Attenuation of Smooth Muscle Cell Phenotypic Switching by Angiotensin 1-7 Protects against Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8-10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.

Adventitial Fibroblasts in Aortic Aneurysm: Unraveling Pathogenic Contributions to Vascular Disease.

Aortic aneurysm (AA) is a degenerative vascular disease that involves aortic dilatation, and, if untreated, it can lead to rupture. Despite its significant impact on the healthcare system, its multifactorial nature and elusive pathophysiology contribute to limited therapeutic interventions that prevent the progression of AA. Thus, further research into the mechanisms underlying AA is paramount. Adventitial fibroblasts are one of the key constituents of the aortic wall, and they play an essential role in maintaining vessel structure and function. However, adventitial fibroblasts remain understudied when compared with endothelial cells and smooth muscle cells. Adventitial fibroblasts facilitate the production of extracellular matrix (ECM), providing structural integrity. However, during biomechanical stress and/or injury, adventitial fibroblasts can be activated into myofibroblasts, which move to the site of injury and secrete collagen and cytokines, thereby enhancing the inflammatory response. The overactivation or persistence of myofibroblasts has been shown to initiate pathological vascular remodeling. Therefore, understanding the underlying mechanisms involved in the activation of fibroblasts and in regulating myofibroblast activation may provide a potential therapeutic target to prevent or delay the progression of AA. This review discusses mechanistic insights into myofibroblast activation and associated vascular remodeling, thus illustrating the contribution of fibroblasts to the pathogenesis of AA.

Occurrence of peritoneal carcinomatosis in patients with rectal cancer undergoing staging pelvic MRI: clinical observations.

OBJECTIVES: Describe the cumulative incidence (CUIN) of peritoneal carcinomatosis (PC) and survival in patients presenting with advanced rectal cancer at staging pelvic MRI. METHODS: From 2013 to 2018, clinicopathologic records of patients with pretreatment rectal MRI clinical (c)T3c, cT3d, cT4a, and cT4b primary rectal adenocarcinoma were retrospectively reviewed by two radiologists. Standard MRI descriptors and pathologic stages were recorded. Recurrence-free (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Development of PC was explored using competing risk analysis. Differences in survival were compared using the log-rank test. Gray's test was used to test for differences in CUIN of PC. RESULTS: Three hundred forty-three patients (147 women; median age, 56 years) had MRI stages cT3cd, n = 170; cT4a, n = 40; and cT4b, n = 133. Median follow-up among survivors was 27 months (0.36-70 months). For M1 patients, OS differed only by cT stage (2-year OS: cT3 88.1%, cT4a 79.1%, cT4b 64.7%, p = 0.045). For M0 patients, OS and RFS differed only by pathological (p)T stage. We observed a statistically significant difference in the cumulative incidence of PC by cT stage (2-year CUIN: cT3 3.2%, cT4a 8.5%, cT4b 1.6%, p = 0.01), but not by pT stage. Seventy-nine patients (23%) presented with metastatic disease (M1), eight with PC (2.3%). Overall, eight patients presented with PC (cT4a: n = 4, other stages: n = 4) and 22 developed PC (cT4a: n = 5, other stages: n = 17). CONCLUSIONS: PC is uncommon in rectal cancer. MRI-based T stage exhibited an overall association with the cumulative incidence of PC, and descriptively, cT4a stage appears to have the highest CUIN. KEY POINTS: • In a retrospective study of 343 patients with rectal cancer undergoing baseline MRI and clinical follow-up, we found that peritoneal carcinomatosis was rare. • We observed a significant overall association between PC at presentation and cT stage that appeared to be driven by the higher proportion of cT4a patients presenting with PC. • Among patients that did not present with PC, we observed a significant overall association between time to PC and cT stage that may be driven by the higher cumulative incidence of PC in cT4a patients.

Variation in chemotherapy prescribing rates and mortality in early breast cancer over two decades: a national data linkage study.

BACKGROUND: Regional variation in clinical practice may identify differences in care, reveal inequity in access, and explain inequality in outcomes. The study aim was to measure geographical variation in Scotland for adjuvant chemotherapy use and mortality in early-stage breast cancer. PATIENTS AND METHODS: In this retrospective cohort study using population cancer registry-based data linkage, patients with surgically treated early breast cancer between 2001 and 2018 were identified from the Scottish Cancer Registry. Geographical regions considered were based on NHS Scotland organisational structure including 14 territorial Health Boards as well as three regional Cancer Networks. Regional variation in the proportion receiving chemotherapy, breast cancer mortality and all-cause mortality was investigated. Inter-regional comparisons of chemotherapy use were adjusted for differences in case mix using logistic regression. Comparison of breast cancer-specific mortality and all-cause mortality used regression with a parametric survival model. Time trends were assessed using moving average plots. RESULTS: Chemotherapy use ranged from 35% to 46% of patients across Health Boards without adjustment. Variation reduced between 2001 and 2018. Following adjustment for clinical case mix, variation between cancer networks was within 3 percentage points, but up to 10 percentage points from the national average in some Health Boards. Differences in breast cancer mortality and all-cause mortality between cancer networks were modest, with hazard ratios of between 0.933 (95% confidence interval 0.893-0.975) and 1.041 (1.002-1.082) compared with the national average. Survival improved over the time period studied. CONCLUSION: With adequate case mix adjustment, variation in adjuvant chemotherapy use for early breast cancer in Scotland is small, with a trend towards greater convergence in practice and improved mortality outcomes in more recent cohorts. This suggests very limited regional inequity in access and convergence of clinical practice towards risk-stratified treatment recommendations. Outliers require assessment to understand the reasons for variance.

Pre-treatment CT imaging in stage IIIA lung cancer: Can we predict local recurrence after definitive chemoradiotherapy?

OBJECTIVES: The aim of this study was to delineate computed tomography (CT) features of stage IIIA non-small cell lung cancers on pre-treatment staging studies and identify features that could predict local recurrence after definitive concurrent chemoradiotherapy. MATERIALS AND METHODS: We retrospectively reviewed pre- and post-treatment CT scans for 91 patients with Stage IIIA non-small cell lung cancer undergoing definitive concurrent chemoradiotherapy. Pre-treatment CT qualitative features were evaluated by consensus. The primary endpoint was local recurrence as determined on post-treatment CT scans along with the radiotherapy fields. Local recurrence was defined as intrathoracic in-field and marginal as opposed to out-of-field failures. Competing risk regressions were used to examine associations between CT features and recurrence. RESULTS: The median follow-up was 51.5 months (range 2.4-111.2). Median overall survival was 25.6 months (95% CI: 20.4-30). At last follow-up, 72 (79.1%) patients had died, 48 (52.7%) had in-field recurrence, and 30 (32.9%) presented with out-of-field recurrence. On pre-treatment CT scans, tumors presenting as pulmonary consolidations (hazard ratio = 2.34, 95% CI: 1.05-5.22; p 0.038) were more likely to have in-field failure. Tumors with 50-100% necrosis (hazard ratio = 0.15, 95% CI: 0.02-1.06) were associated with decreased out-of-field failure (overall p = 0.038). However, these were rare features in our sample which limit the ability of these features to be associated with such outcomes. CONCLUSIONS: Pre-treatment CT features alone are limited in predicting locoregional recurrence. Larger studies using quantitative tools are needed to predict such outcomes.

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.

Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. Clinical trials number: NCT01958021.

Benign Posttraumatic Pseudopneumoperitoneum.

OBJECTIVE: The objective of our study was to retrospectively determine the anatomic distribution of chest wall ectopic gas resembling pneumoperitoneum (i.e., pseudopneumoperitoneum) and its relationship with trauma mechanisms and clinical outcomes using CT. MATERIALS AND METHODS: Investigators from two separate trauma referral centers screened 492 chest, abdomen, and pelvis CT examinations of patients who had sustained any form of trauma between 2010 and 2015. After excluding 186 patients with recognized causes of ectopic gas, 306 patients (211 men and 95 women; mean age, 44.5 years; range, 6-95 years) remained for analysis by two radiology residents in center 1 and a radiology resident in center 2. Positive cases were reviewed by all investigators, including an experienced fellowship-trained abdominal radiologist. The anatomic location of the pseudopneumoperitoneum, injury severity score, trauma velocity (high speed vs low or unknown speed), trauma mechanism, clinical findings on follow-up, and exploratory laparotomy data were collected for patients with pseudopneumoperitoneum. Two hundred consecutive nontrauma CT examinations from 2015 were selected as control cases by a resident in center 1. The t test and chi-square test were used for determining associations. RESULTS: Pseudopneumoperitoneum was identified in 5.2% of patients, occurring bilaterally adjacent to the lower six costochondral junctions, and was significantly more common with high-velocity trauma than with low-velocity trauma (p = 0.010). None of the patients with pseudopneumoperitoneum had evidence of perforated hollow viscus at surgery (n = 2) or on clinical follow-up (n = 14). No patients had unnecessary surgery due to pseudopneumoperitoneum. CONCLUSION: Pseudopneumoperitoneum is a posttraumatic phenomenon centered near the lower six costochondral junctions. Recognizing these findings may help prevent unnecessary laparotomy in the trauma setting.

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.

Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial.

BACKGROUND: We have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown. PATIENTS AND METHODS: The ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed. RESULTS: Of the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78-4.85; P < 0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24-3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033-0.31; P < 0.001). CONCLUSIONS: Lymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers for cancer patients. CLINICALTRIALS.GOV: NCT01093235.

The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer.

INTRODUCTION: SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. PATIENTS AND METHODS: A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. RESULTS: The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N-) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N- cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N- cases, 4.1% of all cases). CONCLUSIONS: These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Peer assisted learning: teaching dental skills and enhancing graduate attributes.

This study describes a pilot project in which peer assisted learning (PAL) is used to teach dental clinical skills. A cluster randomised controlled trial compared opinions of Bachelor of Dental Surgery (BDS) students from peer-led groups versus staff-led groups in a clinical (impression taking) and a pre-clinical (handpiece skills) task. BDS5 (peer tutors) in their final year delivered teaching to BDS1 (tutees) for each task. Quantitative data from tutees and the peer tutors was gathered from questionnaires, along with open written comments. PAL was well received by both tutees and peer tutors. BDS1 tutees rated BDS5 peer tutors highly for delivery of information, and level of feedback. The tutees considered peer tutors more approachable and less intimidating than staff. Peer tutors reported their own knowledge had increased as a result of teaching. In a summative OSCE (objective structured clinical examination) four months following the teaching, no statistical significant difference between the performance of peer-led and staff-led groups was found at stations related to the subject matter in question. It is argued that PAL, as well as being a useful method of delivering subject-specific teaching, is able to contribute to the development of graduate attributes.

Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer.

BACKGROUND: We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial. METHODS: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years. RESULTS: We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21. CONCLUSIONS: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole.

BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.