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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warra

Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes. Secondary end-points of NEOPAL included progression-free survival (PFS) and invasive-disease free survival (iDFS) in the intent-to-treat population. Exploratory end-points were overall survival (OS) and breast cancer specific survival (BCSS) in the intent-to-treat population, as well as iDFS, OS and BCSS according to the administration of chemotherapy. Hundred and six patients were randomised. Pathological complete response rates were 3.8% and 5.9%. Twenty-three of the 53 patients in the letrozole-palbociclib arm received postoperative adjuvant chemotherapy. At a median follow-up of 40.4 months [0-56.6], 11 progressions have been observed, of which three were in the letrozole-palbociclib and 8 in the control arm. PFS (HR = 1.01; [95%CI 0.36-2.90], p = 0.98) and iDFS (HR = 0.83; [95%CI 0.31-2.23], p = 0.71) did not differ between both arms. The 40 months PFS rate was 86.7% [95%CI 78.0-96.4] and 89.9% [95%CI 81.8-98.7] in letrozole-palbociclib and control arms, respectively. Outcomes of patients who did not receive chemotherapy were not statistically different from those who received it. NEOPAL suggests that a neoadjuvant letrozole-palbociclib strategy may allow sparing chemotherapy in some patients with luminal breast cancer while allowing good long-term outcomes. Larger confirmatory studies are needed.

Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes. Secondary end-points of NEOPAL included progression-free survival (PFS) and invasive-disease free survival (iDFS) in the intent-to-treat population. Exploratory end-points were overall survival (OS) and breast cancer specific survival (BCSS) in the intent-to-treat population, as well as iDFS, OS and BCSS according to the administration of chemotherapy. Hundred and six patients were randomised. Pathological complete response rates were 3.8% and 5.9%. Twenty-three of the 53 patients in the letrozole-palbociclib arm received postoperative adjuvant chemotherapy. At a median follow-up of 40.4 months [0-56.6], 11 progressions have been observed, of which three were in the letrozole-palbociclib and 8 in the control arm. PFS (HR = 1.01; [95%CI 0.36-2.90], p = 0.98) and iDFS (HR = 0.83; [95%CI 0.31-2.23], p = 0.71) did not differ between both arms. The 40 months PFS rate was 86.7% [95%CI 78.0-96.4] and 89.9% [95%CI 81.8-98.7] in letrozole-palbociclib and control arms, respectively. Outcomes of patients who did not receive chemotherapy were not statistically different from those who received it. NEOPAL suggests that a neoadjuvant letrozole-palbociclib strategy may allow sparing chemotherapy in some patients with luminal breast cancer while allowing good long-term outcomes. Larger confirmatory studies are needed.

PurposeFatigue is common and troublesome among breast cancer survivors; however, limited tools exist to predict its risk.Patients and methodsParticipants with stage I-III breast cancer were prospectively included from CANTO (ClinicalTrials.gov identifier: NCT01993498), collecting longitudinal data at diagnosis (before the initiation of any cancer treatment) and 1 (T1), 2 (T2), and 4 (T3) years after diagnosis. The main outcome was severe global fatigue at T2 (score ≥ 40/100, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30). Analyses at T3 were exploratory. Secondary outcomes included physical, emotional, and cognitive fatigue (EORTC Quality of Life Questionnaire-FA12). Multivariable logistic regression models retained associations with severe fatigue by bootstrapped Augmented Backward Elimination. Validation methods included 10-fold internal cross-validation, overoptimism-corrected area under the receiver operating characteristic curves, and external validation.ResultsAmong 5,640, 5,000, and 3,400 patients at T1, T2, and T3, respectively, the prevalence of post-treatment severe global fatigue was 35.6%, 34.0%, and 31.5% in the development cohort. Retained risk factors for severe global fatigue at T2 were severe pretreatment fatigue (adjusted odds ratio v no 3.191 [95% CI, 2.704 to 3.767]); younger age (for 1-year decrement 1.015 [1.009 to 1.022]), higher body mass index (for unit increment 1.025 [1.012 to 1.038]), current smoking behavior (v never 1.552 [1.291 to 1.866]), worse anxiety (v noncase 1.265 [1.073 to 1.492]), insomnia (for unit increment 1.005 [1.003 to 1.007]), and pain at diagnosis (for unit increment 1.014 [1.010 to 1.017]), with an area under the receiver operating characteristic curve of 0.73 (95% CI, 0.72 to 0.75). Receipt of hormonal therapy was a risk factor for severe fatigue at T3 (v no 1.448 [1.165 to 1.799]). Dimension-specific risk factors included body mass index for physical fatigue and

Gamma-ray astronomy has become one of the main experimental ways to test the modified dispersion relations (MDRs) of photons in vacuum, obtained in some attempts to formulate a theory of quantum gravity. The MDRs in use imply time delays that depend on the energy and that increase with distance following some function of redshift. The use of transient, or variable, distant and highly energetic sources already allows us to set stringent limits on the energy scale related to this phenomenon, usually thought to be of the order of the Planck energy, but robust conclusions on the existence of MDR-related propagation effects still require the analysis of a large population of sources. In order to gather the biggest sample of sources possible for MDR searches at teraelectronvolt energies, the H.E.S.S., MAGIC, and VERITAS collaborations enacted a joint task force to combine all their relevant data to constrain the quantum gravity energy scale. In the present article, the likelihood method used to combine the data and provide a common limit is described in detail and tested through simulations of recorded data sets for a gamma-ray burst, three flaring active galactic nuclei, and two pulsars. Statistical and systematic errors are assessed and included in the likelihood as nuisance parameters. In addition, a comparison of two different formalisms for distance dependence of the time lags is performed for the first time. In a second article, to appear later, the method will be applied to all relevant data from the three experiments.

Some Quantum Gravity (QG) theories, aiming at unifying general relativity and quantum mechanics, predict an energy-dependent modified dispersion relation for photons in vacuum leading to a Violation of Lorentz Invariance (LIV). One way to test these theories is to monitor TeV photons time-of-flight emitted by distant, highly energetic and highly variable astrophysical sources such as flaring active galactic nuclei. Only one time-lag detection was reported so far. We have recently shown however that significant intrinsic time-lags should arise from in situ blazar emission processes at TeV energies and should consequently interfere with LIV searches. In this contribution we will review how intrinsic time delays and LIV-induced propagation effects can simultaneously impact blazars' observed spectral energy distributions and lightcurves. Using a time-dependent approach, we provide predictions on both contributions for various cases in the frame of a standard one zone synchrotron-self-Compton (SSC) model. We will also introduce hints and methods on how to disentangle intrinsic time delays from extrinsic ones in order to highlight LIV effects., Comment: 8 pages, 5 figures, Proceedings of the 37th International Cosmic Ray Conference (ICRC2021)

PURPOSE: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC. SUBJECTS AND METHODS: Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1-21 in combination with weekly P 80 mg/m2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review. RESULTS: 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH+ and CD24-/CD44+ CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups. CONCLUSION: fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met.

Some Quantum Gravity (QG) theories, aiming at unifying general relativity and quantum mechanics, predict an energy-dependent modified dispersion relation for photons in vacuum leading to a Violation of Lorentz Invariance (LIV). One way to test these theories is to monitor TeV photons time-of-flight emitted by distant, highly energetic and highly variable astrophysical sources such as flaring active galactic nuclei. Only one time-lag detection was reported so far. We have recently shown however that significant intrinsic time-lags should arise from in situ blazar emission processes at TeV energies and should consequently interfere with LIV searches. In this contribution we will review how intrinsic time delays and LIV-induced propagation effects can simultaneously impact blazars' observed spectral energy distributions and lightcurves. Using a time-dependent approach, we provide predictions on both contributions for various cases in the frame of a standard one zone synchrotron-self-Compton (SSC) model. We will also introduce hints and methods on how to disentangle intrinsic time delays from extrinsic ones in order to highlight LIV effects., Comment: 8 pages, 5 figures, Proceedings of the 37th International Cosmic Ray Conference (ICRC2021)

BackgroundWe aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data.MethodsWe accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P < .001) variables, a multivariable preconditioned random-forest regression model was built and validated on a hold-out subset to predict fatigue. Gene set enrichment analysis identified key biological correlates (MetaCore). All statistical tests were 2-sided.ResultsStatistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P < .001) with the different fatigue endpoints, although there were no genome-wide statistically significant (P < 5.00 × 10-8) associations. Only for Cognitive Fatigue, the predictive ability of the genomic multivariable model was statistically significantly better than random (area under the curve = 0.59, P = .01) and marginally improved with clinical variables (area under the curve = 0.60, P = .005). Single nucleotide polymorphisms found to be associated (P < .001) with Cognitive Fatigue belonged to genes linked to inflammation (false discovery rate adjusted P = .03), cognitive disorders (P = 1.51 × 10-12), and synaptic transmission (P = 6.28 × 10-8).ConclusionsGenomic analyses i

BackgroundWe aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data.MethodsWe accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P < .001) variables, a multivariable preconditioned random-forest regression model was built and validated on a hold-out subset to predict fatigue. Gene set enrichment analysis identified key biological correlates (MetaCore). All statistical tests were 2-sided.ResultsStatistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P < .001) with the different fatigue endpoints, although there were no genome-wide statistically significant (P < 5.00 × 10-8) associations. Only for Cognitive Fatigue, the predictive ability of the genomic multivariable model was statistically significantly better than random (area under the curve = 0.59, P = .01) and marginally improved with clinical variables (area under the curve = 0.60, P = .005). Single nucleotide polymorphisms found to be associated (P < .001) with Cognitive Fatigue belonged to genes linked to inflammation (false discovery rate adjusted P = .03), cognitive disorders (P = 1.51 × 10-12), and synaptic transmission (P = 6.28 × 10-8).ConclusionsGenomic analyses i

BACKGROUND: Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. PATIENTS AND METHODS: NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0-I rate). Secondary end points included clinical response, proliferation-based markers, and safety. RESULTS: Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22-93)]. RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7-25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). CONCLUSION: LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less

PURPOSE: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). PATIENTS AND METHODS: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)-/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m2) or ixabepilone (40 mg/m2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. RESULTS: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III-IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone). CONCLUSION: After adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II-III lymphocytic infiltration) requires further evaluation.

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

BACKGROUND Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. METHODS We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P = 0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P = 0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment, SCOPUS: ar.j, info:eu-repo/semantics/published

Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6-8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64-1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but i

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cancer