Survival and disease characteristics of de novo versus recurrent metastatic breast cancer in a cohort of young patients

Abstract: Background: It is not clear how the pathology, presentation and outcome for patients who present with de novo metastatic breast cancer (dnMBC) compare with those who later develop distant metastases. DnMBC is uncommon in younger patients. We describe these differences within a cohort of young patients in the United Kingdom. Methods: Women aged 40 years or younger with a first invasive breast cancer were recruited to the prospective POSH national cohort study. Baseline clinicopathological data were collected, with annual follow-up. Overall survival (OS) and post-distant relapse-free survival (PDRS) were assessed using Kaplan–Meier curves. Results: In total, 862 patients were diagnosed with metastatic disease. DnMBC prevalence was 2.6% (76/2977). Of those with initially localised disease, 27.1% (786/2901) subsequently developed a distant recurrence. Median follow-up was 11.00 years (95% CI 10.79–11.59). Patients who developed metastatic disease within 12 months had worse OS than dnMBC patients (HR 2.64; 1.84–3.77). For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation. Conclusions: Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. A gBRCA2 mutation was overrepresented in dnMBC

Age standardisation – an indigenous standard?

The study of inequities in health is a critical component of monitoring government obligations to uphold the rights of Indigenous Peoples. In Aotearoa/New Zealand the indigenous Māori population has a substantially younger age structure than the non-indigenous population making it necessary to account for age differences when comparing population health outcomes. An age-standardised rate is a summary measure of a rate that a population would have if it had a standard age structure. Changing age standards have stimulated interest in the potential impact of population standards on disparities data and consequently on health policy

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Hertfordshire Cohort Study: an overview [version 1; referees: 3 approved]

The Hertfordshire Cohort Study is a nationally unique study of men and women born in the English county of Hertfordshire in the early part of the 20th century. Records that detail their health in infancy and childhood have been preserved, their sociodemographic, lifestyle, medical and biological attributes have been characterised in later life, and routinely collected data on their hospital use and mortality have been acquired. This paper provides an overview of the study since its inception in the 1980s, including its methods, findings, and plans for its future

Survival and disease characteristics of de novo versus recurrent metastatic breast cancer in a cohort of young patients

Background: It is not clear how the pathology, presentation and outcome for patients who present with de novo metastatic breast cancer (dnMBC) compare with those who later develop distant metastases. DnMBC is uncommon in younger patients. We describe these differences within a cohort of young patients in the United Kingdom. Methods: Women aged 40 years or younger with a first invasive breast cancer were recruited to the prospective POSH national cohort study. Baseline clinicopathological data were collected, with annual follow-up. Overall survival (OS) and post-distant relapse-free survival (PDRS) were assessed using Kaplan–Meier curves. Results: In total, 862 patients were diagnosed with metastatic disease. DnMBC prevalence was 2.6% (76/2977). Of those with initially localised disease, 27.1% (786/2901) subsequently developed a distant recurrence. Median follow-up was 11.00 years (95% CI 10.79–11.59). Patients who developed metastatic disease within 12 months had worse OS than dnMBC patients (HR 2.64; 1.84–3.77). For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation. Conclusions: Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. A gBRCA2 mutation was overrepresented in dnMBC

Markers of inflammatory status associated with hearing threshold in older people: findings from the Herfordshire ageing study

Background: age-related hearing loss is a common disabling condition but it causes are not well understood and the role of inflammation as an influencing factor has received little consideration in the literature.Objective: to investigate the association between inflammatory markers and hearing in community dwelling older men and women.Design: cross-sectional analysis within a cohort study.Setting: the Hertfordshire Ageing Study.Participants: 343 men and 268 women aged 63 to 74 years on whom data on audiometric testing, inflammatory markers and covariates were available at follow-up in 1995.Main outcome measures: average hearing threshold level (across 500 to 4000 Hz) of the worst hearing ear and audiometric slope in dB/octave from 500 to 4000Hz.Results: older age, smoking, history of noise exposure and male gender (all p&lt;0.001) were associated with higher mean hearing threshold in the worse ear in univariate analysis. After adjustment for these factors in multiple regression models, four measures of immune or inflammatory status were significantly associated with hearing threshold, namely white blood cell count (r=0.13,p=0.001), neutrophil count (r=0.13,p=0.002), IL-6 (r=0.10,p=0.05) and CRP (r=0.11,p=0.01). None of the inflammatory markers were associated with maximum audiometric slope in adjusted analyses.Conclusions: markers of inflammatory status were significantly associated with degree of hearing loss in older people. The findings are consistent with the possibility that inflammatory changes occurring with ageing may be involved in age-related hearing loss. Longitudinal data would enable this hypothesis to be explored further<br/