Bone marrow micrometastases in early breast cancer–30-year outcome

Background: Micrometastases in bone marrow of women with early breast cancer were first identified immunocytochemically in the 1980s. We report on the original cohort of women with a median follow-up of 30 years. Patients and Methods: In total, 350 women with primary breast cancer had eight bone marrow aspirates examined with antibody to epithelial membrane antigen. Data on long-term mortality were obtained via record linkage to death certification. Results: At a 30-year median follow-up, 79 out of 89 (89%) patients with micrometastases have died compared with 202 out of 261 (77%) without (hazard ratio = 1.46 (95% CI 1.12-1.90), P = 0.0043). Most marked effect of micrometastases on overall survival (OS) was seen in patients aged <= 50 at surgery (N = 97, P = 0.012), and on all patients within 10 years of diagnosis. In multivariable analyses, the presence of micrometastases was no longer a statistically significant prognostic factor. Conclusions: Bone marrow micrometastases are predictive for OS, particularly in the first decade and in younger patients

Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma

BACKGROUND: Patients with stage I testicular seminoma are typically diagnosed at a young age and treatment is associated with low relapse and mortality rates. The long-term risks of adjuvant radiotherapy in this patient group are therefore particularly relevant. METHODS: We identified patients and obtained treatment details from 12 cancer centres (11 United Kingdom, 1 Norway) and ascertained second cancers and mortality through national registries. Data from 2629 seminoma patients treated with radiotherapy between 1960 and 1992 were available, contributing 51,151 person-years of follow-up. RESULTS: Four hundred and sixty-eight second cancers (excluding non-melanoma skin cancers) were identified. The standardised incidence ratio (SIR) was 1.61 (95% confidence interval (CI): 1.47-1.76, P<0.0001). The SIR was 1.53 (95% CI: 1.39-1.68, P<0.0001) when the 32 second testicular cancers were also excluded. This increase was largely due to an excess risk to organs in the radiation field; for pelvic-abdominal sites the SIR was 1.62 (95% CI: 1.43-1.83), with no significant elevated risk of cancers in organs elsewhere. There was no overall increase in mortality with a standardised mortality ratio (SMR) of 1.06 (95% CI: 0.98-1.14), despite an increase in the cancer-specific mortality (excluding testicular cancer deaths) SMR of 1.46 (95% CI: 1.30-1.65, P<0.0001). CONCLUSION: The prognosis of stage I seminoma is excellent and it is important to avoid conferring long-term increased risk of iatrogenic disease such as radiation-associated second cancers

Can patient decision aids reduce decisional conflict in a de-escalation of breast radiotherapy clinical trial? The PRIMETIME Study Within a Trial implemented using a cluster stepped-wedge trial design

Background For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design.Methods PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect.Results Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video.Conclusion The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids

A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology

Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as 'AD' or 'non-AD' on the basis of their CSF T-tau and amyloid Aβ1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aβ1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility

Women's Free-text Comments on their Quality of Life: An Exploratory Analysis from the UK Standardisation of Breast Radiotherapy (START) Trials for Early Breast Cancer.

Aims Exploratory analysis of patients' unsolicited written comments in the first 2 years of the Standardisation of Breast Radiotherapy (START) trial quality of life study highlighted a potential effect of non-treatment-related problems on the ratings and interpretation of patient self-reported questionnaires. At 5 years of follow-up all eligible subjects were invited to write comments to further explore these findings.Materials and methods Using inductive qualitative methods informed by the exploratory analysis, comments were allocated to relevant themes. Key patient-reported outcome measures (PROMs), clinical and demographic factors were collated for patients who did and did not comment at 5 years and comparisons between the groups explored.Results Of 2208 women completing baseline PROMs, 482 proffered comments from 0 to 24 months, forming nine distinct themes, including chronic conditions, life events and psychosocial concerns. At 5 years, 1041/1727 (60.3%) women contributed comments, of whom 500 randomly selected participants formed the sample for analysis. Findings revealed comorbidity, impaired physical functioning and psychosocial problems as key themes, with prevalent adverse effects from local and systemic treatments. Eight new themes emerged at 5 years, including ageing, concerns about future cancer and positive aspects of care. Women commenting were better educated, slightly older and more likely to have had chemotherapy compared with non-commenters. They had significantly worse PROM scores for global health and key quality of life domains relevant to the difficulties they revealed.Conclusions Difficult personal circumstances and other health concerns affected many women's PROM ratings at 5 years of follow-up, in addition to ongoing cancer treatment effects. Greater attention to multiple sources of distress and adversity could facilitate personalised care and aid interpretation of PROMs

<i>ESR1</i> Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor-Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials.

Purpose ESR1 mutations are acquired frequently in hormone receptor-positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.Experimental design The phase III EFECT and SoFEA trials randomized patients with hormone receptor-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.Results ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0-2.6] on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39-0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (P = 0.69).Conclusions Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant