Factors Associated With False-Positive Recalls in Mammography Screening.

BACKGROUND: We aimed to identify factors associated with false-positive recalls in mammography screening compared with women who were not recalled and those who received true-positive recalls. METHODS: We included 29,129 women, aged 40 to 74 years, who participated in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) between 2011 and 2013 with follow-up until the end of 2017. Nonmammographic factors were collected from questionnaires, mammographic factors were generated from mammograms, and genotypes were determined using the OncoArray or an Illumina custom array. By the use of conditional and regular logistic regression models, we investigated the association between breast cancer risk factors and risk models and false-positive recalls. RESULTS: Women with a history of benign breast disease, high breast density, masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have mammography recalls, including both false-positive and true-positive recalls. Further analyses restricted to women who were recalled found that women with a history of benign breast disease and dense breasts had a similar risk of having false-positive and true-positive recalls, whereas women with masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have true-positive recalls than false-positive recalls. CONCLUSIONS: We found that risk factors associated with false-positive recalls were also likely, or even more likely, to be associated with true-positive recalls in mammography screening.

Hyperthyroidism is associated with breast cancer risk and mammographic and genetic risk predictors.

BACKGROUND: Despite the biological link between thyroid hormones and breast cancer cell proliferation shown in experimental studies, little is known about the association between hyperthyroidism and breast cancer, as well as its association with the most common mammographic and genetic risk predictors for breast cancer. METHODS: This study estimates the incidence rate ratios (IRRs) of breast cancer among women diagnosed with hyperthyroidism, compared to those who are not, using two cohorts: a Swedish national cohort of the general female population (n = 3,793,492, 2002-2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n = 69,598, 2002-2017). We used logistic regression to estimate the odds ratios (ORs) of hyperthyroidism according to the mammographic and genetic risk predictors for breast cancer. RESULTS: An increased risk of breast cancer was observed in patients in the national cohort with hyperthyroidism (IRR = 1.23, 95% CI = 1.12-1.36), particularly for toxic nodular goiter (IRR = 1.38, 95% CI = 1.16-1.63). Hyperthyroidism was associated with higher body mass index, early age at first birth, and lower breastfeeding duration. Higher mammographic density was observed in women with toxic nodular goiter, compared to women without hyperthyroidism. Additionally, among genotyped women without breast cancer in the KARMA cohort (N = 11,991), hyperthyroidism was associated with a high polygenic risk score (PRS) for breast cancer overall (OR = 1.98, 95% CI = 1.09-3.60) and for estrogen receptor-positive specific PRS (OR = 1.90, 95% CI = 1.04-3.43). CONCLUSION: Hyperthyroidism is associated with an increased risk of breast cancer, particularly for patients with toxic nodular goiter. The association could be explained by higher mammographic density among these women, as well as pleiotropic genetic variants determining shared hormonal/endocrine factors leading to the pathology of both diseases.

Disease trajectories and mortality among women diagnosed with breast cancer.

PURPOSE: Breast cancer is a common disease with a relatively good prognosis. Therefore, understanding the spectrum of diseases and mortality among breast cancer patients is important, though currently incomplete. We systematically examined the incidence and mortality of all diseases following a breast cancer diagnosis, as well as the sequential association of disease occurrences (trajectories). METHODS: In this national cohort study, 57,501 breast cancer patients (2001-2011) were compared to 564,703 matched women from the general Swedish population and followed until 2012. The matching criteria included year of birth, county of residence, and socioeconomic status. Based on information from the Swedish Patient and Cause of Death Registries, hazard ratios (HR) were estimated for disease incidence and mortality. Conditional logistic regression models were used to identify disease trajectories among breast cancer patients. RESULTS: Among 225 diseases, 45 had HRs > 1.5 and p < 0.0002 when comparing breast cancer patients with the general population. Diseases with highest HRs included lymphedema, radiodermatitis, and neutropenia, which are side effects of surgery, radiotherapy, and chemotherapy. Other than breast cancer, the only significantly increased cause of death was other solid cancers (HR = 1.16, 95% CI = 1.08-1.24). Two main groups of disease trajectories were identified, which suggest menopausal disorders as indicators for other solid cancers, and both neutropenia and dorsalgia as diseases and symptoms preceding death due to breast cancer. CONCLUSIONS: While an increased incidence of other diseases was found among breast cancer patients, increased mortality was only due to other solid cancers. Preventing death due to breast cancer should be a priority to prolong life in breast cancer patients, but closer surveillance of other solid cancers is also needed.

Inherited factors contribute to an inverse association between preeclampsia and breast cancer.

BACKGROUND: Preeclampsia is frequently linked to reduced breast cancer risk. However, little is known regarding the underlying genetic association and the association between preeclampsia and mammographic density. METHODS: This study estimates the incidence rate ratios (IRRs) of breast cancer in patients with preeclampsia, when compared to women without preeclampsia, using Poisson regression models in two cohorts of pregnant women: a Swedish nationwide cohort (n = 1,337,934, 1973-2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n = 55,044, 1958-2015). To identify the genetic association between preeclampsia and breast cancer, we used logistic regression models to calculate the odds ratios (ORs) of preeclampsia in sisters of breast cancer patients, and in women with different percentiles of breast cancer polygenic risk scores (PRS). Linear regression models were used to estimate the mammographic density by preeclampsia status in the KARMA cohort. RESULTS: A decreased risk of breast cancer was observed among patients with preeclampsia in both the nationwide (IRR = 0.90, 95% CI = 0.85; 0.96) and KARMA cohorts (IRR = 0.75, 95% CI = 0.61; 0.93). Women with high breast cancer PRS and sisters of breast cancer patients had a lower risk of preeclampsia (OR = 0.89, 95% CI = 0.83; 0.96). Mammographic density was lower in women with preeclampsia compared to women without preeclampsia (-2.04%, 95% CI = -2.65; -1.43). Additionally, among sisters in the KARMA cohort (N = 3500), density was lower in sisters of patients with preeclampsia compared to sisters of women without preeclampsia (-2.76%, 95% CI = -4.96; -0.56). CONCLUSION: Preeclampsia is associated with reduced risk of breast cancer and mammographic density. Inherited factors contribute to this inverse association.

High education and increased parity are associated with breast-feeding initiation and duration among Australian women.

OBJECTIVE: Breast-feeding is associated with positive maternal and infant health and development outcomes. To assist identifying women less likely to meet infant nutritional guidelines, we investigated the role of socio-economic position and parity on initiation of and sustaining breast-feeding for at least 6 months. DESIGN: Prospective cohort study. SETTING: Australia. SUBJECTS: Parous women from the Australian Longitudinal Study on Women's Health (born 1973-78), with self-reported reproductive and breast-feeding history (N 4777). RESULTS: While 89 % of women (83 % of infants) had ever breast-fed, only 60 % of infants were breast-fed for at least 6 months. Multiparous women were more likely to breast-feed their first child (~90 % v. ~71 % of primiparous women), and women who breast-fed their first child were more likely to breast-feed subsequent children. Women with a low education (adjusted OR (95 % CI): 2·09 (1·67, 2·62)) or a very low-educated parent (1·47 (1·16, 1·88)) had increased odds of not initiating breast-feeding with their first or subsequent children. While fewer women initiated breast-feeding with their youngest child, this was most pronounced among high-educated women. While ~60 % of women breast-fed their first, second and third child for at least 6 months, low-educated women (first child, adjusted OR (95 % CI): 2·19 (1·79, 2·68)) and women with a very low (1·82 (1·49, 2·22)) or low-educated parent (1·69 (1·33, 2·14)) had increased odds of not breast-feeding for at least 6 months. CONCLUSIONS: A greater understanding of barriers to initiating and sustaining breast-feeding, some of which are socio-economic-specific, may assist in reducing inequalities in infant breast-feeding.

Educational mobility and weight gain over 13 years in a longitudinal study of young women.

BACKGROUND: Limited evidence exists about the role of education and own educational mobility on body weight trajectory. A better understanding of how education influences long term weight gain can help us to design more effective health policies. METHODS: Using random effects models, the association between i) highest education (n = 10 018) and ii) educational mobility over a 9 year period (n = 9 907) and weight gain was analysed using five waves of data (over 13 years) from the Australian Longitudinal Study on Women's Health 1973-78 cohort (from 18-23 years to 31-36 years). RESULTS: Highest educational attainment was inversely associated with weight at baseline and weight gain over 13 years. Compared to high educated women, those with a low (12 years or less) or intermediate (trade/certificate/diploma) education, respectively, weighed an additional 2.6 kg (95% CI:1.9 to 3.1) and 2.5 kg (95% CI:1.9 to 3.3) at baseline and gained an additional 3.9 kg (95% CI:2.6 to 5.2) and 3.1 kg (95% CI:2.6 to 3.9) over 13 years. Compared to women who remained with a low education, women with the greatest educational mobility had similar baseline weight to the women who already had a high education at baseline (2.7 kg lighter (95% CI:-3.7 to -1.8) and 2.7 kg lighter (95% CI:-3.4 to -1.9), respectively) and similarly favourable weight gain (gaining 3.1 kg less (95% CI:-4.0 to -2.21) and 4.2 kg less (95% CI:-4.8 to -3.4) over the 13 years, respectively). CONCLUSIONS: While educational attainment by mid-thirties was positively associated with better weight management, women's weight was already different in young adult age, before their highest education was achieved. These findings highlight a potential role of early life factors and personality traits which may influence both education and weight outcomes.

Breast Cancer Incidence After a False-Positive Mammography Result.

Importance: False-positive mammography results are common. However, long-term outcomes after a false-positive result remain unclear. Objectives: To examine long-term outcomes after a false-positive mammography result and to investigate whether the association of a false-positive mammography result with cancer differs by baseline characteristics, tumor characteristics, and time since the false-positive result. Design, Setting, and Participants: This population-based, matched cohort study was conducted in Sweden from January 1, 1991, to March 31, 2020. It included 45 213 women who received a first false-positive mammography result between 1991 and 2017 and 452 130 controls matched on age, calendar year of mammography, and screening history (no previous false-positive result). The study also included 1113 women with a false-positive result and 11 130 matched controls with information on mammographic breast density from the Karolinska Mammography Project for Risk Prediction of Breast Cancer study. Statistical analysis was performed from April 2022 to February 2023. Exposure: A false-positive mammography result. Main Outcomes and Measures: Breast cancer incidence and mortality. Results: The study cohort included 497 343 women (median age, 52 years [IQR, 42-59 years]). The 20-year cumulative incidence of breast cancer was 11.3% (95% CI, 10.7%-11.9%) among women with a false-positive result vs 7.3% (95% CI, 7.2%-7.5%) among those without, with an adjusted hazard ratio (HR) of 1.61 (95% CI, 1.54-1.68). The corresponding HRs were higher among women aged 60 to 75 years at the examination (HR, 2.02; 95% CI, 1.80-2.26) and those with lower mammographic breast density (HR, 4.65; 95% CI, 2.61-8.29). In addition, breast cancer risk was higher for women who underwent a biopsy at the recall (HR, 1.77; 95% CI, 1.63-1.92) than for those without a biopsy (HR, 1.51; 95% CI, 1.43-1.60). Cancers after a false-positive result were more likely to be detected on the ipsilateral side of the false-positive result (HR, 1.92; 95% CI, 1.81-2.04) and were more common during the first 4 years of follow-up (HR, 2.57; 95% CI, 2.33-2.85 during the first 2 years; HR, 1.93; 95% CI, 1.76-2.12 at >2 to 4 years). No statistical difference was found for different tumor characteristics (except for larger tumor size). Furthermore, associated with the increased risk of breast cancer, women with a false-positive result had an 84% higher rate of breast cancer death than those without (HR, 1.84; 95% CI, 1.57-2.15). Conclusions and Relevance: This study suggests that the risk of developing breast cancer after a false-positive mammography result differs by individual characteristics and follow-up. These findings can be used to develop individualized risk-based breast cancer screening after a false-positive result.

Pregnancy Weight Gain After Gastric Bypass or Sleeve Gastrectomy.

Importance: Pregnancy weight gain may affect the association of bariatric surgery with postsurgery pregnancy outcomes. However, the association of pregnancy weight gain with bariatric surgery is unclear. Objective: To compare pregnancy weight gain among women with a history of bariatric surgery vs those without and to investigate whether pregnancy weight gain differs by surgical procedure, surgery-to-conception interval, and/or surgery-to-conception weight loss. Design, Setting, and Participants: This nationwide, population-based matched cohort study was conducted in Sweden from 2014 to 2021. Singleton pregnancies with a history of bariatric surgery were propensity score matched (1:1) to pregnancies without such a history according to early-pregnancy body mass index (BMI), prepregnancy diabetes, prepregnancy hypertension, maternal age, smoking status, education level, height, country of birth, and delivery year. In addition, post-gastric bypass pregnancies were matched to post-sleeve gastrectomy pregnancies using the same matching strategy. Data analysis was performed from November 2022 to May 2023. Exposure: History of bariatric surgery. Main Outcomes and Measures: Pregnancy weight gain was standardized by gestational age into early-pregnancy BMI-specific z scores. Results: This study included 12 776 pregnancies, of which 6388 had a history of bariatric surgery and 6388 were matched controls. The mean (SD) age was 31.6 (4.9) years for the surgery group and 31.4 (5.2) for the matched controls, with an early-pregnancy mean (SD) BMI of 29.4 (5.2) in both groups. Across all early-pregnancy BMI strata, women with a history of bariatric surgery had lower pregnancy weight gain than matched controls. The differences in pregnancy weight gain z score values between the 2 groups were -0.33 (95% CI, -0.43 to -0.23) for normal weight, -0.33 (95% CI, -0.40 to -0.27) for overweight, -0.21 (95% CI, -0.29 to -0.13) for obese class I, -0.16 (95% CI, -0.29 to -0.03) for obese class II, and -0.08 (95% CI, -0.28 to 0.13) for obese class III. Pregnancy weight gain did not differ by surgical procedure. A shorter surgery-to-conception interval (particularly within 1 year) or lower surgery-to-conception weight loss was associated with lower pregnancy weight gain. Conclusions and Relevance: In this nationwide matched cohort study, women with a history of bariatric surgery had lower pregnancy weight gain than matched controls with similar early-pregnancy characteristics. Pregnancy weight gain was lower in those with a shorter surgery-to-conception interval or lower surgery-to-conception weight loss, but did not differ by surgical procedure.

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.

Heritability of Mammographic Breast Density, Density Change, Microcalcifications, and Masses.

Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer (N = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm2/year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%-67%) for MD, 23% (2%-45%) for microcalcifications, and 13% (1%-25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, -8% to 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer. SIGNIFICANCE: These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk.

Combined effect of education and reproductive history on weight trajectories of young Australian women: A longitudinal study.

OBJECTIVE: To investigate the combined effect of education and reproductive history on weight trajectory. METHODS: The association of education with weight trajectory (1996-2012) in relation to reproductive history was analyzed among 9,336 women (born 1973-1978) from the Australian Longitudinal Study on Women's Health using random effects models. RESULTS: Compared with women with a university degree/higher, lower-educated women were 2 kg heavier at baseline and gained an additional 0.24 kg/year. Giving birth was associated with an increase in weight which was more pronounced among women having their first birth <26 years of age (2.1 kg, 95% CI: 1.5-2.7), compared with 26 to 32 years or >32 years. While younger first-time mothers had a steeper weight trajectory (∼+0.16 kg/year, 95% CI: 0.1-0.3), this was less steep among lower-educated women. High-educated women with a second birth between 26 and 32 years had 0.9 kg decreased weight after this birth, while low-educated women gained 0.9 kg. CONCLUSIONS: While the effect of having children on weight in young adulthood was minimal, women having their first birth <26 years of age had increased risk of weight gain, particularly primiparous women. Educational differences in weight persisted after accounting for reproductive history, suggesting a need to explore alternative mechanisms through which social differences in weight are generated.

Social inequality in pre-pregnancy BMI and gestational weight gain in the first and second pregnancy among women in Sweden.

BACKGROUND: High pre-pregnancy body mass index (BMI) and inappropriate gestational weight gain (GWG) are associated with adverse short and long-term maternal and neonatal outcomes and may act as modifiable risk factors on the path to overweight/obesity, but their social patterning is not well established. This study investigates the association of education with BMI and GWG across two consecutive pregnancies. METHODS: The study includes 163,352 Swedish women, having their first and second singleton birth in 1982-2010. In both pregnancies, we investigated the association of women's education with (1) pre-pregnancy weight status and (2) adequacy of GWG. We used multinomial logistic regression, adjusting for child's birth year, mother's age and smoking status. RESULTS: Overall, the odds of starting either pregnancy at an unhealthy BMI were higher among women with a low education compared to more highly-educated women. Lower education also predicted a greater increase in BMI between pregnancies, with this effect greatest among women with excessive GWG in the first pregnancy (p<0.0001 for interaction). Education was also inversely associated with odds of excessive GWG in both pregnancies among healthy weight status women, but this association was absent or even weakly reversed among overweight and obese women. CONCLUSIONS: Lower educated women had the largest BMI increase between pregnancies, and these inequalities were greatest among women with excessive GWG in the first pregnancy. The importance of a healthy pre-pregnancy BMI, appropriate GWG and a healthy postpartum weight should be communicated to all women, which may assist in reducing existing social inequalities in body weight.