Tumor Estrogen Receptor Status Research Articles

Mammographic density and breast cancer risk among Black American women.

High mammographic density is a well-established risk factor for breast cancer; however, data from Black women are limited. It is largely unknown how mammographic density is associated with breast cancer subtypes among Black women. We examined the association between percent mammographic density (PMD) and breast cancer risk among participants in the Black Women's Health Study. Digital screening mammograms were available for 363 cases and 5541 non-cases. Cumulus software was used to assess PMD. We used inverse probability of sampling weights and Cox proportional hazards models, adjusted for age and body mass index, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and by age at mammography and estrogen receptor (ER) status of the breast tumors. Multivariable models included additional breast cancer risk factors. Tests of statistical significance were 2-sided. In simple models, women in the highest quartile of PMD had 53% increased odds of breast cancer compared to those in the lowest quartile (HR 1.53; 95% CI: 1.11, 2.11). HRs were 1.37 (95% CI: 0.83, 2.24) among women <55 years of age and 1.68 (95% CI: 1.10, 2.56) among women aged ≥55 years. HRs were 1.49 (95% CI: 1.02, 2.16) for ER+ cancer and 1.45 (95% CI: 0.73, 2.87) for ER- cancer. Associations were largely unchanged in multivariable models. In this study of U.S. Black women, higher PMD was associated with ER+ and ER- breast cancer risk. Findings from this study reinforce the importance of breast density as a risk factor for breast cancer in Black women.

Abstract A036: Hair relaxers use and breast cancer risk by tumor estrogen receptor status: Results from the Ghana Breast Health study

Abstract Background: Hair relaxer use is highly prevalent among women of African descent world-wide and in previous analyses within the Ghana Breast Health Study (GBHS) ever use was associated with a 60% elevated risk of breast cancer. Subsequent studies in the GBHS showed selected alterations in estrogen metabolites with hair relaxer use among controls, suggesting a possible hormonal mechanism may underlie the relation of hair relaxers to breast cancer risk. We investigated if the association between relaxer use and breast cancer risk differed by tumor estrogen-receptor (ER) status and hypothesized ever-users would be at a higher risk of ER+ tumors. Methods: The GBHS is a population-based case-control study conducted between 2013– 2015 in Accra and Kumasi of 1,071 cases with pathologically confirmed invasive breast cancer and 2,106 controls, aged 18-74 years. A standardized interview-based questionnaire collected information on currency and duration of use of hair relaxers and whether products used were lye or non-lye formulations. ER status was available for 915 cases, determined using either mRNA expression data from nCounter® Breast Cancer 360™ Panel (65% of 915 cases) or immunohistochemistry. We used multivariable multinomial logistic regression models to estimate odds ratios (OR) with 95% confidence intervals (CI) for ER+ vs. ER- breast cancers. Models were adjusted for age, hospital site, education, body size, age at menarche, parity, age at first birth, median breastfeeding months/child, menopausal status. To determine if risk related to exposure to relaxers differed by ER status, we used logistic regression analyses with ER+ tumors as the reference and calculated heterogeneity p-values (p-het). Results: The majority of women reported ever use of relaxers (96% of cases and 94% of controls). Of the 1,071 cases included in analyses, 422 (44%) were ER+, 438 (41%) ER-, and 156 (15%) unknown for ER. Elevated risk did not differ by ER status for ever compared to never use (OR ER+ =1.67, 95% CI [0.95–2.93]; OR ER - =1.59, 95% CI [0.92–2.76], p-het=0.90). Risks were highest among former users (OR ER+ =2.19, 95% CI [1.21–3.95]; OR ER- =2.21, 95% CI [1.24–3.93], p-het=0.98. Additional analyses showed elevated risk for those with long durations of use, and those who predominantly used non-lye products, but associations did not differ according to ER tumor status. Conclusion: Our analysis of relaxer use in Ghanaian women showed elevated breast cancer risk, particularly for former, long-term users of non-lye formulations, irrespective of tumor ER status. Additional analyses by tumor and other characteristics related to biologically aggressive tumor types needed to determine if associations differ beyond ER consistent with disparities seen in African ancestry women. Further, future research is warranted regarding specific products used that may provide insights into hormonal and non-hormonal mechanisms underlying observed associations. Citation Format: Kaitlin E. White, Quiera Booker, Nicholas Titiloye, Lawrence Edusei, Louise Brinton, Beatrice Wiafe, Ernest Adjei, Jonine Figueroa, On behalf of the Ghana Breast Health Study Team. Hair relaxers use and breast cancer risk by tumor estrogen receptor status: Results from the Ghana Breast Health study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A036.

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review.

Breast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

Abstract PO4-12-08: Changes in peripheral immune cell composition in women who do and do not develop breast cancer

Abstract Background: Breast cancer survivors have higher age-specific rates of hypertension and other chronic diseases than women without a history of breast cancer. We and others have shown that alterations to the immune system are associated with risk of these conditions in the general population, leading to the hypothesis that the increased chronic disease risk in breast cancer survivors may be driven, in part, by lasting changes in immunity. Peripheral immune cell composition appears to become altered years before a breast cancer diagnosis, but little is currently known about the influence of different breast cancer treatments on subsequent changes to leukocyte composition and the persistence of these associations over time. Methods: Among 410 women enrolled in the Sister Study, paired blood samples collected an average of 7.6 years apart were analyzed for DNA methylation (DNAm). Deconvolution methods were applied to these DNAm data to estimate circulating percentages of 12 leukocyte subsets. Approximately half the women sampled were diagnosed and treated for breast cancer between the blood draws (n= 185) whereas the other half remained breast cancer-free (n= 225). Breast tumor characteristics and treatment information were abstracted from medical records. Mixed-effect linear regression models were used to estimate changes in leukocyte composition over time comparing women with breast cancer to those who remained breast cancer-free. A case-only analysis of breast cancer survivors was performed to examine the persistence of changes over time and to explore whether changes in leukocyte composition were associated with the types of therapies received (endocrine therapy, radiation therapy, chemotherapy). All models were adjusted for age and self-reported race. In the treatment analysis, because tumor characteristics can guide clinical decisions, tumor estrogen receptor status and stage at diagnosis were additionally included as model covariates. Results: At baseline, women who developed breast cancer between the blood draws had lower mean circulating percentages of CD8+ cytotoxic T cells than women who remained breast cancer-free (3.8% vs 4.6%; P-diff= 0.04). After accounting for differences in leukocyte composition at baseline, compared to women who remained breast cancer-free, women diagnosed and treated for breast cancer between the blood draws had decreases in total circulating CD4+ helper T cell percentage (adjusted mean difference [β]= -1.50, 95% CI: -2.56, -0.44, P= 0.006) and alterations to both naïve and memory B cell percentages (naïve B cells, β= 0.46, 95% CI: 0.17, 0.75, P= 0.002; memory B cells, β= -0.22, 95% CI: -0.34, -0.09, P= 0.001). Although associations did not vary by tumor characteristics or participant race, the changes in leukocyte composition appeared to persist over time as changes were not associated with time since diagnosis. In the case-only analysis of different breast cancer therapies, radiation was associated with decreases in CD4+ T cells (β= -2.56, 95% CI: -4.26, -0.88, P= 0.003) and chemotherapy was associated with increases in B cells (β= 0.62, 95% CI: 0.07, 1.16, P= 0.03). Surgery and endocrine therapy were not meaningfully associated with changes in leukocyte composition. Conclusions: Breast cancer survivors have lasting changes in peripheral leukocyte composition that may be related to the types of treatments received. These findings add to our understanding of the biological changes that underlie the long-term health of breast cancer survivors. Citation Format: Jacob Kresovich, Katie O'Brien, Zongli Xu, Clarice Weinberg, Dale Sandler, Jack Taylor. Changes in peripheral immune cell composition in women who do and do not develop breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-08.

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. To determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs. This prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023. Time between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years. The primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status. Among 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]). These findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review of the literature.

Breast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

Abstract B083: Association of socioeconomic deprivation with breast cancer incidence, survival and ipsilateral recurrence by molecular subtype in Scotland, United Kingdom

Abstract Cancer disparities reflect the interplay of biological, environmental, and socioeconomic determinants. In the United States, disentangling racial and ethnic disparities in breast cancer (BC) including the effects of health care access and socioeconomic deprivation is challenging, given the latter highly correlated with race and ethnicity. In Scotland, United Kingdom (UK), the population is 96% White and there is a single payer National Health Service (NHS). The Scottish Index of Multiple Deprivation (SIMD) measures the extent to which a geographic area is deprived across seven domains: income, employment, education, health, access to services, crime and housing. Scotland is renowned for high-quality electronic health records including breast tumor estrogen receptor (ER) status collected since 1997 and Progesterone Receptor and HER2 since 2009, which can be linked to hospital data and mortality. To gain a better understanding of individual patients’ SIMD status (measured in quintiles) at BC diagnosis with incidence and survival, we used data on 62,378 women diagnosed with invasive BC between 2000 and 2016. For ipsilateral breast recurrence (IBR) outcomes, we used a subset of data for BC diagnosed 2007-2008 where manual case-note review was performed for 3495 patients from 10 years post-diagnosis. Screen-detected ER+ tumor incidence increased over time, particularly in the least deprived quintile [Average Annual Percentage Change = 2.9% with 95% CI from 1.2 to 4.7]. No marked differences were observed for non-screen-detected ER+ tumors or ER- tumors by SIMD. Most versus least deprived SIMD-quintile was associated with significantly higher mortality for luminal A and HER2-enriched tumors in multivariable Cox proportional hazard models adjusted for mode of detection and confounders (aHR = 1.46 [1.13, 1.88] and 2.10 [1.23, 3.59] respectively) but weaker non-significant associations for luminal B and triple negative BC tumors (aHR &amp;lt;1.20). Among 2,819 ER+ tumors, 423 patients had IBR (15%) and 438 died: SIMD was related to death (p=0.018) with the most deprived more likely to have died in the first decade of follow-up (17.7% vs 12.9%). We found no significant differences by SIMD in prognostic tumor characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumors, 185 had IBR (27%) and 105 died: 50% had mastectomy and the most deprived had an increased 5-year IBR risk compared to the least deprived (aHR 3.03 [1.41-6.53]). Our analysis shows socioeconomic deprivation is associated with differential BC incidence trends for screen-detected ER+ tumors and higher mortality and IBR for selected tumor subtypes. The lack of inequities for triple negative tumors by SIMD and survival, and IBR for ER+ tumors may be due to standardized treatment protocols and healthcare access. The association with socioeconomic deprivation and survival for HER2+ and recurrence among ER- tumors requires further study on potential other factors such as co-morbidities and adherence to treatment. Citation Format: Ines Mesa-Eguiagaray, Hayley Dunlop, Sarah Wild, Sheila M. Bird, Linda Williams, Peter S. Hall, Jonine D. Figueroa. Association of socioeconomic deprivation with breast cancer incidence, survival and ipsilateral recurrence by molecular subtype in Scotland, United Kingdom [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 B083.

18F-FES Whole-Body Imaging Protocol for Evaluating Tumor Estrogen Receptor Status in Patients with Recurrent or Metastatic Breast Cancer.

In September 2020, the Journal of Nuclear Medicine and Technology published a continuing education article, "Breast Cancer: Evaluating Tumor Estrogen Receptor Status with Molecular Imaging to Increase Response to Therapy and Improve Patient Outcomes," that reviewed a promising new PET tracer, 16α-18F-fluoro-17β-fluoroestradiol (18F-FES). This tracer had the potential to be a valuable tool for medical oncologists and breast surgeons in noninvasively evaluating the estrogen receptor site status of their patients' recurrent tumor and secondary metastatic lesions. In May 2020, 18F-FES received Food and Drug Administration approval and began being marketed by Zionexa using the trade name Cerianna and manufactured by PETNET. In May 2021, GE Healthcare acquired Zionexa, and Cerianna and is now being marketed by GE Healthcare and is still being manufactured by PETNET. This article will review the 18F-FES package insert information and imaging protocol, as well as important guidelines for imaging with 18F-FES.

Abstract GS4-04: Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&amp;lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &amp;gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &amp;lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [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 GS4-04.

Abstract P6-01-08: Gene signatures provide independent prognostic information in elderly breast cancer patients

Abstract Background: Elderly breast cancer patients (≥70 years old) are under-represented in clinical trials and remain an undertreated population. Gene expression signatures have been shown to add additional prognostic information beyond that of routine clinicopathological factors, however their utility in elderly breast cancer patients remains unclear. As such, the main aim of this study is to determine if gene signatures can provide prognostic information that may help to aid treatment decisions for elderly breast cancer patients. Material and methods: Research versions of the genomic grade index (GGI), 70-gene, 21-gene recurrence score (RS), cell cycle score (CCS), PAM50 and PAM50 Risk of Relapse score - Proliferation (ROR-P) signatures were applied to 39 open access breast cancer datasets totalling 9583 patients. After filtering based on age ≥ 70 years old, the presence of Estrogen Receptor (ER) and survival information availability 871 patients remained. The prognostic capacity of signatures was tested in all (N=871), Estrogen Receptor positive/Lymph node positive (ER+/LN+, N=335) and Estrogen Receptor positive/Lymph node negative (ER+/LN-, N=374) patients using Kaplan-Meier and multi-variable Cox proportional hazard modeling. Models were adjusted for tumor size, grade, ER and lymph node status in all patients, and tumor size and grade in the ER+/LN+ and ER+/LN- subgroup analyses. Recurrence Free Survival (RFS) censored at 10 years was used as clinical endpoint and defined as the time from date of curative surgery to the time of recurrence or death. Both loco-regional recurrences and distant metastatic events were included in this endpoint. Results: Tumours from patients ≥ 70 years of age showed high levels of ER (87%), were large (69% ≥ 20 mm) and were of intermediate or high grade (82%). All gene signatures were statistically significant in Kaplan-Meier analysis of all and ER+/LN+ patients (Logrank P &amp;lt; 0.001). This significance remained in multi-variable analysis (Cox proportional hazards, P ≤ 0.05) with the exception of PAM50 which showed a trend (P ≤ 0.1) in ER+/LN+ patients. In ER+/LN- patients the GGI, 70-gene, PAM50, ROR-P, and CCS signatures were significant in Kaplan-Meier analysis (Logrank P ≤ 0.05) but only the 70-gene, PAM50, ROR-P, and CCS signatures remained so in multi-variable analysis (Cox proportional hazards, P ≤ 0.05). Conclusions: In general, we found that gene signatures provide statistically significant prognostic information in Kaplan-Meier and multi-variable analyses of all, ER+/LN+ and ER+/LN- breast patients over the age of 70. Table 1: Multivariable proportional hazard (Cox) analyses for all gene signatures for patients above age of 70. NOTE: Bold values indicate P &amp;lt; 0.05. aAdjusted for tumor size, tumor grade, estrogen receptor status, and lymph node status. bAdjusted for tumor size and tumor grade. Citation Format: Miguel Castresana Aguirre, Annelie Johansson, Linda S. Lindström, Nick Tobin. Gene signatures provide independent prognostic information in elderly breast cancer patients [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 P6-01-08.

Fibroblast growth factor 2 expression on lymph node metastasis in early-stage breast cancer

Introduction: Axillary lymph node involvement is an important aspect of breast cancer diagnosis in determining treatment and predicting distant metastasis. Lymph node metastasis is associated with higher recurrence and survival rates. Lymph node status is a significant prognostic factor and is widely used. Several factors affect lymph node metastasis, including tumor size, grade, and invasive ductal histological type. FGF2, a lymphangiogenesis factor, influences the occurrence of lymph node metastasis. The present study aimed to determine the association between FGF2 expression and axillary lymph node metastasis in early-stage breast cancer and evaluate the association between FGF2 expression and clinicopathologic factors. Methods: A cross-sectional design was used to evaluate the expression of FGF2 in 47 early-stage breast cancer patients who underwent either a mastectomy or breast-conserving surgery procedure at Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from January 2014 to December 2018. FGF2 expression was examined by immunohistochemistry. Results: FGF2 expression was significantly correlated with axillary lymph node metastasis incidence [p = 0.044, odds ratio 4.22 (95% CI 0.983-18.1)]. Higher FGF2 expression was significantly correlated with the grade, subtype, estrogen receptor (ER) status, and progesterone receptor (PR) status of the tumor (p = 0.017, p = 0.031, p = 0.002, p = 0.013, respectively). Conclusions: Increased FGF2 expression and tumor size significantly correlated with axillary lymph node metastasis. The tumor's grade, intrinsic subtype, ER and PR status were significantly correlated with increased FGF2 expression. Our study indicated that FGF2 expression might aid in determining the presence of axillary lymph node metastasis.

Ethylene oxide emissions and incident breast cancer and non-Hodgkin lymphoma in a US cohort.

Ethylene oxide (EtO) is a carcinogenic gas used in chemical production and to sterilize medical equipment that has been linked to risk of breast and lymphohematopoietic cancers in a small number of occupational studies. We investigated the relationship between environmental EtO exposure and risk of these cancers. Using the US Environmental Protection Agency's Toxics Release Inventory, we estimated historical exposures for National Institutes of Health-AARP Diet and Health Study participants enrolled in 1995-1996. We constructed 2 metrics at 3, 5, and 10 km: 1) distance between residences and EtO-emitting facilities, weighted by the proportion of time the home was downwind of each facility, and 2) distance-weighted, wind direction-adjusted average airborne emissions index (AEI=∑[lbs EtO/km2]). We estimated risk (hazard ratio [HR], 95% confidence interval [CI]) of incident breast cancer (in situ and invasive) among postmenopausal women (n = 173 670) overall and by tumor estrogen receptor status and non-Hodgkin lymphoma in the full cohort (n = 451 945). We observed an increased risk of breast cancer associated with EtO-emitting facilities within 10 km (HR[≤10vs>10] = 1.05, 95% CI = 1.00 to 1.10) that appeared stronger for in situ (HR[≤10vs>10] = 1.13, 95% CI = 1.00 to 1.27) than invasive (HR[≤10vs>10] = 1.03, 95% CI = 0.97 to 1.09) disease. Risk of breast cancer in situ was also increased in the top AEI quartiles, and associations weakened with larger distances (HR[Q4vs0] = 1.60, 95% CI = 0.98 to 2.61; HR[Q4vs0] = 1.28, 95% CI = 0.92 to 1.79; HR[Q4vs0] = 1.25, 95% CI = 1.02 to 1.53 at 3, 5, and 10 km, respectively). No differences in breast cancer risk were observed by estrogen receptor status. We found no clear pattern of increased non-Hodgkin lymphoma risk. A novel potential association between EtO emissions and risk of in situ, but not invasive, breast cancer warrants additional evaluation.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Clinical Validity of 16α-[18F]Fluoro-17β-Estradiol Positron Emission Tomography/Computed Tomography to Assess Estrogen Receptor Status in Newly Diagnosed Metastatic Breast Cancer.

Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[18F]fluoro-17β-estradiol positron emission tomography ([18F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [18F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [18F]FES-PET assessment to predict ER expression by immunohistochemistry in a metastasis. In a prospective multicenter trial, 200 patients with newly diagnosed MBC underwent extensive workup including molecular imaging. For this subanalysis, ER expression in the biopsied metastasis was related to qualitative whole-body [18F]FES-PET evaluation and quantitative [18F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [18F]FES-PET diagnostic performance were performed. Whole-body [18F]FES-PET assessment predicted ER expression in the biopsied metastasis with good accuracy: a sensitivity of 95% (95% CI, 89 to 97), a specificity of 80% (66 to 89), a positive predictive value (PPV) of 93% (87 to 96), and a negative predictive value (NPV) of 85% (72 to 92) in 181 of 200 evaluable patients. Quantitative [18F]FES uptake predicted ER immunohistochemistry in the corresponding metastasis with a sensitivity/specificity of 91%/69% and a PPV/NPV of 90%/71% in 156 of 200 evaluable patients. For bone metastases, PPV/NPV was 92%/81%. Meta-analysis with addition of our data has increased diagnostic performance and narrowed the 95% CIs compared with previous studies with a sensitivity/specificity of both 86% (81 to 90 and 73 to 93, respectively). In this largest prospective series so far, we established the clinical validity of [18F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [18F]FES-PET, this noninvasive imaging modality can be considered a valid alternative to a biopsy of a metastasis to determine ER status in newly MBC (ClinicalTrials.gov identifier: NCT01957332).

Association Between Vascular Index Measured via Superb Microvascular Imaging and Molecular Subtype of Breast Cancer.

BackgroundTo determine whether vascular index (VI; defined as the ratio of Doppler signal pixels to pixels in the total lesion) measured via superb microvascular imaging in breast cancer correlates with immunohistochemically defined subtype and is able to predict molecular subtypes.MethodsThis prospective study involved 225 patients with 225 mass-type invasive breast cancers (mean size 2.6 ± 1.4 cm, range 0.4~5.9 cm) who underwent ultrasound and superb microvascular imaging (SMI) at Peking Union Medical College Hospital before breast surgery from December 2016 to June 2018. The correlations between primary tumor VI measured via SMI, clinicopathological findings, and molecular subtype were analyzed. The performance of VI for prediction of molecular subtypes in invasive breast cancer was investigated.ResultsThe median VI of the 225 tumors was 7.3% (4.2%~11.8%) (range 0%~54.4%). Among the subtypes of the 225 tumors, 41 (18.2%) were luminal A, 91 (40.4%) were luminal B human epidermal growth factor receptor-2 (HER-2)-negative, 26 (11.6%) were luminal B HER-2-positive, 17 (7.6%) were HER-2-positive, and 50 (22.2%) were triple-negative, and the corresponding median VI values were 5.9% (2.6%~11.6%) (range 0%~47.1%), 7.3 (4.4%~10.5%) (range 0%~29.5%), 6.3% (3.9%~11.3%) (range 0.6%~22.2%), 8.2% (4.9%~15.6%) (range 0.9%~54.4%), and 9.2% (5.1%~15.3%) (range 0.7%~32.9%), respectively. Estrogen receptor (ER) negativity, higher tumor grade, and higher Ki-67 index (≥20%) were significantly associated with a higher VI value. Tumor size, ER status, and Ki-67 index were shown to independently influence VI. A cutoff value of 4.1% yielded 79.9% sensitivity and 41.5% specificity with an area under the receiver operating characteristic curve (AUC) of 0.58 for predicting that a tumor was of the luminal A subtype. A cutoff value of 16.4% yielded 30.0% sensitivity and 90.3% specificity with an AUC of 0.60 for predicting a triple-negative subtype.ConclusionsVI, as a quantitative index obtained by SMI examination, could reflect histologic vascular changes in invasive breast cancer and was found to be higher in more biologically aggressive breast tumors. VI shows a certain degree of correlation with the molecular subtype of invasive breast cancer and plays a limited role in predicting the luminal A with high sensitivity and triple-negative subtype with high specificity.

Breast Cancer Incidence, Hormone Receptor Status, Historical Redlining, and Current Neighborhood Characteristics in Massachusetts, 2005-2015.

BackgroundScant research has analyzed contemporary US cancer incidence rates in relation to historical redlining (ie, 1930s US federally imposed residential segregation), implemented via the color-coded federal Home Owners’ Loan Corporation (HOLC) maps.MethodsWe analyzed Massachusetts Cancer Registry data for all patients with primary invasive breast cancer (BC) diagnosed in 2005-2015 among women in the 28 Massachusetts municipalities with digitized 1930s HOLC maps. Multilevel Poisson regression estimated BC incidence rate ratios (IRR), overall and by tumor estrogen receptor (ER-positive, ER-negative) and progesterone receptor (PR-positive, PR-negative) status, in relation to HOLC grade and contemporary census tract (CT) social characteristics.ResultsNet of age and racialized group, the extremes of BC incidence were detected by combinations of HOLC grade and contemporary CT racialized economic segregation. Compared with CTs with the best HOLC grade (A + B) and most privileged contemporary characteristics (T1), for all, ER-positive and PR-positive BC, incidence was highest in T1 and mixed HOLC grade CTs (eg, IRRER+; Mixed-T1 = 1.10, 95% confidence interval [CI] = 1.01 to 1.21) and lowest in CTs with most concentrated racialized economic deprivation (T3) and no HOLC grade (eg, IRRER+; No Grade-T3 = 0.85, 95% CI = 0.75 to 0.95). For ER-negative and PR-negative BC, incidence was highest in CTs with the most contemporary deprivation, but the best HOLC grade (eg, IRRER-; A+B-T3 = 1.27, 95% CI = 0.93 to 1.75) and lowest in T1 and worst HOLC-graded CTs (eg, IRRER-; D-T1 = 0.84, 95% CI = 0.56 to 1.25).ConclusionBreast cancer risk may be shaped by combined histories of redlining and present-day CT characteristics.

Residential proximity to emissions of dioxins and furans and risk of breast cancer in the Sister Study cohort

BACKGROUND AND AIM: Few studies have investigated the relationship between ambient polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) and risk of breast cancer. We evaluated associations between proximity-based residential exposure to industrial emissions of PCDD/F and breast cancer risk in a U.S. cohort. METHODS: Sister Study participants, who have a sister with breast cancer but no history of breast cancer themselves at enrollment, were followed for incident breast cancer. PCDD/F exposures were estimated using a historical U.S. Environmental Protection Agency database of 4,478 facilities (85% of PCDD/F air emissions) and their toxic equivalency quotient (TEQ) emissions. After restricting to participants with at least 10 years of continuous residential history prior to enrollment (2003-2009; n=34,103), we generated 10-year distance- and TEQ-weighted average emissions indices (AEI [g TEQ/km2]) within 3, 5, or 10km of participants’ residences, overall and by facility type. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between AEI (dichotomized, quartiles) and risk of breast cancer (invasive or ductal carcinoma in situ). Models were adjusted for breast cancer risk factors and residential outdoor air pollutants. We evaluated whether associations differed by smoking status and tumor estrogen receptor (ER) status. RESULTS:There were 2,583 incident breast cancer cases over a median of 11 years of follow-up. We found an increased risk of breast cancer associated with AEI exposure within 3km (HR Q4.vs.0:1.19, 95% CI: 1.00,1.42, Ptrend=0.03). The relationship was stronger for exposure to emissions from municipal solid waste facilities (HR ≥median.vs.0:1.46, 95% CI: 0.96,2.24; Ptrend=0.08) and among former smokers (HR Q4.vs.0: 1.46, 95% CI: 1.14,1.87, Ptrend=0.004), but did not differ by ER status (Pheterogeneity=0.47). No associations were observed for the AEI at 5 or 10km. CONCLUSIONS:Our findings suggest that increased residential exposure to PCDD/F emissions may confer a higher risk of breast cancer. KEYWORDS: air pollution, chemical exposures, long-term exposure, cancer and cancer precursors, female, environmental epidemiology

Abstract 790: A Utah Population Data Base Study of young women's breast cancer outcomes by parity status

Abstract Importance: A diagnosis of breast cancer after childbirth is reported to increase risk for metastasis and death in patients ≤45 years of age. Data to discern if a postpartum diagnosis is an independent risk factor for poor outcomes remain limited. Objective: Determine associations between time since last pregnancy and time to metastasis and breast cancer-specific death using cases available from the Utah Population Data Base (UPDB). Secondary objectives are time to metastasis and breast cancer specific-death delineated by tumor stage and ER status. Study Design: This is a population-based study of 2,977 women with stage I, II, or III breast cancer (BC) diagnosed at ≤ 45 years of age from 1996 to 2017. The study population was identified from the UPDB, a statewide dynamic database of linked data received from the Utah SEER Cancer Registry, birth certificates, death certificates, and medical records. Clinical prognostic factors include patient age at diagnosis, year of diagnosis, tumor size, stage, and estrogen receptor (ER) status. The primary exposures are no prior childbirth or time between the most recent childbirth and a breast cancer diagnosis, and primary outcomes are distant metastasis-free survival and breast cancer specific death. Results: Among the 2,977 predominantly white women from the state of Utah, USA, the reproductive histories of the breast cancer patients were grouped as nulliparous (n = 867), and parous: diagnosed 0-5 years (n = 614), &amp;gt;5-10 years (n = 615) and &amp;gt;10 years (n = 881) since last childbirth. We find a breast cancer diagnosis within 5 years of childbirth is associated with elevated risk for metastasis after controlling for diagnosis year, diagnosis age, tumor stage, and ER status [HR (95% CI) =1.64 (1.16, 2.32)], particularly in Stage I/II disease [HR (95% CI) =1.89 (1.24, 2.87)]. The 0-5 year group also had elevated risk of breast cancer-specific death [HR (95% CI) =1.57 (1.07, 2.32)]. While ER-negative tumors were enriched in women diagnosed 0-5 years postpartum, this enrichment could be attributed largely to the younger age of this reproductive group. Further, postpartum breast cancer patients diagnosed with ER-positive disease within 5 years of a completed pregnancy had significantly worse distant metastasis-free survival than nulliparous patients with ER-negative disease. Conclusions: In this population level study from the state of Utah, a diagnosis of breast cancer within 5 years postpartum is a risk factor for metastasis and breast cancer-specific death that is independent of known clinical parameters, including ER status. The increased risk for poor outcomes is highest in stage I/II diagnoses. Relevance: For women with breast cancers classically considered as having good prognostic tumor features, i.e. stage I or II and ER-positive, a postpartum diagnosis is a dominant demographic feature of increased risk for metastasis and death. Citation Format: Pepper Schedin, Sonali Jindal, Solange Bassale, Zhenzhen Zhang, Alison Fraser, Emily Guinto, Virginia F. Borges, Motomi Mori, Ken R. Smith. A Utah Population Data Base Study of young women's breast cancer outcomes by parity status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 790.

Early-Life Body Adiposity and the Breast Tumor Transcriptome.

Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood. We assessed the association of early-life adiposity, defined as self-reported body size during ages 10-20 years from a validated 9-level pictogram, with the transcriptome of breast tumor (N = 835) and tumor-adjacent histologically normal tissue (N = 663) in the Nurses' Health Study. We conducted multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue, respectively. Molecular pathway analysis using Hallmark gene sets (N = 50) was further performed to gain biological insights. Analysis was stratified by tumor estrogen receptor (ER) protein expression status (n = 673 for ER+ and 162 for ER- tumors). No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly (false discovery rate < 0.05) upregulated or downregulated gene sets. In stratified analyses by tumor ER status, larger body size during ages 10-20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. In ER+ tumors, larger body size was also associated with upregulation in genes involved in TNFα/NFkB signaling. In ER- tumors, larger body size was additionally associated with downregulation in genes involved in interferon α and interferon γ immune response and Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling; the INFγ response pathway was also downregulated in ER- tumor-adjacent tissue, though at borderline statistical significance (false discovery rate = 0.1). These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.

The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study.

A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.