Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine ...therapy.
We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed.
A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval CI, 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups.
Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).
Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in ...the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
Summary Background For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed ...to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. Methods Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1–T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumour histology or lymphovascular invasion, but not both, were permitted), who had had breast-conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomised controlled trial at 76 centres in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40–50 Gy in 15–25 fractions) or no radiotherapy by computer-generated permuted block randomisation, stratified by centre, with a block size of four. The primary endpoint was ipsilateral breast tumour recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomised patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com , number ISRCTN95889329. Findings 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84–6·05), ipsilateral breast tumour recurrence was 1·3% (95% CI 0·2–2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4–5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumour recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99–13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8–96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. Interpretation Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. Funding Chief Scientist Office (Scottish Government), Breast Cancer Institute (Western General Hospital, Edinburgh).
Enhancer elements are genomic regulatory sequences that direct the selective expression of genes so that genetically identical cells can differentiate and acquire the highly specialized forms and ...functions required to build a functioning animal. To differentiate, cells must select from among the ∼106 enhancers encoded in the genome the thousands of enhancers that drive the gene programs that impart their distinct features. We used a genetic approach to identify transcription factors (TFs) required for enhancer selection in fibroblasts. This revealed that the broadly expressed, growth-factor-inducible TFs FOS/JUN (AP-1) play a central role in enhancer selection. FOS/JUN selects enhancers together with cell-type-specific TFs by collaboratively binding to nucleosomal enhancers and recruiting the SWI/SNF (BAF) chromatin remodeling complex to establish accessible chromatin. These experiments demonstrate how environmental signals acting via FOS/JUN and BAF coordinate with cell-type-specific TFs to select enhancer repertoires that enable differentiation during development.
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•Screen for TFs required for enhancer selection using divergent mouse strains•AP-1 TFs (FOS/JUN) are broadly required for enhancer selection in fibroblasts•AP-1 TFs collaborate with cell-type-specific TFs to select enhancers•AP-1 TFs recruit the BAF complex to enhancers to establish accessible chromatin
Natural genetic variation between divergent mouse strains reveals that enhancer selection requires the broadly expressed, growth-factor-inducible AP-1 TFs, which recruit the BAF chromatin remodeling complex to establish accessible chromatin. This demonstrates an essential role for external signals in determining which enhancers are selected in a given cell during development.
The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent ...plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response.
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•Inducible gene programs are adapted to reflect the function of a neuron in a circuit•Neuronal activity induces a distinct transcriptional response in inhibitory neurons•Npas4 promotes development of excitatory synapses on SST-positive inhibitory neurons•Npas4 activates a set of inducible genes in SST neurons that function at synapses
Activity induces the same set of early transcription factors in inhibitory neurons as it does in excitatory ones, but the downstream targets in each cell type differ in a manner that likely preserves an excitatory-inhibitory balance in cortical circuits.
In a prospective 5-year study of women with breast cancer, pre-chemotherapy anti-Müllerian hormone concentration predicted long-term ovarian function.
Context:
Administration of chemotherapy to ...premenopausal women shortens their reproductive lifespan by depleting nonrenewable oocytes. Preservation of fertility is a priority for many such women, and identification of women at risk of infertility is therefore important. However, age is the only patient characteristic currently recognized to be predictive of long-term ovarian function after chemotherapy.
Objective:
Our objective was to assess markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy.
Design and Setting:
We conducted a prospective, longitudinal study at a university hospital and research institute.
Patients:
Patients included women who were premenopausal at the time of diagnosis of early breast cancer.
Main Outcome Measures:
Ovarian function was assessed at 5 yr follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve.
Results:
Forty-two women received (neo-)adjuvant chemotherapy. Continuing menses 4–5 yr after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and anti-Müllerian hormone (AMH). Pretreatment serum AMH, FSH, antral follicle count, and age predicted late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5–66.7); 0.71 ng/ml gave peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over the 4–5 yr after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 yr (P < 0.02).
Conclusion:
Measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to future fertility.
Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment
. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic ...therapy
. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery
were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with ...hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.
Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.
After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval CI, 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.
First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).
We explore the cosmological implications of the angle-averaged correlation function, ...(s), and the clustering wedges, ...(s) and ...(s), of the LOWZ and CMASS galaxy samples from Data Releases 10 ...and 11 of the Sloan Digital Sky Survey III (SDSS-III) Baryon Oscillation Spectroscopic Survey. Our results show no significant evidence for a deviation from the standard ... cold dark matter model. The combination of the information from our clustering measurements with recent data from the cosmic microwave background is sufficient to constrain the curvature of the Universe to ...k = 0.0010 ± 0.0029, the total neutrino mass to ... < 0.23 eV (95 per cent confidence level), the effective number of relativistic species to Neff = 3.31 ± 0.27 and the dark energy equation of state to wDE = -1.051 ± 0.076. These limits are further improved by adding information from Type Ia supernovae and baryon acoustic oscillations from other samples. In particular, this data set combination is completely consistent with a time-independent dark energy equation of state, in which case we find wDE = -1.024 ± 0.052. We explore the constraints on the growth rate of cosmic structures assuming f(z) = ... and obtain ... = 0.69 ± 0.15, consistent with the predictions of general relativity of ... = 0.55. (ProQuest: ... denotes formulae/symbols omitted.)
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