In a study in women with early breast cancer, those with high-risk clinical features and a low-risk gene-expression profile were assigned to chemotherapy or no chemotherapy. At 5 years, omission of ...chemotherapy led to a 1.5-percentage-point lower rate of survival without distant metastasis.
Women with early-stage breast cancer are often treated with adjuvant systemic therapy consisting of chemotherapy, endocrine therapy, agents against human epidermal growth factor receptor 2 (HER2), or combinations of these drugs when appropriate. Treatment decisions are based on characteristics of the tumor (hormonal receptor and HER2 status, tumor grade and size, and lymph-node status) and of the patient (age, menopausal status, and performance status).
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Tools that incorporate these features, such as Adjuvant! Online
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,
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and PREDICT Plus,
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were created to assist in such decision making. However, these algorithms do not take into account the individual biologic characteristics of the patient’s . . .
Summary 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.
The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for ...time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.
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.
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.
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.
Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.
Multivariate Functional Halfspace Depth Claeskens, Gerda; Hubert, Mia; Slaets, Leen ...
Journal of the American Statistical Association,
03/2014, Letnik:
109, Številka:
505
Journal Article
Recenzirano
Odprti dostop
This article defines and studies a depth for multivariate functional data. By the multivariate nature and by including a weight function, it acknowledges important characteristics of functional data, ...namely differences in the amount of local amplitude, shape, and phase variation. We study both population and finite sample versions. The multivariate sample of curves may include warping functions, derivatives, and integrals of the original curves for a better overall representation of the functional data via the depth. We present a simulation study and data examples that confirm the good performance of this depth function. Supplementary materials for this article are available online.
Abstract Background The current debate on overdiagnosis and overtreatment of screen-detected ductal carcinoma in situ (DCIS) urges the need for prospective studies to address this issue. A ...substantial number of DCIS lesions will never form a health hazard, particularly if it concerns non- to slow-growing low-grade DCIS. The LORD study aims to evaluate the safety of active surveillance in women with low-risk DCIS. Design This is a randomised, international multicentre, open-label, phase III non-inferiority trial, led by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organization for Research and Treatment of Cancer (EORTC-BCG 1401). Standard treatment will be compared to active surveillance in 1240 women aged ⩾45 years with asymptomatic, screen-detected, pure low-grade DCIS based on vacuum-assisted biopsies of microcalcifications only. Both study arms will be monitored with annual digital mammography for a period of 10 years. The primary end-point is 10-year ipsilateral invasive breast cancer free percentage. Secondary end-points include patient reported outcomes, diagnostic biopsy rate during follow-up, ipsilateral mastectomy rate and translational research. Feasibility To explore interest in and feasibility of the LORD study we conducted a survey among EORTC and BOOG centres. A vast majority of EORTC and BOOG responding centres expressed interest in participation in the LORD study. The proposed study design is endorsed by nearly all centres.
Abstract Purpose Identification of clinicopathological factors predicting for a locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC) could help to decide on the optimal locoregional ...radiotherapy. The objective of this trial is to identify those factors in the context of a phase III trial (European Organisation for Research and Treatment of Cancer 10994). Methods Patients received NAC followed by surgery with or without radiotherapy. Radiotherapy was administered according to pre-specified guidelines. Patients with hormone receptor positive tumours received adjuvant hormonal therapy. A proportion of patients with human epidermal growth factor receptor 2 (HER2) positive cancer received adjuvant trastuzumab. The predictive factors for LRR were identified by multivariate analysis with time to LRR as first event as the primary end-point. Results The median follow-up was 4.4 years. In 1553 eligible patients, there were 76 LRRs with a 5-year cumulative incidence of 4.9% (95% confidence interval, CI 3.76–6.04). In multivariate analysis, breast cancer subtype was a significant predictor of LRR (p < 0.0001): hazard ratio (HR) 6.44 (95% CI 2.83–14.69) for triple negative, 6.26 (95% CI 2.81–13.93) for HER2+ without trastuzumab (T) and 3.37 (95% CI 1.10–10.34) for HER2+ with T cancers, all compared to luminal A patients. Lack of pathological response was also associated with significantly higher LRR risk in case of ≥4 pathologically positive nodes, HR 2.43 (95% CI 1.34–4.40, p < 0.0001). Conclusion Breast cancer subtype and lack of pathological response are predictive factors for high LRR after NAC.
Abstract Aim Several prognostic histological features have been established in female breast cancer (BC), but it is unknown whether these can be extrapolated to male BC patients. The aim of this ...study was to evaluate the prognostic value of several histological features in a large series of male BC. Methods Central pathology review was performed for 1483 male BCs collected through part 1 of the European Organisation for Research and Treatment of Cancer (EORTC) International Male BC Program. Pathology review included histological subtype, grade, mitotic activity index (MAI), presence of a fibrotic focus and density of tumour-infiltrating lymphocytes (TILs). These features were correlated with clinical outcome. The relationship between these features and surrogate molecular subtypes using immunohistochemistry was also assessed. Results Median follow-up for overall survival (OS) was 7.1 years. Overall histological grade was not significantly associated with OS (p = 0.129). MAI, the presence of a fibrotic focus and a low TIL density however were correlated with unfavourable OS (p = 0.023, p = 0.004 and p = 0.011, respectively). BC subtype correlated with TIL density (p = 0.015), as we observed a higher density for human epidermal growth factor receptor type 2 (HER2) positive BC compared to luminal HER2-negative subtype. No association was observed between subtype and fibrotic focus. Conclusions Histologic grade was not significantly correlated with clinical outcome in this series, unlike what is seen in female patients. These results contribute to our understanding of male BC and indicate the importance of further research on the optimisation of risk stratification and treatment decisions for male BC patients.
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