Evidence into practice: a national cohort study of NICE-recommended oncological drug therapy utilisation among women diagnosed with invasive breast cancer in England.

BACKGROUND: Multiple drug treatments are approved for invasive breast cancer (IBC). We investigated uptake of NICE-recommended oncological drugs and variation by age, comorbidity burden and geographical region. METHODS: Women (aged 50+ years) diagnosed with IBC from 2014 to 2019, were identified from England Cancer Registry data and drug utilisation from Systemic Anti-Cancer Therapy data. Interrupted time series analysis assessed national-level changes in drug use after publication of NICE recommendations. Regression models analysed variation in use. RESULTS: This national cohort included 168,449 women. Use of drugs recommended for first-line treatment varied, from 26.6% for CDK 4/6 inhibitors to 63.8% for HER2-targeting therapies. Utilisation of drugs with a NICE recommendation published between 2014 and 2019, increased among patients diagnosed around the time of publication, except in the case of pertuzumab for metastatic breast cancer (MBC) which was previously accessible via the Cancer Drugs Fund (though use of pertuzumab for MBC increased from 34.1% to 75.0% across the study period). Use of trastuzumab and neoadjuvant/adjuvant pertuzumab varied by geographical region. Use was low for ribociclib (2.2%), abemaciclib (2.3%) and for drugs recommended beyond the first-line setting. For all drugs, use after NICE recommendation varied by age at diagnosis and increased as stage increased. CONCLUSIONS: Use of NICE-recommended drugs for IBC in routine care is variable, with lowest use among women aged 70+ years. Improving access to effective treatments is an important step in improving outcomes.

The current status of risk-stratified breast screening.

Apart from high-risk scenarios such as the presence of highly penetrant genetic mutations, breast screening typically comprises mammography or tomosynthesis strategies defined by age. However, age-based screening ignores the range of breast cancer risks that individual women may possess and is antithetical to the ambitions of personalised early detection. Whilst screening mammography reduces breast cancer mortality, this is at the risk of potentially significant harms including overdiagnosis with overtreatment, and psychological morbidity associated with false positives. In risk-stratified screening, individualised risk assessment may inform screening intensity/interval, starting age, imaging modality used, or even decisions not to screen. However, clear evidence for its benefits and harms needs to be established. In this scoping review, the authors summarise the established and emerging evidence regarding several critical dependencies for successful risk-stratified breast screening: risk prediction model performance, epidemiological studies, retrospective clinical evaluations, health economic evaluations and qualitative research on feasibility and acceptability. Family history, breast density or reproductive factors are not on their own suitable for precisely estimating risk and risk prediction models increasingly incorporate combinations of demographic, clinical, genetic and imaging-related parameters. Clinical evaluations of risk-stratified screening are currently limited. Epidemiological evidence is sparse, and randomised trials only began in recent years.

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)-results from the UK Sloane Project.

BACKGROUND: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. METHODS: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. RESULTS: Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005). CONCLUSIONS: The higher breast cancer mortality with microinvasion indicates a more aggressive disease.

Palliative chemotherapy for breast cancer: A population-based cohort study of emergency hospital admissions and place of death.

OBJECTIVE: Patients with incurable breast cancer may be treated with chemotherapy to improve cancer-related symptoms, quality of life and survival. We examined the association between use of palliative chemotherapy towards the end of life in breast cancer patients and outcomes including unplanned hospital admission and place of death. METHODS: A total of 10,966 women, treated with palliative chemotherapy for breast cancer (diagnosed 1995-2017 in England) within the 2 years prior to death (death between 2014 and 2017), were analysed. Logistic regression (outcome = emergency hospital admission in last 90 days of life yes/no; outcome = place of death hospital/other) was performed, adjusting for line of palliative chemotherapy in the last 90 days of life and patient demographics. RESULTS: The odds of hospital admission reduced with increasing line of chemotherapy received (1st line odds ratio [OR] = 2.7, 2nd line OR = 2.1, 3rd line OR = 1.9, 4th+ line OR = 1.7; baseline chemotherapy) in last 90 days of life. A similar relationship was observed for hospital death (1st line OR = 2.4, 2nd line OR = 2.1, 3rd line OR = 1.7, 4th+ line OR = 1.5). CONCLUSION: This study finds palliative chemotherapy towards the end of life to be associated with increased odds of unplanned hospital admissions and hospital death. These findings can be used to inform discussions between patients and healthcare professionals towards the end of life.

The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

BACKGROUND: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. METHODS: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. RESULTS: Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. CONCLUSIONS: The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.

Costs of Early Invasive Breast Cancer in England Using National Patient-Level Data.

OBJECTIVES: This study aimed to use patient-level data to provide up-to-date estimates of early invasive breast cancer care costs by stage in England and to explore to what extent these costs varied based on patients' ages and geographic regions. METHODS: This study identified women aged 50 years and older who had been diagnosed with early invasive breast cancer between January 1, 2014, and December 31, 2015, using linked cancer registrations and routine hospital data sets generated from the usual care for all National Health Service trusts in England. Cost estimates were derived from hospital records in Hospital Episodes Statistics with additional chemotherapy and radiotherapy information from the national data sets. We fitted general linear regression models to analyze the cost data. The model that best fit the data was selected using the model selection criteria of Akaike information criterion. RESULTS: 55 662 women with early invasive breast cancer in England were included. The generalized linear model with log-gamma distribution fit the data best. The costs of breast cancer care for 1 year after diagnosis were strongly dependent on stage at diagnosis, controlling for other covariates. The estimated average per-patient hospital-related costs were £5167 at stage I, £7613 at stage II, and £13 330 at stage IIIA. Costs decreased with increasing age (P < .001) and varied across region (P < .001), deprivation level (P < .001), referral source (P < .01), presence of comorbidities (P< .001), and tumor receptor (ER/PR/HER2) status (P < .001). CONCLUSIONS: In England, the costs of breast cancer care increased with advancing stage of the disease at diagnosis. Breast cancer costs varied by age and geographic region.

Human Epidermal Growth Factor 2-positive Breast Cancer with Mammographic Microcalcification: Relationship to Pathologic Complete Response after Neoadjuvant Chemotherapy.

Purpose To determine the relationship between the presence or absence of mammographic calcifications in human epidermal growth factor receptor 2 (HER2)-positive breast cancers and pathologic complete response (pCR) to neoadjuvant chemotherapy and to determine other tumor and clinical characteristics that may be predictive of such a response. Materials and Methods A database of all patients with HER2-positive breast cancer who underwent neoadjuvant chemotherapy between 2007 and 2015 was retrospectively reviewed. Patient demographic characteristics, mammographic appearance, molecular subtype of cancer (luminal or nonluminal), radiologic response (based on breast magnetic resonance images), surgery, and pathologic response to treatment were recorded. Inter- and subgroup comparison was performed for presence of mammographic microcalcification and cancer subtype by using Mann-Whitney and χ2 tests and logistic regression. Results A total of 111 patients with a median age of 49 years (interquartile range, 40-57 years) were evaluated. Of these, 64.9% (72 of 111) had mammographic microcalcifications, 63.1% (70 of 111) had luminal B cancer, and 36.9% (41 of 111) had nonluminal HER2-positive cancer. Radiologic response to neoadjuvant chemotherapy was observed in 70.3% (78 of 111) of patients. Surgery was performed in 97.3% (108 of 111) of patients, and 30.6% (34 of 111) of patients underwent breast conservation. pCR was observed in 33.3% (37 of 111) of patients; 16.2% (18 of 111) showed residual ductal carcinoma in situ and 50.5% (56 of 111) had residual invasive disease. The pCR rate was the same (P = .21) in patients with mammographic microcalcification (29.2% [21 of 72]) as in those without calcification (41.0% [16 of 39]). The pCR rate in patients with nonluminal HER2-positive cancers (46.3% [19 of 41]) was higher (P = .01) than in those with luminal B cancers (25.7% [18 of 70]). pCR was associated with nonluminal HER2-positive subtype (odds ratio, 5.4; 95% confidence interval: 1.8, 16.0; P = .01) and complete radiologic response (odds ratio, 20.4; 95% confidence interval: 3.3, 126.6; P = .01). Conclusion Patients with HER2-positive cancer and mammographic microcalcification can achieve pCR after neoadjuvant chemotherapy. Nonluminal HER2-positive subtype and complete radiologic response are predictors of pCR.

Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial.

BACKGROUND: Adjuvant use of bisphosphonates can reduce the incidence of bone metastases in early breast cancer. Recurrence and survival seem to be improved only in postmenopausal patients, but the underlying mechanisms remain unclear. We investigated whether MAF amplification (a biomarker for bone metastasis) in primary tumours could predict the treatment outcomes of adjuvant zoledronic acid. METHODS: The study population included patients enrolled in the international, open-label, randomised, controlled, phase 3 AZURE trial at eligible UK sites who had stage II or III breast cancer and who gave consent for use of their primary tumour samples. Patients were randomly assigned (1:1) to receive standard adjuvant systemic therapy alone (control group) or with zoledronic acid every 3-4 weeks for six doses, then every 3-6 months until the end of 5 years. Minimisation took into account the number of involved axillary lymph nodes, clinical tumour stage, oestrogen-receptor status, type and timing of systemic therapy, menopausal status, statin use, and treating centre. The primary endpoint was disease-free survival; the secondary endpoint, invasive-disease-free survival, was the primary disease endpoint for the analysis in this report. MAF amplification was assessed by fluorescence in-situ hybridisation of two cores of breast tumour tissue in a microarray, done in a central laboratory by technicians unaware of treatment assignment. We used multivariate analyses to assess disease outcomes by intention to treat. We also assessed interactions between MAF-positive status and menopausal status on efficacy of zoledronic acid. The AZURE trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN79831382. FINDINGS: 1739 AZURE patients contributed primary tumour samples, of whom 865 (50%) had two assessable cores (445 in the control groups and 420 in the zoledronic acid group). 184 (21%) tumours were MAF positive (85 in the control groups and 99 in the zoledronic acid group) and the remaining tumours were MAF negative. At a median follow-up of 84·6 months (IQR 72·0-95·8), MAF status was not prognostic for invasive-disease-free survival in the control group (MAF-positive vs MAF-negative: hazard ratio [HR] 0·92, 95% CI 0·59-1·41), but was in the zoledronic acid group (0·52, 0·36-0·75). In patients with MAF-negative tumours, zoledronic acid was associated with higher invasive-disease-free survival than was control treatment (HR 0·74, 95% CI 0·56-0·98), but not in patients who had MAF-positive tumours. Additionally, among 121 patients not postmenopausal at randomisation with MAF-positive tumours, zoledronic acid was associated with lower invasive-disease-free survival (HR 2·47, 95% CI 1·23-4·97) and overall survival (2·27, 95% CI 1·04-4·93) than control treatment. INTERPRETATION: MAF status can predict likelihood of benefit from adjuvant zoledronic acid and merits further investigation as a potential companion diagnostic. FUNDING: Novartis Global and Inbiomotion.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study.

BACKGROUND: 30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved. METHODS: In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot. FINDINGS: Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040-1·132; p<0·0001; NSCLC curative: 1·045, 1·013-1·079; p=0·00033; breast palliative: 0·987, 0·977-0·996; p=0·00034; NSCLC palliative: 0·987, 0·976-0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634-3·312; p<0·0001; NSCLC curative: 3·371, 1·554-7·316; p<0·0001; NSCLC palliative: 2·667, 2·109-3·373; p<0·0001), and for patients with worse general wellbeing (performance status 2-4) versus those who were generally well (breast curative: 6·057, 1·333-27·513; p=0·0021; breast palliative: 6·241, 4·180-9·319; p<0·0001; NSCLC palliative: 3·384, 2·276-5·032; p<0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC. INTERPRETATION: Our findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical decision making in these hospitals. Furthermore, our results highlight the importance of collecting routine data beyond clinical trials to better understand the factors placing patients at higher risk of 30-day mortality, and ultimately improve clinical decision making. Our insights into the factors affecting risk of 30-day mortality will help treating clinicians and their patients predict the balance of harms and benefits associated with SACT. FUNDING: Public Health England.

Radiological and Pathological Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Brief Literature Review.

BACKGROUND: Early clinical response to neoadjuvant chemotherapy (NACT) in breast cancer correlates with pathological response at surgery. A tailored approach using biomarkers to predict response to NACT has become a research priority. Predictors of response can be divided into pathological and radiological biomarkers. Advances in gene expression profiling and diffusion-weighted MRI techniques are used to predict tumour response, and combinations thereof are the future of predicting response to NACT in early-stage breast cancer. METHODS: We searched Medline, CINAHL and Embase databases for studies on NACT. Key words used were NACT, breast cancer, pathological* complete response, primary chemotherapy, radiological*, predictor*, gene expression and biomarkers limited to the English language. Pathological markers such as tumour subtypes, topoisomerase IIα expression, Ki67, apoptosis-related markers and gene expression profiling were included. RESULTS: From 119 articles, 42 studies were reviewed; the majority of studies identified used pathological clinical response as an end point to NACT, whilst others used complete clinical response. Despite extensive studies, results regarding long-term survival following NACT and potential predictors are inconclusive. CONCLUSION: Future development of a predictive model combining key pathological and radiological biomarkers could provide personalised treatment regimens that improve pathological complete response rates and longer-term outcomes.

Retrospective analyses of optical coherence tomography in recurrent macular edema following intravitreal therapy in patients with retinal vein occlusion.

BACKGROUND: Optical coherence tomography has focused mainly on central subfield thickness to quantify macular edema in central and branch retinal vein occlusion. We examined macular fields other than the central subfield to determine if they are possibly independent indicators of recurrent macular edema. METHODS: Single center, retrospective, consecutive case study of patients with recurrent macular edema secondary to either central or branch retinal vein occlusion. Thickness estimates of serial domain optical coherence tomography macular fields were obtained at the time of recurrent macular edema and analyzed retrospectively. Changes were expressed as a percentage of previous baseline levels. Change in thickness at each retreatment episode as well as average changes in thickness were calculated for each macular field for each eye. Data were analyzed via analysis of variance and Fisher's post hoc analyses. The macular field which most frequently had the largest percent increase at the time of recurrence was also assessed using averages for each subject as well as for each retreatment episode. Individual episodes of recurrent macular edema were also examined to ascertain the frequency in which there was minimal foveal edema (<15 µm increase), but non-foveal edema was considered severe enough to warrant retreatment. RESULTS: 429 episodes of recurrent macular edema in 80 eyes were examined. In addition to the central subfield, the average mean change in thickness of the most affected quadrant (central vein occlusion) or hemisphere (branch vein occlusion) of the extrafoveal 3 mm band had the largest mean changes and also most frequently had the largest increases at the time of recurrent macular edema. In approximately 20 % of both central and branch occlusions, recurrent macular edema was detected in non-central macular fields in the absence of significant edema in the central subfield. CONCLUSIONS: Analyses of non-central macular fields as well as the central subfield may be useful in the early detection and treatment of recurrent macular edema in retinal vein occlusion.

Two or more dexamethasone intravitreal implants in treatment-naïve patients with macular edema due to retinal vein occlusion: subgroup analysis of a retrospective chart review study.

BACKGROUND: Dexamethasone intravitreal implant (DEX implant) is a biodegradable, sustained-release implant that releases dexamethasone for up to 6 months. We evaluated the efficacy and safety of DEX implant in the treatment of macular edema secondary to retinal vein occlusion (RVO) in treatment-naïve patients. METHODS: A multicenter, retrospective, open-label chart review study investigated the efficacy and safety of DEX implant treatment in 289 patients with macular edema secondary to branch or central RVO (BRVO, CRVO) who received ≥2 treatments with DEX implant in the study eye. Concomitant adjunctive RVO treatments were permitted. Data collected from the time of the first implant (baseline) to 3-6 months after the last implant included best-corrected visual acuity (BCVA) and central retinal thickness measured with optical coherence tomography. In this subgroup analysis, we evaluated outcomes in patients who had received no previous treatment for RVO complications. RESULTS: Thirty-nine patients were treatment-naïve at the time of their first DEX implant (18 BRVO, 21 CRVO). Before the initial DEX implant, the mean duration of macular edema in treatment-naïve patients was 4.9 months, mean central retinal thickness was 550 µm, and mean Early Treatment Diabetic Retinopathy Study BCVA was 8.5 lines (20/125 Snellen). Treatment-naïve patients received a mean of 2.9 implants, either as monotherapy (n = 12) or with adjunctive RVO treatments (n = 27). The mean interval between implants was 177 days. After the first through sixth implants, mean changes from baseline BCVA ranged from +3.0 - +8.0 lines, and mean decreases from baseline central retinal thickness ranged from 241-459 µm. BCVA improved in both BRVO and CRVO and in both phakic and pseudophakic eyes. Overall, 83.8 % of treatment-naïve patients gained ≥2 lines in BCVA, 70.3 % gained ≥3 lines in BCVA, and 56.4 % achieved central retinal thickness ≤250 µm. The most common adverse event was increased intraocular pressure. Fifteen treatment-naïve patients had intraocular pressure ≥25 mm Hg; none required laser or incisional glaucoma surgery. CONCLUSION: Treatment with 2 or more DEX implants had a favorable safety profile and improved visual acuity and anatomic outcomes when used, either alone or with adjunctive RVO therapy, as initial treatment for RVO-associated macular edema. TRIAL REGISTRATION: ClinicalTrials.gov NCT01411696 , registered on August 5, 2011.

Two or more dexamethasone intravitreal implants as monotherapy or in combination therapy for macular edema in retinal vein occlusion: subgroup analysis of a retrospective chart review study.

BACKGROUND: Dexamethasone intravitreal implant (DEX implant) is a sustained-release biodegradable implant approved for treatment of macular edema associated with retinal vein occlusion (RVO). The safety and efficacy of treatment of RVO-associated macular edema with sequential DEX implants in clinical practice was evaluated in patients who received DEX implant as monotherapy compared with patients who received DEX implant in combination with other RVO treatments. METHODS: A multicenter, retrospective, open-label chart review study (one study eye/patient) evaluated use of DEX implant and outcomes in 289 patients with branch or central RVO who received at least 2 DEX implant treatments in the study eye. Data were collected from the time of the first implant (baseline) to 3-6 months after the last implant. Subgroup analysis evaluated outcomes in patients receiving only DEX implant during the study versus patients receiving DEX implant plus adjunctive RVO treatments. Endpoints included best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change from baseline. RESULTS: DEX implant was used as monotherapy in 84 (29.1%) patients and in combination with other therapy in 205 (70.9%) patients. Mean number of DEX implant treatments received was 3.1 in the monotherapy group and 3.3 in the combination therapy group (P = 0.344). Mean time between implants was longer in the combination therapy group (177 vs. 151 days, P < 0.001). Mean change from baseline BCVA after the first through sixth DEX implants ranged from +0.6 to +3.4 lines in the monotherapy group and +1.3 to +2.8 lines in the combination therapy group. Mean decrease from baseline CRT ranged from 165 to 230 µm in the monotherapy group and 136 to 175 µm in the combination therapy group. Increased intraocular pressure was more common in the combination therapy group. CONCLUSIONS: Treatment of RVO-associated macular edema with at least 2 sequential DEX implants was safe and effective both when used alone and when combined with other RVO treatments. Improvements in BCVA and CRT were generally similar in the monotherapy and combined therapy groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01411696 .

Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.

BACKGROUND: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. FINDINGS: 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). INTERPRETATION: These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. FUNDING: Novartis Global and NIHR Cancer Research Network.

PSMD9 expression predicts radiotherapy response in breast cancer.

BACKGROUND: More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines. METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation. RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy. CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

Breast-cancer adjuvant therapy with zoledronic acid.

BACKGROUND: Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. METHODS: In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. RESULTS: At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. CONCLUSIONS: These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).