Search

Abstract Background External causes of death, such as accidents, substance use, and suicide, contribute substantially to mortality during adolescence and early adulthood and show marked sex differences. Individuals born preterm are at increased risk of mental disorders, and impaired cognitive and executive functions, potentially increasing their vulnerability to death from external causes. We investigated sex-specific associations between gestational age at birth and mortality from external causes during late adolescence and early adulthood. Methods Individual level data from national health registries in Denmark (1978–2001), Finland (1987–2003), Norway (1967–2002), and Sweden (1974–2001) were linked to form nationwide cohorts. In total, 6,924,697 participants were followed from age 15 years to a maximum of 50 years in 2016–2018. Gestational age was categorized as “very/moderately preterm” (23–33 weeks), “late preterm” (34–36 weeks), “early term” (37–38 weeks), “full term” (39–41 weeks), and “post term” (42–44 weeks). Outcomes were mortality from external causes overall and from the largest subgroups transport accidents, suicide, and drugs or alcohol. We estimated sex-specific hazard ratios (HRs), with full term as the reference, and pooled each country’s estimates in meta-analyses. Results Across gestational ages mortality was higher for males than females. Individuals born very/moderately preterm had higher mortality from external causes, with HRs 1.11 (95% confidence interval [CI] 0.99–1.24) for males and 1.55 (95% CI 1.28–1.88) for females. Corresponding estimates for late preterm born were 1.11 (95% CI 1.04–1.18) and 1.15 (95% CI 1.02–1.29), respectively. Those born very/moderately preterm had higher mortality from transport accidents, but precision was low. For females, suicide mortality was higher following very/moderately preterm birth (HR 1.76, 95% CI 1.34–2.32), but not for males. Mortality from drugs or alcohol was higher in very/moderately and late preterm born males (HRs 1.23 [95% CI 0.99–1.53] and 1.29 [95% CI 1.16–1.45], respectively) and females (HRs 1.53 [95% CI 0.97–2.41] and 1.35 [95% CI 1.07–1.71], respectively, with some heterogeneity across countries). Conclusions Mortality from external causes overall was higher in preterm than full term born among both males and females. A clear sex difference was seen for suicide, where preterm birth was a risk factor in females, but not in males.

Abstract Background Some breast carcinomas detected at screening, especially ductal carcinoma in situ, may have limited potential for progression to symptomatic disease. To determine non-progression is a challenge, but if all screening-detected breast tumors eventually reach a clinical stage, the cumulative incidence at a reasonably high age would be similar for women with or without screening, conditional on the women being alive. Methods Using high-quality population data with 24 years of follow-up from the gradually introduced BreastScreen Norway program, we studied whether all breast carcinomas detected at mammography screening 50–69 years of age would progress to clinical symptoms within 85 years of age. First, we estimated the incidence rates of breast carcinomas by age in scenarios with or without screening, based on an extended age-period-cohort incidence model. Next, we estimated the frequency of non-progressive tumors among screening-detected cases, by calculating the difference in the cumulative rate of breast carcinomas between the screening and non-screening scenarios at 85 years of age. Results Among women who attended BreastScreen Norway from the age of 50 to 69 years, we estimated that 1.1% of the participants were diagnosed with a breast carcinoma without the potential to progress to symptomatic disease by 85 years of age. This proportion of potentially non-progressive tumors corresponded to 15.7% [95% CI 3.3, 27.1] of breast carcinomas detected at screening. Conclusions Our findings suggest that nearly one in six breast carcinomas detected at screening may be non-progressive.

Abstract Background Long-term breast cancer incidence trends according to proliferation status are poorly described. We studied time-trends in breast cancer incidence, using mitotic count and Ki-67 as markers of proliferation. Methods Among 83,298 Norwegian women followed for breast cancer occurrence 1961–2012, 2995 incident breast cancers were diagnosed. Ki-67 was assessed using immunohistochemistry on tissue microarrays and mitoses were counted on whole sections. We compared incidence rates according to proliferation status among women born 1886–1928 and 1929–1977, estimating age-specific incidence rate ratios. We performed multiple imputations to account for unknown proliferation status. Mean values of Ki-67 and mitotic counts were calculated, according to age and birth year. We performed separate incidence analyses for HER2+ and triple negative breast cancers. Results Among women aged 40–69 years, incidence rates of tumours with low-proliferative activity were higher among those born in 1929 or later, compared to before 1929, according to Ki-67 and mitotic count. Incidence rates of tumours with high-proliferative activity were also higher in women born in 1929 or later compared to before 1929 according to Ki-67, but not according to mitotic count. Mean values of Ki-67 and mitotic count varied according to age and birth year. In subtype-specific analyses we found an increase of high-proliferative HER2+ tumours according to Ki-67 in women born in 1929 or later, compared to before 1929. Conclusions There has been a temporal increase in both low- and high-proliferative breast cancers.

Abstract Background In breast cancer (BC) Ki-67 cut-off levels, counting methods and inter- and intraobserver variation are still unresolved. To reduce inter-laboratory differences, it has been proposed that cut-off levels for Ki-67 should be determined based on the in-house median of 500 counted tumour cell nuclei. Digital image analysis (DIA) has been proposed as a means to standardize assessment of Ki-67 staining in tumour tissue. In this study we compared digital and visual assessment (VA) of Ki-67 protein expression levels in full-face sections from a consecutive series of BCs. The aim was to identify the number of tumour cells necessary to count in order to reflect the growth potential of a given tumour in both methods, as measured by tumour grade, mitotic count and patient outcome. Methods A series of whole sections from 248 invasive carcinomas of no special type were immunohistochemically stained for Ki-67 and then assessed by VA and DIA. Five 100-cell increments were counted in hot spot areas using both VA and DIA. The median numbers of Ki-67 positive tumour cells were used to calculate cut-off levels for Low, Intermediate and High Ki-67 protein expression in both methods. Results We found that the percentage of Ki-67 positive tumour cells was higher in DIA compared to VA (medians after 500 tumour cells counted were 22.3% for VA and 30% for DIA). While the median Ki-67% values remained largely unchanged across the 100-cell increments for VA, median values were highest in the first 1-200 cells counted using DIA. We also found that the DIA100 High group identified the largest proportion of histopathological grade 3 tumours 70/101 (69.3%). Conclusions We show that assessment of Ki-67 in breast tumours using DIA identifies a greater proportion of cases with high Ki-67 levels compared to VA of the same tumours. Furthermore, we show that diagnostic cut-off levels should be calibrated appropriately on the introduction of new methodology.

Abstract Background Because birth size appears to be positively associated with breast cancer risk, we have studied whether this risk may differ according to molecular breast cancer subtypes. Methods A cohort of 22,931 women born 1920–1966 were followed up for breast cancer occurrence from 1961 to 2012, and 870 were diagnosed during follow-up. Archival diagnostic material from 537 patients was available to determine molecular breast cancer subtype, specified as Luminal A, Luminal B (human epidermal growth factor receptor 2 (HER2)-), Luminal B (HER2+), HER2 type, and Triple negative (TN) breast cancer. Information on the women’s birth weight, birth length and head circumference at birth was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for each molecular subtype, applying Cox regression, and stratified by maternal height. Results Birth length (per 2 cm increments) was positively associated with Luminal A (HR = 1.2, 95% CI, 1.0–1.3), Luminal B (HER2+) (HR = 1.3, 95% CI, 1.0–1.7), and TN breast cancer (HR = 1.4, 95% CI, 1.0–1.9). No clear association was found for birth weight and head circumference. The positive associations of birth length were restricted to women whose mothers were relatively tall (above population median). Conclusion We found a positive association of birth length with risk of Luminal A, Luminal B (HER2+) and TN breast cancer that appears to be restricted to women whose mothers were relatively tall. This may support the hypothesis that breast cancer risk is influenced by determinants of longitudinal growth and that this finding deserves further scrutiny.