Clinically relevant gene signatures provide independent prognostic information in older breast cancer patients.

BACKGROUND: The clinical utility of gene signatures in older breast cancer patients remains unclear. We aimed to determine signature prognostic capacity in this patient subgroup. METHODS: Research versions of the genomic grade index (GGI), 70-gene, recurrence score (RS), cell cycle score (CCS), PAM50 risk-of-recurrence proliferation (ROR-P), and PAM50 signatures were applied to 39 breast cancer datasets (N = 9583). After filtering on age ≥ 70 years, and the presence of estrogen receptor (ER) and survival data, 871 patients remained. Signature prognostic capacity was tested in all (n = 871), ER-positive/lymph node-positive (ER + /LN + , n = 335) and ER-positive/lymph node-negative (ER + /LN-, n = 374) patients using Kaplan-Meier and multivariable Cox-proportional hazard (PH) modelling. RESULTS: All signatures were statistically significant in Kaplan-Meier analysis of all patients (Log-rank P < 0.001). This significance remained in multivariable analysis (Cox-PH, P ≤ 0.05). In ER + /LN + patients all signatures except PAM50 were significant in Kaplan-Meier analysis (Log-rank P ≤ 0.05) and remained so in multivariable analysis (Cox-PH, P ≤ 0.05). In ER + /LN- patients all except RS were significant in Kaplan-Meier analysis (Log-rank P ≤ 0.05) but only the 70-gene, CCS, ROR-P, and PAM50 signatures remained so in multivariable analysis (Cox-PH, P ≤ 0.05). CONCLUSIONS: We found that gene signatures provide prognostic information in survival analyses of all, ER + /LN + and ER + /LN- older (≥ 70 years) breast cancer patients, suggesting a potential role in aiding treatment decisions in older patients.

Fetal growth after fresh and frozen embryo transfer and natural conception: A population-based register study.

OBJECTIVE: To investigate fetal growth trajectories and risks of small and large for gestational age (SGA and LGA), and macrosomia in pregnancies after fresh and frozen embryo transfer (ET), and natural conception (NC). DESIGN: Longitudinal population-based cohort study. SETTING: Swedish national registers. POPULATION: A total of 196 008 singleton pregnancies between 2013 and 2017. METHODS: Of all singleton pregnancies resulting in live births in the Swedish Pregnancy Register, 10 970 fresh ET, 6520 frozen ET, and 178 518 NC pregnancies with ultrasound data were included. A general least squares model was used to examine the effect of fresh or frozen ET on fetal growth while adjusting for confounders. MAIN OUTCOME MEASURES: Fetal growth velocity. SGA, LGA and macrosomia. RESULTS: At 120 days, fetal weights were lower in fresh ET pregnancies compared with NC pregnancies. Thereafter fresh ET as well as FET fetuses had higher fetal weights than NC fetuses, with no differences between themselves until the second trimester. From 210 days, FET fetuses were heavier than fresh ET fetuses, whereas fresh ET fetuses had lower fetal weights than NC fetuses from 245 days. After fresh ET, SGA was more frequent, whereas LGA and macrosomia were less frequent, than after FET. CONCLUSIONS: This study gives new insights into the differences in fetal growth dynamics between fresh and frozen ET and NC pregnancies. Clinically relevant differences in proportions of SGA, LGA and macrosomia were observed.

Polycystic ovary syndrome and risk of pre-eclampsia: A national register-based cohort study.

OBJECTIVE: To explore whether the association between polycystic ovary syndrome (PCOS) and pre-eclampsia depends on treated clinical hyperandrogenism and whether PCOS is associated with different subtypes of pre-eclampsia. DESIGN: Nationwide register-based cohort study. SETTING: Sweden. POPULATION: Nulliparous women with PCOS (n = 22 947) and non-PCOS controls (n = 115 272) giving singleton birth at ≥22 gestational weeks during 1997-2015. Treated clinical hyperandrogenism was defined as filled prescriptions of anti-androgenic drugs during 2005-2017 (n = 2301 among PCOS women). METHODS: The risk of pre-eclampsia was estimated with conditional logistic regression, expressed as adjusted odds ratio (OR) with 95% confidence interval (CI). Adjustments were performed individually for confounders and predictors. MAIN OUTCOME MEASURES: Overall pre-eclampsia. Early/late (delivery <34/≥34 weeks) pre-eclampsia. Pre-eclampsia with or without a small-for-gestational-age (SGA) infant. RESULTS: Compared with controls, women with PCOS had a 29% increased risk of pre-eclampsia (predictor adjusted OR 1.29, 95% CI 1.20-1.39), with similar risk estimates for PCOS women with and without treated clinical hyperandrogenism. The association between PCOS and early pre-eclampsia seemed stronger than its association with late pre-eclampsia (predictor adjusted OR 1.64 (95% CI 1.33-2.02) and 1.26 (95% CI 1.17-1.37). Additionally, the association seemed slightly stronger between PCOS and pre-eclampsia in women with an SGA infant than without. CONCLUSIONS: Women with PCOS face an increased risk for pre-eclampsia, especially early pre-eclampsia and pre-eclampsia with an SGA infant. We were unable to determine on the basis of available data, whether hyperandrogenism is associated with pre-eclampsia.

Accuracy and precision of sonographic fetal weight estimation in Sweden.

INTRODUCTION: Fetal growth assessment by ultrasound is an essential part of modern obstetric care. The formula by Persson and Weldner for estimated fetal weight (EFW), used in Sweden since decades, has not yet been evaluated. The objective of this study was to evaluate accuracy and precision of the formula by Persson and Weldner, and to compare it to two other formulae using biparietal diameter instead of head circumference. MATERIAL AND METHODS: The study population consisted of 31 521 singleton pregnancies delivered at 22+0 gestational weeks or later, with an ultrasound EFW performed within 2 days before delivery, registered in the Swedish Pregnancy Register between 2014 and 2021. Fetal biometric ultrasound measurements were used to calculate EFW according to the formulae by Persson and Weldner, Hadlock 2 and Shepard. Bland-Altman analysis, systematic error (mean percentage error), random error (standard deviation [SD] of mean percentage error), proportion of weight estimates within ±10% of birthweight, and proportion with underestimated and overestimated weight was calculated. Moreover, calculations were made after stratification into small, appropriate, and large for gestational age (SGA, AGA and LGA), respectively, and gestational age at examination. RESULTS: For the formula by Persson and Weldner, MPE was -2.7 (SD 8.9) and the proportion of EFW within ±10% from actual birthweight was 76.0%. MPE was largest for fetuses estimated as severe SGA (<3rd percentile, -5.4) and for the most preterm fetuses (<24 weeks, -5.4). For Hadlock 2 and Shepard's formulae, MPE were 3.9 (SD 8.9) and 3.4 (SD 9.7), respectively, and the proportions of EFW within ±10% from actual birthweight were 69.4% and 67.1%, respectively. MPE was largest for fetuses estimated as severe LGA (>97th percentile), 7.6 and 9.4, respectively. CONCLUSIONS: The recommended Swedish formula by Persson and Weldner is generally accurate for fetal weight estimation. The systematic underestimation of EFW and random error is largest in extreme preterm and estimated SGA-fetuses, which is of importance in clinical decision making. The accuracy of EFW with the formula by Persson and Weldner is as good as or better than Hadlock 2 and Shepard's formulae.

Clinical and molecular characteristics of estrogen receptor-positive ultralow risk breast cancer tumors identified by the 70-gene signature.

The metastatic potential of estrogen receptor (ER)-positive breast cancers is heterogeneous and distant recurrences occur months to decades after primary diagnosis. We have previously shown that patients with tumors classified as ultralow risk by the 70-gene signature have a minimal long-term risk of fatal breast cancer. Here, we evaluate the previously unexplored underlying clinical and molecular characteristics of ultralow risk tumors in 538 ER-positive patients from the Stockholm tamoxifen randomized trial (STO-3). Out of the 98 ultralow risk tumors, 89% were luminal A molecular subtype, whereas 26% of luminal A tumors were of ultralow risk. Compared to other ER-positive tumors, ultralow risk tumors were significantly (Fisher's test, P < .05) more likely to be of smaller tumor size, lower grade, progesterone receptor (PR)-positive, human epidermal growth factor 2 (HER2)-negative and have low Ki-67 levels (proliferation-marker). Moreover, ultralow risk tumors showed significantly lower expression scores of multi-gene modules associated with the AKT/mTOR-pathway, proliferation (AURKA), HER2/ERBB2-signaling, IGF1-pathway, PTEN-loss and immune response (IMMUNE1 and IMMUNE2) and higher expression scores of the PIK3CA-mutation-associated module. Furthermore, 706 genes were significantly (FDR < 0.001) differentially expressed in ultralow risk tumors, including lower expression of genes involved in immune response, PI3K/Akt/mTOR-pathway, histones, cell cycle, DNA repair, apoptosis and higher expression of genes coding for epithelial-to-mesenchymal transition and homeobox proteins, among others. In conclusion, ultralow risk tumors, associated with minimal long-term risk of fatal disease, differ from other ER-positive tumors, including luminal A molecular subtype tumors. Identification of these characteristics is important to improve our prediction of nonfatal vs fatal breast cancer.

Ameliorating Child poverty through Connecting Economic Services with child health Services (ACCESS): study protocol for a randomised controlled trial of the healthier wealthier families model in Sweden.

BACKGROUND: Sweden is often held up as an example of a country with low child deprivation; yet, rates of relative deprivation are rising. Every municipality in Sweden is required to provide free, timely and accessible budget and debt counselling under the Social Services Act. The services have been encouraged to perform preventative practice with families; however, this has not been realised. The Healthier Wealthier Families (HWF) model embeds universal screening for economic hardship into child health services and creates a referral pathway to economic support services. Given the universal child health system in Sweden, which is freely available and has excellent coverage of the child population, implementation of the HWF model has potential to support families to access the freely available municipal budget and debt counselling and ultimately improve rates of child deprivation in Sweden. METHODS/DESIGN: We will conduct a two-arm randomised waitlist-control superiority trial to examine the effectiveness and cost-effectiveness of the HWF model in the Sweden. A longitudinal follow-up with the cohort will explore whether any effects are maintained in the longer-term. DISCUSSION: HWF is a collaborative and sustainable model that could maximise the effectiveness of current services to address child deprivation in Sweden. The study outlined in this protocol is the first effectiveness evaluation of the HWF model in Sweden and is a crucial step before HWF can be recommended for national implementation within the child health services. TRIAL REGISTRATION: Clinicaltrials.gov; NCT05511961. Prospectively registered on 23 August 2022. https://clinicaltrials.gov/ct2/show/NCT05511961.

Maternal and Perinatal Outcomes in Singleton Nulliparous Spontaneous Preterm Birth with and without Preterm Premature Rupture of Membranes-A National Population-Based Cohort Study.

OBJECTIVE: Preterm birth (PTB, birth before 37 gestational weeks) is the leading cause of neonatal death and a major challenge for obstetric and neonatal care. About two-thirds of PTBs are spontaneous PTB (sPTB), of which approximately 30% start with preterm premature rupture of membranes (PPROM). The aim of the study was to investigate risk factors and maternal and perinatal outcomes in sPTB with and without PPROM. STUDY DESIGN: This is a national population-based cohort study including all singleton pregnancies in nulliparous women with spontaneous onset of labor and vaginal births (n = 266,968) registered in the Swedish Medical Birth Register 2005 to 2014. sPTB with PPROM (sPTB-PPROM) and sPTB without PPROM were compared regarding risk factors and maternal and perinatal outcomes. Logistic regression was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age, body mass index, country of birth, smoking, chronic hypertension, pregestational and gestational diabetes, and gestational length. RESULTS: sPTB-PPROM (n = 5,037), compared with sPTB without PPROM (n = 8,426), was more common in women with previous spontaneous abortions, prepregnancy urinary tract infections, chronic hypertension, and gestational diabetes and had a higher risk of postpartum endometritis (aOR: 2.78, 95% CI: 1.55-5.00). Infants born to women with sPTB-PPROM had a lower risk of birth asphyxia (aOR: 0.60, 95% CI: 0.43-0.83), respiratory distress syndrome (aOR: 0.86, 95% CI: 0.70-1.00), retinopathy of prematurity (aOR: 0.93, 95% CI: 0.92-0.94), necrotizing enterocolitis (aOR: 0.95, 95% CI: 0.94-0.96), and higher risk of hypoglycemia (aOR: 1.14, 95% CI: 1.01-1.28), and hyperbilirubinemia (aOR: 1.28, 95% CI: 1.19-1.38) compared with infants born to sPTB without PPROM. CONCLUSION: Our findings of risk factors and distinct differences in adverse outcomes after sPTB-PPROM compared with sPTB without PPROM are of vital importance and might serve as a basis when elaborating programs for the prevention and management of PPROM. KEY POINTS: · This is a large cohort study of spontaneous preterm birth (sPTB).. · Singleton nulliparous sPTB with/without preterm premature rupture of membrane (PPROM) were studied.. · Distinct differences in adverse perinatal outcomes in sPTB with and without PPROM were observed..

Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-based cohort study.

BACKGROUND: Lithium is prescribed during pregnancy, but there is limited information about pregnancy and neonatal outcomes following in utero exposure. Thus, this study aimed to investigate the associations between lithium use and adverse pregnancy and neonatal outcomes. METHODS: This population-based cohort study examined associations between maternal lithium use and major adverse pregnancy and neonatal outcomes via inverse probability weighted propensity score regression models. RESULTS: Of 854,017 women included in this study, 434 (0.05%) used lithium during pregnancy. Among pre-specified primary outcomes, lithium use during pregnancy was associated with an increased risk of spontaneous preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64 95% CI 1.82, 3.82) and birth of a large for gestational age infant (9.0% vs 3.5%; aRR 2.64 95% CI 1.91, 3.66), but not preeclampsia nor birth of a small for gestational age infant. Among secondary outcomes, lithium use was associated with an increased risk of cardiac malformations (2.1% vs 0.8%; aRR 3.17 95% CI 1.64, 6.13). In an analysis restricted to pregnant women with a diagnosed psychiatric illness (n=9552), associations remained between lithium and spontaneous preterm birth, birth of a large for gestational age infant, and cardiovascular malformations; and a positive association with neonatal hypoglycaemia was also found. These associations were also apparent in a further analysis comparing women who continued lithium treatment during pregnancy to those who discontinued prior to pregnancy. CONCLUSIONS: Lithium use during pregnancy is associated with an increased risk of spontaneous preterm birth and other adverse neonatal outcomes. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

Second trimester induced abortions due to fetal anomalies-a population-based study of diagnoses, examinations and clinical management.

INTRODUCTION: Two-thirds of induced abortions after gestational week (gw) 18 are performed due to fetal anomalies. The potential of the fetus to survive outside the uterus after birth is the upper limit for induced abortions in Sweden. Due to advances in neonatal medicine, fetal viability and the upper limit of late induced abortions have been converging over the last few decades. The aim of the study was to examine clinical management of fetal anomalies, including time frames, leading to second trimester abortions. MATERIAL AND METHODS: All induced abortions due to fetal anomalies after gw 11+6 in Uppsala county, Sweden, from 2010 to 2017, were reviewed from electronic medical records in a retrospective descriptive study. In total, 180 women underwent 185 abortions divided into 107 (57.8%) in an early group (gw 12+0 to 18+0), and 78 (42.2%) in a late group (≥ gw 18+1). Examinations performed were genetic testing, fetal echocardiography, magnetic resonance imaging (MRI) and pediatric counseling. Time frames from suspicion of fetal anomaly to abortion were reviewed. RESULTS: Anomalies were subdivided into groups of diagnosis: chromosomal (n = 104), central nervous system (n = 22), heart (n = 12), urinary tract (n = 10) and others (n = 37). Chromosomal anomaly was present in 82 (76.6%) in the early group and 22 (28.2%) in the late group. In the early group, examinations performed preceding a conclusive diagnosis were mainly QF-PCR for trisomies (n = 97), microarray (n = 13), and genetic counseling (n = 14). In the late group, trisomy test was performed in 68, microarray in 31, MRI in 24, fetal echocardiography in 28, and pediatric or genetic counseling in 43 and six cases, respectively. Mean time interval from suspicion of fetal anomaly to the woman's decision was 5 days before gw 18+1, 7 days in gw 18, and 13 days in gw 21. More than two examinations before reaching the decision to terminate the pregnancy were needed in two abortions (25.0%) in gw 18, increasing to 16 (80.0%) in gw 21. CONCLUSIONS: Increasing complexity and diversity in fetal diagnoses require time-consuming examinations in late-induced abortions compared with earlier gestational weeks. A structured expedient process is necessary to allow for decision time and minimize terminations approaching the legal limit.

The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumours.

BACKGROUND: Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses. METHODS: CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes. RESULTS: When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours. CONCLUSIONS: Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.

Postnatal growth in children born small for gestational age with and without smoking mother.

BACKGROUND: Maternal smoking impairs fetal growth; however, if postnatal growth differs between children born small for gestational age (SGA) with smoking and non-smoking mother is unknown. METHODS: Cohort-study of term born children born appropriate for gestational age with non-smoking mother (AGA-NS, n = 30,561), SGA (birthweight <10th percentile) with smoking mother (SGA-S, n = 171) or SGA with non-smoking mother (SGA-NS, n = 1761). Means of height and weight measurements, collected at birth, 1.5, 3, 4, and 5 years, were compared using a generalized linear mixed effect model. Relative risks of short stature (<10th percentile) were expressed as adjusted risk ratios (aRR). RESULTS: At birth, children born SGA-S were shorter than SGA-NS, but they did not differ in weight. At 1.5 years, SGA-S had reached the same height as SGA-NS. At 5 years, SGA-S were 1.1 cm taller and 1.2 kg heavier than SGA-NS. Compared with AGA-NS, SGA-S did not have increased risk of short stature at 1.5 or 5 years, while SGA-NS had increased risk of short stature at both ages; aRRs 3.0 (95% CI 2.6;3.4) and 2.3 (95% CI 2.0;2.7), respectively. CONCLUSIONS: Children born SGA-S have a more rapid catch-up growth than SGA-NS. This may have consequences for metabolic and cardiovascular health in children with smoking mothers.

Site-specific familial risk and survival of familial and sporadic head and neck cancer.

The vast majority of head and neck cancers (HNCs) are sporadic squamous cell carcinomas, smoking and heavy drinking being the main risk factors. However, little is known about the possible role of family history and the importance of inherited factors versus shared environment. We used Swedish population-based registries to study the family history of HNC. In order to estimate the risk for family members to get the same cancer, and the risk for cancer-specific death in patients with a family history of HNC compared with patients without a family history, multivariate Cox proportional hazards analyses were performed. A 1.43-fold increased risk for developing HNC in the first-degree relatives (FDRs) of HNC patients [hazard ratio (HR), 1.43; 95% CI, 1.28-1.61] was found, when compared with relatives of healthy controls. In spouses of patients with HNC, the risk for developing any HNC was moderately increased (HR, 1.25; 95% CI, 1.01-1.53), compared with spouses of healthy controls. In addition, a 1.34-fold increased risk for death of HNC was found in HNC patients with a family history of HNC (HR, 1.34; 95% CI, (1.03-1.73) compared with HNC patients without a family history. We found an increased risk for HNC in relatives and spouses of HNC patients, when compared with family members of healthy controls. This suggests that in addition to inherited factors, shared environmental factors have a significant role in the development of the cancer. Family history of HNC was associated with worse survival in a newly diagnosed HNC patient.

Cause-specific mortality in women with breast cancer in situ.

The long-term mortality remains unknown in women diagnosed with breast cancer in situ (BCIS). Here, we assessed the cause-specific mortality in BCIS patients. This population-based cohort study included 12,243 women diagnosed with BCIS in Sweden between 1980 and 2011. Patients were followed until death, emigration, or 31 December 2013, whichever came first. The 30-year cumulative incidence of breast cancer-specific mortality was 6.3%, which is considerably lower than 49.7% observed for other-cause mortality. Women diagnosed with BCIS were more likely to die from breast cancer (standardized mortality ratio [SMR], 3.85; 95% CI, 3.47-4.27) but less likely to die from cardiovascular disease (SMR, 0.88; 95% CI, 0.82-0.95) than women in the general population. Specifically, the SMRs for breast cancer-specific mortality decreased over time from 5.19 (95% CI, 3.95-6.81) among BCIS diagnosed during 1980-1989 to 3.03 (95% CI, 2.35-3.91) among those diagnosed during 2000-2011. Furthermore, higher risk of death from other causes was seen among those with older age at BCIS diagnosis, lower levels of education, nulliparity, higher Charlson Comorbidity Index, and being hospitalized before BCIS diagnosis; whereas, lower risk of death from breast cancer was seen among BCIS diagnosed in the later time period and those with younger age at first birth. We conclude that most women diagnosed with BCIS die from causes other than breast cancer, which highlights the need for actions not only to reduce nonbreast cancer mortality but also to identify patient where extensive curative BCIS treatment is not adding to survival.

Differences in survival for patients with familial and sporadic cancer.

Family history of cancer is a well-known risk factor but the role of family history in survival is less clear. The aim of this study was to investigate the association between family history and cancer survival for the common cancers in Sweden. Using the Swedish population-based registers, patients diagnosed with the most common cancers were followed for cancer-specific death during 1991-2010. We used multivariate proportional hazards (Cox) regression models to contrast the survival of patients with a family history of cancer (individuals whose parent or sibling had a concordant cancer) to the survival of patients without a family history. Family history of cancer had a modest protective effect on survival for breast cancer (hazard ratio (HR) = 0.88, 95% confidence interval (95% CI) = 0.81 to 0.96) and prostate cancer (HR = 0.82, 95% CI = 0.75 to 0.90). In contrast, family history of cancer was associated with worse survival for nervous system cancers (HR = 1.24, 95% CI = 1.05 to 1.47) and ovarian cancer (HR = 1.20, 95% CI = 1.01 to 1.43). Furthermore, the poorer survival for ovarian cancer was consistent with a higher FIGO stage and a greater proportion of more aggressive tumors of the serous type. The better survival for patients with a family history of breast and prostate cancer may be due to medical surveillance of family members. The poor survival for ovarian cancer patients with an affected mother or sister is multifactorial, suggesting that these cancers are more aggressive than their sporadic counterparts.

Tamoxifen therapy benefit for patients with 70-gene signature high and low risk.

BACKGROUND: Breast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients. METHODS: We assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics. RESULTS: Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p < 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinico-pathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p < 0.0001). CONCLUSIONS: Patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over 10 years from adjuvant tamoxifen therapy, even when given for a relatively short duration.

Chronic Hypertension in Women after Perinatal Exposure to Preeclampsia, Being Born Small for Gestational Age or Preterm.

BACKGROUND: There is an established association between adverse events during perinatal life and chronic hypertension in adult life. However, disadvantageous conditions often co-exist in the same pregnancy. We investigated single and joint perinatal exposure to preeclampsia, being born small for gestational age (SGA) or preterm and subsequent risk of chronic hypertension. METHODS: The study population consisted of 731 008 primiparous women from Norway and Sweden registered in the Medical Birth Registers, both as infants and as first time mothers between 1967-2009 (Norway) and 1973-2010 (Sweden). Risk of chronic hypertension in early pregnancy was calculated in women with perinatal exposures to preeclampsia, born SGA or preterm by log-binominal regression analysis, and adjusted for maternal age and level of education in the first generation. RESULTS: The rate of chronic hypertension was 0.4%. Risk of chronic hypertension was associated with single perinatal exposure to preeclampsia, being born SGA or preterm with adjusted relative risk (95% confidence interval, CI) of 2.2 (95% CI 1.8, 2.7), 1.1 (95% CI 1.0, 1.3), and 1.3 (95% CI 1.0, 1.5) respectively. The risks increased after joint exposures, with an almost fourfold risk increase after perinatal exposure to preeclampsia and preterm birth. Additional adjustment for BMI and smoking in the second generation in a subset of the cohort only had a minor impact on the results. CONCLUSIONS: Perinatal exposure to preeclampsia, being born SGA or preterm is independently associated with increased risk of chronic hypertension. The highest risk was seen after exposure to preeclampsia, especially if combined with SGA or preterm birth.

Long-term outcome in young women with breast cancer: a population-based study.

PURPOSE: Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered. METHODS: From a population-based cohort of 22,017 women with breast cancer, all women <35 years (n = 471) were compared to a random sample of 700 women aged 35-69 years from the same cohort. Information on patient and tumor characteristics, treatment, and follow-up was collected from the medical records. Tissue microarrays were produced for analysis of classical biomarkers. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS), and locoregional recurrence-free survival (LRFS) by age were compared using women 50-69 years as reference. RESULTS: At 10 years follow-up, women <35 years and 35-39 years had a worse BCSS [age <35 years 69 % (HR 2.75, 95 % CI 1.93-3.94), age 35-39 years 76 % (HR 2.33, 95 % CI 1.54-3.52), age 40-49 years 84 % (HR 1.53, 95 % CI 0.97-2.39), and age 50-69 years 89 % (reference)]. The worse BCSS was statistically significant in stages I-IIa and Luminal B tumors. At multivariate analysis age <35 years and 35-39 years confined a risk in LRFS (HR 2.13, 95 % CI 1.21-3.76 and HR 1.97, 95 % CI 1.06-3.68) but not in DDFS and BCSS. In the subgroup of women <40 years with luminal tumors stage I-IIa, low age remained an independent risk factor also in DDFS (HR 1.87, 95 % CI 1.03-3.44). CONCLUSION: Young women have a high risk of systemic disease even when diagnosed in an early stage. The excess risk of relapse is most pronounced in Luminal B tumors, where low age is an independent prognostic factor of DDFS and LRFS.

Does Developing Interpregnancy Hypertension Affect the Recurrence Risk of Preeclampsia? A Population-Based Cohort Study.

BACKGROUND: Preeclampsia in a first pregnancy is a strong risk factor for preeclampsia in a second pregnancy. Whether chronic hypertension developed after a first pregnancy (interpregnancy hypertension) affects the recurrence risk of preeclampsia is unknown. METHODS: This is a population-based cohort study of 391,645 women with their first and second singleton births between 2006 and 2017. Exposure groups were women with preeclampsia in their first pregnancy, interpregnancy hypertension, or both risk factors. Women with neither risk factor were used as a reference group. We calculated the adjusted relative risk (aRR) with 95% confidence intervals (CIs) for overall preeclampsia in the second pregnancy as well as preterm (<37 gestational weeks) and term (≥37 gestational weeks) subgroups of the disease. RESULTS: Women with preeclampsia in their first pregnancy who did or did not develop interpregnancy hypertension had rates of preeclampsia in their second pregnancy of 21.5% and 13.6%, respectively. In the same population, the corresponding rates of preterm preeclampsia were 5.5% and 2.6%, respectively. After adjusting for maternal factors, women with preeclampsia in their first pregnancy who developed interpregnancy hypertension and those who did not have almost the same risk of overall preeclampsia in their second pregnancy (aRRs with 95% CIs: 14.51; 11.77-17.89 and 12.83; 12.09-13.62, respectively). However, preeclampsia in the first pregnancy and interpregnancy hypertension had a synergistic interaction on the outcome of preterm preeclampsia (aRR with 95% CI 26.66; 17.44-40.80). CONCLUSIONS: Women with previous preeclampsia who developed interpregnancy hypertension had a very high rate of preterm preeclampsia in a second pregnancy, and the two risk factors had a synergistic interaction.

Prediction of breast cancer risk for sisters of women attending screening.

BACKGROUND: Risk assessment is important for breast cancer prevention and early detection. We aimed to examine whether common risk factors, mammographic features, and breast cancer risk prediction scores of a woman were associated with breast cancer risk for her sisters. METHODS: We included 53 051 women from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Established risk factors were derived using self-reported questionnaires, mammograms, and single nucleotide polymorphism genotyping. Using the Swedish Multi-Generation Register, we identified 32 198 sisters of the KARMA women (including 5352 KARMA participants and 26 846 nonparticipants). Cox models were used to estimate the hazard ratios of breast cancer for both women and their sisters, respectively. RESULTS: A higher breast cancer polygenic risk score, a history of benign breast disease, and higher breast density in women were associated with an increased risk of breast cancer for both women and their sisters. No statistically significant association was observed between breast microcalcifications and masses in women and breast cancer risk for their sisters. Furthermore, higher breast cancer risk scores in women were associated with an increased risk of breast cancer for their sisters. Specifically, the hazard ratios for breast cancer per 1 standard deviation increase in age-adjusted KARMA, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), and Tyrer-Cuzick risk scores were 1.16 (95% confidence interval [CI] = 1.07 to 1.27), 1.23 (95% CI = 1.12 to 1.35), and 1.21 (95% CI = 1.11 to 1.32), respectively. CONCLUSION: A woman's breast cancer risk factors are associated with her sister's breast cancer risk. However, the clinical utility of these findings requires further investigation.

The dyslexia candidate gene DYX1C1 is a potential marker of poor survival in breast cancer.

BACKGROUND: The dyslexia candidate gene, DYX1C1, shown to regulate and interact with estrogen receptors and involved in the regulation of neuronal migration, has recently been proposed as a putative cancer biomarker. This study was undertaken to assess the prognostic value and therapy-predictive potential of DYX1C1 mRNA and protein expression in breast cancer. METHODS: DYX1C1 mRNA expression was assessed at the mRNA level in three independent population-derived patient cohorts. An association to estrogen/progesterone receptor status, Elston grade, gene expression subtype and lymph node status was analyzed within these cohorts. DYX1C1 protein expression was examined using immunohistochemistry in cancer and normal breast tissue. The statistical analyses were performed using the non-parametric Wilcoxon rank-sum test, ANOVA, Fisher's exact test and a multivariate proportional hazard (Cox) model. RESULTS: DYX1C1 mRNA is significantly more highly expressed in tumors that have been classified as estrogen receptor α and progesterone receptor-positive. The expression of DYX1C1 among the molecular subtypes shows the lowest median expression within the basal type tumors, which are considered to have the worst prognosis. The expression of DYX1C1 is significantly lower in tumors graded as Elston grade 3 compared with grades 1 and 2. DYX1C1 protein is expressed in 88% of tumors and in all 10 normal breast tissues examined. Positive protein expression was significantly correlated to overall survival (Hazard ratio 3.44 [CI 1.84-6.42]) of the patients but not to any of the variables linked with mRNA expression. CONCLUSION: We show that the expression of DYX1C1 in breast cancer is associated with several clinicopathological parameters and that loss of DYX1C1 correlates with a more aggressive disease, in turn indicating that DYX1C1 is a potential prognostic biomarker in breast cancer.