Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1).

BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Associations between patient-reported late effects and systemic cytokines in long-term survivors of head and neck cancer treated with radiotherapy.

PURPOSE: Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related quality of life of survivors. Knowledge on long-term late effects after radiotherapy (RT) and potential underlying biological mechanisms is lacking. We assessed the prevalence of xerostomia, dysphagia, and chronic fatigue (CF) in HNC survivors ≥ 5 years post-RT, and examined associations between pro-inflammatory cytokines and late effects. METHODS: In a cross-sectional study, 263 HNC survivors treated between 2007 and 2013 were enrolled. They completed validated questionnaires assessing xerostomia and dysphagia (the EORTC QLQ-H&N35), and CF (the Fatigue Questionnaire), and underwent blood sampling and clinical examination. Pro-inflammatory cytokines were analyzed in 262 survivors and 100 healthy age- and gender-matched controls. RESULTS: Median time since treatment was 8.5 years. The proportions of survivors reporting xerostomia, dysphagia, and CF were 58%, 31%, and 33%, respectively, with a preponderance of females. We found no significant associations between IL-6, IL-8, IP-10, TARC, TNF, or ENA-78 and the three late effects. The odds of having elevated levels of IL-6 and IP-10 were significantly higher in the survivors compared to the controls. CONCLUSIONS: More than one-third of long-term HNC survivors experienced xerostomia, dysphagia, and CF. Persistent inflammation, with elevated systemic cytokines, was not associated with these late effects, although HNC survivors had higher levels of some cytokines than the controls. IMPLICATIONS FOR CANCER SURVIVORS: This study provides new knowledge on late effects that can serve as grounds for informing patients with HNC about risk of late effects more than 5 years after RT.

Work ability 8 years after breast cancer: exploring the role of social support in a nation-wide survey.

INTRODUCTION: As the 5-year survival rate after breast cancer in Norway is 92%, the population of breast cancer survivors (BCSs) is increasing. Knowledge of work ability in this population is scarce. In a population-based cohort of BCSs, we explored work ability 8 years after diagnosis and the association between work ability and social support, and cancer-related variables including late effects and lifestyle factors. METHODS: In 2019, all Norwegian women < 59 years when diagnosed with stage I-III breast cancer in 2011 or 2012, were identified by the Cancer Registry of Norway and invited to participate in a survey on work life experiences. Work ability was assessed using the Work Ability Index (scale 0-10). Factors associated with excellent work ability (score ≥ 9) were identified using univariate and multivariate logistic regression analyses, and adjusted for socioeconomic-, health- and cancer-related variables. RESULTS: Of the 1951 eligible BCSs, 1007 (52.8%) responded. After excluding survivors with relapse (n = 1), missing information on work ability score (n = 49), or work status (n = 31), the final sample comprised 926 BCSs within working age at survey (< 67 years). Mean age at survey was 56 years and 8 years (SD 0.7) had passed since diagnosis. Work ability had been reduced from 8.9 (SD 2.3) at diagnosis to 6.3 (SD 3.1). One in three BCSs reported poor work ability (WAS ≤ 5), and seven out of ten reported that their physical work ability had been reduced due to cancer. Social support from colleagues during cancer therapy was associated with excellent work ability, which was not observed for social support provided by supervisors or the general practitioner. Cognitive impairment and fatigue were inversely associated with work ability. None of the cancer-related variables, including treatment, were associated with work ability 8 years after diagnosis. CONCLUSION: In this population-based sample, one in three BCSs reported poor work ability 8 years after diagnosis. Collegial social support during cancer therapy appears to be a protective factor for sustained work ability, whilst survivors struggling with fatigue and cognitive impairments may represent a particularly vulnerable group for reduced work ability.

Long-term quality of life among breast cancer survivors eligible for screening at diagnosis: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to explore the long-term quality of life (QoL) among breast cancer survivors eligible for mammographic screening at diagnosis and compare that to QoL among women with no history of breast cancer. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of randomised controlled trials and observational studies published between January 2000 and July 2019 was performed. Eight studies were included in the review. Six studies with QoL measurement scales (0-100) were included in the meta-analysis. We used fixed and random effects models to obtain Cohen's d with 95% confidence interval (CI). Heterogeneity among studies was evaluated by the I2 statistics. RESULTS: Information about 6145 breast cancer survivors diagnosed between 1995 and 2012 and followed for >1-10 years was analysed. Four studies used SF-36/RAND-36, three studies used EORTC QLQ-C30, one study used FACT-G and one study used FACT-B. The mean score of QoL for breast cancer survivors varied from 63.0 (RAND SF-36, 0-100) to 110.5 (FACT-B, 0-123). Two studies showed better, three studies showed similar and two studies showed poorer mean scores for breast cancer survivors compared with women with no history of breast cancer. The meta-analysis showed no significant differences in QoL for breast cancer survivors compared with women with no history of breast cancer (Cohen's d = -0.07, 95% confidence interval [CI] -0.14 to 0.00 and I2 = 83.7% for the fixed effect model; Cohen's d = -0.00, 95% CI -0.18 to 0.17 and I2 = 82.4% for the random effects model). CONCLUSION: QoL did not differ between breast cancer survivors eligible for mammographic screening at diagnosis and followed for >1-10 years and women with no history of breast cancer.

ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. DISCUSSION: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198.

ALICE: a randomized placebo-controlled phase II study evaluating atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CI) represents an important novel development in cancer treatment. Metastatic triple-negative breast cancer (mTNBC) is incurable, with a median survival of only ~ 13 months. We have initiated the randomized placebo-controlled phase IIb study ALICE, evaluating PD-L1 blockade combined with immunogenic chemotherapy in mTNBC patients (n = 75). Intriguingly, the host immune response is strongly predictive for the effect of chemotherapy in mTNBC. In the ALICE trial, we release the brake on the immune response by use of atezolizumab, an inhibitory antibody against PD-L1. We utilize anthracyclines, shown to trigger the immune system, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ALICE is a randomized, double-blind, placebo-controlled exploratory phase II study evaluating the safety and efficacy of atezolizumab when combined with immunogenic chemotherapy in subjects with mTNBC. The trial will enroll 75 evaluable subjects, randomized 2:3 into two arms (A:B). The patients receive identical chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (50 mg per day, first 2 weeks in each 4 week cycle). Patients in arm A receive placebo, while patients in arm B receive atezolizumab. The primary objectives are assessment of toxicity and progression-free survival. The secondary objectives include overall survival, tumor response rate, clinical benefit rate, patient reported outcomes, biomarkers and assessment of tumor-immune evolution during therapy. DISCUSSION: The question of how CI should be combined with chemotherapy, is a key challenge facing the field. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with PD-L1 blockade, and if low-dose cyclophosphamide counters tumor tolerance. However, the data from patients is as yet very limited, and the clinical evaluation of these hypotheses is among the key objectives in the ALICE trial. The study includes extensive biobanking and translational sub-projects, also addressing other clinically important questions. These analyses may uncover mechanisms of drug efficacy or tumor resistance, and identify biomarkers allowing personalized therapy. If the trial suggests acceptable safety of the ALICE therapy and provide a signal of clinical efficacy, further studies are warranted. Trial registration NCT03164993, May 24th 2017; https://clinicaltrials.gov/ct2/show/record/NCT03164993.

Evolution and risk factors of anal incontinence during the first 6 years after first delivery: a prospective cohort study.

OBJECTIVE: To explore changes in prevalence of anal incontinence (AI) from late first pregnancy to 6 years postpartum, and to evaluate possible risk factors for changes in AI during the 6-year period. DESIGN: Prospective longitudinal cohort study. SETTING: Two Norwegian health regions. POPULATION OR SAMPLE: Women with first deliveries between May 2009 and December 2010. METHODS: Participants reported AI in late pregnancy, 6 months, 1 and 6 years after first delivery using postal or digital questionnaires. AI prevalence was calculated, and mixed effects Poisson regression analyses with robust variance were applied. MAIN OUTCOME MEASURES: AI from late pregnancy to 6 years postpartum. RESULTS: Among 1571 participants, 65% had normal vaginal first deliveries, 20% had vaginal deliveries complicated by instrumental intervention and/or obstetric anal sphincter injury (IVD ± OASIS). Nearly 1 in 10 women reported persistent incontinence during the 6 years. The overall AI prevalence was reduced from late pregnancy to 1 year postpartum for all modes of delivery. At 6 years postpartum, women with IVD ± OASIS had a higher AI prevalence (23%; 95% CI 16-30%) compared with women with caesarean section (8%; 95% CI 2-13%) or normal vaginal delivery (12%; 95% CI 9-16%). Moreover, women who were <23 years, ≥34 years, unemployed during first pregnancy, who had active bowel disease (PR: 2.4; 95% CI 2.0-2.7), or bowel evacuation problems during the 6-year period had higher AI prevalence. CONCLUSIONS: Mode of first delivery modified AI prevalence during the 6-year period, whereas age, bowel disease and bowel evacuation problems were associated with higher prevalence of AI from late first pregnancy to 6 years postpartum. TWEETABLE ABSTRACT: Complicated vaginal delivery, age and bowel emptying problems increase the risk of long-term anal incontinence.

Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study.

OBJECTIVE: We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study. METHODS: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one-year follow-up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed-effects models. RESULTS: sTNF-R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL-1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow-up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF-R1 and IL-1Ra. There were no significant associations between change in symptoms and inflammatory markers. CONCLUSION: Persistently increased sTNF-R1 and IL-1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress-related mechanisms associated with acute episodes.

Response to Intravenous Glucose-Tolerance Test and Risk of Cancer: A Long-Term Prospective Cohort Study.

BACKGROUND: Impaired glucose regulation, measured with an oral glucose-tolerance test, has been associated with the risk of cancer. Here, we explored whether the response to an intravenous glucose-tolerance test (IVGTT) is associated with the risk of cancer. METHODS: A cohort of 945 healthy men, aged 40-59years in 1972-75, was followed for 40years. An IVGTT was performed at baseline. Blood samples for glucose determinations were drawn immediately before glucose injection and thereafter every 10min for 1h. Associations were assessed with incidence rate ratios (IRR) and Cox models. FINDINGS: Cancer incidence was higher among men with 10-min glucose levels below the median than in men with levels above the median (IRR: 1.5, 95% CI: 1.2-1.9). This association remained significant after adjusting for relevant confounders (HR: 1.6, 95% CI: 1.3-2.1) and when excluding the first 10years of follow-up to minimize the possibility of reverse causality (HR: 1.5, 95% CI: 1.2-2.0). INTERPRETATION: Healthy middle-aged males that responded to an intravenous glucose injection with rapid glucose elimination during the first phase had an elevated risk of cancer during 40years of follow-up. First phase response to a glucose load might be related to cancer development.

Ethnic differences in postpartum weight retention: a Norwegian cohort study.

OBJECTIVE: To explore ethnic differences in weight retention 14 weeks postpartum. DESIGN: Population-based cohort study. SETTING: The STORK Groruddalen Study. POPULATION: A multi-ethnic cohort of healthy pregnant women attending primary antenatal care at three public Child Health Clinics, in Oslo, Norway (n = 642). METHODS: An explanatory linear regression was performed to model the relationship between ethnicity and postpartum weight retention. Forward selection of 12 explanatory factors was used to adjust for potential confounding factors, based on univariate analysis and adjusted R(2) . MAIN OUTCOME MEASURE: Postpartum weight retention. RESULTS: Unadjusted mean postpartum weight retention was 2.3 (4.9) kg for women from Western Europe and varied from 3.7 (3.5) to 6.3 (4.7) kg among the five ethnic minority groups. The proportion of women in the highest quintile (postpartum weight retention >8.5-24.4 kg) significantly differed by ethnicity (P < 0.01 for the proportion of women from South Asia, the Middle East and Africa compared with Western Europeans). Women from all ethnic minority groups had a higher relative increase in weight from pre-pregnancy to postpartum (P < 0.01) compared with Western Europeans. After adjustments for significant exposures, women from the Middle East retained 2.0 kg (95% CI: 1.0-3.0), South Asia 2.8 kg (91.9-3.6), and Africa 4.4 kg (3.1-5.8) more than Western Europeans (P < 0.01). CONCLUSIONS: Significantly more women with an ethnic origin from South Asia, the Middle East and Africa had high postpartum weight retention compared with Western European women.

Breast cancer and ductal carcinoma in situ among women with prior squamous or glandular precancer in the cervix: a register-based study.

BACKGROUND: Human papillomavirus and hormonal contraceptives may be risk factors for cervical precancer and malignant breast tumours. METHODS: Standardised incidence ratios (SIRs) of malignant breast tumours during 1970-2008 were estimated separately for women with prior squamous and glandular cervical precancer. RESULTS: Women with squamous precancer and women with glandular precancer in the cervix had a significantly higher risk of malignant breast tumours than the general female population (SIR, 95% confidence interval: 1.10, 1.05-1.14 and 1.52, 1.11-2.08, respectively). INTERPRETATION: Shared risk factors or screening attendance may explain the excess risk of malignant breast tumours among women with a history of cervical precancer.

Nonintrusive optical measurements of aircraft engine exhaust emissions and comparison with standard intrusive techniques.

Nonintrusive systems for the measurement on test rigs of aeroengine exhaust emissions required for engine certification (CO, NO(x), total unburned hydrocarbon, and smoke), together with CO(2) and temperature have been developed. These results have been compared with current certified intrusive measurements on an engine test. A spectroscopic database and data-analysis software has been developed to enable Fourier-transform Infrared measurement of concentrations of molecular species. CO(2), CO, and NO data showed agreement with intrusive techniques of approximately ?30%. A narrow-band spectroscopic device was used to measure CO(2) (with deviations of less than ?10% from the intrusive measurement), whereas laser-induced incandescence was used to measure particles. Future improvements to allow for the commercial use of the nonintrusive systems have been identified and the methods are applicable to any measurement of combustion emissions.