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.

What women emphasise as important aspects of care in childbirth - an online survey.

OBJECTIVE: To explore and describe what women who have given birth in Norway emphasise as important aspects of care during childbirth. DESIGN: The study is based on data from the Babies Born Better online survey, version 2. SETTING: The maternity care system in Norway. STUDY POPULATION: Women who gave birth in Norway between 2013 and 2018. METHOD: Descriptive statistics were used to describe sample characteristics and to compare data from the B3 survey with national data from the Medical Birth Registry of Norway. The open-ended questions were analysed with an inductive thematic analysis. MAIN OUTCOME MEASURES: Themes developed from two open-ended questions. RESULTS: The final sample included 8401 women. There were no obvious differences between the sample population and the national population with respect to maternal age, marital status, parity, mode of birth and place of birth, except for the proportion of planned home births. Four themes and one overarching theme were identified; Compassionate and Respectful Care, A Family Focus, Sense of Continuity and Consistency, and Sense of Security. Overarching theme: Coherence in Childbearing. CONCLUSIONS: Norwegian women across all birth settings emphasise maternity care that authentically focuses on both socio-cultural and psychological aspects of care, and physical and clinical factors. If the positive aspects of care identified in this study are adopted at all levels of the maternity care system and from all care providers, there is a high chance that most women will have a safe outcome, and a strong sense of coherence related to a positive birth and motherhood experience. TWEETABLE ABSTRACT: Having a baby is a pivotal life changing experience and not just a clinical event, according to a survey of 8400 women in Norway. Positive birth and motherhood experiences depend on maternity staff who are both skilled and kind.

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.

BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.

BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973.

Risk factors for obstetric anal sphincter injury after a successful multicentre interventional programme.

OBJECTIVE: To evaluate and compare the risk profile of sustaining obstetric anal sphincter injuries (OASIS) and associated risks in five risk groups (low to high), after the OASIS rate was reduced from 4.6% to 2.0% following an interventional programme. The main focus of the intervention was on manual assistance during the final part of second stage of labour. DESIGN: A multicentre interventional cohort study with before and after comparison. SETTING: Four Norwegian obstetric departments. SAMPLE: A total of 40,154 vaginal deliveries in 2003-09. METHODS: Pre-intervention and postintervention analyses. The associations of OASIS with possible risk factors were estimated using odds ratios obtained by logistic regression. MAIN OUTCOME MEASURE: Risk factors of OASIS. RESULTS: The risk of sustaining OASIS decreased by 59% (odds ratio [OR] 0.41; 95% confidence interval [95% CI] 0.36-0.46) after the intervention. Associations with obstetric risks for OASIS were largely unchanged after the intervention, including first vaginal delivery (OR 3.84; 95% CI 2.90-5.07), birthweight ≥ 4500 g (OR 4.42; 95% CI 2.68-7.27), forceps delivery (OR 3.54; 95% CI 1.99-6.29) and mediolateral episiotomy (OR 0.89; 95% CI 0.70-1.12). However, the highest reduction of OASIS, (65%), was observed in group 0 (low-risk) (OR 0.35; 95% CI 0.24-0.51), and a 57% (OR 0.43; 95% CI 0.35-0.52), 61% (OR 0.39; 95% CI 0.31-0.48), and 58% (OR 0.42; 95% CI 0.30-0.60) reduction in groups with one, two and three risk factors, respectively. No change was observed in the group with four risk factors. CONCLUSION: After the intervention the most significant decrease of OASIS was observed in low-risk births, although the main risk factors for OASIS remained unchanged.

Episiotomy characteristics and risks for obstetric anal sphincter injuries: a case-control study.

OBJECTIVES: To investigate the association between the geometrical properties of episiotomy and obstetric anal sphincter injuries (OASIS) because episiotomies angled at 40-60° are associated with fewer OASIS than episiotomies with more acute angles. DESIGN: Case-control study. SETTING: University Hospital of North Norway, Tromsø and Nordland Hospital, Bodø, Norway. SAMPLE: Seventy-four women who had one vaginal birth and episiotomy. Cases (n = 37) have sustained OASIS at birth, while controls (n = 37) had not. The groups were matched for instrumental delivery. METHODS: Two groups of women with history of only one vaginal birth were compared. Episiotomy scar was identified and photographed and relevant measures were taken. Data were analysed using conditional logistic analysis. MAIN OUTCOME MEASURES: Mean episiotomy angle, length, depth, incision point. RESULTS: The risk of sustaining OASIS decreased by 70% (odds ratio [OR] 0.30; 95% CI 0.14-0.66) for each 5.5-mm increase in episiotomy depth, decreased by 56% (OR 0.44; 95% CI 0.23-0.86) for each 4.5-mm increase in the distance from the midline to the incision point of the episiotomy, and decreased by 75% (OR 0.25; 95% CI 0.10-0.61) for each 5.5-mm increase in episiotomy length. Lastly, there was no difference in mean angle between groups but there was a "U-shaped" association between angle and OASIS (OR 2.09; 95% CI 1.02-4.28) with an increased risk (OR 9.00; 95% CI 1.1-71.0) of OASIS when the angle was either smaller than 15° or >60°. CONCLUSION: The present study showed that scarred episiotomies with depth > 16 mm, length > 17 mm, incision point > 9 mm lateral of midpoint and angle range 30-60° are significantly associated with less risk of OASIS. Shrinkage of tissue must be considered.

Is the operative delivery rate in low-risk women dependent on the level of birth care? A randomised controlled trial.

OBJECTIVE: To investigate possible differences in operative delivery rate among low-risk women, randomised to an alongside midwifery-led unit or to standard obstetric units within the same hospital. DESIGN: Randomised controlled trial. SETTING: Department of Obstetrics and Gynaecology, Østfold Hospital Trust, Tromsø, Norway. POPULATION: A total of 1111 women assessed to be at low risk at onset of spontaneous labour. METHODS: Randomisation into one of three birth units: the special unit; the normal unit; or the midwife-led unit. MAIN OUTCOME MEASURES: Total operative delivery rate, augmentation, pain relief, postpartum haemorrhage, sphincter injuries and intrapartum transfer, Apgar score <7 at 5 minutes, metabolic acidosis and transfer to neonatal intensive care unit. RESULTS: There were no significant differences in total operative deliveries between the three units: 16.3% in the midwife-led unit; 18.0% in the normal unit; and 18.8% in the special unit. There were no significant differences in postpartum haemorrhage, sphincter injuries or in neonatal outcomes. There were statistically significant differences in augmentation (midwife-led unit versus normal unit RR 0.73, 95% CI 0.59-0.89; midwife-led unit versus special unit RR 0.69, 95% CI 0.56-0.86), in epidural analgesia (midwife-led unit versus normal unit RR 0.68, 95% CI 0.52-0.90; midwife-led unit versus special unit RR 0.64, 95% CI 0.47-0.86) and in acupuncture (midwife-led unit versus normal unit RR 1.45, 95% CI 1.25-1.69; midwife-led unit versus special unit RR 1.45, 95% CI 1.22-1.73). CONCLUSIONS: The level of birth care does not significantly affect the rate of operative deliveries in low-risk women without any expressed preference for level of birth care.

Birth outcomes in primiparous women who were raped as adults: a matched controlled study.

OBJECTIVE: To compare the duration of labour and the birth outcome in a group of primiparous women who had been raped after the age of 16, with a control group from the same birth cohort. DESIGN: Cohort study. SETTING: University Hospital of North Norway. SAMPLE: Fifty women raped as adults and 150 controls. METHODS: Data about birth outcomes in the first pregnancy were collected from the patient files and data concerning the assault were obtained in a subsequent pregnancy through consultations with the women who had been raped. Birth outcomes in the group of women who had been raped were compared with matched controls using a multivariable logistic regression model. MAIN OUTCOME MEASURES: Caesarean section, operative vaginal delivery and duration of labour. RESULTS: During their first delivery, the women who had been raped had an increased risk for caesarean section (adjusted odds ratio 15.7, 95% CI 5.0-49.1) and for assisted vaginal delivery (adjusted odds ratio 13.1, 95% CI 4.9-34.5) when compared with controls. The group of women who had been raped had a longer second stage of labour than the control group (120 versus 55 minutes, P < 0.01). They were more often single mothers, unemployed and smokers, and had a higher body mass index and more previous pregnancy terminations and miscarriages than the control group. CONCLUSIONS: The women who had been raped had a longer second stage of labour, and an increased risk of caesarean section and operative vaginal delivery compared with controls from the general birth cohort. These findings indicate that the consequences for delivery for women who had been raped as adults could be specific and may warrant particular attention. The birth experience of women who had been raped should also be illuminated in future studies.

Labor admission test: an assessment of the test's value as screening for fetal distress in labor.

BACKGROUND: To determine if the labor admission test (LAT) can predict fetal distress in a population of laboring women, and in subgroups of low- or high-risk women, who delivered within six hours or between six and 24 hours after LAT. METHODS: The data charts of all women who delivered at Hammerfest Hospital in 1996, 1997 and 1998 were retrospectively read. If the woman was admitted to the hospital because of onset of labor, was in the first stage of labor and delivered within 24 hours after admission, she was included. In the study period, 1639 gave birth and 932 were included in the study. A descriptive analysis of the population and assessment of LAT's sensitivity, positive predictive value, specificity and negative predictive value at different cut-off values was done. RESULTS: In the study population 5.8% had fetal distress, and 5.3% had an operative delivery because of fetal distress. LAT's sensitivity in the whole population was 0.15 and positive predictive value was 0.16. Specificity was 0.95 and positive predictive value was 0.95. In the subgroups of low- and high-risk women, who delivered within six hours or between six and 24 hours after LAT, sensitivity varied between 0 and 0.36, and positive predictive value varied between 0 and 0.27. Specificity varied between 0.92 and 0.96, and negative predictive value varied between 0.89 and 0.97. CONCLUSIONS: According to these results, LAT cannot be recommended as a screening test for fetal distress in labor in low-risk women. Sensitivity is too low, and there are too many false-positive tests. It is unclear if LAT has benefits among high-risk women.