Subsequent Breast Cancer Risk Research Articles

Understanding benign breast disease and subsequent breast cancer in Hispanic white females; a step closer to evidence-based management.

Background While Hispanic white females (HW) have lower incidence of breast cancer (BC) than non-Hispanic white females (NHW), BC risk is unclear for HW females after benign breast disease (BBD). Methods We compared BBD characteristics and subsequent BC risk among HW and NHW females in New Mexico using a population-based collection of benign breast biopsies (1996-2007). BBD was categorized as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BC risk was assessed as absolute risk (AR) using cumulative incidence and relative risk (RR) by comparing the number of BC events in BBDs to non-BBD. Results This study included 3,684 HW and 6,587 NHW females with BBD. HW females had similar proportions of NPD (58.6%vs.54.3%), PDWA (21.4%vs.23.5%), and AH (3.6%vs.3.3%) as NHW. BC risk among all females with BBD was higher than population-based expected rates (RR=1.87) and was similar for HW and NHW subgroups (RR=1.99vs.1.84). As expected, BC risk increased with increasing BBD severity, both overall [RR=1.81 (NPD), 1.85 (PDWA) and 3.10 (AH)] and in the HW and NHW subgroups. Adjusted AR of BC at 5 years also increased with the severity of BBD (HW vs. NHW;NPD: 1.4 vs. 2.1%; PDWA: 1.5 vs. 2.7%; AH: 6 vs. 4.8%). Conclusions We found similar BC RRs and ARs in HW and NHW. Risk counseling should ensure that HW females receive breast cancer clinical management warranted by their similar absolute risks. Impact The present population-based provides evidence for clinical management of HW females with BBD for the prevention of BC.

Tamoxifen for breast cancer prevention among survivors of pediatric lymphoma previously treated with chest radiation: Clinical benefits, harms and tradeoffs.

10025 Background: Survivors of pediatric lymphoma previously treated with chest radiation are at high risk for subsequent breast cancer. Although early initiation of breast cancer screening is recommended, the clinical benefits and harms of adding tamoxifen to reduce breast cancer deaths among these women are unknown. Methods: We adapted a Cancer Intervention and Surveillance Modeling Network (CISNET) breast model using data from the Childhood Cancer Survivor Study (CCSS) to reflect the elevated risks for breast cancer and competing mortality for 5-year survivors previously treated with chest radiation (RT). Breast cancer risk was based on age, chest RT field, timing of RT relative to menarche, menopause status, anthracycline exposure, and family history. Premature menopause risk varied by cumulative ovarian RT and alkylator dose. Based on the US Preventive Services Task Force 2019 Evidence Summary, we assumed tamoxifen (20mg daily for 5 years) reduced estrogen receptor positive (ER+) breast cancer risk by 42% (RR = 0.58 [0.42-0.81]) for 20 years and increased risks for venous thromboembolism, deep vein thrombosis, coronary heart disease, stroke and endometrial cancer during treatment. Strategies included no screening or tamoxifen, annual screening with mammography and MRI starting at age 25, annual screening with mammography and MRI starting at age 25 with the addition of tamoxifen at ages 25, 30 or 35. Model outcomes included cumulative breast cancer risk, number of childbearing years before age 45 (defined as years menstruating without tamoxifen use or a breast cancer diagnosis or having survived breast cancer for at least 3 years), and number of tamoxifen-related side-effects. Results: Among a cohort of 20-year-old 5-year lymphoma survivors previously treated with mediastinal RT without primary ovarian failure, an estimated 20% were projected to develop breast cancer and 2.6% would die from the disease before age 50 in the absence of screening or tamoxifen use. Survivors would have on average 22 childbearing years before age 45. Early initiation of breast cancer screening at age 25 would reduce breast cancer deaths before age 50 by 56.3%. Depending on age at initiation, tamoxifen would further reduce breast cancer deaths by 8.0 to 9.6 percentage points for an overall 64.3% to 65.9% reduction and reduce the average number of childbearing years by 17% to 21%. For each breast cancer death averted, a reduction of 1950 to 3740 childbearing life years and 11 to 20 side-effects would occur and varied by the tamoxifen start age compared to mammography and MRI screening. Conclusions: Tamoxifen use for primary breast cancer prevention among pediatric lymphoma survivors may further reduce breast cancer deaths but decisions might depend on survivor preferences for side effects vs. avoiding breast cancer and consideration of timing for childbearing.

Multiplicity of benign breast disease lesions and breast cancer risk in African American women.

The risk of developing subsequent breast cancer is higher in women diagnosed with benign breast disease (BBD) but these studies were primarily performed in non-Hispanic white populations. Still, these estimates have been used to inform breast cancer risk models that are being used clinically across all racial and ethnic groups. Given the high breast cancer mortality rates among African American (AA) women, it is critical to study BBD in this population, to ensure the risk models that include this information perform adequately. This study utilized data from AA women who underwent benign breast biopsies at a hospital served by the University Pathology Group in Detroit, Michigan, from 1998 to 2010. Patients were followed for subsequent breast cancers through the population-based Metropolitan Detroit Cancer Surveillance System (MDCSS). BBD lesion scores were assigned to represent the severity or extent of benign breast lesions, with higher scores indicating a greater number of distinct lesion types. Of 3,461 eligible AA women with BBD in the cohort, 6.88% (n=238) subsequently developed breast cancer. Examined individually, six of the eleven lesions (apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, intraductal papilloma, sclerosing adenosis, columnar alterations and radial scars) were significantly associated with increased risk of breast cancer after adjustment for age and year of biopsy and were further considered in multiple lesion models. For every different type of benign breast lesion, subsequent risk of breast cancer increased by 25% (RR=1.25, 95% CI: 1.10, 1.42) after adjustment for age at biopsy and proliferative versus non-proliferative disease. In summary, this study affirms the increased breast cancer risk in AA women with BBD, particularly in those with multiple lesions. These findings have implications for the management of breast cancer risk in millions of women affected by BBD, a high risk group that could benefit from personalized surveillance and risk reduction strategies.

Abstract 4867: Longitudinal latent class analysis to further understand trajectory of density over time and risk of breast cancer

Abstract Background: It is clinically important to refine strategies to manage women with dense breasts as they represent approximately 50% of all women screened. Change in breast density is related to risk of breast cancer.1 We also must understand this change in density over time in women with dense and non-dense breasts. While population level data have been reported to estimate decrease in density with age, this has largely used digitized film images.2 Expanding use of digital mammography and repeated screening generates a large library of images for each woman, offering the potential to use more of the image data. Methods: We use longitudinal latent class analysis to cluster women and estimate their change in density over time. To evaluate the groups of women with different patterns of change in density we fit latent class models to our previously published data.1 This includes 289 pathology confirmed cases of breast cancer and 658 controls among women followed from November 3, 2008 to October 31, 2020. Results: Among women with dense breasts, there are 107 who developed breast cancer during follow-up and 267 control women who remained free from breast cancer. In the women without dense breasts, 173 cases and 383 controls were evaluated and showed similar age and BMI within the controls as seen in women with dense breasts. Prevalence of family history and history of benign breast biopsy did not differ between the two groups. We observe this latent class and trajectory of density phenomenal separately for dense and non-dense groups in our data. We show that the data define 2 classes, those who have decrease in density over time and those who have increase over time. The odds ratio (OR) for cancer comparing decline vs. incline is 4.9 in women with dense breasts (BI-RADS C, D) and 6.17 on women with non-dense breasts (BI-RADS A, B). Discussion: To refine our understanding of patterns of change in breast density over time in relation to breast cancer risk we fit latent class models. Longitudinal change matters as reflected in the 2-class model. This is independent of starting density and confirms that a one-time measure of density is not enough to define level of risk for subsequent breast cancer. Further work is needed to better define the drivers and inhibitors of decline in breast density over time given this change over time as women age is a universal phenomenon.2 1. Jiang S, Bennett DL, Rosner BA, Colditz GA. Longitudinal Analysis of Change in Mammographic Density in Each Breast and Its Association With Breast Cancer Risk. JAMA Oncol 2023;9(6):808-814. (In English). DOI: 10.1001/jamaoncol.2023.0434. 2. Burton A, Maskarinec G, Perez-Gomez B, et al. Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide. PLoS Med 2017;14(6):e1002335. DOI: 10.1371/journal.pmed.1002335. Citation Format: Graham A. Colditz, Debbie L. Bennett, Shu Jiang. Longitudinal latent class analysis to further understand trajectory of density over time and risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4867.

Risk of Breast Cancer After Diabetes in Pregnancy: A Population-based Cohort Study

ObjectivesDiabetes is associated with an increased risk of several cancers, including postmenopausal breast cancer. The evidence for higher breast cancer risk after diabetes in pregnancy is conflicting. We compared the incidence of breast and other cancers between pregnant women with and without diabetes. MethodsThis work was a propensity-matched, retrospective cohort study using population-based health-care databases from Ontario, Canada. Those deliveries with gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (pregestational DM) were identified and matched to deliveries without diabetes mellitus (non-DM). Deliveries from each diabetes cohort were matched 1:2 on age, parity, year of delivery, and propensity score to non-DM deliveries. Matched subjects were followed from delivery for incidence of breast cancer as a primary outcome, and other site-specific cancers as secondary outcomes. We performed Cox proportional hazards regression to compare rates of breast cancer between matched groups. ResultsOver a median of 8 (interquartile range 4 to 13) years of follow-up, compared with non-DM deliveries, the incidence of breast cancer was significantly lower for GDM but similar for pregestational DM deliveries (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.82 to 0.98; and HR 0.92, 95% CI 0.80 to 1.07, respectively). GDM was associated with a significantly higher incidence of pancreatic and hepatocellular cancer, and pregestational DM was associated with a higher incidence of thyroid, hepatocellular, and endometrial cancers. ConclusionsDiabetes in pregnancy does not have a higher short-term risk of subsequent breast cancer, but there may be a higher incidence of other cancers.

Is there an association between endometriosis and subsequent breast cancer? A retrospective cohort study from Germany

PurposeGiven the relatively high incidence of both endometriosis and breast cancer, investigating the potential connection between these gynecological diseases is of substantial clinical significance. However, there is no clear consensus in the literature on the extent to which the risk of breast cancer is increased in patients with endometriosis. Therefore, we conducted a large-scale observational study investigating the association between endometriosis and breast cancer risk.MethodsThis study included women aged ≥ 18 years with an initial endometriosis diagnosis from one of 315 office-based gynecologists in Germany between January 2005 and December 2021. Non-endometriosis patients were matched 1:1 to patients with endometriosis based on age, index year, average yearly consultation frequency, and predefined co-diagnoses within 12 months before or on the index date, including obesity and benign breast disorders. The association between endometriosis and the 10-year incidence of breast cancer was studied using Kaplan–Meier curves and log-rank tests. Finally, a univariable Cox regression analysis was conducted to assess the association between endometriosis and breast cancer.ResultsOver a follow-up period of up to 10 years, no significant difference was observed between the endometriosis (2.4%) and the matched non-endometriosis group (2.5%) with regard to breast cancer diagnoses. Furthermore, the regression analysis revealed no significant association between endometriosis and subsequent breast cancer.ConclusionIn summary, our comprehensive 10-year study involving a substantial sample of women indicates that endometriosis is not significantly associated with an increased risk of subsequent breast cancer.

Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study.

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.

Abstract B067: Markers of vitamin D3 activity in normal breast tissue and subsequent breast cancer: A pilot study

Abstract Vitamin D3 (1,25-dihydroxyvitamin D3 (1,25(OH)2D3)), has been hypothesized to be associated with breast cancer initiation and progression through several different mechanisms. In addition to playing a key role calcium and phosphate homeostasis, it has been shown to be involved in various processes associated with carcinogenesis, including immune modulation, proliferation, and cellular differentiation. Population-based studies have consistently shown circulating levels of vitamin D3 are lower among African American populations compared to other racial and ethnic groups in the United States. Epidemiologic evidence is mixed as to whether circulating vitamin D3 levels are associated with risk of developing breast cancer, with a recent meta-analysis reporting null results. Fewer reports examine the association between tissue-based markers of vitamin D3 metabolism and breast cancer risk. Here, we seek to determine whether the target of vitamin D3, the Vitamin D Receptor (VDR), and vitamin D3 synthesizing and degrading enzymes (CYP24A1, CYP27B1, respectively) are present in normal breast tissue, and if so, whether presence in the tissue is associated with risk of subsequent breast cancer. We utilized tissue specimens from the Susan G. Komen Tissue Bank at Indiana University to determine the expression of VDR, CYP24a1 and CYP27b1 in tissue from healthy, cancer-free donors. We selected n=14 women who developed a subsequent breast cancer, age, self-reported race and ethnicity-matched to n=28 women who did not develop cancer. Healthy breast tissue from n=4 men were also included, although results are preliminary and will only be described. Immunohistochemistry (IHC) was performed for VDR (Cell Signaling), CYP24A1 (Invitrogen) and CYP27B1 (Santa Cruz Biotechnology) on the formalin-fixed, paraffin-embedded tissue. Slides will be scored by a breast pathologist to determine the amount and intensity of the staining. Descriptive statistics will be used to summarize donor characteristics and IHC markers, including results stratified by self-reported race. Correlations between IHC markers will also be assessed. Logistic regression models will be performed to determine if an association exists between VDR, CYP24A1, CYP27B1 and development of breast cancer. Understanding the protein expression of normal breast tissue in those who do and do not develop breast cancer may identify pathways amenable to prevention strategies. Citation Format: Anastasia Ebersole, Rana German, Michele L. Cote. Markers of vitamin D3 activity in normal breast tissue and subsequent breast cancer: A pilot study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B067.

Prospective analysis of sleep characteristics, chronotype, and risk of breast cancer in the california teachers study

PurposePoor sleep quality and evening chronotype were associated with increased risk of breast cancer in a previous retrospective study in the California Teachers Study (CTS). The present analysis examines these sleep factors prospectively in the same cohort of women.MethodsFrom the CTS, we included 1,085 incident breast cancer cases and 38,470 cancer-free participants from 2012 through 2019. We calculated time at risk and used Cox proportional hazards regression models to estimate the hazard ratios (HRs) and control for risk factors such as age, race, body mass index, family history of breast cancer, and reproductive history. The sleep factors examined were quality, latency, duration, disturbance, and sleep medication use, based on a shortened version of the Pittsburgh Sleep Quality Index, as well as chronotype (preference for morning or evening activity). This analysis was limited to women who were post-menopausal at the time they answered these sleep-related questions.ResultsMeasures of sleep quality did not appear to be associated with subsequent breast cancer risk. The HR for evening chronotypes compared to morning chronotypes was somewhat elevated (HR 1.19, 95% CI 1.04, 1.36).ConclusionWhile the measures of sleep quality and duration were not associated with post-menopausal breast cancer risk in this prospective analysis, the modestly elevated risk observed for evening chronotypes was consistent with the prior retrospective analysis.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m−2: 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m−2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m−2, HR: 2.33 for 300–399 mg m−2 and HR: 2.78 for ≥400 mg m−2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m−2 of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m−2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Risk of Subsequent Breast Cancer in Women with Early Stage HER2-Positive Breast Cancer in a Large Community Health Plan.

Clinical outcomes have improved for women with early stage, HER2-positive breast cancer following the FDA approval of adjuvant trastuzumab use in 2006. However, only limited information exists on such patients' outcomes in real-world settings outside of clinical trials. We examined the risk of subsequent breast cancer in women with HER-2 positive disease, and the impact of trastuzumab use, in a large California community-based health plan. A cohort of 3550 women with HER2-positive breast cancer (stages I-III) from 2009-2017 were followed through December 2018. We calculated subsequent breast cancer (SBC) rates overall and by trastuzumab use. Multivariable Cox proportional hazards modeling was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for SBC by trastuzumab use. Within the cohort diagnosed with HER2-positive disease, 81% received adjuvant trastuzumab. After 4.1 mean years follow-up (maximum 10 years), the risk of SBC was 22% lower with adjuvant trastuzumab use (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) compared with non-use. The cumulative incidence of SBC precipitously rose two years after diagnosis and by the 10th year, the cumulative incidence was 31% among those who had trastuzumab therapy versus 34% without this therapy. In community practice settings, the cumulative incidence of SBC in patients with early stage HER2-positive BC was 31% at 10 years in a cohort treated with adjuvant trastuzumab. Trastuzumab use was associated with a 22% reduced risk of developing SBC. This residual disease burden suggests breast cancer outcomes may be improved with further treatment given the advent of next-generation HER2-targeted therapies.

Changes in metabolic syndrome and risk of breast and endometrial cancers according to menopause.

This study investigated how changes in metabolic syndrome (MetS) are associated with the subsequent risk of breast and endometrial cancer according to menopausal status. This cohort study, using data from the National Health Insurance Service database, included women aged ≥40 years who underwent 2 biennial cancer screenings (2009-2010 and 2011-2012) and were followed up until 2020. Participants were grouped into MetS-free, MetS-recovery, MetS-development, and MetS-persistent groups. Menopausal status (premenopausal, perimenopausal, and postmenopausal) was assessed at 2 screenings. Cox proportional hazard regression was used to assess the association between MetS changes and cancer risk. In 3,031,980 women, breast and endometrial cancers were detected in 39,184 and 4,298, respectively. Compared with the MetS-free group, those who recovered, developed, or had persistent MetS showed an increased risk of breast cancer, with adjusted hazard ratios (aHRs) of 1.05, 1.05, and 1.11, respectively (p<0.005). MetS persistence was associated with an increased risk of breast cancer in postmenopausal women (aHR=1.12, 95% CI, 1.08-1.16) but not in premenopausal or perimenopausal women. MetS persistence was associated with an increased risk of endometrial cancer in premenopausal, perimenopausal, and postmenopausal women, with aHRs of 1.41 (95% CI, 1.17-1.70), 1.59 (95% CI, 1.19-2.12), and 1.47 (95% CI, 1.32-1.63), respectively. Increased breast cancer risk was associated with recovered, developed, and persistent MetS in postmenopausal women. Meanwhile, increased endometrial cancer risk was found in obese women who recovered from MetS or persistently had MetS, regardless of menopausal status, when compared to MetS-free women.

The association between the multiple birth and breast cancer incidence: an update of a systematic review and meta-analysis from 1983 to 2022

BackgroundIt has been assumed that perinatal factors such as multiple pregnancies may affect subsequent breast cancer risk in the mother. Considering the inconsistencies in the results of case-control and cohort studies published in the world, this meta-analysis was conducted in order to determine the exact association between multiple pregnancies (twins or more) and the breast cancer incidence.MethodsThis study was performed as a meta-analysis based on PRISMA guidelines by searching the international databases of PubMed (Medline), Scopus, and Web of Science as well as by screening selected articles based on their subject, abstract and full text. The search time was from January 1983 to November 2022. Then the NOS checklist was used to evaluate the quality of the final selected articles. The indicators considered for the meta-analysis included the odds ratio (OR) and the risk ratio (RR) along with the confidence interval reported in the selected primary studies. The desired analyzes were performed with STATA software version 17 to be reported.ResultsIn this meta-analysis, 19 studies were finally selected for analysis, which fully met the inclusion criteria. Of these, 11 were case-control studies and 8 were cohort ones. Their sample size was 263,956 women (48,696 with breast cancer and 215,260 healthy) and 1,658,378 (63,328 twin or multiple pregnancies and 1,595,050 singleton pregnancies), respectively. After combining the results of cohort and case-control studies, the effect of multiple pregnancies on the breast cancer incidence was equal to 1.01 (95% CI: 0.89–1.14; I2: 44.88%, P: 0.06) and 0.89 (95% CI: 0.83–0.95; I2: 41.73%, P: 0.07), respectively.ConclusionThe present meta-analysis results showed, in general, multiple pregnancies were one of the preventive factors of breast cancer.

Longitudinal Analysis of Change in Mammographic Density in Each Breast and Its Association With Breast Cancer Risk

Although breast density is an established risk factor for breast cancer, longitudinal changes in breast density have not been extensively studied to determine whether this factor is associated with breast cancer risk. To prospectively evaluate the association between change in mammographic density in each breast over time and risk of subsequent breast cancer. This nested case-control cohort study was sampled from the Joanne Knight Breast Health Cohort of 10 481 women free from cancer at entry and observed from November 3, 2008, to October 31, 2020, with routine screening mammograms every 1 to 2 years, providing a measure of breast density. Breast cancer screening was provided for a diverse population of women in the St Louis region. A total of 289 case patients with pathology-confirmed breast cancer were identified, and approximately 2 control participants were sampled for each case according to age at entry and year of enrollment, yielding 658 controls with a total number of 8710 craniocaudal-view mammograms for analysis. Exposures included screening mammograms with volumetric percentage of density, change in volumetric breast density over time, and breast biopsy pathology-confirmed cancer. Breast cancer risk factors were collected via questionnaire at enrollment. Longitudinal changes over time in each woman's volumetric breast density by case and control status. The mean (SD) age of the 947 participants was 56.67 (8.71) years at entry; 141 were Black (14.9%), 763 were White (80.6%), 20 were of other race or ethnicity (2.1%), and 23 did not report this information (2.4%). The mean (SD) interval was 2.0 (1.5) years from last mammogram to date of subsequent breast cancer diagnosis (10th percentile, 1.0 year; 90th percentile, 3.9 years). Breast density decreased over time in both cases and controls. However, there was a significantly slower decrease in rate of decline in density in the breast that developed breast cancer compared with the decline in controls (estimate = 0.027; 95% CI, 0.001-0.053; P = .04). This study found that the rate of change in breast density was associated with the risk of subsequent breast cancer. Incorporation of longitudinal changes into existing models could optimize risk stratification and guide more personalized risk management.

Abstract 776: Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease

Abstract Introduction: Benign breast disease (BBD) is associated with increased breast cancer risk, and the magnitude of this risk is characterized by the severity of the histological classification of the biopsy lesion. High mammographic density (MBD) is an independent risk factor for invasive breast cancer. Given that MBD is altered by endogenous and exogenous factors, its temporal changes may impact future breast cancer risk, but this is poorly studied, particularly among high risk BBD patients. In this study, we examined whether MBD changes following a BBD diagnosis were associated with subsequent breast cancer risk. Methods: We conducted a case-control study within a cohort of 15,395 women aged 18-86 years who were members of the Kaiser Permanente Northwest Region health care system, had a diagnosis of BBD between 1970 and 2012 and were followed through mid-2015. Cases (n=261) were BBD patients who developed invasive breast cancer at least one year after the index BBD diagnosis. Controls were matched (1:1), on age at BBD diagnosis and health plan membership duration and did not develop breast cancer during the follow-up duration. Standardized change in percent MBD per 2 years, categorized as an increase (≥0%), stable/minimal decrease (-5%&amp;lt; to &amp;lt;0) or decrease (≤-5%), was determined from baseline (pre-biopsy) and follow-up (prior to breast cancer diagnosis for cases or matched selection date for controls) mammograms, using computer-assisted software. Associations between MBD change and breast cancer risk overall and stratified by BBD diagnosis age and histology were determined using unconditional logistic regression adjusted for matching factors and other covariates. Results: At BBD diagnosis (median age (range)=54.6 years (32.4, 86.6)), 64.5% (n=329: n=151 cases and n=178 controls) of women had non-proliferative and 35.5% (n=181: n=110 cases and n=71 controls) had proliferative BBD with or without atypia. Compared to women with stable/minimal MBD decrease, those who experienced a decline ≥5% per 2 years were less likely to develop breast cancer (odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.38, 1.07). However, among women aged ≥50 years at BBD diagnosis, an MBD decrease ≥5% was significantly associated with reduced breast cancer risk (OR: 0.48; 95%CI: 0.25, 0.92), with the protective effect most apparent for those with proliferative (OR: 0.32; 95%CI: 0.11, 0.99) versus non-proliferative (OR: 0.70; 95%CI: 0.30, 1.64) BBD. Discussion: Temporal MBD declines were associated with reduced risk of subsequent breast cancer particularly among BBD patients aged ≥50 years and with proliferative BBD diagnoses. These findings suggest that monitoring MBD may be useful in determining risk and that strategies to actively reduce MBD may be helpful in reducing breast cancer risk among high-risk BBD patients. Funding: Dr. Rohan is supported in part by the Breast Cancer Research Foundation (BCRF-22-140). Citation Format: Maeve Mullooly, Shaoqi Fan, Ruth M. Pfeiffer, Erin Aiello Bowles, Máire A. Duggan, Roni T. Falk, Kathryn Richert-Boe, Terry Kimes, Jonine D. Figueroa, Thomas E. Rohan, Mustapha Abubakar, Gretchen L. Gierach. Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 776.

Abstract 5241: Association of polygenic risk scores with breast cancer risk among women with benign breast disease

Abstract Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a 1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated. To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR). Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study. These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients. Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval. Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.

Choice of Assessment and Subsequent Risk of Breast Cancer among Women with False-Positive Mammography Screening

Women with false-positive mammography screening results have a two- to four-fold higher risk of breast cancer. This study aimed to investigate if the subsequent risk of breast cancer after a false-positive mammography screening is associated with the received diagnostic assessment. The study population consisted of women who underwent false-positive mammography screening from January 2010 to June 2019. They were categorised into seven groups depending on the elements in the assessment (standard care: additional mammography, ultrasound, and if they had a relevant biopsy). Risks of interval cancer, next-round screen-detected cancer, and long-term breast cancer for non-standard care assessments were compared to standard care assessments using Binomial and Cox regression models. We included 44,279 women with a false-positive result. Invasive assessments that lacked an ultrasound or additional mammography were not more associated with an increased risk of subsequent cancers compared to that of 'all three elements'. The few assessments that included 'only ultrasound' or 'only mammography' resulted in higher relative risks of next-round screen-detected cancer of 1.52 (95% CI: 0.93-2.47) and 1.67 (95% CI: 0.54-5.16), respectively, compared to that of standard care. The increased subsequent risk of breast cancer among women with a previous false-positive result was not found to be correlated with the choice of elements in the assessment process.

Abstract P4-03-09: Risk of breast cancer after false-positive mammography recalls: a matched cohort study

Abstract Background: False-positive mammography recalls are common and associated with an increased risk of subsequent breast cancer. But the long-term risk and whether the risk restricts to the breast cancer detected on the false-positive recalled side remain unclear. Objective: To examine long-term risk of breast cancer after false-positive recalls by side of breasts, mode of detection and tumor characteristics. Design: Matched cohort. Setting: The mammography screening program in Stockholm, Sweden. Participants: We included 45,588 women who received false-positive recalls (1991-2017) and 455,880 matched women who were not recalled, and then followed them until March 31st, 2020. Measurement: Breast cancer incidence; mode of breast cancer detection; tumor characteristics; re-attendance at mammography screening. Results: With Kaplan-Meier curves, we showed that women with false-positive recalls were more likely than those without to have breast cancers, on not only the previously recalled (false-positive) side but also the unrecalled side, up to at least 20 years since the next scheduled screen. We further found that risks were particular higher for breast cancer diagnosed on the false-positive side within first four years of follow-up (hazard ratio [HR]: 2.40; 95% confidence interval [CI]: 2.17-2.65), by the use of stratified Cox model while allowing for time-varying effects. In addition, when stratifying by age at matched mammograms, we found the association was stronger among old women (60-74) than young women (40-59). This was consistent with the result that the risk of breast cancer was higher among women with low density than those with high density. Of note, within the first four years, women with false-positive recalls were at an increased risk of clinical detected cancers (cancer detected among women who did not attend last scheduled screen or were at an age out of screening age ranges) on the false-positive side compared with those who were not recalled. In addition, we found that women with false-positive recalls had statistically significantly lower re-attendance rates at every of next five scheduled screenings. Conclusion: Women with false-positive recalls are at an increased risk of breast cancer for at least two decades, while these women are less likely to adhere to subsequent mammography screens comparing to women who were not recalled. Thus, women with false-positive recalls, especially older women, should be encouraged to re-attend the mammography screening program. Citation Format: Xinhe Mao, Wei He, Keith Humphreys, Haomin Yang, Kamila Czene. Risk of breast cancer after false-positive mammography recalls: a matched cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-09.

Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort

PurposeThe International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast...

Oral Contraceptive Use and Breast Cancer Risk According to Molecular Subtypes Status: A Meta-Analysis

Abstract Background Breast cancer is a heterogeneous disease with distinct molecular signatures of disease etiology, evidenced by the joint expression of molecular tumor markers. Differential effects of oral contraceptive use on breast cancer risk by molecular subtypes have been reported. This is the first meta-analysis to investigate associations between oral contraceptive use and subsequent breast cancer risk stratified by combined estrogen receptor (ER) and progesterone receptor (PR) status alongside the Luminal A and B subtypes, which additionally consider the human epidermal growth factor receptor 2 (HER2) status. Methods A systematic review and meta-analysis of case-control and cohort studies was conducted in PubMed and Web of Science. The odds ratios (ORs) were summarized using a random-effects model. Results Eleven studies met the inclusion criteria for qualitative and quantitative analysis. Random effects meta-analyses revealed significant risk increasing effects for ever-users of oral contraception on ER-PR- breast cancer compared to never-users (OR = 1.30, 95% CI; 1.07 to 1.56, p &amp;lt; 0.01). Ever-use of oral contraception was not associated with breast cancer risk when stratified by the ER+PR+ breast cancer subtype (OR = 1.00, 95% CI; 0.86 to 1.16, p = 0.99). Data on Luminal A and B subtypes was limited and not suggestive for associations with breast cancer risk in ever-users of OCs compared to never-users. Furthermore, a significant increased risk of ER-PR- breast cancer was observed for OC use duration of &amp;gt; 4 years compared to never-users (OR = 1.74, 95% CI: 1.15 to 2.63, p &amp;lt; 0.01). Conclusions The current state of the evidence suggests that OC use longer than 4 years is associated with an increased breast cancer risk, pertaining to the estrogen and progesterone double negative breast cancer subtype. Large-scale prospective observational studies including more comprehensive molecular signature of breast cancer aetiology, including HER2 status, are needed. Key messages • The use of oral contraception was associated with estrogen and progesterone receptor double negative breast cancer, but not hormone receptive positive cancer. • This is the first meta-analysis to investigate oral contraceptive use and associations with breast cancer risk by combined estrogen and progesterone receptor status.