Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity.

OBJECTIVES: The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BACKGROUND: Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. METHODS: A total of 222 patients with early-stage human epidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. RESULTS: TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. CONCLUSIONS: Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).

Modeling Working Memory Tasks on the Item Level.

Item responses to Digit Span and Letter-Number Sequencing were analyzed to develop a better-refined model of the two working memory tasks using the finite mixture (FM) modeling method. Models with ordinal latent traits were found to better account for the independent sources of the variability in the tasks than those with continuous traits, and the discretely distributed factors appeared to represent short-term storage (STS), general attention control (GAC), and the specific control mechanisms initiated by the interfering operations of mental sorting (MS) and backward ordering (BO). When related to the general ability factor (G) defined by the WISC-R verbal and performance scores and the total achievement score, the general working memory factors STS and GAC both seemed to share substantial variances with G, but the roles of specific factors MS and BO were less definitive. These WM factors accounted for the majority of the variability in G, with the multiple correlation between the factor mean scores of the WM factors and that of G above 0.80. Moreover, there seemed to be a discontinuity in the distribution of the ordinal GAC factor, as the two lowest subcategories of GAC were separated from the rest of the overall sample by the virtually empty third lowest subcategory, and the two outlying low subcategories contained the majority (80%) of the cases with mild mental retardation. The theoretical implications of these results were discussed.