A multiresolution approach to time warping achieved by a Bayesian prior-posterior transfer fitting strategy.

The procedure known as warping aims at reducing phase variability in a sample of functional curve observations, by applying a smooth bijection to the argument of each of the functions. We propose a natural representation of warping functions in terms of a new type of elementary function named `warping component functions' which are combined into the warping function by composition. A sequential Bayesian estimation strategy is introduced, which fits a series of models and transfers the posterior of the previous fit into the prior of the next fit. Model selection is based on a warping analogue to wavelet thresholding, combined with Bayesian inference.Bayesian inference; Functional data analysis; Markov chain Monte Carlo sampling; Time warping; Warping components; Warping function;

Warping Functional Data in R and C via a Bayesian Multiresolution Approach

Phase variation in functional data obscures the true amplitude variation when a typical cross-sectional analysis of these responses would be performed. Time warping or curve registration aims at eliminating the phase variation, typically by applying transformations, the warping functions τn, to the function arguments. We propose a warping method that jointly estimates a decomposition of the warping function in warping components, and amplitude components. For the estimation routine, adaptive MCMC calculations are performed and implemented in C rather than R to increase computational speed. The R-C interface makes the program user-friendly, in that no knowledge of C is required and all input and output will be handled through R. The R package MRwarping contains all needed files

Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer

Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes

Background: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Methods: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and “other”. The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. Results: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Conclusions: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.)

Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis

"Background Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response—ypT0 ypN0, ypT0/is ypN0, and ypT0/is—for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39–0·51; ypT0/is ypN0: 0·48, 0·43–0·54) and OS (0·36, 0·30–0·44; 0·36, 0·31–0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55–0·66; OS 0·51, 0·45–0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18–0·33; OS: 0·16, 0·11–0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09–0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0·03, 95% CI 0·00–0·25) and OS (R2=0·24, 0·00–0·70). Interpretation Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. Funding US Food and Drug Administration.

Analyzing phase and amplitude variation of functional data.

status: publishe

Phase and amplitude-based clustering for functional data

Functional data that are not perfectly aligned in the sense of not showing peaks and valleys at the precise same locations possess phase variation. This is commonly addressed by pre-processing the data via a warping procedure. As opposed to treating phase variation as a nuisance effect, we explicitly recognize it as a possible important source of information for clustering. We illustrate how results from a multiresolution warping procedure can be used for clustering. This approach allows to address detailed questions to find local clusters that differ in phase, or clusters that differ in amplitude, or both simultaneous.status: publishe