Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study.

BACKGROUND: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC). PATIENTS AND METHODS: Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib. RESULTS: Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel. CONCLUSIONS: T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations. CLINICALTRIALSGOV IDENTIFIER: NCT00934856.

Sequence analysis and structural implications of rotavirus capsid proteins.

Rotavirus is the major cause of severe virus-associated gastroenteritis worldwide in children aged 5 and younger. Many children lose their lives annually due to this infection and the impact is particularly pronounced in developing countries. The mature rotavirus is a non-enveloped triple-layered nucleocapsid containing 11 double stranded RNA segments. Here a global view on the sequence and structure of the three main capsid proteins, VP2, VP6 and VP7 is shown by generating a consensus sequence for each of these rotavirus proteins, for each species obtained from published data of representative rotavirus genotypes from across the world and across species. Degree of conservation between species was represented on homology models for each of the proteins. VP7 shows the highest level of variation with 14-45 amino acids showing conservation of less than 60%. These changes are localised to the outer surface alluding to a possible mechanism in evading the immune system. The middle layer, VP6 shows lower variability with only 14-32 sites having lower than 70% conservation. The inner structural layer made up of VP2 showed the lowest variability with only 1-16 sites having less than 70% conservation across species. The results correlate with each protein's multiple structural roles in the infection cycle. Thus, although the nucleotide sequences vary due to the error-prone nature of replication and lack of proof reading, the corresponding amino acid sequence of VP2, 6 and 7 remain relatively conserved. Benefits of this knowledge about the conservation include the ability to target proteins at sites that cannot undergo mutational changes without influencing viral fitness; as well as possibility to study systems that are highly evolved for structure and function in order to determine how to generate and manipulate such systems for use in various biotechnological applications.

A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation.

Genetic variants in il2 and il2ra have been associated with autoimmune disease susceptibility in both genome-wide association studies (GWAS) in humans and in genetic linkage studies in experimental models of autoimmunity. Specifically, genetic variants resulting in a low IL-2 phenotype are susceptibility alleles while variants resulting in a high IL-2 phenotype are resistance alleles. The association of high IL-2 phenotypes with resistance has been attributed primarily to the T cell intrinsic promotion of regulatory T cell development, maintenance, and function; however, IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells. Here, we have uncovered a novel T cell extrinsic mechanism whereby IL-2 promotes both IFN-γ and IL-27 production from tissue resident macrophages which in turn dampen the differentiation of pathogenic Th17 cells.

Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study.

BACKGROUND: Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease. METHODS: A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). RESULTS: Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable. CONCLUSION: Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.

Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality.

BACKGROUND: Adjuvant endocrine therapy is recommended for women with oestrogen receptor-positive breast cancer, but many women do not take the medication as directed and they stop treatment before completing the standard 5-year duration. METHODS: This retrospective cohort study conducted between 1993 and 2008 of all women with incident breast cancer, who are residing in the Tayside region of Scotland, examined adherence to prescribed adjuvant tamoxifen or aromatase inhibitors (AIs). Survival analysis examined the effect of adherence on all-cause mortality, breast cancer death and recurrence, using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. RESULTS: A total of 3361 women with breast cancer were followed for a median 4.47 years (interquartile range (IQR)=2.04-8.55). The median overall adherence was 90% (IQR=90-100%), but the annual adherence reduced after a longer period from diagnosis. Low adherence of <80% was associated with poorer survival (hazard ratios=1.20; 95% confidence interval=1.03-1.40, P=0.019). There was no significant difference for low adherence over the treatment period and recurrence, or breast cancer death, but patients with high annual adherence for 5 years had better outcomes than those with 3 or less. CONCLUSION: Low adherence to all adjuvant endocrine therapy for women with breast cancer, whether tamoxifen or AI, increases the risk of death.

Impact of multidisciplinary team management in head and neck cancer patients.

BACKGROUND: We analysed the outcomes of 726 cases of primary head and neck cancer patients managed between 1996 and 2008, including those managed in the multidisciplinary clinic or team setting (MDT) and those managed outside of an MDT by individual disciplines (non-MDT) in the same institution. METHODS: Data were collected from the Hospital Based Cancer Registry and a database within the Head and Neck Cancer Clinic. Univariable comparisons and multivariable analyses were performed using a logistic regression model. Survival by staging was analysed. Comparisons of management and outcomes were made between MDT and non-MDT patients. RESULTS: 395 patients (54%) had been managed in the MDT vs 331 patients (46%) non-MDT. MDT patients were more likely to have advanced disease (likelihood ratio χ(2)=44.7, P<0.001). Stage IV MDT patients had significantly improved 5-year survival compared with non-MDT patients (hazard ratio=0.69, 95% CI=0.51-0.88, P=0.004) and more synchronous chemotherapy and radiotherapy (P=0.004), and the non-MDT group had more radiotherapy as a single modality (P=0.002). CONCLUSIONS: The improved survival of MDT-managed stage IV patients probably represents both the selection of multimodality treatment and chemotherapeutic advances that these patients received in a multidisciplinary team setting by head and neck cancer specialists as opposed to cancer generalists in a non-MDT setting.

Characterization and molecular epidemiology of rotavirus strains recovered in Northern Pretoria, South Africa during 2003-2006.

Rotavirus infection is the most common cause of severe dehydrating gastroenteritis in infants and young children and remains a significant clinical problem worldwide. The severity and the burden of rotavirus disease could be reduced through the implementation of an effective vaccine. The aim of this study was to characterize rotavirus strains circulating in the local community as part of an ongoing hospital burden of disease study when a G1P[8] rotavirus vaccine candidate was being evaluated in the same community. From 2003 through 2006, 729 rotavirus-positive stool specimens were collected from children <5 years of age who were treated for diarrhea at Dr George Mukhari Hospital, Ga-Rankuwa, South Africa. Molecular characterization of the strains was performed by polyacrylamide gel electrophoresis and genotyping of the VP4 and VP7 alleles using well-established seminested multiplex reverse-transcription polymerase chain reaction methods. In 2003, 62% of strains exhibited the short rotavirus electropherotype, and the most common rotavirus strain was G2P[4]. In subsequent years, predominant rotavirus strains included G1P[8] and G1P[6] in 2004, G3P[8] and G3P[6] in 2005, and G1P[8] in 2006. For the 4 years of the study, rotavirus strains with P[6] genotype were detected in 25% of all rotavirus-positive specimens. In addition, unusual G12P[6] and G8 strains were detected at a low frequency. These results reflect the diversity of rotavirus strains circulating in South African communities.

Diversity of rotavirus VP7 and VP4 genotypes in Northwestern Nigeria.

BACKGROUND: Nigeria has recently been ranked third among the 10 countries with the greatest number of rotavirus disease-associated deaths per year. Estimates attribute up to 33,000 deaths annually to rotavirus disease in Nigerian children <5 years old. Although the introduction of the new oral, live attenuated rotavirus vaccines may not occur for another 4-6 years in developing countries, background data on burden of disease, cost of rotavirus disease, and characterization of circulating strains is required to hasten this introduction to children who would clearly benefit from the intervention. METHODS: Between July 2002 and July 2004, fecal specimens were collected from 869 infants and young children <5 years of age presenting with diarrhea in Kaduna, Kebbi, Sokoto, and Zamfara states in northwestern Nigeria. In addition, 194 control specimens were also collected from children matched for age. Specimens were screened for the presence of rotavirus antigens. Rotavirus-positive specimens were further analyzed to determine electropherotype, subgroup specificity, and G and P genotypes. RESULTS: Rotavirus was detected in 18% of children with diarrhea and 7.2% of the age-matched case control subjects. The highest rotavirus burden was detected in children aged <6 months. The majority of the rotavirus-positive specimens revealed viruses of long electropherotypes, subgroup II specificity, and G1P[8] genotypes. Furthermore, more than a quarter of specimens (37%) displayed mixed G and P genotypes, and almost a third could not be genotyped. CONCLUSIONS: The high numbers of mixed rotavirus infections highlight the multitude of enteric pathogens to which children in African countries are exposed. Data on circulating rotavirus strains serve to inform African government officials to the serious health threat posed by rotavirus in their respective countries and to document the diversity of strains before vaccine introduction.

p53 mutation, deprivation and poor prognosis in primary breast cancer.

BACKGROUND: The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities. METHODS: p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival. RESULTS: p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan-Meier logrank chi(2)=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan-Meier logrank chi(2)=6.791, P=0.009) than women of deciles 1-9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths). CONCLUSION: p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.

Increased mortality in HER2 positive, oestrogen receptor positive invasive breast cancer: a population-based study.

BACKGROUND: This study assessed the impact of human epidermal growth factor receptor 2 (HER2) status on the outcomes in an unselected population of breast cancer patients who did not receive HER2-targeted therapy. METHODS: HER2 status by immunohistochemistry and fluorescence in situ hybridisation was compared with clinicopathological data, overall survival (OS) and disease-free survival (DFS) for all patients presenting with breast cancer over 3 years. RESULTS: In 865 patients (median follow up 6.02 years), HER2 positivity was identified in 13.3% of all cancers and was associated with higher tumour grade (P<10(-8)), lymphovascular invasion (P<0.001) and axillary nodal metastasis (P=0.003). There was a negative association with oestrogen-receptor (ER) and progesterone-receptor expression (P<10(-8)), but the majority (57%) of HER2+tumours were ER+HER2 positivity was associated with poorer OS (P=0.0046) and DFS (P=0.0001) confined to the lymph node-positive (LN+) and ER+ subgroups. CONCLUSION: HER2-positive cancers were less common in this population-based cohort than most selected series. The association of HER2 positivity with poor prognosis was confined to the ER+ and LN+ subgroups. The survival deficit for the 7.5% of patients with ER+/HER2+ cancer compared with ER+/HER2- patients points to a significant subgroup of women who may not (currently) be considered for HER2-directed therapy.

Evaluation of a surveillance programme for women with a family history of breast cancer.

AIM: To establish health related costs and benefits of clinical services for women at increased familial risk of breast cancer. METHODS: Analysis of costs and outcomes for one UK regional service, supplemented with data from a multinational collaborative study. Main outcome measures were aggregate costs for regular clinical examination, mammographic screening and further investigations; breast cancer incidence; proportion of cancers detected at "early" or "late" stage, compared with corresponding data for unscreened women of comparable age; survival in relation to stage at diagnosis; itemised and aggregate costs of management for "early" and "late" stage breast cancer; hence direct health care costs per quality adjusted life-year (QALY) gained. RESULTS: The surveillance programme costs pound1500 (euro1600, US$2100) per woman (over 15 years). Breast cancer incidence is close to 6 per thousand examinations; 75% of tumours are detected through screening and 77% are "early" (path stage 1 or 2). Corresponding figures for unscreened women (including relatives of those attending the breast cancer family clinic) indicate that surveillance achieves a beneficial "stage shift", with reduction in treatment costs and improvement in survival, in about 22% of cases. CONCLUSIONS: The current clinical service for women at familial risk of breast cancer costs about pound4800 (euro5200, US$6800) per QALY gained. That figure is sensitive to the rate of detection of breast cancer and the degree of beneficial stage shift achieved. Within the realistic range of estimates for these two parameters, the cost per QALY may be as high as pound14,000 (euro15,300, US$20,000) or as low as pound1000 (euro1100, US$1400).

Suspected malignant cord compression - improving time to diagnosis via a 'hotline': a prospective audit.

The aim of the study was to achieve earlier diagnosis of malignant cord compression (MCC) using urgent magnetic resonance imaging (MRI) for selected patients. A comparison was carried out of the current prospective audit of 100 patients referred by a general practitioner or a consultant over 32 months with both a previous national Clinical Research and Audit Group (CRAG) prospective audit (324 cases of MCC) and an earlier retrospective audit of 104 patients referred with suspected MCC. A telephone hotline rapid-referral process for patients with known malignancy and new symptoms (severe nerve root pain +/- severe back pain) was designed. Patients were considered for urgent MRI after discussion with a senior clinician responsible for the hotline. Appropriate referrals were discussed with radiology and oncology ensuring timely MRI reporting and intervention. The main outcome measures are as follows: time from referral to diagnosis; time from the onset of symptoms to diagnosis; and mobility at diagnosis. A total of 50 patients (52%) of those scanned had either MCC (44) or malignant nerve root compression (6) compared with the earlier rate of 23 out of 104 patients (22%). Ten out of 44 MCC patients (23%) were paralysed at diagnosis, compared with 149 out of 324 (46%) in the CRAG audit. Time from reporting pain to diagnosis was 32 days compared with 89 days in the CRAG audit. Median time from referral to diagnosis was 1 day, again considerably shorter than the CRAG audit time of 15 days (interquartile (IQ) range: 3-66). In patients at risk of MCC, fast-track referral with rapid access to MRI reduces time between symptom onset and diagnosis, improves mobility at diagnosis and reduces the number of negative MRI scans.

The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

A genomewide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, Cdc13 binds telomeric DNA to recruit telomerase and to "cap" chromosome ends. In temperature-sensitive cdc13-1 mutants telomeric DNA is degraded and cell-cycle progression is inhibited. To identify novel proteins and pathways that cap telomeres, or that respond to uncapped telomeres, we combined cdc13-1 with the yeast gene deletion collection and used high-throughput spot-test assays to measure growth. We identified 369 gene deletions, in eight different phenotypic classes, that reproducibly demonstrated subtle genetic interactions with the cdc13-1 mutation. As expected, we identified DNA damage checkpoint, nonsense-mediated decay and telomerase components in our screen. However, we also identified genes affecting casein kinase II activity, cell polarity, mRNA degradation, mitochondrial function, phosphate transport, iron transport, protein degradation, and other functions. We also identified a number of genes of previously unknown function that we term RTC, for restriction of telomere capping, or MTC, for maintenance of telomere capping. It seems likely that many of the newly identified pathways/processes that affect growth of budding yeast cdc13-1 mutants will play evolutionarily conserved roles at telomeres. The high-throughput spot-testing approach that we describe is generally applicable and could aid in understanding other aspects of eukaryotic cell biology.

The detection and molecular characterization of human G12 genotypes in South Africa.

The last decade has seen an increase in the detection of rotavirus strains other than G1-G4 emerging or even predominating in some settings. The performance of the current rotavirus vaccines against unusual or rare circulating rotavirus serotypes cannot be predicted and continuous monitoring of wild type rotaviruses will remain a priority. Routine molecular rotavirus surveillance conducted in the Gauteng Province, South Africa during 2004, resulted in the detection of strains that could not typed using standard G specific genotyping primers. Sequencing of the first round amplicons revealed 19 serotype G12P[6] strains and one G12P[8] strain. Phylogenetic analyses of the G12 strains indicated that these strains are probably a recent introduction into South Africa and emerged from a strain related to the Indian isolate ISO-5. The association of the South African G12s with the P[6] genotype may suggest a mechanism for unusual strains to become more ecologically suited to local population transmission dynamics. This is the first report of serotype G12 strains on the African continent and continued surveillance will be required to track the emergence of G12 strains in Africa.

Effect of postoperative radiotherapy on autologous deep inferior epigastric perforator flap volume after immediate breast reconstruction.

BACKGROUND: The effect of postoperative radiotherapy following autologous flap breast reconstruction is controversial. The aim of this study was to measure whether adjuvant radiotherapy following immediate deep inferior epigastric perforator (DIEP) free flap breast reconstruction affected flap volume. METHODS: Sixty-eight women underwent immediate autologous DIEP flap reconstruction following mastectomy for breast cancer. Twenty-two of the 68 received postoperative radiotherapy (45Gy in 20 fractions over 4 weeks). Intraoperative flap volume data were collected prospectively. Volumetric assessment was carried out a minimum of 1 year after surgery. Patients who had volume adjustment surgery after initial reconstruction were analysed separately. RESULTS: The mean age of the women was 52 (range 37-69) years and median follow-up was 3.5 (range 1-10) years. There was no statistically significant difference in volume change between patients who had and those who did not have postreconstruction radiotherapy for the whole cohort (median reduction 65 versus 0 ml) or when women who had undergone further volume adjustment surgery were excluded. CONCLUSION: In this study postoperative radiotherapy did not significantly affect breast volume after DIEP flap reconstruction. The potential need for postoperative radiotherapy should not deter women from undergoing immediate DIEP flap breast reconstruction.

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size. METHODS: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). INTERPRETATION: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer.

Increasing duration of tamoxifen therapy improves survival in women with breast cancer but the impact of adherence to tamoxifen on mortality is unclear. This study investigated whether women prescribed tamoxifen after surgery for breast cancer adhered to their prescription and whether adherence influenced survival. A retrospective cohort study of all women with incident breast cancer in the Tayside region of Scotland between 1993 and 2002 was linked to encashed prescription records to calculate adherence to tamoxifen. Survival analysis was used to determine the effect of adherence on all-cause mortality. In all 2080 patients formed the study cohort with 1633 (79%) prescribed tamoxifen. The median duration of use was 2.42 years (IQR=1.04-4.89 years). Longer duration was associated with better survival but this varied over time. The hazard ratio for mortality in relation to duration at 2.4 years was 0.85, 95% CI=0.83-0.87. Median adherence to tamoxifen was 93% (interquartile range=84-100%). Adherence <80% was associated with poorer survival, hazard ratio 1.10, 95% CI=1.001-1.21. Persistence with tamoxifen was modest with only 49% continuing therapy for 5 years of those followed up for 5 years or more. Increased duration of tamoxifen reduces the risk of death, although one in two women do not complete the recommended 5-year course of treatment. A significant proportion of women have low adherence to tamoxifen and are at increased risk of death.