Lifetime Risk Of Breast Cancer Research Articles

Association of polygenic-based breast cancer risk prediction with patient management.

10527 Background: Guidelines recommend individuals with ≥20% lifetime risk of breast cancer (BC) undergo enhanced management, including annual screening mammography (SM) as early as age 30, annual breast MRI, and genetic counseling (GC). Lifetime BC risk can be estimated using a validated risk model, such as Tyrer-Cuzick (TC). A risk predictor that combines TC with a polygenic risk score (“combined risk score” or CRS) significantly improves risk prediction over TC alone. Little is known about how clinicians manage patients based on CRS. Here, we describe management following receipt of CRS results. Methods: De-identified administrative claims data from the Optum Labs Data Warehouse were linked with de-identified TC and CRS results originally provided to ordering clinicians. Patients were divided into four subgroups based on their lifetime risk predicted by CRS and by TC alone (high risk: ≥20%, average risk: <20%): A (CRS-high/TC-high), B (CRS-high/TC-avg), C (CRS-avg/TC-high), and D (CRS-avg/TC-avg). Patient management claims were compared 360 days before and after the CRS test date and differences evaluated with McNemar’s test. Differences in post-test management were analyzed using multivariable logistic regression with adjustment for clinical factors. Results: Before receiving risk results, 11.9%, 7.7%, 8.8%, and 5.0% of patients in A, B, C, and D received a SM before age 40, respectively; 3.4%, 2.6%, 2.3%, and 0.9% received an MRI, respectively; and 4.3%, 4.7%, 6.0%, and 3.6% received GC, respectively. After receiving risk results, SM in those under age 40 significantly increased 1.6-2.2-fold in A, B, and C; MRI significantly increased 4.7-5.6-fold in A, B, and C; and GC significantly increased 1.9-2.3-fold in A and B. SM, MRI, and GC did not increase in D. Prophylactic mastectomy occurred in only 0.17% of all patients after receiving results. After adjustment for confounders, those in A, B, and C were 3.8-5.2 times more likely to undergo SM; 11.6-23.1 times more likely to undergo MRI; and 2.0-2.9 times more likely to undergo GC, compared to those in Group D (all p<0.001). Conclusions: Patients with a ≥20% lifetime risk for BC were more likely to undergo enhanced management compared to those with a lifetime risk <20%, regardless of whether their risk was based on the CRS or on TC. These results suggest that clinicians recommended management aligned with guidelines for those with ≥20% lifetime risk, even when such risk was predicted by the CRS. [Table: see text]

Feasibility of universal breast cancer risk assessment in a diverse, publicly insured obstetrician gynecology clinic.

e13759 Background: Breast cancer is the most diagnosed cancer among women in the United States. Established breast cancer risk assessment (BCRA) tools can estimate a woman’s lifetime risk and inform the need for enhanced breast screening which can improve cancer-associated morbidity and mortality. Currently, critical disparities exist both in breast cancer prognosis and screening uptake. We aimed to evaluate the feasibility of routine BCRA in a diverse, publicly insured obstetrician gynecology clinic. Methods: All patients presenting to the obstetrician gynecology clinic were offered a BCRA using the Tyrer Cuzick (TC) risk model. Patients completed paper surveys and the information was input into the TC model to generate lifetime risk estimates. Printed evidence-based management guidelines were reviewed with and provided to those at ≥ 20% lifetime breast cancer risk and shared with the patient’s provider. Results: Between June 2023 and February 2024, 300 patients were approached and 208 (69.3%) completed the survey. One hundred seven (51.4%) survey respondents were presenting for obstetrical care and 101 (48.6%) for gynecologic care. Respondents had a median age of 33 years (IQR: 12). Ninety-six (46.2%) responding patients self-identified as Hispanic, 45 (21.6%) as Black, 25 (12.0%) as Asian, 28 (13.5%) as Non-Hispanic White, and 14 (6.7%) did not identify in these categories. One hundred eighty-nine (90.9%) survey respondents were publicly-insured. Ten (4.8%) patients were assisted by an interpreter. Overall, 12 (5.8%) patients had an elevated lifetime breast of breast cancer, defined as ≥ 20% based on the TC model (6 (50.0%) among obstetrical patients and 6 (50.0%) among gynecology patients). All patients at elevated risk were referred to a genetics clinic for counseling on options for enhanced breast surveillance. Conclusions: As leaders in women’s cancer care, gynecologic oncologists can lead and support programs to identify those women at highest risk for cancer, especially among historically underserved populations. Our feasibility study demonstrated that 69.3% of patients were willing to complete a BRCA and this tool identified 5.8% of patients to have a significantly elevated lifetime breast cancer risk. Providers should consider incorporating such tools in gynecologic oncology and obstetrical/gynecology clinics.

Abstract PO1-20-01: A Prospective Single-Arm Pilot Interventional Trial to Assess Individual Breast Cancer Risk Prior to Gender-Affirming Chest Masculinization Surgery

Abstract Background: The number of individuals who identify as transgender and/or gender-diverse (TGD) is steadily increasing and the number of individuals seeking chest masculinization surgery, commonly called “top-surgery,” is also increasing. In persons assigned female at birth, top surgery removes most breast tissue to allow the chest to appear masculine. However, top surgery is not equivalent to oncologic risk-reducing mastectomies (RRM), which aim to remove all breast tissue to reduce future breast cancer (BC) risk. While top surgery has significant psychological and health benefits, its impact on future BC risk is unclear, especially for those individuals who are at high-risk for future BC development (defined as ≥17% by international consensus guidelines) and/or have a pathogenic germline mutation for BC. The aims of this study are to 1) determine the percentage of TGD persons assigned female at birth who are considering undergoing top surgery and are at elevated BC risk using validated risk models, 2) determine the percentage of TGD persons at elevated BC risk who choose to undergo RRM as part of top surgery, and 3) assess and compare self-perceived BC risk compared to calculated risk. Methods: A single-institution prospective single-arm pilot study is currently underway from March 2023 through January 2024. Individuals assigned female at birth, who are age ≥18 years, and considering undergoing top surgery, but have not yet undergone top surgery, are eligible to enroll (goal accrual N=35). Participants are being actively recruited form our institution’s Comprehensive LGBTQIA+ Inclusion Health Clinic and Plastic Surgery Clinic. Consented participants undergo a personalized BC risk assessment the validated IBIS and Gail (for those ≥35 years old) BC risk models. Those with an average lifetime BC risk (< 17%) are recommended to continue top surgery as planned/no intervention, participants with a moderate lifetime BC risk (17-30%) are counseled they may consider RRM as part of their top surgery operation given that sparse data exists in this space, while those with a high lifetime BC risk ( >30% or pathogenic germline variant) are counseled on the potential benefits of RRM. Participants with a family history suggestive of a hereditary cancer syndrome meet with a certified Genetics counselor for consideration of genetic testing, per NCCN guidelines. Results: We anticipate reporting 1) general demographic description of the cohort, 2) the percentage who have an elevated lifetime BC risk and/or a pathogenic genetic mutation, 3) the percentage of those with an elevated risk who choose to undergo RRM as part of top surgery, and 4) report the differences between self-perceived vs calculated lifetime BC risk. Conclusion: Our findings will inform TGD persons and surgeons on the utility of a personalized BC risk assessment prior to top surgery to assist in surgical decision-making, report the accuracy of self-perceived BC risk in TGD persons, and potentially change the standard pre-operative evaluation for TGD persons considering top surgery to include a formal BC risk assessment to ensure high-risk individuals have the option to undergo RRM to appropriately reduce their future BC risk. Citation Format: Chandler Cortina, Anna Purdy, Samantha Stachowiak, Kristen Klement, Sarah Sasor, Kate Krucoff, Andrew Petroll, Kevin Robertson, Annie Lakatos, Erin Doren. A Prospective Single-Arm Pilot Interventional Trial to Assess Individual Breast Cancer Risk Prior to Gender-Affirming Chest Masculinization Surgery [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 PO1-20-01.

Quantitative assessment of background parenchymal enhancement is associated with lifetime breast cancer risk in screening MRI.

To compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI. This study included screening MRI of 535 women divided into three groups based on lifetime risk: nonhigh-risk women, high-risk women without BRCA mutation, and BRCA1/2 mutation carriers. Six quantitative BPE measurements, including percent enhancement (PE) and signal enhancement ratio (SER), were calculated on DCE-MRI after segmentation of the whole breast and fibroglandular tissue (FGT). The associations between lifetime risk factors and BPE were analyzed via linear regression analysis. We adjusted for risk factors influencing BPE using propensity score matching (PSM) and compared the BPE between different groups. A two-sided Mann-Whitney U-test was used to compare the BPE with a threshold of 0.1 for multiple testing issue-adjusted p values. Age, BMI, menopausal status, and FGT level were significantly correlated with quantitative BPE based on the univariate and multivariable linear regression analyses. After adjusting for age, BMI, menopausal status, hormonal treatment history, and FGT level using PSM, significant differences were observed between high-risk non-BRCA and BRCA groups in PEFGT (11.5 vs. 8.0%, adjusted p = 0.018) and SERFGT (7.2 vs. 9.3%, adjusted p = 0.066). Quantitative BPE varies in women with different lifetime breast cancer risks and BRCA mutation status. These differences may be due to the influence of multiple lifetime risk factors. Quantitative BPE differences remained between groups with and without BRCA mutations after adjusting for known risk factors associated with BPE. BRCA germline mutations may be associated with quantitative background parenchymal enhancement, excluding the effects of known confounding factors. This finding can provide potential insights into the cancer pathophysiological mechanisms behind lifetime risk models. Expanding understanding of breast cancer pathophysiology allows for improved risk stratification and optimized screening protocols. Quantitative BPE is significantly associated with lifetime risk factors and differs between BRCA mutation carriers and noncarriers. This research offers a possible understanding of the physiological mechanisms underlying quantitative BPE and BRCA germline mutations.

Dual role of pregnancy in breast cancer risk

Reproductive history is one of the strongest risk factors for breast cancer in women. Pregnancy can promote short-term breast cancer risk, but also reduce a woman’s lifetime risk of breast cancer. Changes in hormone levels before and after pregnancy are one of the key factors in breast cancer risk. This article summarizes the changes in hormone levels before and after pregnancy, and the roles of hormones in mammary gland development and breast cancer progression. Other factors, such as changes in breast morphology and mammary gland differentiation, changes in the proportion of mammary stem cells (MaSCs), changes in the immune and inflammatory environment, and changes in lactation before and after pregnancy, also play key roles in the occurrence and development of breast cancer. This review discusses the dual effects and the potential mechanisms of pregnancy on breast cancer risk from the above aspects, which is helpful to understand the complexity of female breast cancer occurrence.

Personalized survivorship care: Routine breast cancer risk assessment in the gynecologic oncology clinic

IntroductionGynecologic and breast cancers share several risk factors. Breast cancer risk assessment tools can identify those at elevated risk and allow for enhanced breast surveillance and chemoprevention, however such tools are underutilized. We aim to evaluate the use of routine breast cancer risk assessment in a gynecologic oncology clinic. MethodsA patient-facing web-based tool was used to collect personal and family history and run four validated breast cancer risk assessment models (Tyrer-Cuzick (TC), Gail, BRCAPRO, and Claus) in a gynecologic oncology clinic. We evaluated completion of the tools and identification of patients at elevated risk for breast cancer using the four validated models. ResultsA total of 99 patients were included in this analysis. The BRCAPRO model had the highest completion rate (84.8%), followed by the TC model (74.7%), Gail model (74.7%), and the Claus model (52.1%). The TC model identified 21.6% of patients completing the model as having ≥20% lifetime risk of breast cancer, compared to 6.8% by the Gail model, and 0% for both the BRCAPRO and Claus models. The Gail model identified 52.5% of patients as having ≥1.67% 5-year risk of breast cancer. Among patients identified as high-risk for breast cancer and eligible for screening, 9/9 (100%) were referred to a high-risk breast clinic. ConclusionAmong patients that completed the TC breast cancer risk assessment in a gynecologic oncology clinic, approximately 1 in 5 were identified to be at significantly elevated lifetime risk for breast cancer. The gynecologic oncologist's office might offer a convenient and feasible setting to incorporate this risk assessment into routine patient care, as gynecologic oncologists often have long-term patient relationships and participate in survivorship care.

Patterns and Predictors of Referral for Screening Breast MRI: A Mixed-Methods Study.

Introduction: Women with ≥20% lifetime breast cancer risk can receive supplemental breast cancer screening with MRI. We examined factors associated with recommendation for screening breast MRI among primary care providers (PCPs), gynecologists (GYNs), and radiologists. Methods: We conducted a sequential mixed-methods study. Quantitative: Participants (N = 72) reported recommendations for mammogram and breast MRI via clinical vignettes describing hypothetical patients with moderate, high, and very high breast cancer risk. Logistic regressions assessed the relationships of clinician-level factors (gender, specialty, years practicing) and practice-level factors (practice type, imaging facilities available) with screening recommendations. Qualitative: We interviewed a subset of survey participants (n = 17, 17/72 = 24%) regarding their decision-making about breast cancer screening recommendations. Interviews were audio-recorded, transcribed, and analyzed with directed content analysis. Results: Compared with PCPs, GYNs and radiologists were significantly more likely to recommend breast MRI for high-risk (ORs = 4.09 and 4.09, respectively) and very-high-risk patients (ORs = 8.56 and 18.33, respectively). Qualitative analysis identified two key phases along the clinical pathway for high-risk women. Phase 1 was "identifying high-risk women," which included three subthemes (systems for risk assessment, barriers to risk assessment, scope of practice issues). Phase 2 was "referral for screening," which included three subthemes (conflicting guidelines, scope of practice issues, legal implications). Frequency of themes differed between specialties, potentially explaining findings from the quantitative phase. Conclusions: There are significant differences between specialties in supplemental breast cancer screening recommendations. Multilevel interventions are needed to support identification and management of women with high breast cancer risk, particularly for PCPs.

Decision-making for bilateral risk-reducing mastectomy for an increased lifetime breast cancer risk: A qualitative metasynthesis.

Previvor is a term applied to a person with an identified, elevated lifetime cancer risk but without an actual cancer diagnosis. Previvorship entails the selection of risk management strategies. For women with a genetic mutation that increases their predisposition for a breast cancer diagnosis, bilateral risk-reducing mastectomy (BRRM) is the most effective prevention strategy. However, BRRM can change a woman's breast appearance and function. The purpose of this qualitative metasynthesis (QMS) was to better understand the decision-making process for BRRM among previvors. A theory-generating QMS approach was used to analyze and synthesize qualitative findings. Research reports were considered for inclusion if: (1) women over 18years of age possessed a genetic mutation increasing lifetime breast cancer risk or a strong family history of breast cancer; (2) the sample was considering, or had completed, BRRM; (3) the results reported qualitative findings. Exclusion criteria were male gender, personal history of breast cancer, and research reports which did not separate findings based on cancer diagnosis and/or risk-reduction surgery. A theory and corresponding model emerged, comprised of seven themes addressing the decision-making process for or against BRRM. While some factors to decision-making were decisive for surgery, others were more indefinite and contributed to women changing, processing, or suspending their decision-making for a period of time. Regardless of the decision previvors make about BRRM, physical and psychosocial well-being should be considered and promoted through shared decision-making in the clinical setting.

MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Entrance into an MRI surveillance program. Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

CHEK2 Founder Variants and Thyroid Cancer Risk.

Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.

Breast Cancer Risk Perceptions Among Underserved, Hispanic Women: Implications for Risk-Based Approaches to Screening.

Understanding factors that shape breast cancer risk perceptions is essential for implementing risk-based approaches to breast cancer detection and prevention. This study aimed to assess multilevel factors, including prior screening behavior, shaping underserved, Hispanic women's perceived risk for breast cancer. Secondary analysis of survey data from Hispanic women (N = 1325, 92% Spanish speaking, 64% < 50) enrolled in a large randomized controlled trial. Analyses were performed in two cohorts to account for the role of age on screening guideline recommendations (< 50 and 50 +). For each cohort, we examined differences in three common measures of perceived risk of breast cancer (percent lifetime, ordinal lifetime, comparative) by participant factors with chi-square or Kruskal-Wallis tests, as appropriate. Multivariate analyses examined the association between mammography history with percent perceived lifetime risk (outcome > 10 vs ≤ 10%). Overall, 75% reported a lifetime risk between 0 and 10%, 96% rated their ordinal risk as "not high," and 50% rated their comparative risk as "much lower." Women < 50 with a family history of breast cancer reported significantly higher levels of perceived risk across all three measures. Among women 50 + , those reporting lower levels of perceived risk were significantly more likely to be Spanish speaking. No significant association was observed between mammography history and percent lifetime risk of breast cancer. Factors shaping breast cancer risk perceptions differ by age. Prior screening may play less of role in constructing risk perceptions. Research is needed to develop culturally and linguistically appropriate strategies to improve implementation of risk-based screening.

Risk-management decision-making data from a community-based sample of racially diverse women at high risk of breast cancer: rationale, methods, and sample characteristics of the Daughter Sister Mother Project survey

BackgroundTo understand the dynamics that limit use of risk-management options by women at high risk of breast cancer, there is a critical need for research that focuses on patient perspectives. Prior research has left important gaps: exclusion of high-risk women not in risk-related clinical care, exclusion of non-white populations, and lack of attention to the decision-making processes that underlie risk-management choices. Our objective was to create a more inclusive dataset to facilitate research to address disparities related to decision making for breast cancer risk management.MethodsThe Daughter Sister Mother Project survey collects comprehensive information about the experiences of women at high risk of breast cancer. We collected novel measures of feelings about and reactions to cancer screenings; knowledge, barriers, and facilitators of risk-management options; beliefs related to cancer risk and risk management; and involvement with loved ones who had cancer. Eligible individuals were non-Hispanic white and non-Hispanic Black adult women who self-identified as having high risk of breast cancer and had no personal history of cancer. Between October 2018 and August 2019, 1053 respondents completed the online survey. Of these, 717 were confirmed through risk prediction modeling to have a lifetime breast cancer risk of ≥ 20%. Sociodemographic characteristics of this sample were compared to those of nationally representative samples of the US population: the 2019 Health Information National Trends Survey and the Pew Research Center report: Jewish Americans in 2020.ResultsThe sample of 717 women at objectively high risk of breast cancer was largely (95%) recruited from non-clinical sources. Of these respondents, only 31% had seen a genetic counselor, 34% had had genetic testing specific to breast cancer risk, and 35% had seen at least one breast or cancer care specialist. The sample includes 35% Black respondents and 8% with Ashkenazi Jewish ancestry. Although encompassing a substantial range of ages, incomes, and education levels, respondents are overall somewhat younger, higher-income, and more educated than the US population as a whole.ConclusionsThe DSM dataset offers comprehensive data from a community-based, diverse sample of women at high risk of breast cancer. The dataset includes substantial proportions of Black and Ashkenazi Jewish women and women who are not already in clinical care related to their breast cancer risk. This sample will facilitate future studies of risk-management behaviors among women who are and are not receiving high-risk care, and of variations in risk-management experiences across race and ethnicity.

Counselling Framework for Germline BRCA1/2 and PALB2 Carriers Considering Risk-Reducing Mastectomy.

Female BRCA1/2 and PALB2 germline pathogenic variant carriers have an increased lifetime risk of breast cancer and may wish to consider risk-reducing mastectomy (RRM) for surgical prevention. Quantifying the residual lifetime risk and absolute benefit from RRM requires careful consideration of a patient's age, pathogenic variant, and their personal history of breast or ovarian cancer. Historically, patients have been counselled that RRM does not necessarily prolong survival relative to high-risk surveillance, although recent studies suggest a possible survival benefit of RRM in BRCA1 carriers. The uptake of RRM has increased dramatically over the last several decades yet varies according to sociodemographic factors and geographic region. The increased adoption of nipple-sparing mastectomy techniques, ability to avoid axillary staging, and availability of reconstructive options for most germline pathogenic variant carriers has helped to minimize the morbidity of RRM. Preoperative discussions should include evidence regarding postmastectomy sensation, the potential for supplemental surgery, pregnancy-related chest wall changes, and the need for continued clinical surveillance. Approaches that include sensation preservation and robotic nipple-sparing mastectomy are an area of evolving research that may be more widely adopted in the future.

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse models of elevated integrin mechanosignaling and collagen density, syngeneic manipulations, and spheroid models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation invivo. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.

Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers.

Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo progenitors could generate both ER+ and ER- cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.

Breast Cancer Polygenic-Risk Score Influence on Risk-Reducing Endocrine Therapy Use: Genetic Risk Estimate (GENRE) Trial 1-Year and 2-Year Follow-Up.

Risk-reducing medications for breast cancer are considerably underused. Informing women at risk with precise and individualized risk assessment tools may substantially affect the incidence of breast cancer. In our study, a risk assessment tool (IBIS-polygenic-risk score) yielded promising results, with 39% of women at highest risk starting preventive medication.

Abstract C118: Racial disparities in insurance coverage for supplemental breast cancer screening

Abstract Introduction and Purpose: Women with dense breasts have increased risk both for developing breast cancer and false-negative mammograms. Supplemental screening with breast MRI has been shown to shown to significantly increase cancer detection among women with dense breasts. In May 2023, Pennsylvania (PA) mandated insurance coverage of one supplemental screening study (breast MRI or ultrasound ) annually for women with dense breasts. Prior research suggests that Black women have lower breast density on average than white women based on subjective grading from the American College of Radiology Breast Imaging and Reporting Data System (BI-RADS), partially due to larger average breast size and higher body mass index (BMI) than white women. The purpose of this study was to estimate the potential impact of this supplemental screening law on different patient populations in a large health system. Methods: Women without prior breast cancer or known BRCA1/2 mutations who underwent mammographic screening at a large PA health system from April 2015-December 2017and completed a risk factor questionnaire were included (N=83,579). Under PA law, women must have either heterogeneously dense breasts plus &amp;gt;20% lifetime risk of breast cancer or extremely dense breasts to be eligible for insurance coverage for supplemental screening, both of which involve subjectively graded breast measurements. Breast cancer risk for each patient was estimated using the Gail model. The cancer detection rate (CDR) for mammographic screening was calculated as the number of cancers diagnosed within one year of a positive mammographic screen; the interval cancer rate was calculated as the number of cancers diagnosed within one year of a non-actionable screening mammogram per 1000 women. Logistic regression was used to calculate the odds of eligibility adjusted for age and BMI. Results: Black women were less likely to have extremely or heterogeneously dense breasts than white women (23.7% vs. 45.0%, p&amp;lt;0.001). Under PA law, 2.5% of Black women and 9.9% of white women would qualify for insurance coverage for supplemental screening (p&amp;lt;0.001). Only 0.2% of Black women and 2.3% of white women had heterogeneously dense breasts and &amp;gt;20% lifetime risk. Black women were more likely to have triple-negative breast cancer (TNBC) than white women (p&amp;lt;0.001). After adjusting for age and BMI, Black women remained 54% less likely to be eligible for supplemental screening than white women (OR=0.46, 95% 0.42-0.51, p&amp;lt;0.001).Conclusions: Black women are less likely to qualify for insurance coverage for supplemental breast cancer screening than white women under PA law. Given that Black women have lower prevalence of subjectively graded dense breasts and higher prevalence of TNBC, the new supplemental screening law is unlikely to meaningfully reduce racial disparities in breast cancer mortality. Methods to better assess breast cancer risk among Black women, particularly the risk of TNBC, are urgently needed to identify Black women that may benefit from supplemental screening. Citation Format: Mattia A. Mahmoud, Sarah Ehsan, Oluwadamilola M. Fayanju, Susan M. Domchek, Katherine L. Nathanson, Despina Kontos, Emily F. Conant, Anne Marie McCarthy. Racial disparities in insurance coverage for supplemental breast cancer screening [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 C118.

Clinician and patient perspectives on screening mammography among women age 75 and older: A pilot study of a novel decision aid

Supporting patient-clinician communication is key to implementing tailored, risk-based screening for older adults. Objectives of this multiphase mixed methods study were to identify factors that primary care clinicians consider influential when making screening mammography recommendations for women ≥ 75 years, develop a patient decision aid that incorporates these factors, and gather feasibility and acceptability from the patients' perspective. Clinicians from a Mid-Atlantic practice network completed online surveys. Women in the same network completed surveys before and after receiving a tailored booklet that included information about the benefits and harms of screening for women ≥ 75 years, a breast cancer risk-estimate, and a question prompt list to support patient-clinician communication. Clinicians (N = 21) were primarily women [57.1%] and practiced family medicine [81.0%]. They cited patients' age ≥ 75 years [95.4%], comorbidity [86.4%], functional status [77.3%], cancer family history [63.6%], U.S. Preventive Services Task Force guidelines [81.8%] and new research [77.3%] as factors influencing their recommendations. Fourteen women completed baseline surveys and received personalized decision aids (Mean age = 79.1 years). Eleven completed the post-intervention survey. All were satisfied with the booklet length, 81.8% found the booklet easy to understand and 72.7% helpful in decision-making Perceived lifetime breast cancer risk decreased significantly from pre- to post-intervention (p = 0.02). Results suggest this decision aid, which incorporates key decisional factors from the clinician's perspective, is feasible and acceptable to patients. A tailored decision aid booklet is innovative as it provides information on personalized risk and potential benefits and harms to older women considering screening.

Lifetime dairy product consumption and breast cancer risk: a prospective cohort study by tumor subtypes

BackgroundPrevious literature on dairy products and risk of breast cancer is inconsistent, and the relationship may depend on the life-period of dietary assessment. ObjectiveWe examined dairy consumption from adolescence through later adulthood and incidence of breast cancer by menopausal status and tumor molecular subtypes in the Nurses’ Health Study (NHS), a prospective cohort study. MethodsWe analyzed data from 63,847 females in the NHS collected from 1980 to 2018. Average intake of dairy products during adulthood was assessed by validated semiquantitative food frequency questionnaires throughout follow-up. Participants recalled adolescent dietary intake in 1986. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) relating dairy product consumption to breast cancer risk overall, by menopausal status, and by subtypes. ResultsWe documented 5733 incident cases of invasive breast cancer during 32 y of follow-up (n = 5298 postmenopausal). Lifetime, adolescent, adulthood, and postmenopausal total dairy and milk intakes were not associated with overall breast cancer risk (nonsignificant HRs comparing highest with lowest quintile range = 0.97–1.08), although there was a suggestive positive association between adolescent milk intake and breast cancer risk (HR: 1.09; 95% CI: 1.00, 1.18). Higher lifetime and premenopausal cheese intakes were associated with modestly lower risks of breast cancer (comparing highest with lowest quintile, HR for lifetime cheese intake: 0.90; 95% CI: 0.82, 0.98; HR for premenopausal cheese intake: 0.89; 95% CI: 0.79, 1.00). Results varied by tumor subtype and some evidence for heterogeneity was observed for an association between premenopausal milk intake and breast cancer (HR for estrogen receptor [ER]-positive: 0.84; 95% CI: 0.72, 0.99; ER-negative: 1.36; 95% CI: 1.00, 1.84; P heterogeneity = 0.04). ConclusionsThese findings suggest that overall dairy consumption was not associated with risk of breast cancer. However, heterogeneity was observed for type of dairy food, period of life, and tumor subtypes.

Breast cancer surveillance in BRCA positive Sri Lankan women: health equity for a high-risk group at a limited resource setting

BackgroundBRCA1 and BRCA2 pathogenic variants account for 90% of hereditary breast malignancies, incurring a lifetime breast cancer risk of 85% and 40–45% respectively, in affected individuals. Well-resourced health care settings offer genetic counselling and genetic screening for susceptible individuals, followed by intense breast cancer surveillance programmes for those identified at high risk of breast cancer. Such high standards of care are not available in countries with limited resources. This study assessed breast cancer surveillance behaviors among a cohort of BRCA positive Sri Lankan women.MethodsA retrospective case review of all patients diagnosed with pathogenic variants in BRCA1 and BRCA2 genes from 2015 to 2022 at the Human Genetics Unit, Faculty of Medicine, University of Colombo was carried out followed by telephone interviews of the respondents. Patients who were not contactable, deceased, undergone bilateral mastectomy and males were excluded from the interview component of the study. Standard descriptive statistics were used to analyze the data using SPSS statistics version 25.ResultsOnly 25 patients were diagnosed during the study period:14/25 women responded (6/25 deceased, 3/25 non-contactable; 2/25 excluded). 71.4% (10/14) had performed breast self-examination during the preceding month; 35.7% (5/14) had a clinical breast examination (CBE), and 50% (7/14) had undergone a screening/diagnostic mammogram during the last one year. 28.5% (4/14) had undergone both mammography and CBE; 21.45% (3/14) mammogram only, 7.1% (1/14) had CBE only. 42.8%(6/14) had not undergone any surveillance(mammography, CBE or MRI). None had dual screening with mammogram and MRI. 85.71% (12/14) women expressed willingness to participate in a regular screening programme if made available.ConclusionFifty percent of BRCA1/2 positive women in our study had not undergone annual imaging-based surveillance by mammography or MRI, and none had undergone annual dual screening with mammography and MRI, indicating inadequate breast cancer surveillance in this high-risk group.