Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Combination of acellular dermal matrix with a de-epithelialised dermal flap during skin-reducing mastectomy and immediate breast reconstruction.

Introduction Patients with large ptotic breasts undergoing immediate implant-based reconstruction often require skin-reducing mastectomy to optimise the aesthetic outcome. However, healing complications, especially at the resulting inverted T-junction, leading to wound dehiscence, infection, skin necrosis, implant exposure and failed reconstruction have been widely reported. We present an innovative approach for immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling to protect and support the implant, while improving clinical outcomes in this challenging group of patients. Materials and methods Demographic, tumour and surgical data were reviewed for patients undergoing Wise pattern (T-scar) skin-reducing mastectomies with immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling. Results This technique was successfully employed to reconstruct five large pendulous breasts in four breast cancer patients with a median age of 50.5 years (range 34-61 years) who were not suitable for, or had declined, flap-based reconstruction. The acellular dermal matrices used were SurgiMend®, StratticeTM and Braxon® and the expandable implants were placed in the sub-pectoral (n = 3) and pre-pectoral (n = 1) planes. The technical steps and clinical outcomes are presented. One patient experienced T-junction breakdown overlying the de-epithelialised dermis without implant loss. Conclusion The combination of an acellular dermal matrix and a dermal sling provides a double-layer 'water-proofing' and support for the implants inferiorly, avoiding T-junction breakdown complications, since any dehiscence is on to well-vascularised dermis. Furthermore, the acellular dermal matrix stabilises the implant in the large mastectomy cavity (pocket control). This approach provides a viable option which facilitates mastectomy and immediate implant reconstruction in large-breasted patients.

An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis.

BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine.

Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

Tumour bed clip localisation for targeted breast radiotherapy: compliance is proportional to trial-related research activity: tumour bed clip localisation in breast radiotherapy.

BACKGROUND: In breast cancer, with the increasing use of intensity-modulated radiotherapy (IMRT), the need for accurate tumour bed localisation is paramount. We determined current practice of clip usage in patients referred to a regional centre for radiotherapy following breast conserving surgery. We also investigated whether participation of surgical units in IMRT trials, where tumour bed clip use is emphasised, was associated with clip insertion. METHODS: A retrospective cohort study of consecutive CT planning images (n = 205), of breast cancer patients treated with radiotherapy following breast conserving surgery. Presence and number of clips; referring hospital and referring surgeon of the patient was recorded. This was correlated to previous participation of referring hospital to IMRT trials. RESULTS: Of 196 eligible patients, 126 (64%) had clips sited, of which 15 (12%) had two or fewer clips. Five referring hospitals were high recruiters (≥14 patients), and five hospitals were low/non-recruiters (≤1 patient) to IMRT trials. Of patients from low/non-recruiting centres, 29 of 43 (67%) had clips omitted, compared to 41 of 153 (27%) from high-recruiting centres (p < 0.001). Median number of clips used in centres recruiting high numbers of patients was four, compared to zero in low recruiting centres. Ten of 31 referring surgeons routinely omitted clips. CONCLUSION: Despite inclusion in national guidelines, clip insertion has not become routine in the UK in patients undergoing breast conserving surgery. However, hospitals involved in breast radiotherapy randomised controlled trials are more compliant with clip usage recommendations. Auditing of clip insertion should be considered as a quality control marker in breast surgery.

Patterns of metastatic spread in early breast cancer.

AIMS: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. PATIENTS AND METHODS: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. RESULTS: Of the 177 patients, 114 (64%) were BM-/LN-, 38 (22%) BM-/LN+, 19 (11%) BM+/LN- and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non-significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF-C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. CONCLUSION: These findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers.

Results of a national training programme in sentinel lymph node biopsy for breast cancer.

BACKGROUND: New Start, a structured, validated, multidisciplinary training programme in sentinel lymph node biopsy (SLNB), was established to allow the introduction and rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice across the UK. METHODS: Multidisciplinary teams attended a theory/skills laboratory course, following which they performed 30 consecutive SLNBs, either concurrently with their standard axillary staging procedure (training model A) or as stand-alone SLNB (training model B). SLNB was performed according to a standard protocol using the combined technique of isotope ((99m) Tc-labelled albumin colloid) and blue dye. An accredited New Start trainer mentored the first five procedures in the participant's hospital, or all 30 if stand-alone. Validation standards for model A and B were a localization rate of at least 90 per cent. In addition, for model A only, in which a minimum of ten patients were required to be node-positive, a false-negative rate (FNR) of 10 per cent or less was required. RESULTS: From October 2004 to December 2008, 210 SLNB-naive surgeons, in 103 centres, performed 6685 SLNB procedures. The overall sentinel lymph node (SLN) localization rate was 98·9 (95 per cent confidence interval 98·6 to 99·1) per cent (6610 of 6685) and the FNR 9·1 (7·9 to 10·5) per cent (160 of 1757). The FNR was related to nodal yield, ranging from 14·8 per cent for one node and declining to 9·7, 6·6, 4·7 and 4·1 per cent for two, three, four and more than four SLNs respectively. No learning curve was identified for localization or FNR. CONCLUSION: The programme successfully trained a wide range of UK breast teams to perform safe SLNB and suggested that a standard injection protocol and structured multidisciplinary training can abolish learning curves.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer.

BACKGROUND: There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid. METHODS: One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients. RESULTS: Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%. CONCLUSION: The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope.

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial.

AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.

Measuring the accuracy of diagnostic imaging in symptomatic breast patients: team and individual performance.

OBJECTIVE: The combination of mammography and/or ultrasound remains the mainstay in current breast cancer diagnosis. The aims of this study were to evaluate the reliability of standard breast imaging and individual radiologist performance and to explore ways that this can be improved. METHODS: A total of 16,603 separate assessment episodes were undertaken on 13,958 patients referred to a specialist symptomatic breast clinic over a 6 year period. Each mammogram and ultrasound was reported prospectively using a five-point reporting scale and compared with final outcome. RESULTS: Mammographic sensitivity, specificity and receiver operating curve (ROC) area were 66.6%, 99.7% and 0.83, respectively. The sensitivity of mammography improved dramatically from 47.6 to 86.7% with increasing age. Overall ultrasound sensitivity, specificity and ROC area was 82.0%, 99.3% and 0.91, respectively. The sensitivity of ultrasound also improved dramatically with increasing age from 66.7 to 97.1%. Breast density also had a profound effect on imaging performance, with mammographic sensitivity falling from 90.1 to 45.9% and ultrasound sensitivity reducing from 95.2 to 72.0% with increasing breast density. CONCLUSION: The sensitivity ranges widely between radiologists (53.1-74.1% for mammography and 67.1-87.0% for ultrasound). Reporting sensitivity was strongly correlated with radiologist experience. Those radiologists with less experience (and lower sensitivity) were relatively more likely to report a cancer as indeterminate/uncertain. To improve radiology reporting performance, the sensitivity of cancer reporting should be closely monitored; there should be regular feedback from needle biopsy results and discussion of reporting classification with colleagues.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS: The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS: Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS: On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS: In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

A population-based validation of the prognostic model PREDICT for early breast cancer.

INTRODUCTION: Predict (www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! (www.adjuvantonline.com). METHOD: The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989-1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes. RESULTS: Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20-35. CONCLUSION: In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer.

Patient and tumour characteristics, management, and age-specific survival in women with breast cancer in the East of England.

BACKGROUND: Breast cancer relative survival (BCRS), which compares the observed survival of women with breast cancer with the expected survival of women for the whole population of the same age, time period, and geographical region, tends to be poorer in older women, but the reasons for this are not clear. We examined the influence of patient and tumour characteristics, and treatment on BCRS to see whether these could explain the age-specific effect. METHODS: Data for 14,048 female breast cancer patients diagnosed from 1999 to 2007, aged 50 years or over were obtained from the Eastern Cancer Registration and Information Centre. We estimated relative 5- and 10-year survival for patients in four age groups (50-69, 70-74, 75-79, and 80+ years). We also modelled relative excess mortality (REM) rate using Poisson regression adjusting for patient characteristics and treatment. The REMs derived from these models quantify the extent to which the hazard of death differs from the hazard in the reference category, after taking into account the background risk of death in the general population. We compared the results with those obtained for breast cancer-specific mortality, analysed using multivariate Cox regression. RESULTS: Median follow-up time was 4.7 years. Relative 5-year survival was 89, 81, 76, and 70% for patients aged 50-69, 70-74, 75-79, and 80+ years, respectively. Corresponding relative 10-year survival was 84, 77, 67, and 66%. Unadjusted REM was 1.93, 2.74, and 3.88 for patients aged 70-74, 75-79, and 80+ years, respectively, (50-69 years as reference). The equivalent hazard ratios from the Cox model were 1.88, 2.45, and 3.81. These were attenuated after adjusting for confounders (REM - 1.49, 1.36, and 1.23; Cox - 1.47, 1.50, and 1.76). CONCLUSION: We confirmed poorer BCRS in older women in our region. This was partially explained by known prognostic factors. Further research is needed to determine whether biological differences or suboptimal management can explain the residual excess mortality.

Measuring performance in clinical breast examination.

BACKGROUND: Clinical breast examination (CBE) remains an essential part of triple assessment of breast lumps, but to date there are no performance measures for clinicians using this technique. The aim of this retrospective audit was to compare the performance and accuracy of CBE to identify key indicators that could be used to monitor performance prospectively. METHODS: Clinical examination findings (E1, normal, to E5, malignant) for 16,585 patients who had CBE as part of triple assessment were obtained from electronic medical records. The performance of CBE, by age group, mammographic density and clinician, was assessed by calculating the sensitivity, specificity and area under the receiver operating characteristic (ROC) curve. RESULTS: There was marked variation in sensitivity between clinicians (range 44.6-65.9 per cent). There was a strong downward trend in the percentage classified as E5 as sensitivity for breast cancer detection decreased, and a corresponding strong downward trend in the proportion of E4 and E5 cancers classified as E5. Both of these measures could be used as indicators to monitor CBE performance. CONCLUSION: The performance measures outlined here could help to identify clinicians who have a lower sensitivity for CBE and who may therefore require feedback and further training.

The accuracy of digital infrared imaging for breast cancer detection in women undergoing breast biopsy.

BACKGROUND: Mammography has a lower sensitivity for breast cancer detection in younger women and those with dense breasts. Recent improvements in digital infrared breast imaging suggest there may be a role for this technology and we have studied its performance in 100 women prior to breast needle core biopsy (CB). METHODS: All patients were imaged using a digital infrared breast (DIB) scan (Sentinel BreastScan) prior to breast biopsy. Analysis of the infrared scans was performed, blinded to biopsy results, in four different ways: Sentinel screening report, Sentinel artificial intelligence (neural network), expert manual review and NoTouch BreastScan a novel artificial intelligence programme. RESULTS: Of 106 biopsies performed in 100 women, 65 were malignant and 41 were benign. Sensitivity of Sentinel screening (53%) and Sentinel neural network (48%) was low but analysis with NoTouch software (70%) was much closer to expert manual review (78%). Sensitivity (78%) and specificity (75%) using NoTouch BreastScan were higher in women under 50 and the combination of mammography and DIB, with NoTouch interpretation, in this age group resulted in a sensitivity of 89%. CONCLUSION: DIB using NoTouch is an effective adjunctive test for breast cancer detection in women under 70 and appears to be particularly effective in women under 50 where maximal sensitivity (78%) and specificity (75%) were observed. The combined sensitivity of NoTouch BreastScan and mammography in women under 50 was encouraging at 89%, suggesting a potential way forward for a dual imaging approach in this younger age group.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.