Lifetime Risk Of Breast Cancer Research Articles

Breast cancer and ATM mutations: treatment implications.

Genetic testing for breast cancer predisposing genes has expanded beyond BRCA1 and BRCA2 and now includes panels of 20 or more genes. It is now recommended that all women diagnosed with breast cancer at age 65 or below be offered testing for an extended gene panel. The rationale for testing includes personalizing the management of breast cancer according to the mutation found. For BRCA1 and BRCA2 carriers, the finding of a mutation has clear implications for cancer management, but for other genes, such as ATM, the management implications are less clear. Women with an ATM mutation have a lifetime risk of breast cancer of approximately 25%, the majority of which are ER-positive. The risk of ovarian cancer is approximately 5%. It is not yet clear how the identification of an ATM mutation in a patient newly diagnosed with breast cancer should impact on her treatment and follow-up. At present, these women are treated in the same way as women without a mutation. It is important that large prospective studies be conducted looking at various treatment modalities in women with breast cancer and an ATM mutation in order to optimize outcomes.

Society of Surgical Oncology Breast Disease Site Working Group Statement on Bilateral Risk-Reducing Mastectomy: Indications, Outcomes, and Risks.

Bilateral risk-reducing mastectomy (BRRM) is the surgical removal of both breasts to reduce the risk of cancer. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, outcomes, and risks of BRRM to update the society's 2017 statement. We held a virtual meeting to outline key topics and conducted a literature search using PubMed to identify relevant articles. After literature review, recommendations were made according to group consensus. Individuals with a high lifetime risk of breast cancer due to pathogenic variants in high penetrance breast cancer-predisposition genes, early chest or breast radiation exposure, or a compelling family history should be counseled on the option of BRRM. However, BRRM is not recommended for most patients with high-risk lesions and may be contraindicated in patients who have other competing cancers and/or a high risk of surgical complications. BRRM effectively reduces the risk of breast cancer development, although the survival benefit is unclear. For patients with low-to-moderate breast cancer risk, alternative management strategies should be encouraged, including lifestyle modifications, high-risk screening, and risk-reducing medications. Discussions of BRRM should cover: (1) breast-cancer risk estimates; (2) the procedure's degree of risk reduction and impact on survival; (3) surgical techniques, potential surgical complications and long-term sequelae; and (4) alternatives to surgery. Surgeons should encourage shared and informed decision making with patients who have an elevated lifetime risk of developing breast cancer.

Clinical, histological and receptor profiles of invasive breast cancer and ductal carcinoma in situ in females with germline pathogenic variants in PTEN and implications for germline testing

PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant hereditary cancer syndrome, caused mostly by germline pathogenic variants in PTEN. Female carriers have an up to 80% lifetime risk of breast cancer. Pathologic features of breast cancer in PHTS have seldom been reported.In a collaboration between all histopathology laboratories in our state and our statewide familial cancer service, we tracked the breast biopsies of 12 females with known PTEN pathogenic or likely pathogenic variants (Jan 1990 to Jan 2018). Two further cases were added by a Victorian cancer genetics unit.Breast cancer, inclusive of invasive cancer or ductal carcinoma in situ (DCIS), was diagnosed in 12 of 14 cases (85.7%). One case had a family history of PHTS and six a family history of breast cancer. The mean age at first breast cancer diagnosis was 41.6 years (range 27-63). Six cases developed more than one breast cancer. Five (42%) developed contralateral breast cancer. Ten of the 12 invasive cancers were of no special type, two were reported as lobular carcinomas. None were grade 1. When reported, all cancers were hormone receptor positive and HER2 negative. All were associated with DCIS. The DCIS spanned all grades.The two cases without breast cancer still required surgery for exuberant benign changes, including papillomas, fibroadenomatoid change, florid ductal epithelial hyperplasia, adenosis and stromal fibrosis.We note that the morphology and receptor profiles of breast cancer in individuals with P/LP PTEN variants are not distinctive. Contrary to prevalent beliefs, these cancers do not conform to the contemporary definition of apocrine breast carcinoma. Greater familiarity of healthcare professionals with the overall clinical and pathologic findings in PHTS and the validated Cleveland Clinic PTEN calculator (http://www.lerner.ccf.org/gmi/ccscore) would improve the recognition of female PHTS individuals with breast cancer. Earlier identification of their cancer predisposition syndrome would benefit these patients and their families who are at high risk of a range of cancers.

Defining the Need for Services for Patients at High Risk of Breast Cancer at a Safety-Net Hospital: An Approach to Narrowing the Disparities Gap.

The National Accreditation Program for Breast Cancer (NAPBC) standards were recently revised to promote breast cancer (BC) risk assessment and subsequent referral for high-risk services. This project sought to estimate the proportion of patients at high risk for BC in the authors' safety-net hospital system, gauge patient interest in high-risk services, and define resources for program development. Women presenting for breast imaging during 2 weeks in 2023 were surveyed. Thirty-five patients with a history or diagnosis of BC were excluded. The Tyrer-Cuzick (TC) model version 8 was used to calculate BC risk. High/intermediate risk was defined as a 10-year risk of 5% or more, a lifetime risk of 15% or more, or both. The criteria for genetic counseling and testing referral were based on National Comprehensive Cancer Network guidelines. A total of 257 patients had a TC risk assessment showing 14.8% (n = 38) with a 10-year BC risk of 5% or more (consideration of endocrine therapy), 6.2% (n = 16) with a lifetime BC risk of 20% or more (qualifying for annual screening MRI), and 10.5% (n = 27) with a lifetime BC risk of 15% or more (consideration of high-risk screening). The criteria for genetic counseling/testing were met by 61 (23.7%) of the 257 patients. Overall, 31.5% (n = 81) qualified for high/intermediate-risk screening, risk reduction, and/or genetic assessment/testing, 92.8% of whom were interested in referrals for additional information and care. In the authors' community, almost one third of patients undergoing breast imaging qualify for BC high-risk assessment and services. The majority of the patients expressed interest in pursuing such services. These data will be used in financial planning and resource allocation to develop a high-risk program at the authors' institution in line with NAPBC guidelines. They are hopeful that these efforts will improve oncologic outcomes and survival from BC in their community.

Prevalence Estimation of the PALB2 Germline Variant in East Asians and Koreans through Population Database Analysis.

PALB2 is a tumor suppressor gene. Heterozygous germline pathogenic variants of PALB2 significantly increase the lifetime risk of breast cancer and moderately increase the risk of ovarian and pancreatic cancers. This study analyzed the estimated prevalence of PALB2 variants globally, focusing on East Asian and Korean populations, where limited data were previously available. We examined 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9197 East Asians, and additional data from 5305 individuals in the Korean Variant Archive and 1722 in the Korean Reference Genome Database. All PALB2 variants were interpreted according to guidelines from the American College of Medical Genetics and Genomics and the Clinical Genome Resource. The global prevalence of PALB2 variants was 0.18%, with the highest prevalence in Finnish populations (0.41%) and the lowest in Ashkenazi Jewish populations (0.04%). East Asians had a prevalence of 0.09%. By combining data from Korean genome databases and gnomAD totaling 8936 individuals, the overall prevalence of PALB2 variants in the Korean population was determined to be 0.13%. This study is the first comprehensive investigation of PALB2 variant prevalence in East Asians and Koreans using gnomAD and Korean genome databases. These findings provide essential reference data for future research and highlight the importance of region-specific genetic studies that will inform genetic counseling and hereditary cancer risk management.

Implementing the Risk Stratification and Clinical Management of Breast Cancer Families Using Polygenic Risk Score Evaluation: A Pilot Study.

The identification of women at high risk of breast cancer (BC) is crucial for personalized screening strategies. Pathogenic and likely pathogenic variants (PVs/LPVs) in susceptibility risk genes explain part of the individual risk. Moreover, a polygenic background, summarized as a polygenic risk score (PRS), contributes to the risk of BC and may modify the individual risk in carrier and non-carrier members of BC families. We performed a retrospective pilot study evaluating PRS in women from a subset of high- (BRCA1 and BRCA2) and moderate-risk (PALB2 and ATM) BC families. We included PVs/LPVs carriers and non-carriers and evaluated a PRS based on 577,113 BC-associated variants. Using BOADICEA, we calculated the adjusted lifetime BC risk. Our data showed that in BRCA1/BRCA2 carriers, PVs have a major role in stratifying the lifetime risk, while PRS improves risk estimation in non-carriers of these families. A different scenario may be observed in PALB2 and ATM families where PRS combined with PV/LPV carrier status gives a more informative lifetime risk. This study showed that in BC families, the PRS might help to quantify the weight of the genetic familial background, improving the individual risk stratification and contributing to personalized clinical management for carrier and non-carrier women.

Abstract C150: Evaluating breast cancer risk by race and ethnicity using the Tyrer Cuzick and Gail models in the Komen Tissue Bank cohort

Abstract Introduction: Breast cancer is the second leading cause of cancer death in women after lung cancer in the United States. While early detection is critical to reducing morbidity and mortality, predication of individualized risk is important in prevention and could also reduce unnecessary costs related to screening. The Susan G. Komen Tissue Bank (KTB) at Indiana University is the only tissue bank in the world that provides breast tissue specimens donated by healthy individuals to further to breast cancer research; however, as donors are volunteers, it is not clear how representative they are with respect to breast cancer risk compared to the general population. Methods: In this study, we calculated Breast Cancer Risk Assessment scores using Tyrer Cuzick (TCZ) and the Breast Cancer Risk Assessment Tool (The Gail Model, GM) in the KTB cohort by race and ethnicity. Recruited between 2007 and 2023, the participants completed a questionnaire encompassing their demographics, personal health and reproductive history, family history, and modifiable risk factors like smoking and alcohol use. In both models, participants with a lifetime risk of breast cancer of more than 15% were classified as having higher than average risk, while those with a risk of less than 15% were classified as having an average risk. Data analysis was performed using SAS v.9.4 software. Statistical significance was determined by p-values <0.05. Results: Out of 5118 participants, 206 with prior breast cancer and 37 male donors were excluded, resulting in a final sample of 4875 participants (aged 18–90) for analysis. The cohort was predominantly non-Hispanic white (NHW, 69.73%), followed by non-Hispanic black (NHB, 16.7%), Hispanic (8. 6%), and Asian individuals (3.3%), with 1.8% reporting multiracial or other race. The GM consistently categorized fewer women as having higher than average risk compared to the TZM. Across both TCZ and GM, the percentages of individuals classified as higher than average risk was greatest for NHW women, with 29.2% being categorized as higher than average risk in the TCZ, compared to 21.0% in the GM. The greatest discordance between the models was seen in NHB women, with the TCZ estimating 25.2% were at greater than average risk, and the GM only reporting 3.7% to be at greater than average risk. Overall, risk assessment scores varied across racial and ethnic groups (p- value<0.001). Factors driving these differences will be presented in additional analyses. Conclusion: There are known limitations in breast cancer risk assessment models by race and ethnicity that were confirmed in the women who comprise the KTB cohort. Donors to the KTB are generally representative of the US population with respect to breast cancer risk. As the KTB cohort continues to grow and mature, it can be utilized to assess breast cancer risk models for various racial and ethnic groups to assist in the identification of high-risk individuals that may benefit from prevention strategies and targeted screening. Citation Format: Vidya Patil, Michele L. Cote, Jenny Cui. Evaluating breast cancer risk by race and ethnicity using the Tyrer Cuzick and Gail models in the Komen Tissue Bank cohort [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C150.

Development of a Breast Cancer Risk Prediction Model Integrating Monogenic, Polygenic, and Epidemiologic Risk.

Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited. We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population. These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification. Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

Barriers and facilitators to breast cancer screening among high-risk women: a qualitative study.

Women with greater than 20-25% lifetime breast cancer risk are recommended to have breast cancer screening with annual mammogram and supplemental breast MRI. However, few women follow these screening recommendations. The objective of this study was to identify barriers and facilitators of screening among women at high risk for breast cancer, guided by the Health Services Utilization Model (HSUM). Unaffected high-risk women (N=63) completed semi-structured qualitative interviews exploring their experiences with breast cancer screening. Interviews were audio recorded, transcribed verbatim, and analyzed using a combined deductive and inductive approach. Most participants (84%) had received a screening mammogram; fewer (33%) had received a screening breast MRI. Only 14% had received neither screening. In line with the HSUM, qualitative analysis identified predisposing factors, enabling factors, and need factors associated with receipt of breast cancer screening. Enabling factors - including financial burden, logistic barriers, social support, and care coordination - were most frequently discussed. Predisposing factors included knowledge, health beliefs, and self-advocacy. Need factors included healthcare provider recommendation, family history of breast cancer, and personal medical history. Although HSUM themes were consistent for both mammography and breast MRI, participants did highlight several important differences in barriers and facilitators between the two screening modalities. Barriers and enabling factors associated with supplemental screening for high-risk women represent possible intervention targets. Future research is needed to develop and test multilevel interventions targeting these factors, with the ultimate goal of increasing access to supplemental screening for high-risk women.

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: &lt;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&lt;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 &lt;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 (&amp;lt; 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 ( &amp;gt;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

ObjectivesTo compare the quantitative background parenchymal enhancement (BPE) in women with different lifetime risks and BRCA mutation status of breast cancer using screening MRI.Materials and methodsThis 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.ResultsAge, 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).ConclusionQuantitative 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.Clinical relevance statementBRCA 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.Key PointsExpanding 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.