Cumulative meta-analysis.

<p>Plotting cumulative global efficacy estimate with time shows a steady trend for values to become more conservative with time. Plot size is representative of the number of studies, values for which are included on the right hand side, and error bars represent the 95%CI of the mean.</p

PRISMA flowchart of study selection.

<p>The first search was performed on 4 July 2013, using the terms relating to (breast tumor OR breast cancer) AND (trastuzumab OR Herceptin) (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158240#pone.0158240.s002" target="_blank">S1 Table</a>). On 18 September 2014, we added three further terms to expand the search with previous names of trastuzumab: (breast tumor OR breast cancer) AND ("rhuMAb HER2" OR "Anti-p185HER2 Monoclonal Antibody" OR "muMAb 4D5”).</p

Stratification by animal and tumour model characteristics.

<p>(A) The specific xenograft model used were associated with a significant proportion of the between-study heterogeneity (χ² = 4416, df = 23, P<0.00385). (B) Overexpression of HER2 in breast cancer tumours was associated with greater efficacy (χ² = 160, df = 1, P<0.00385). (C) A greater reduction in tumour volume was observed with subcutaneous inoculation compared to intramammary route (χ² = 810, df = 2, P<0.00385). (D) There is comorbidity related between-study heterogeneity (χ² = 5130, df = 9, P<0.00385). The more commonly used athymic and SCID mice were associated with lower efficacies. (E) A significant proportion of between-study heterogeneity is accounted for by the tumour volume at treatment initiation, with a smaller treatment effect seen at either extreme (χ² = 1042, df = 6, P<0.00385). The grey bands represent global 95% confidence intervals; diamonds (A) and columns (B-E) represent mean±95% CI and diamond size (A) column width (B-E) a measure of number of comparisons within each stratum; the number of comparisons is included inside the y-axis (A) and at the base of each column (B-E). The solid lines in A, C and E represent the level of neutral treatment effect.</p

Evaluation of study quality and publication bias.

<p>(A) Quality score is associated with between-study heterogeneity tumour volume studies, with a trend for higher quality studies to report smaller effect sizes (χ² = 1373, df = 6, p<0.00385). (B) Randomized studies were associated with smaller tumour volume reductions than non-randomised studies (χ² = 68.1, df = 1, p<0.00385). (C and D) Both funnel plot and Egger regression indicate a presence of publication bias in tumour volume data (t = 8.772, p<0.001). Trim and Fill analysis added 38 ‘missing’ studies, with a sizeable reduction in global efficacy estimate (red plots). (E and F) For survival studies, funnel plot does not show any obvious asymmetry, but Egger regression suggests a publication bias (t = 8.772, p<0.001). The grey bands in A and B represent global 95% confidence intervals; columns represent mean ± 95%CI and column width a measure of number of comparisons within each stratum; the number of comparisons is included at the base of each column. Dotted lines in C and E represent global estimates of efficacy before (grey) and after (red) Trim and fill analysis. Dotted lines in D and F represent 95%CI of the regression. The vertical solid lines in A, C, D and F represent the level of neutral treatment effect.</p

Stratification by trastuzumab treatment characteristics.

<p>Total trastuzumab dose (A. χ² = 723, df = 6, P<0.00385), route of drug delivery (B. χ² = 62, df = 3, P<0.00385), cotreatment with oestradiol (C. χ² = 336, df = 1, P<0.00385) and the choice of control (D. χ² = 956, df = 3, P<0.00385), accounted for significant between-study variability in reduction of tumour volume. The grey band represents global 95% confidence intervals; columns represent mean ± 95% CI and column width a measure of number of comparisons within each stratum; the number of comparisons is included at the base of each column.</p