had a longer survival than patients who were not treated with trastuzumab&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
      ]
    ]
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            "apendice" => "<p id="para260" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="tbl1"></elsevierMultimedia></p> <p id="para270" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fig5"></elsevierMultimedia></p> <p id="para280" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fig6"></elsevierMultimedia></p> <p id="para290" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fig7"></elsevierMultimedia></p>"
            "titulo" => "APPENDIX"
            "identificador" => "cesec110"
          ]
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    ]
    "multimedia" => array:8 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Forest graph showing the results of the meta-analysis of the incidence rate of CNS metastases in patients with HER2-positive MBC treated with trastuzumab&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig2"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Forest graph showing the results of the meta-analysis of the incidence rate of CNS metastases in patients with HER2-positive MBC treated with and without trastuzumab&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig3"
        "etiqueta" => "Figure 3"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Forest graph showing the results of the meta-analysis of the median survival of patients with HER2-positive MBC treated with trastuzumab or control therapies&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig4"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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            "Tamanyo" => 26483
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        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Meta-regression scatterplot showing the relationship of the incidence rate of CNS metastases in patients with HER2-positive MBC treated with trastuzumab to the study sample size&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig5"
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        "descripcion" => array:1 [
          "en" => "<p id="spara110" class="elsevierStyleSimplePara elsevierViewall">Flowchart of the screening and selection of the included studies&#46;</p>"
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        "identificador" => "fig6"
        "etiqueta" => "Figure S2"
        "tipo" => "MULTIMEDIAFIGURA"
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            "imagen" => "gr6.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara120" class="elsevierStyleSimplePara elsevierViewall">Funnel plot showing the results of Begg&#39;s test for publication bias assessment&#46;</p>"
        ]
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      6 => array:7 [
        "identificador" => "fig7"
        "etiqueta" => "Figure S3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spara130" class="elsevierStyleSimplePara elsevierViewall">Forest graph showing the results of the meta-analysis of the survival difference between MBC patients with and without CNS metastases&#46;</p>"
        ]
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        "identificador" => "tbl1"
        "etiqueta" => "Table S1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spara100" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; CAP&#44; capecitabine&#59; CPD&#44; cyclophosphamide&#59; CT&#44; chemotherapy&#59; DOC&#44; docetaxel&#59; DOX&#44; doxorubicin&#59; ECOG PS&#44; Eastern Ontario Cooperative Group performance status&#59; GEMB&#44; gemcitabine&#59; IQR&#44; interquartile range&#59; PAC&#44; paclitaxel&#59; PCI&#44; prophylactic cranial irradiation&#59; RT&#44; radiotherapy&#59; SD&#44; standard deviation&#59; T&#44; trastuzumab&#59; VINO&#44; vinorelbine&#59; ER&#44; estrogen receptor&#59; PR&#44; progesterone receptor&#59; KPS&#44; Karnofsky Performance Status&#46;</p>"
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t  " rowspan="2" align="center" valign="\n
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                  \t\t\t\t  " rowspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment duration &#40;months&#41;</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="5" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Therapy line</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ER&#47;PR status &#40;&#37; &#43;&#41;</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cancer stage</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ECOG PS</th></tr><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2nd&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">3rd&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">4th&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">5th&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ER&#47;PR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Awada 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">237&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">242&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T-PAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neratinib-PAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23 &#40;IQR&#58; 13&#46;8-32&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;5 &#40;IQR&#58; 5&#46;8-18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;IQR&#58; 47-62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bartsch 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T-CAP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">19 &#40;range&#58; 3-42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">58&#46;5 &#40;range&#58; 29-73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">52&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">27&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">42&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">17&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bartsch 2008&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">T-GEMB&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">60 &#40;range&#58; 29-83&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">80-100 KPS 100&#37;</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">Burnstein 2003&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Burnstein 2005&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7 &#40;95&#37; CI&#58; 6&#46;4-7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
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                  \t\t\t\t">KPS 90-100 68&#37;</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">Canney 2015&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">T-taxane&#47;PC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">T&#47;CT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Harbeck 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">T-VINO&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Afatinib-VINO&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Lapatinib-CAP&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">No T&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Lower 2003&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Montemurro 2020&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Park 2009&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Puente V&#225;zquez 2006&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Swain 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">808&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">T-DOC&#47;pertuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">53 &#40;range&#58; 22-80&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Witzel 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">75&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">T&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">24 &#40;range&#58; 1-98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">11 &#40;range&#58; 1-50&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">55 &#40;31-84&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">45&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">37&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">30&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Yau 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">87&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">T-CT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#46;8 &#40;range&#58; 0-34&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Important characteristics of the included studies&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:46 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "About Breast Cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              American Cancer Society \n
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ISSN: 18075932
Original language: English
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2023 October 31 30 61
2023 September 17 28 45
2023 August 31 5 36
2023 July 22 21 43
2023 June 39 7 46
2023 May 44 1 45
2023 April 27 1 28
2023 March 27 1 28
2023 February 12 1 13
2023 January 3 0 3
2022 December 7 2 9
2022 November 7 1 8
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos