Incident Breast Cancer Research Articles

Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status.

Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.

Residual Risk of Breast Cancer After Bariatric Surgery

Excess adiposity confers higher risk of breast cancer for women. For women who have lost substantial weight, it is unclear whether previous obesity confers residual increased baseline risk of breast cancer compared with peers without obesity. To determine whether there is a residual risk of breast cancer due to prior obesity among patients who undergo bariatric surgery. Retrospective matched cohort study of 69 260 women with index date between January 1, 2010, and December 31, 2016. Patients were followed up for 5 years after bariatric surgery or index date. Population-based clinical and administrative data from multiple databases in Ontario, Canada, were used to match a cohort of women who underwent bariatric surgery for obesity (baseline body mass index [BMI] ≥35 with comorbid conditions or BMI ≥40) to women without a history of bariatric surgery according to age and breast cancer screening history. Nonsurgical controls were divided into 4 BMI categories (<25, 25-29, 30-34, and ≥35). Data were analyzed on October 21, 2021. Weight loss via bariatric surgery. Residual hazard of breast cancer after washout periods of 1, 2, and 5 years. Comparisons were made between the surgical and nonsurgical cohorts overall and within each of the BMI subgroups. In total, 69 260 women were included in the analysis, with 13 852 women in each of the 5 study cohorts. The mean (SD) age was 45.1 (10.9) years. In the postsurgical cohort vs the overall nonsurgical cohort (n = 55 408), there was an increased hazard for incident breast cancer in the nonsurgical group after washout periods of 1 year (hazard ratio [HR], 1.40 [95% CI, 1.18-1.67]), 2 years (HR, 1.31 [95% CI, 1.12-1.53]), and 5 years (HR, 1.38 [95% CI, 1.21-1.58]). When the postsurgical cohort was compared with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different regardless of the washout period, whereas there was a reduced hazard for incident breast cancer among postsurgical patients compared with nonsurgical patients in all high BMI categories (BMI ≥25). Findings suggest that bariatric surgery was associated with a reduced risk of developing breast cancer for women with prior obesity equivalent to that of a woman with a BMI less than 25 and a lower risk when compared with all groups with BMI greater than or equal to 25.

Abstract 3011: Psychosocial stress, social support, and incident breast cancer by estrogen receptor status

Abstract Introduction: Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. We investigated the relationship between stressful life events and incident breast cancer by ER status among postmenopausal women. We further evaluated whether this association is modified by social support. Methods: Our analysis included 76,951 postmenopausal women enrolled in the Women’s Health Initiative. Participants were followed for events for up to 26 years (median, 16.7). We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for associations between baseline self-reported stressful life events and incident breast cancer by ER status. Results: The mean age was 63 (SD 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared to women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs Quartile 1; HR=1.30; 95%CI 1.01-1.68; Ptrend=0.050). Additionally, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR=2.39; 95%CI 1.29-4.44; Pinteraction&amp;lt;0.001). Moreover, while the interaction was not statistically significant, we observed an elevated risk for ER-negative breast cancer among women in the highest quartile of stressful life events reporting lower social support. Conclusion: In this cohort of postmenopausal women, higher experiences of pre-diagnostic stressful life events were associated with increased risk of ER-negative breast cancer. Citation Format: Wayne R. Lawrence, Jasmine A. McDonald, Faustine Williams, Meredith S. Shiels, Neal D. Freedman, Ziqiang Lin, Jared W. Magnani. Psychosocial stress, social support, and incident breast cancer by estrogen receptor status [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 3011.

Abstract 4174: Incorporating continuous mammographic density into the BOADICEA breast cancer risk prediction model

Abstract BOADICEA, implemented in the CanRisk tool (www.canrisk.org) can be used to calculate future breast cancer risk using data on cancer family history, genetics (rare high- or moderate-risk pathogenic variants; polygenic scores (PGS)), questionnaire-based risk factors and mammographic density (MD) measured using the BI-RADS classification. The BI-RADS categorization requires manual reading which is not feasible at population level. Moreover, BI-RADS captures MD in 4 categories, whereas continuous measures are stronger risk predictors. Here, BOADICEA was extended to incorporate continuous breast density measured by the fully automated Volpara and STRATUS software, working on raw and processed images, respectively. We used data from the KARMA prospective screening cohort (60,276 participants; 1,167 incident breast cancers). The associations between Volpara or STRATUS density measurements and incident breast cancer risk were estimated in a randomly selected training subset consisting of two-thirds of the full dataset. For this, we calculated density residuals after regressing on participant’s age at mammography. Hazard ratios (HR) for the normalized residuals were calculated using a Cox proportional hazards model, adjusting for family history, BMI and all risk factors included in BOADICEA. Multiple Imputation by Chained Equations (MICE) was used to impute missing data. The remaining one-third of the KARMA cohort was used to assess the performance of BOADICEA in predicting 5-year risks, after including the estimated Volpara and STRATUS associations.Under the best fitting multivariable model including PGS, the HRs per SD of residual STRATUS density were estimated to be 1.67 (95%CI: 1.44-1.93) and 1.38 (95%CI: 1.26-1.51) for pre- and post-menopausal women, respectively. The HR estimates per SD of residual Volpara density were 1.38 (95%CI: 1.19-1.59) and 1.39 (95%CI: 1.27-1.52) for pre- and post-menopausal women, respectively. After incorporating these associations in BOADICEA, there was a marked improvement in the model discriminatory ability in the test dataset, compared to using the BI-RADS classification. The largest increase in AUC was observed for STRATUS residual density, with a 3% increase compared to using BI-RADS vs a 1.6% increase in AUC when using Volpara residual density. These increases were consistent across BOADICEA models considering different combinations of risk factors, including PGS.Including continuous breast density in BOADICEA can lead to improved breast cancer risk stratification and could allow for automated measures of MD to be more readily deployed in breast cancer risk prediction. Additional prospective studies are required to further validate the findings. The models will be implemented in the CanRisk tool. Citation Format: Lorenzo Ficorella, Mikael Eriksson, Kamila Czene, Goska Leslie, Xin Yang, Tim J. Carver, Douglas F. Easton, Per F. Hall, Antonis C. Antoniou. Incorporating continuous mammographic density into the BOADICEA breast cancer risk prediction model. [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 4174.

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort

BackgroundRecurrence and metastases are still frequent outcomes after initial tumour control in women diagnosed with breast cancer. Although therapies are selected based on tumour characteristics measured at baseline, prognostic biomarkers can identify those at risk of poor outcomes. Circulating progastrin or hPG80 was found to be associated with survival outcomes in renal and hepatocellular carcinomas and was a plausible prognostic biomarker for breast cancer.MethodsWomen with incident breast cancers from Calgary, Alberta, Canada enrolled in the Breast to Bone (B2B) study between 2010 to 2016 and provided blood samples prior to any treatment initiation. Plasma from these baseline samples were analysed for circulating progastrin or hPG80. Participant characteristics as well as tumour ones were evaluated for their association with hPG80 and survival outcomes (time to recurrence, recurrence – free survival, breast cancer specific survival and overall survival) in Cox proportional hazards regression models.ResultsThe 464 participants with measurable hPG80 in this study had an average age of 57.03 years (standard deviation of 11.17 years) and were predominantly diagnosed with Stage I (52.2%) and Stage II (40.1%) disease. A total of 50 recurrences and 50 deaths were recorded as of June 2022. In Cox PH regression models adjusted for chemotherapy, radiation therapy, cancer stage and age at diagnosis, log hPG80 (pmol/L) significantly increased the risks for recurrence (Hazard Ratio (HR) = 1.330, 95% Confidence Interval (CI) = (0.995 – 1.777, p = 0.054)), recurrence-free survival (HR = 1.399, 95% CI = (1.106 – 1.770), p = 0.005) and overall survival (HR = 1.385, 95% CI = (1.046 – 1.834), = 0.023) but not for breast cancer specific survival (HR = 1.015, 95% CI = (0.684 – 1.505), p = 0.942).ConclusionshPG80 levels measured at diagnosis were significantly associated with the risk of recurrence or death from any cause in women with breast cancer. Since the recurrence rates of breast cancer are still relatively high amongst women diagnosed at an early stage, identifying women at high risk of recurrence at their time of diagnosis is important. hPG80 is a promising new prognostic biomarker that could improve the identification of women at higher risk of poor outcomes.

Abstract 4213: Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico

Abstract Introduction: Benign breast disease (BBD) is an important breast cancer (BC) risk factor, which may be classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) for risk stratification. Data related to the frequency of specific types of BBD and their relationship to BC risk in the Hispanic American population are limited. To address this knowledge gap, we compared BBD and associated BC risk among Hispanic white (HW) and non-Hispanic white (NHW) in New Mexico (NM). Methodology: A retrospective IRB-approved study was performed of women 19 years or older residing in six counties in NM (Bernalillo, Sandoval, Sante Fe, Socorro, Torrance, Cibola/Valencia) between 1996 and mid-2007 to compare the frequency of BBD subtypes and BC risk among HW and NHW. We excluded women who had a history of BC prior to BBD diagnosis or who were diagnosed with BC within 6 months after BBD biopsy. Race and ethnicity were self-reported by women at the time of biopsy. BBD was categorized as NPD, PDWA, or AH based on medical records. Incident BC (in-situ or invasive) was ascertained via linkage to the NM Surveillance Epidemiology End Results (SEER) Registry and BC risk was assessed using standardized incidence ratios (SIRs), comparing the observed number of BC events to that expected based on the NM SEER six-county race- and ethnicity-specific incidence rates, accounting for age and calendar period. Results: Our analysis included 3,870 HW and 6,996 NHW women with BBD. The HW were younger (47.1 vs. 51 years) compared to NHW. HW women had slightly more NPD (69.4% vs. 66.6%) but less PDWA (26.2% vs. 29.4%) and similar frequency of AH (4.3% vs. 3.9%) as compared to NHW. Over a median post-BBD follow-up period of 13 years (range 6 months-17 years), 644 BCs were observed (4.81% in HW and 6.55% in NHW). The observed BC risk among women with BBD was higher than population-based expected rates (SIR 1.98, 95% CI 1.82-2.13, p&amp;lt;0.001) and showed expected increases in risk with increasing degrees of BBD abnormality: SIR=1.90 for NPD, 2.00 for PDWA, and 3.01 for AH. Comparing BC risk by ethnic subgroups, HW women had an overall risk of BC after BBD that was statistically indistinguishable from NHW women (SIR=2.17, 95% CI 1.86-2.48 in HW women, and SIR=1.91, 95% CI 1.73-2.08 in NHW women). Within the major subgroups of the BBD findings, there were no significant differences in risk of BC after BBD for HW versus NHW women. Conclusions: In this population-based study, benign breast disease subtypes and their associated breast cancer risk were similar among the Hispanic and non-Hispanic white women. Citation Format: Kush Raj Lohani, Andrea M. Nibbe, Robert A. Vierkant, Laura M. Pacheco-Spann, Lisa R. Seymour, Celine M. Vachon, Mark E. Sherman, Amy C. Degnim, Deirdre Hill. Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico. [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 4213.

Abstract 5263: Licochalcone A is a candidate for breast cancer prevention through its reprogramming of metabolic and antioxidant pathways

Abstract Background: Increased adiposity is a risk factor for postmenopausal breast cancer. It is accompanied by protumorigenic effects: chronic low-grade inflammation and elevated levels of reactive oxygen species. Breast cancer risk reducing drugs with proven efficacy have adverse side effects, significantly minimizing their uptake and impact. Effective alternative strategies with lower toxicity are needed. We have shown that licochalcone A (LicA) suppresses aromatase expression and activity, enhances the activity of detoxifying enzymes, and reduces estrogen genotoxic metabolism in cell lines and animal models. However, no previous data exist on the breast tissue of women at substantial risk of breast cancer. We hypothesize that LicA creates a tumor preventive environment in the breast by modulating antioxidant/anti-inflammatory responses in the breast and adipogenesis leading to decreased proliferation. Methods: We prepared microstructures from the fresh tissue of contralateral unaffected mastectomy specimens of 6 postmenopausal women with incident unilateral breast cancer. After exposing them to DMSO (control) and LicA (5 µM), we performed total RNA sequencing. Differentially expressed genes were identified, and analyzed by gene ontology and pathway membership. The RNA-seq data was utilized also to conduct metabolism flux analysis. Combined enrichment scores &amp;gt; 4 and FDR &amp;lt; 0.05 was considered significant. The NanoString metabolism panel was employed in 6 additional subjects. We performed live cell imaging to monitor proliferation of pre-malignant DCIS.COM, DCIS.COM/ER+ PR+; and malignant MDA-MB-231 (ER- PR-), MCF-7 (ER+ PR+), MCF-7aro, and BRCA1 defective HCC-1937, and HCC3153 cells. Results: We observed upregulation of antioxidant genes (up to 8-fold), consistent with upregulation of NRF2 and the thioredoxin system, the major regulators of antioxidant pathways. This was accompanied with the significant downregulation of RELA- and NF-kB1-dependent inflammatory pathways. In addition, we observed decreased expression of the pro-adipogenic transcription factors SREBF1 and SREBF2, which may explain the downregulation (4 to 32-fold) of cholesterol biosynthesis and transport, and lipid metabolism genes. Metabolism studies confirmed these data and demonstrated a robust increase in the pentose phosphate shunt and NAD(P)H generation without enhancing ribose 5 phosphate formation, suggesting an antioxidant and anti-proliferative environment. LicA also suppressed proliferation of pre-malignant and malignant cells, with sustained effects on aggressive cells at doses &amp;lt; 10 µM. Conclusion: Our data suggest that LicA is a good candidate for breast cancer prevention through modulation of metabolic and antioxidant pathways leading to decreased proliferation. Our ongoing in vivo study will further demonstrate the efficacy of LicA for breast cancer prevention. Citation Format: Atieh Hajirahimkhan, Elizabeth Bartom, Sriram Chandrasekaran, Xiaoling Xuei, Susan Clare, Seema Khan. Licochalcone A is a candidate for breast cancer prevention through its reprogramming of metabolic and antioxidant pathways. [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 5263.

Abstract 6469: Associations between serum iron levels and breast cancer tumor size

Abstract Background: Iron metabolism is disrupted in cancer cells, with well-established associations between increased iron availability and cancer growth. Excess iron can be toxic, and animal models have demonstrated that excess iron promotes tumor growth, whereas iron deficiency reduces or slows tumor growth. Few observational studies have assessed associations between serum iron levels and human tumor characteristics. The objective of this study is to estimate the associations between serum iron levels and tumor size at diagnosis in breast cancer cases from The Sister Study, a large prospective cohort based in the United States. Methods: Data are from a case-cohort sample of the Sister Study selected in 2016 to study serum iron levels. Of the 3,007 invasive or ductal carcinoma in situ cases included, we used the 2,494 incident breast cancer cases with information on tumor size and iron levels. Serum iron (mcg/dL), ferritin (mcg/dL), and percent transferrin saturation were measured in samples collected at baseline (median time from collection to diagnosis 4.6 years). Prior to modeling, we applied a natural log transformation to the largest tumor size and ferritin levels. To estimate the associations between body iron levels and tumor size, we used Spearman’s rank correlation and linear regression models adjusting for body mass index and age at study entry. If there were multiple tumor measures for one person, we selected the largest tumor size. Sensitivity analyses included: 1) restricting analyses to diagnoses more than 6 months after or less than 4 years after baseline iron measures, 2) excluding women who reported taking iron supplements, and 3) stratifying analyses by tumor subtypes. Results: Associations between all three serum iron levels and tumor size were close to the null, indicating no evidence of an association between iron and tumor size. Spearman’s rank correlations were all close to zero. Adjusted regression slopes (95% confidence interval) were -0.0005 (-0.0010, 0.0005) for serum iron, -0.0163 (-0.055, 0.022) for ferritin, and -0.0009 (-0.004, 0.0021) for percent transferrin saturation. Results from the sensitivity analyses did not substantively differ from our primary findings. Conclusions: We did not find evidence to support the hypothesis of a positive association between breast cancer tumor size at the time of diagnosis and serum iron levels. The conflicting evidence between this study and previous research in animal models suggests that iron in the human tumor microenvironment may operate independently of circulating iron or body iron stores. Citation Format: Ann Von Holle, Rachel L. Thompson, Katie M. O'Brien, Dale P. Sandler, Clarice R. Weinberg. Associations between serum iron levels and breast cancer tumor size [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 6469.

Abstract 4175: Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study

Abstract Purpose: Widely used breast cancer risk prediction tools are based on data from Western countries, but risk factors may differ for Asian women. Hence, we aimed to develop a risk assessment tool for breast cancer in Asian women, using a nationwide, population-based cohort in Korea. Methods: Women aged ≥ 40 years who participated in both breast cancer screening and general health examination in 2009 were eligible for this study. Age, body mass index (BMI), breast density, lifestyle and reproductive factors, and comorbidities were used to develop 5-year breast cancer risk prediction models in premenopausal (n=771,856) and postmenopausal (n=1,108,047) women at baseline. Backward stepwise selection in the Cox proportional hazards model was used to construct the best-fit risk prediction model, which was then converted into a risk score nomogram, representing an individual probability estimate of incident breast cancer. Model performance was evaluated by discrimination and calibration. Results: Among premenopausal women, high BMI, low parity, short breastfeeding period, early age at menarche, high breast density, history of benign breast mass, and family history of breast cancer contributed to breast cancer risk prediction. The appropriate predictors in postmenopausal women additionally included age, type 2 diabetes, dyslipidemia, late age at menopause, hormone replacement therapy use, except for number of parities. The concordant statistic of risk prediction model was 0.58 (95% confidence interval [CI] 0.57-0.59) for premenopausal women, and 0.64 (95% CI 0.63-0.65) for postmenopausal women. Our model correlated well in the calibration plot in both premenopausal and postmenopausal women.Conclusions: Our breast cancer risk prediction model showed good performance for postmenopausal women, providing the background for risk-based screening recommendations in Asian women. Citation Format: Wonyoung Jung, Yong-Moon Mark Park, Sang Hyun Park, Kyungdo Han, Junhee Park, Yohwan Yeo, Jung Kwon Lee, Dale P. Sandler, Dong Wook Shin. Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study. [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 4175.

Abstract 1000: Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer

Abstract Purpose: Young women’s breast cancers (YBCs), defined herein as breast cancer (BC) diagnosed at age ≤ 40 years, are etiologically and biologically distinct from postmenopausal BCs, demonstrating a higher proportion of estrogen receptor (ER) negative subtypes and a worse prognosis. Studies have not assessed whether risk factors such as recent parity and body mass index (BMI) are linked to protein expression profiles in YBCs. Accordingly, we examined protein expression assessed with GeoMx® Digital Spatial Profiling (DSP) in 640 YBCs prepared as tissue microarrays (TMAs) in the Young Women’s BC Study (YWBCS). Methods: The YWBCS is a multi-institutional cohort of 1,297 women with incident BC diagnosed at age &amp;lt;40 years identified through medical record review, with risk factor data collected via questionnaires. TMAs including 1,505 cores of 640 YBCs that were collected prior to therapy and were suitable for molecular analysis were evaluated for 72 markers with NanoString GeoMx DSP. Associations of log-transformed biomarker expression with BMI and time from last live birth to BC diagnosis were carried out using linear mixed modeling approaches, accounting for multiple tumor tissue cores per individual. Results: Mean age at BC was 35.5 years (range 17-40). Tumor subtypes based on clinical immunostaining were the following: luminal B 46%; luminal A 36%; triple negative 12% and HER2+ 6%. Of 72 biomarkers tested, 53 (74%) were evaluable after QC and normalization. GeoMx ER and PR protein levels were higher in luminal A and luminal B YBCs than in HER2+ and TNBC (p=2x10-94 and 2x10-52, respectively), supporting the accuracy of the GeoMx assay. Compared to nulliparas or those with most recent birth &amp;gt; 3 years before BC, those who gave birth ≤ 3 years prior to BC had tumors with higher expression of PR (8x10-6) and ER (p=0.006), and lower expression of BCL-2 (p=0.006). In contrast, women with last birth ≥ 6 years prior to BC had higher expression of CD8 (p=0.006) and PD-1 (p=0.001) than nulliparas and those with more recent births. Compared to women with BMI between 18.5 and 29.9, those with higher or lower BMIs had higher expression of CD34 (p=0.0003), CD4 (p=0.0009) and CD14 (p=0.001). BCL-2 expression was higher among women with BMI &amp;lt; 18.5 compared to those with higher values (p=0.005). Women with BMI of 30+ had higher β2-microglobulin levels than those with lower BMIs (p=0.003). Inverse dose-response associations (with higher BMI related to lower levels) were observed for expression of ER (p=0.01), pan cytokeratin (p=0.004) and four proteins in the p13K/AKT signaling pathway (p ≤ 0.01 for each). Conclusions: Preliminarily, we identify differences in hormonal and immune markers in YBCs in relation to timing of births and BMI, suggesting that these factors may contribute to etiologic heterogeneity. Multivariate modeling is ongoing to incorporate molecular subtype and other risk factors. Citation Format: Robert A. Vierkant, Laura M. Pacheco-Spann, Stacey J. Winham, Jennifer M. Kachergus, Ji Shi, Craig Snow, Fergus J. Couch, Janet E. Olson, Chen Wang, Derek C. Radisky, Amy C. Degnim, E. Aubrey Thompson, Laura C. Collins, Kathryn J. Ruddy, Ann H. Partridge, Mark E. Sherman. Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer [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 1000.

The Effect of Risk-Reducing Salpingo-Oophorectomy on Breast Cancer Incidence and Histopathological Features in Women with a BRCA1 or BRCA2 Germline Pathogenic Variant

Risk-reducing salpingo-oophorectomy (RRSO) is advised for female BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV (HR: 1.48, 95% CI: 0.91-2.39) or BRCA2 GPV (HR: 0.95, 95% CI: 0.43-2.07) carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO (15 mm, p: 0.08). There were no statistically significant differences in histopathological features. RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.

The association between night shift work and breast cancer risk in the Finnish twins cohort

Breast cancer is highly prevalent yet a more complete understanding of the interplay between genes and probable environmental risk factors, such as night work, remains lagging. Using a discordant twin pair design, we examined the association between night shift work and breast cancer risk, controlling for familial confounding. Shift work pattern was prospectively assessed by mailed questionnaires among 5,781 female twins from the Older Finnish Twin Cohort. Over the study period (1990–2018), 407 incident breast cancer cases were recorded using the Finnish Cancer Registry. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for potential confounders. Within-pair co-twin analyses were employed in 57 pairs to account for potential familial confounding. Compared to women who worked days only, women with shift work that included night shifts had a 1.58-fold higher risk of breast cancer (HR = 1.58; 95%CI, 1.16–2.15, highest among the youngest women i.e. born 1950–1957, HR = 2.08; 95%CI, 1.32–3.28), whereas 2-shift workers not including night shifts, did not (HR = 0.84; 95%CI, 0.59–1.21). Women with longer sleep (average sleep duration > 8 h/night) appeared at greatest risk of breast cancer if they worked night shifts (HR = 2.91; 95%CI, 1.55–5.46; Pintx=0.32). Results did not vary by chronotype (Pintx=0.74). Co-twin analyses, though with limited power, suggested that night work may be associated with breast cancer risk independent of early environmental and genetic factors. These results confirm a previously described association between night shift work and breast cancer risk. Genetic influences only partially explain these associations.

Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Patients

The only breast cancer (BC) subtype without targeted therapies is triple negative breast cancer (TNBC), which makes for 15–20% of incident breast cancers. TNBC is HER2 (human epidermal growth factor receptor 2) negative using clinical tests, and immunostaining reveals a negligible (1%) expression of ER and PR. It has the most dismal prognosis of all BC subtypes due to its biologically aggressive tumor, which is characterized by moderate/high grade and highly proliferating cancer cells. Although invasive ductal carcinoma is the most frequent presentation of TNBC, there are specific TNBC histologies that require special attention due to differing biology and prognosis. Patients with operable illness are increasingly receiving neoadjuvant chemotherapy, which was formerly reserved for patients with locally progressed or inflamed breast cancer, notably in TNBC patients. More people can have breast-conserving surgery (BCS) thanks to this therapeutic strategy, which also assesses how well it is working. An important prognostic factor with positive long-term results is achieving a pathological complete response (pCR). A higher pCR rate is related to the delivery of NACT regimens with platinum salts. However, at the expense of confusing treatment recommendations there is higher incidence of negative outcomes. Improvements in pathologic complete response rates and patient outcomes in the neoadjuvant setting are the main topics of clinical research.

Long-Term Performance of an Image-Based Short-Term Risk Model for Breast Cancer.

Image-derived artificial intelligence-based short-term risk models for breast cancer have shown high discriminatory performance compared with traditional lifestyle/familial-based risk models. The long-term performance of image-derived risk models has not been investigated. We performed a case-cohort study of 8,604 randomly selected women within a mammography screening cohort initiated in 2010 in Sweden for women age 40-74 years. Mammograms, age, lifestyle, and familial risk factors were collected at study entry. In all, 2,028 incident breast cancers were identified through register matching in May 2022 (206 incident breast cancers were found in the subcohort). The image-based model extracted mammographic features (density, microcalcifications, masses, and left-right breast asymmetries of these features) and age from study entry mammograms. The Tyrer-Cuzick v8 risk model incorporates self-reported lifestyle and familial risk factors and mammographic density to estimate risk. Absolute risks were estimated, and age-adjusted AUC model performances (aAUCs) were compared across the 10-year period. The aAUCs of the image-based risk model ranged from 0.74 (95% CI, 0.70 to 0.78) to 0.65 (95% CI, 0.63 to 0.66) for breast cancers developed 1-10 years after study entry; the corresponding Tyrer-Cuzick aAUCs were 0.62 (95% CI, 0.56 to 0.67) to 0.60 (95% CI, 0.58 to 0.61). For symptomatic cancers, the aAUCs for the image-based model were ≥0.75 during the first 3 years. Women with high and low mammographic density showed similar aAUCs. Throughout the 10-year follow-up, 20% of all women with breast cancers were deemed high-risk at study entry by the image-based risk model compared with 7.1% using the lifestyle familial-based model (P < .01). The image-based risk model outperformed the Tyrer-Cuzick v8 model for both short-term and long-term risk assessment and could be used to identify women who may benefit from supplemental screening and risk reduction strategies.

Female breast cancer subtypes in the Romagna Unit of the Emilia-Romagna cancer registry, and estimated incident cases by subtypes and age in Italy in 2020

PurposeThe aim of this study was to estimate the Italian burden of incident breast cancer (BC) by subtypes, according to the distribution of hormonal receptor (HR) status and expression of human epidermal growth factor 2 (HER2).MethodsFemale breast cancers incidence in the Romagna Unit of the Emilia-Romagna registry (n. 10,711) were grouped into: HR+ /HER2–, HR+ /HER2+ , HR–/HER2+ , HR–/HER2– and missing, and by age: < 50, 50–69 and 70+ years. Data were compared with other published Italian population-bases series before using them for national estimates. We used national and regional numbers of expected breast cancers published by the Italian network of cancer registries considering the age- and geographic-specific variation of the Italian population.ResultsOverall, 70.7% of incident BC cases are expected to be HR+ /HER2-, 8.5% HR+ /HER2+ , 7.5% HR-/HER2-, 4.1% HR-/HER2+ and 9.3% missing. The global ranking is similar across age-groups but with age-specific differences. The proportion of missing was around 3-times lower than in the other Italian published population-based series and similar to the SEER one. In Italy, are estimated 38,841 HR+ /HER2- breast cancer cases, 4665 HR+ /HER2+ , 4098 HR-/HER2-, 2281 HR-/HER2+ , and 5092 not specified. Numbers by age-group were provided.ConclusionsThe present estimates relied on high-quality population-based data and provide a clinically relevant information on the burden of breast cancer subtypes. These data will support the planning of therapy needs for oncologists, decision-makers, and all other stakeholders.

MTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.

Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women. The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression. AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05). Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings.

Abstract PD14-02: PD14-02 Ten-year follow-up of an image-based AI risk model for breast cancer

Abstract Background: Artificial intelligence based, image-derived short-term risk models for breast cancer have shown high discriminatory performance compared to traditional lifestyle familial-based risk models. However, the long-term performance has not yet been investigated. Methds: In this study, we investigated the long-term performance for predicting breast cancer throughout 10 years using an image-based risk model and compared the results to a traditional lifestyle familial-based risk model. We performed a nested case-control study based on a mammography screening cohort conducted since 2010 in Sweden for women aged 40-74. Mammograms, age, lifestyle and familial risk factors were collected at study entry. In the breast cancer register update in 2022; 2,028 incident breast cancers were included together with 8,398 controls that were matched to the cases on year of prior baseline mammogram. The image-based model extracted mammographic features (density, microcalcifications, masses, left-right breast asymmetries of these features) and age from the baseline mammograms. Tyrer-Cuzick risk model used self-reported lifestyle and familial risk factors to estimate risk at study-entry. Absolute risks were estimated using the risk models. We estimated model performances using Area Under the receiver operating characteristic Curves (AUC) statistics of the absolute risks and, risk ratios of women classified as high-risk and low risk using NICE and USPSTF guidelines. Results: The AUCs of the image-derived risk model ranged from 0.76 (95%CI 0.72-0.81) to 0.66 (95%CI 0.65-0.67) for breast cancers developed 1-10 years after study-entry. The corresponding Tyrer-Cuzick AUCs were 0.68 (95%CI 0.63-0.73) to 0.62 (95%CI 0.60-0.63). For estrogen negative and symptomatic cancers, the AUCs for the image-derived model were ≥0.75 during the first 2 years. Women with high and low mammographic density showed similar AUCs. Throughout the 10-years of follow-up, 20% of all women with cancers were deemed high risk at study-entry by the image-derived risk model compared to 6% of all women with cancers identified as high risk by the lifestyle familial-based model (p&amp;lt; 0.01). Conclusion: The image-derived model outperformed the lifestyle familial-based model both for short-term and long-term risk assessment and, could be used for identifying women who possibly could benefit from additional examinations and primary prevention. Citation Format: Mikael Eriksson, Kamila Czene, Emily F. Conant, Per Hall. PD14-02 Ten-year follow-up of an image-based AI risk model for breast cancer [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 PD14-02.

Abstract PD14-05: PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women

Abstract Background: Personalized breast cancer (BC) risk assessment depends on known traditional risk factors, specific germline mutations, and genome-wide polygenic risk scores (PRS). PRS explains a substantial proportion of genetic BC susceptibility. Accuracy of BC risk prediction may be improved by combining a PRS with traditional risk factors. We recently developed and validated a 149-SNP PRS for women of diverse ancestries using ancestry-informative genetic markers and combined this with version 7 of the Tyrer-Cuzick (TC) model to generate a Combined Risk Score (CRS). Here, we describe a pre-specified prospective longitudinal clinical validation of CRS as a predictor of BC risk. Methods: Women in the U.S. who were referred for clinical genetic testing between January 2017 and February 2019 were matched to medical and hospital claims in an anonymized dataset. Women with a pathogenic mutation in a BC-related gene were excluded from analysis. Follow-up began 4 months after testing and extended to the earliest date of BC diagnosis, censoring at the time of BC preventive treatment, or November 1, 2019. Incident BC events were determined by an ICD10 code of C50.* and confirmed by relevant treatment codes. CRS calibration was evaluated by the ratio of observed (O) to expected (E) incident BCs for the full cohort, and for women split into event-based 5-year CRS risk deciles. Cox proportional hazards models were used to evaluate discriminatory accuracy in terms of hazard ratios (HR) with 95% confidence intervals (CI) and p-values from likelihood ratio chi-squared statistics. Kaplan-Meier analysis was used to examine risk for women split into high- or low-risk groups according to a 3% 5-year CRS risk threshold. Results: 130,058 women with 148,349 total patient years met study eligibility criteria and were matched to claims data. Over a median (range) follow-up of 12.1 (4.0-29.5) months, 340 incident BC events were observed. The CRS was well calibrated in the overall cohort with an O/E ratio of 1.11 (95% CI=0.99-1.23) and within deciles of predicted risk (Table). Importantly, in the highest risk decile, the O/E was 0.91 (95% CI=0.63-1.27) with CRS, but 0.67 (95% CI=0.46-0.94) with TC alone, illustrating the superior calibration of CRS. In a Cox model adjusted for age at testing, PRS had an HR per standard deviation (SD) of 1.48 (95% CI=1.33-1.64, p=2.55×10-13); the HR/SD was 1.43 (95% CI=1.29-1.59, p=1.61×10-11) after adjusting for family history. In a bivariate analysis using both CRS and TC to predict time to BC, CRS added significantly to the model after accounting for TC (HR/SD=2.89, 95% CI=2.12-3.94, p=1.20×10-11), whereas TC did not add significant information after accounting for CRS. 15,986 (12.3%) women were above the CRS high-risk threshold, including 123 with events. A total of 10,248 (7.9%) women were reclassified by the CRS model compared to the TC model. Among women who were classified as high-risk by TC, 32.6% were reclassified as low-risk by CRS; among those classified as low-risk by TC, 4.3% were reclassified as high-risk by CRS. The CRS high-risk group experienced events at over three times the rate of the low-risk group (HR=3.75, 95% CI=3.00-4.68, p=6.39×10-27). Conclusion: The CRS was well-calibrated in predicting BC and significantly improved upon a traditional risk factor model. Clinical use of the CRS may lead to improved BC prevention and screening strategies. Table: Absolute risk calibration by 5-year risk decile Incidence is reported per 1,000 women-years. 34 breast cancers were observed per decile. Citation Format: Brent Mabey, Elisha Hughes, Braden Probst, Holly J. Pederson, Timothy Simmons, Brian Morris, Brooke Hullinger, Susan Domchek, Charis Eng, Monique Gary, Jennifer Klemp, Semanti Mukherjee, Vijai Joseph, Kenneth Offit, Olufunmilayo I. Olopade, Sandhya Pruthi, Allison W. Kurian, Mark E. Robson, Pat Whitworth, Susanne Wagner, Jerry Lanchbury, Thomas Slavin, Alexander Gutin. PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women [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 PD14-05.

Abstract P4-03-17: Parity, Use of Statins and Low-dose Aspirin, and Breast Cancer Risk – data from two large cohort studies

Abstract Background: Statins and low-dose aspirin have been associated with a reduced breast cancer (BC) incidence, but results are inconsistent. Based on emerging evidence that parity, a protective factor for breast cancer, and these drugs modulate immunity, we hypothesized that the association between drug use and breast cancer risk may differ by parity. Objectives: To assess the associations of statin and low-dose aspirin use with BC incidence according to parity in French and Danish cohorts. Methods: We conducted two cohort studies, using data from the French E3N study and a Danish nationwide population-based cohort, respectively. From E3N, 51,482 women, mean age 65.5 years, were enrolled in 2005 and followed until 2014. Data on parity (here full-term pregnancies), drug use, and incident BC were acquired from questionnaires, a drug reimbursement database, pathology verified self-reports and the national cause-of-death registry, respectively. From nationwide health registries, we included all Danish women free of BC and aged 45 years in 2000-2005 (n=198,575), with follow-up to 2014. Use of the exposure drugs were defined as at least two reimbursements/filled prescriptions. In both cohorts, multivariable-adjusted Cox regression was used to compute hazard ratios (HR) for drug exposure, treated as time-varying lagged variables, and BC risk stratified by parity (0, 1, 2, 3+). Results: In E3N and Denmark, 1,878 and 5,436 incident BC cases occurred in a mean follow-up of 8.5 and 11.5 years, respectively. At the end of follow-up, 35% and 19% of E3N and 16% and 8% of the Danish cohort had been exposed to statins and low-dose aspirin, respectively. In E3N, effect modification was observed between parity and statins, but not low-dose aspirin. For statins, the HRs for use vs no use were 1.29 (0.97-1.72), 1.27 (0.99-1.65), 1.08 (0.91-1.27), and 0.76 (0.61-0.95) among women with 0, 1, 2, and 3+ full-term pregnancies, respectively (p-het=0.005). The corresponding estimates for low-dose aspirin were: 1.17 (0.80-1.71), 0.81 (0.54-1.20), 1.13 (0.90-1.43), and 1.22 (0.93-1.61; p-het=0.6). In contrast, the Danish data did not suggest any effect modification. HRs for use vs no use of statins were 0.82 (0.60-1.13), 1.05 (0.80-1.37), 0.91 (0.75-1.10), and 1.09 (0.83-1.44) among women with parity of 0, 1, 2, and 3+, respectively (p-het=0.3). For low-dose aspirin HRs were: 1.09 (0.75-1.59), 0.79 (0.54-1.15), 1.04 (0.82-1.32), and 0.99 (0.71-1.40; p-het=0.8). Conclusions: We observed effect modification by parity for the association between statins and breast cancer risk in the French but not the Danish cohort. Whether the age difference between the cohorts explains the inconsistent results should be explored. Citation Format: Julie A. Schmidt, Agnès Fournier, Manon Cairat, Aurélie Mailhac, Henrik Sørensen, Marc Gunter, Deirdre Cronin-Fenton. Parity, Use of Statins and Low-dose Aspirin, and Breast Cancer Risk – data from two large cohort studies [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 P4-03-17.

Abstract P3-03-08: Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study

Abstract Background: The importance of mental health to improve the quality of cancer survivorship and outcomes is gaining increased attention. Major depressive disorder (MDD) has been associated with higher breast cancer (BC) incidence, BC-specific and all-cause mortality. The effect of MDD on BC recurrence remains under-studied. The Veterans Health Administration (VHA) provides a unique opportunity to examine this relationship as it mandates annual MDD screening in the primary care setting and reports national screening rates of 96%. Objective: To examine the relationship between pre-existing MDD and BC recurrence among a diverse cohort of women in the United States. Methods: We established a retrospective cohort of women (age ≥ 18 years) diagnosed with early-stage incident BC from 2010 through 2019 using the VHA’s electronic medical record database. We used a two-year window to identify women with clinically diagnosed MDD prior to their BC diagnosis. Our outcome of interest was BC recurrence (local recurrence/second primary and distant recurrence). We used multivariable proportional hazards regression to examine the association between MDD and BC recurrence, accounting for competing risk of death. Our analyses were adjusted for age, race, ethnicity, marital status, priority group rating (proxy for socioeconomic status), rurality of primary residence, geographical region, cancer stage, year of BC diagnosis, and comorbidity burden. Priority group rating is a metric that incorporates patients’ income, receipt of VHA assistance benefits, capacity for gainful employment, and severity of service-connected conditions. We conducted subgroup analyses by tumor subtype. RESULTS: Our cohort consists of 6,045 women with BC, of whom 1,750 (29.0%) had a pre-existing MDD diagnosis. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall and 56 years (SD=10 years) among women with MDD. Sixty-one percent of women were white, 29% were black, 27% were married, and 28% were rural dwelling. Forty-four percent of invasive carcinomas were localized and 21% were regional. Thirty-five percent of patients had ductal carcinoma in situ. Women with MDD had a higher average Charlson Comorbidity Index score (mean=0.75, SD=1.13 vs. mean=0.58, SD=1.03) and proportion with a priority group rating between 1-4 (40% vs. 32%). The distribution of other described patient characteristics among women with MDD were similar to the overall cohort. On multivariable analysis, women with MDD had a 31% (95% CI: 1.11, 1.56) higher risk of BC recurrence compared to women without MDD. MDD was associated with a 29% (95% CI: 1.01, 1.66) and 33% (95% CI: 1.05, 1.67) higher risk of local recurrence/second primary and distant recurrence, respectively. The relationship between MDD and BC recurrence remained significant after adjusting for tumor subtype (HR=1.40, 95% CI: 1.07, 1.83). In subgroup analyses stratified by tumor subtype, MDD was associated with a higher risk of BC recurrence among women with estrogen receptor positive versus negative tumors (HR=1.65, 95% CI: 1.27, 2.14 vs. HR=0.71, 95% CI: 0.34, 1.46) and HER2/neu negative versus positive tumors (HR=1.53, 95% CI: 1.16, 2.00 vs. HR=1.24, 95% CI: 0.51, 2.96). The interaction between estrogen receptor status and MDD was statistically significant (p-interaction=0.02). CONCLUSION: Women with incident BC should be screened for MDD early in the cancer care continuum given the prevalence of MDD and association with increased risk of local recurrence/second primary and distant BC recurrence. Further research is needed to understand the interplay between these two diseases and their treatments. Citation Format: Maya Aboumrad, Brian Shiner, Avonne Connor, Bradley V. Watts, Kala Visvanathan. Depression and breast cancer recurrence among female veterans in the United States: a retrospective 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 P3-03-08.