Subsequent Breast Cancer Research Articles

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%< to <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.

Abstract 4291: Deconvolution of cell type composition in FFPE tissue: Application to benign breast disease

Abstract Purpose: Benign breast disease (BBD) is viewed as a non-obligate precursor stage in the development of breast cancer (BC). Transcriptome profiling using RNA sequencing (RNA-seq) of bulk formalin-fixed paraffin-embedded (FFPE) tissue blocks has been routinely used in BC research. However, RNA-seq of heterogeneous bulk samples represents an averaged expression profile across all cell mixtures. Downstream analyses, such as biomarker discovery, are likely confounded by differences in cell proportions. There is a lack of research in optimizing strategies for cell type deconvolution especially for FFPE samples. We evaluated and optimized strategies for cell type deconvolution using existing single cell RNA-seq (scRNA-seq) and single nucleus RNA-seq (snRNA-seq) breast tissue references, and applied these to a cohort of BBD FFPE samples to assess risk of subsequent BC. Methods: 7 scRNA-seq and 3 snRNA-seq public samples from women’s breast tissue were normalized using SCTransform, then integrated using Harmony to form a complete reference set. Bioinformatics evaluations examined the performance of existing statistical and deep learning-based deconvolution methods. Computational simulations were conducted to evaluate those methods on three scenarios: 1) baseline; 2) incomplete reference set; 3) FFPE artifacts. FFPE artifacts were simulated based on a generalized additive model using 7 in-house paired FFPE-fresh frozen samples. Finally, we applied the best performing method to our BBD cohort of 62 samples. Differential expression analysis adjusting for cell proportions was performed to identify transcriptomic aberrations in BBD cases. Results: snRNA-seq was more sensitive in capturing adipocytes, while scRNA-seq was more sensitive in detecting lymphocytes in breast tissue. The median number of detectable genes per cell was higher for scRNA-seq than snRNA-seq before integration (1264 vs 558). Marker gene-based regression methods (e.g. CIBERSORT) displayed higher variance and lower bias compared to methods directly using scRNA-seq data (e.g. SCDC). Incomplete reference data led to increased bias and little effect on variance. FFPE artifacts had a higher impact on performance compared to incomplete reference data. Overall, Scaden, a deep learning-based method, was the top performing method across all simulation scenarios and was especially robust to FFPE artifacts. 59 differential expressed genes (DEGs) were identified with fold change > 1.5 and p value < 0.01. DEGs involved in BC, e.g. S100A8, WNT4 and HIST1H3H, would be left out if cell proportions were not properly adjusted. Conclusions: We constructed the first complete single cell reference data for women’s breast tissue and benchmarked existing cell type deconvolution methods. Compared to analyses not adjusting for cell proportions, we observed substantial differences in perturbed genes and pathways associated with BC risk for BBD patients. Citation Format: Yuanhang Liu, Chen Wang, Stacey J. Winham, Aditya Bhagwate, Robert A. Vierkant, Julie M. Cunningham, Bryan M. McCauley, William A. Jons, Derek C. Radisky, Amy C. Degnim. Deconvolution of cell type composition in FFPE tissue: Application to 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 4291.

Excellent results of screening for subsequent breast cancers in long-term survivors of childhood Hodgkin's lymphoma-Results of a population-based study.

Subsequent breast cancer (SBC) represents a major complication in childhood cancer survivors and screening for SBC in survivors after incidental irradiation of breasts is recommended. In this article, we report the results and discuss benefits of SBC screening in female pts treated for Hodgkin's lymphoma (HL) in Slovenia in a period of 45 years. Between 1966 and 2010, 117 females were treated for HL under the age of 19 in Slovenia. One hundred five of them survived for 5 years and were included in our study. They were 3-18 (med. 15) years old at diagnosis and followed for 6-52 (med. 28) years. Eighty-three percent of them had chest RT with a median dose of 30 Gy. Ninety-seven (92%) of 105 pts were regularly followed according to the international guidelines including yearly screening mammography/breast MRI in those who received chest RT. We diagnosed 10 SBCs in eight pts 14-39 (med. 24) years after diagnosis at the age of 28-52 (med. 42) years. At 40 years of follow-up, cumulative incidence of SBCs in females who got chest RT was 15.2%. Seven of eight patients (with 9 SBCs) got chest RT with 24-80 (med. 36) Gy at the age of 12 to 18 (median 17) years. Two patients in this group got bilateral SBC. One patient got invasive SBC after being treated with ChT containing high-dose of anthracyclines without chest RT at the age of 13. All eight invasive SBCs were invasive ductal cancers, HER2 receptors negative, all but one with positive hormonal receptors. Six invasive cancers were of stage T1N0, one T1N1mi, only one, diagnosed before era of screening, was of T2N1. None of 8 pts died of SBC. After introduction of regular breast screening in our female patients, who received chest RT in childhood, all SBCs were of early stage and no patients died of SBC. Survivors of pediatric HL should be informed about the risk of late sequelae of treatment for HL, including SBC. Regular follow-up with breast cancer screening and breast self-examination is of vital importance in those treated with chest RT.

Abstract F1-2: Clonal evolution of DCIS to invasion

Abstract F1-2: Clonal evolution of DCIS to invasion

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.

Prognosis of male lung cancer patients with urinary cancer: a study from a national population-based analysis

Lung cancer accounts for the most cancer-related deaths in the world. Our previous study suggested the improved survival of lung cancer patients, mainly female patients, with subsequent metachronous primary breast cancer. However, whether the survival advantages of the two primaries are associated with patients’ sex and the specific breast cancer is unclear. Whether male lung cancer patients with another primary may encounter the same survival advantage as female patients is also uncertain. The uncertainty hinders these patients from the potential benefit of lung cancer clinical trial. A total of 343 male lung adenocarcinoma patients with subsequent bladder papillary transitional cell carcinoma (LCBC), 1539 lung adenocarcinoma patients with prior bladder papillary transitional cell carcinoma (BCLC), 1181 lung adenocarcinoma patients with subsequent prostate adenocarcinoma (LCPC), 7426 lung adenocarcinoma patients with prior prostate adenocarcinoma (PCLC), and patients with single bladder/prostate/lung (SLC) cancer were identified from the Surveillance, Epidemiology, and End Results. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer 1 (mTPC1), or mTPC2 groups when interval time between two cancers was within 6 months, between 7 and 60 months, or over 60 months, respectively. Propensity matching score program was executed to match the two primary cancers with single primary. Cox regression and competing risk regression were performed to identify confounders associated with all-cause and cancer-specific survival, respectively. The major cancer-related and non-cancer-related death in the two primaries were lung cancer and heart disease, respectively. Median overall survival times since lung primary of LCBC and SLC were 97 and 17 months, respectively, and incidence of all-cause and cancer-specific death in LCBC since lung malignancy was significantly lower (Coef. − 1.24, 95% CI − 1.49 to 0.99; SHR 0.42, 95% CI 0.33–0.53). Among the categorized groups, prognosis values of sTPC and mTPC2 groups were not statically different from that of the matched single lung cancer, whereas increased overall survival time and decreased incidence of all-cause and cancer-specific death relative to the matched patients were observed in mTPC1 group (H.R 0.28, 95% CI 0.19–0.41; SHR 0.33, 95% CI 0.23–0.47). Similar prognosis of LCPC relative to SLC was also observed. Furthermore, a generally improved survival relative to SLC was observed in PCLC (median survival times of PCLC and SLC were 17 and 12 months, respectively; Coef. − 0.32, 95% CI − 0.43 to 0.22; SHR 0.77, 95% CI 0.69–0.85), whereas prognosis of BCLC was similar to the matched ones. These results hinted that survival of lung cancer patients might vary with prior cancer history. Further analysis among groups with the two primaries suggested that advanced bladder cancer was not associated with prognosis of patients with LCBC and BCLC. On the contrary, advanced prostate cancer was associated with all-cause and cancer-specific death in patients with PCLC but not in patients with LCPC. Compared with patients with single lung cancer, male lung cancer patients with subsequent bladder/prostate primary over 6 months experienced generally improved survival. These results were similar to our previous study regarding female lung cancer patients with another breast primary. On the contrary, male lung cancer patients with prior primary malignancy encountered varied prognosis: improved survival relative to single lung primary was observed in lung cancer with prior prostate cancer, whereas prognosis of lung cancer with prior bladder cancer was not different. Therefore, great attention was required to characterize prognosis of lung cancer patients with another primary in advance, which was essential to eliminate the potential bias when these patients were included into the clinical trials.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6nmol/L in consortium-wide decile 1to93.2nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5nmol/L), RRs were not statistically significantly different at either low concentrations (< 20nmol/L, 3% of controls) or high concentrations (100- < 125nmol/L, 3%of controls; ≥ 125nmol/L, 0.7%of controls). RR per 25nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Ovarian removal and subsequent breast cancer prognosis: a nationwide cohort study

To evaluate whether previous ovarian removal concomitant with benign hysterectomy improves prognosis in a cohort of women with breast cancer. In this nationwide register-based cohort study, risk of recurrence and mortality were examined in 4563 women with invasive breast cancer and previous bilateral salpingo-oophorectomy (BSO) concomitant with benign hysterectomy, during 1977-2018. Comparing with benign hysterectomy alone, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated by Cox-proportional hazards regression models. Analyses were stratified on age at hysterectomy as a proxy for menopausal status (< 45, 45-54 and ≥ 55years); tumor characteristics, estrogen receptor (ER)-status, and use of hormone therapy (HT) were included in multivariable models. Compared with hysterectomy alone, premenopausal (< 45years) BSO at benign hysterectomy was associated with an age and calendar period adjusted HR of 1.48 (95% CI 0.83-2.65) for breast cancer recurrence within 10years of follow-up, a HR of 1.07 (95% CI 0.66-1.72) for overall mortality after breast cancer, and a HR of 0.59 (95% CI 0.26-1.32) for breast cancer-specific mortality. The corresponding HRs for postmenopausal (≥ 55years) BSO at benign hysterectomy were 1.51 (95% CI 0.73-3.12) for recurrences, 1.34 (95% CI 0.74-2.44) for overall mortality, and 1.78 (95% CI 0.74-4.30) for breast cancer mortality. Adjusting for tumor characteristics, ER-status and HT did not alter the results. Results from this cohort study did not indicate an improvement in breast cancer prognosis when removing the ovaries at benign hysterectomy prior to the cancer diagnosis.

Abstract B014: Improving prediction of second events after DCIS using whole breast mammogram images

Abstract Purpose: We aim to improve prediction of subsequent events after DCIS. Current models show relatively poor performance predicting subsequent events and often are limited to ipsilateral events. National population-based SEER data including over160,000 cases of DCIS and followed an average of 90 months indicate that second events (including risk of invasive breast cancer – IBC) are equality likely in the ipsilateral and contralateral breast. Thus, additional information on risk may be obtained by more complete modeling of risk estimating recurrence. Mammographic images have been largely ignored despite evidence that even breast density improves prediction of breast cancer in the general population. Furthermore, we have shown whole breast mammogram images (WBI) included in Cox models significantly improves prediction of breast cancer risk over using mammographic breast density alone and breast cancer risk factors. Population: We retrieved digital mammograms for women diagnosed with DCIS at Washington University School of Medicine from 2008 onwards and followed for subsequent diagnosis of pathology confirmed breast lesions. Using more than 100 cases and controls matched on year of mammogram and age we fit Cox models to evaluate risk of ipsilateral invasive breast cancer. To compare and accommodate laterality of subsequent breast lesions, we fit competing risk models using baseline covariates that are available on the women-level as well as WBI that are side-specific. Results: Preliminary analysis shows WBI predicts subsequent invasive breast cancer. Further, we will demonstrate appropriate models adjusting for competing risk gives unbiased estimates of invasive breast cancer. Conclusion: WBI and competing risk analysis improves our understanding of associations for side of occurrence of subsequent breast lesions after an initial diagnosis of DCIS. Citation Format: Shu (Joy) Jiang, Graham A. Colditz. Improving prediction of second events after DCIS using whole breast mammogram images [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B014.

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.

Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors

Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Radiation and chemotherapy dose changes over time. Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

Association of disability with long-term noncompliance of breast cancer screening.

118 Background: Although the U.S. Preventive Services Task Force (USPSTF) recommends a biennial screening mammography for women aged 50 to 74 years at average risk for breast cancer, 24.6% of screening-eligible women do not follow the recommendation. Very little is known regarding the association between various types of disabilities and subsequent breast cancer screening behaviors following the initiation of screening mammography. This study examines the association of disability with short-term vs. long-term noncompliance of having a mammogram. Methods: Using data from 2016, 2018, and 2020 Behavioral Risk Factor Surveillance System annual surveys, we constructed the study cohort of women aged 55 to 74 years who did not have a cancer history and who received a mammogram at least once in the past. Outcomes are short-term (2 years) and long-term (5 years) noncompliance of USPSTF recommendations. Key independent variables are six binary variables of standard functional disability conditions (hearing, vision, cognition, ambulation, self-care, and independent living) in the first model and a categorized total number of disabilities (0, 1, 2, ≥3) in the second model. We employed a multivariable logistic regression model, adjusting individuals’ socio-demographics, general health status, chronic conditions, health risk factors, and metropolitan statistical areas (MSA), and accounting for complex survey design. Results: Among the study cohort (n = 232,143; weighted n = 29,358,431), 18.1% and 7.1% of women reported not having mammography in the past two and five years, respectively, representing short- vs. long-term noncompliance. Of the study cohort, 32.8% had any type of disability (ambulation 22.7%, cognition 11.0%, independent living 8.8%). Notably, the long-term noncompliance rate was highest among women with a disability and residing in non-MSA (10.2%). In multivariable analysis, while only disability in independent living was associated with short-term noncompliance (odds ratio [OR] 1.28; 95% confidence interval [CI] 1.15-1.42), disability in independent living (OR 1.34; 95% CI 1.18-1.52), vision (OR 1.15; 95% CI 1.01-1.32) and ambulation (OR 1.12; 95% CI 1.01-1.24) were all significantly associated with long-term noncompliance. Women with ≥3 disabilities were 1.64 times more likely to be non-compliant in the long term, and the association of disability with noncompliance was more pronounced in non-MSA. Conclusions: This study provides the first empirical evidence on the positive association between disability and screening noncompliance, especially in the long term. It suggests disability could aggravate disparities in timely access to cancer screening, particularly in non-MSA. Understanding how various types of disabilities affect screening behavior is a critical step for public health efforts in cancer prevention and control through identifying vulnerable subgroups for targeted interventions.

Histopathological study of benign proliferative breast lesions in peritumoral area of carcinoma breast - experience in a tertiary care centre

Background: Lesions of breast has gained more importance worldwide due to increase in mortality and morbidity associated with breast cancer. In India increase in incidence is due to life style changes and use of hormones. Presence of different proliferative lesions adjacent to malignancy in the same breast proves that carcinogenesis of breast is a multistep process. Women with proliferative breast lesions are more prone to develop carcinoma. Knowledge in carcinogenesis of breast will define the high risk group that improves the screening for carcinoma and managementAim: The aim is to study the histopathological types of carcinoma breast and benign proliferative breast lesions in peritumoral area. Materials and Method: This study was a cross-sectional study conducted for a period of 2 years. A total of 85 cases that satisfy the inclusion criteria were included in the present study. Samples were collected in 10% formalin. All the tissue specimens were processed and paraffin embedded. The sections were stained with Hematoxylin and Eosin. Histopathology findings were noted. Results thus obtained was analyzed using SPSS 20.0 version. Statistical analysis was done using Chi square test. Results: Common age group affected was between 51 to 60 years seen in 30(35.3%) cases. Lesions were predominantly seen in right breast 39 (45.9%). Invasive carcinoma breast No Special Type was the most common malignant lesion (85.9%). Non proliferative breast lesion was common in peritumoral area 46(54.1%). Statistical significance was observed between histopathological diagnosis, tumour size, lymph node status and peritumoral benign proliferative breast lesions. Conclusion: Proliferative epithelial lesions are at increased risk of subsequent breast cancer. Non proliferative breast diseases are the most common peritumoral lesion in the present study. Even though the risk of transformation to malignancy is less, careful follow-up with clinical breast examination and annual mammographic screening every 6 to 12 months can identify the changes and further it helps to reduce the occurrence of invasive breast cancer.

Imaging Surveillance Options for Individuals With a Personal History of Breast Cancer: AJR Expert Panel Narrative Review.

Annual surveillance mammography is recommended for breast cancer survivors on the basis of observational studies and meta-analyses showing reduced breast cancer mortality and improved quality of life. However, breast cancer survivors are at higher risk of subsequent breast cancer and have a fourfold increased risk of interval breast cancers compared with individuals without a personal history of breast cancer. Supplemental surveillance modalities offer increased cancer detection compared with mammography alone, but utilization is variable, and benefits must be balanced with possible harms of false-positive findings. In this review, we describe the current state of mammographic surveillance, summarize evidence for supplemental surveillance in breast cancer survivors, and explore a risk-based approach to selecting surveillance imaging strategies. Further research identifying predictors associated with increased risk of interval second breast cancers and development of validated risk prediction tools may help physicians and patients weigh the benefits and harms of surveillance breast imaging and decide on a personalized approach to surveillance for improved breast cancer outcomes.

Association of Longitudinal Mammographic Breast Density Changes with Subsequent Breast Cancer Risk.

Background Although Breast Imaging Reporting and Data System (BI-RADS) density classification has been used to assess future breast cancer risk, its reliability and validity are still debated in literature. Purpose To determine the association between overall longitudinal changes in mammographic breast density and breast cancer risk stratified by menopausal status. Materials and Methods In a retrospective cohort study using the Korean National Health Insurance Service database, women aged at least 40 years without a history of cancer who underwent three consecutive biennial mammographic screenings in 2009-2014 were followed up through December 2020. Participants were divided according to baseline breast density: fatty (BI-RADS categories a, b) versus dense (BI-RADS categories c, d) and then into subgroups on the basis of changes from the first to second and from second to third screenings. Women without change in breast density were used as the reference group. Main outcomes were incident breast cancer events, both invasive breast cancer and ductal carcinoma in situ. Cox proportion hazard regression was used to calculate the hazard ratio (HR) with adjustment for other covariables. Results Among 2 253 963 women (mean age, 59 years ± 9) there were 22 439 detected breast cancers. Premenopausal women with fatty breasts at the first screening had a higher risk of breast cancer as density increased in the second and third screenings (fatty-to-dense HR, 1.45 [95% CI: 1.27, 1.65]; dense-to-fatty HR, 1.53 [95% CI: 1.34, 1.74]; dense-to-dense HR, 1.93 [95% CI: 1.75, 2.13]). In premenopausal women with dense breasts at baseline, those in whom density continuously decreased had a 0.62-fold lower risk (95% CI: 0.56, 0.69). Similar results were observed in postmenopausal women, remaining significant after adjustment for baseline breast density or changes in body mass index (fatty-to-dense HR, 1.50 [95% CI: 1.39, 1.62]; dense-to-fatty HR, 1.42 [95% CI: 1.31, 1.53]; dense-to-dense HR, 1.62 [95% CI: 1.51, 1.75]). Conclusion In both premenopausal and postmenopausal women undergoing three consecutive biennial mammographic screenings, a consecutive increase in breast density augmented the future breast cancer risk whereas a continuous decrease was associated with a lower risk. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kataoka et al in this issue.

Association of environmental chemical exposure during pregnancy with subsequent breast cancer risk

Background and Aim: Breast cancer became the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide, according to the World Health Organization. Despite epidemiologic studies establishing a number of risk factors for breast cancer, additional research is needed to elucidate environmental exposures that increase breast cancer risk. In this study, we used highly informative, existing pregnancy cohort biospecimens with an untargeted high-resolution mass spectrometry (HRMS) approach to discover possible environmental chemical exposures associated with subsequent breast cancer occurrence. Methods: Archived pregnancy samples, collected between 1959-1967, from the Child Health and Development Studies in California, one of the largest prospective pregnancy cohorts, were analyzed and searched against the Toxic Exposome Database (T3DB). The samples included 2nd (T2) and 3rd (T3) trimester archival samples of 182 women who subsequently developed breast cancer, compared to T2 and T3 samples from 384 women who did not develop breast cancer. Metabolites and environmental chemicals extracted from 50 &amp;#x3bc;L aliquots of thawed pregnancy serum (n=1,148) were analyzed by HRMS with liquid chromatography followed by advanced data extraction, annotation and pathway enrichment analysis. Results: A large number of mass spectral features differed between cases and controls at p&amp;#x3c;0.05. Annotation of the discriminatory metabolites with T3DB showed increased abundance of accurate mass matches (within 5 ppm) to methylmercury and the organophosphate insecticide, tebupirimfos, in both T2 and T3 breast cancer cases compared to controls (P&amp;#x3c;0.05). Additional verification of chemical identities is ongoing. Available literature is mixed for mercury association with breast cancer; however, methylmercury has been found to stimulate proliferation of breast cancer cells in culture. Conclusions: In addition to a significant metabolic disruption, exposure to methylmercury or/and organophosphate insecticide during pregnancy is associated with subsequent breast cancer risk. Keyword: Breast cancer, environmental chemical exposure, metabolic disruption, high-resolution metabolomics, pregnancy.

Breast cancer mortality of older patients with and without recurrence analysed by novel multi-state models

IntroductionIn older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions of breast cancer mortality versus other-cause mortality after locoregional or distant recurrence in a population-based cohort of older patients analysed by multi-state models. MethodsSurgically treated patients ≥70 years diagnosed with stage I-III breast cancer in 2003–2009 were selected from the Netherlands Cancer Registry. A novel multi-state model with locoregional and distant recurrence that incorporates relative survival was fitted. Other-cause and breast cancer mortality were indicated as population and excess mortality. ResultsOverall, 18,419 patients were included. Ten-year cumulative incidences of locoregional and distant recurrence were 2.8% (95%CI 2.6–3.1%) and 12.5% (95%CI 11.9–13.1%). Other-cause mortality increased from 23.9% (95%CI 23.7–24.2%) in patients 70–74 years to 73.8% (95%CI 72.2–75.4%) in those ≥80 years. Ten-year probabilities of locoregional or distant recurrence with subsequent breast cancer death were 0.4–1.3% and 10.2–14.6%, respectively. For patients with a distant recurrence in the first two years after diagnosis, breast cancer death probabilities were 95.3% (95%CI 94.2–96.4%), 93.1% (95%CI 91.6–94.6%), and 88.6% (95%CI 86.5–90.8%) in patients 70–74, 75–79, and ≥80 years. ConclusionIn older patients without recurrence, prognosis is driven by other-cause mortality. Although locoregional recurrence is a predictor for worse outcome, given its low incidence it contributes little to breast cancer mortality after diagnosis. For patients who develop a distant recurrence, breast cancer remains the dominant cause of death, even at old age.

Background Parenchymal Enhancement at Postoperative Surveillance Breast MRI: Association with Future Second Breast Cancer Risk.

Background Background parenchymal enhancement (BPE) is a known risk factor for breast cancer. However, studies on the association between BPE and second breast cancer risk are still lacking. Purpose To investigate whether BPE at surveillance breast MRI is associated with subsequent second breast cancer risk in women with a personal history of breast cancer. Materials and Methods A retrospective search of the imaging database of an academic medical center identified consecutive surveillance breast MRI examinations performed between January 2008 and December 2017 in women who underwent surgery for primary breast cancer and had no prior diagnosis of second breast cancer. BPE at surveillance breast MRI was qualitatively assessed using a four-category classification of minimal, mild, moderate, or marked. Future second breast cancer was defined as ipsilateral breast tumor recurrence or contralateral breast cancer diagnosed at least 1 year after each surveillance breast MRI examination. Factors associated with future second breast cancer risk were evaluated using the multivariable Fine-Gray subdistribution hazard model. Results Among the 2668 women (mean age at baseline surveillance breast MRI, 49 years ± 8 [SD]), 109 developed a second breast cancer (49 ipsilateral, 58 contralateral, and two ipsilateral and contralateral) at a median follow-up of 5.8 years. Mild, moderate, or marked BPE at surveillance breast MRI (hazard ratio [HR], 2.1 [95% CI: 1.4, 3.1]; P < .001), young age (<45 years) at initial breast cancer diagnosis (HR, 3.4 [95% CI: 1.7, 6.4]; P < .001), positive results from a BRCA1/2 genetic test (HR, 6.5 [95% CI: 3.5, 12.0]; P < .001), and negative hormone receptor expression in the initial breast cancer (HR, 1.6 [95% CI: 1.1, 2.6]; P = .02) were independently associated with an increased risk of future second breast cancer. Conclusion Background parenchymal enhancement at surveillance breast MRI was associated with future second breast cancer risk in women with a personal history of breast cancer. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Niell in this issue.