Risk For Hereditary Breast Cancer Research Articles

196 (PB184): The direct evaluation of homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and the sensitivity to PARP inhibitor

196 (PB184): The direct evaluation of homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and the sensitivity to PARP inhibitor

Screening Familial Risk for Hereditary Breast and Ovarian Cancer.

Most patients with pathogenic or likely pathogenic (P/LP) variants for breast cancer have not undergone genetic testing. To identify patients meeting family history criteria for genetic testing in the electronic health record (EHR). This study included both cross-sectional (observation date, February 1, 2024) and retrospective cohort (observation period, January 1, 2018, to February 1, 2024) analyses. Participants included patients aged 18 to 79 years enrolled in Renown Health, a large health system in Northern Nevada. Genotype was known for 38 003 patients enrolled in Healthy Nevada Project (HNP), a population genomics study. An EHR indicating that a patient is positive for criteria according to the Seven-Question Family History Questionnaire (hereafter, FHS7 positive) assessing familial risk for hereditary breast and ovarian cancer (HBOC). The primary outcomes were the presence of P/LP variants in the ATM, BRCA1, BRCA2, CHEK2, or PALB2 genes (cross-sectional analysis) or a diagnosis of cancer (cohort analysis). Age-adjusted cancer incidence rates per 100 000 patients per year were calculated using the 2020 US population as the standard. Hazard ratios (HRs) for cancer attributable to FHS7-positive status were estimated using cause-specific hazard models. Among 835 727 patients, 423 393 (50.7%) were female and 29 913 (3.6%) were FHS7 positive. Among those who were FHS7 positive, 24 535 (82.0%) had no evidence of prior genetic testing for HBOC in their EHR. Being FHS7 positive was associated with increased prevalence of P/LP variants in BRCA1/BRCA2 (odds ratio [OR], 3.34; 95% CI, 2.48-4.47), CHEK2 (OR, 1.62; 95% CI, 1.05-2.43), and PALB2 (OR, 2.84; 95% CI, 1.23-6.16) among HNP female individuals, and in BRCA1/BRCA2 (OR, 3.35; 95% CI, 1.93-5.56) among HNP male individuals. Being FHS7 positive was also associated with significantly increased risk of cancer among 131 622 non-HNP female individuals (HR, 1.44; 95% CI, 1.22-1.70) but not among 114 982 non-HNP male individuals (HR, 1.11; 95% CI, 0.87-1.42). Among 1527 HNP survey respondents, 352 of 383 EHR-FHS7 positive patients (91.9%) were survey-FHS7 positive, but only 352 of 883 survey-FHS7 positive patients (39.9%) were EHR-FHS7 positive. Of the 29 913 FHS7-positive patients, 19 764 (66.1%) were identified only after parsing free-text family history comments. Socioeconomic differences were also observed between EHR-FHS7-negative and EHR-FHS7-positive patients, suggesting disparities in recording family history. In this cross-sectional study, EHR-derived FHS7 identified thousands of patients with familial risk for breast cancer, indicating a substantial gap in genetic testing. However, limitations in EHR family history data suggested that other identification methods, such as direct-to-patient questionnaires, are required to fully address this gap.

IKNOW—Supporting the counseling of women with hereditary risk of breast and ovarian cancer with digital technologies: A randomized controlled trial

PurposeWe developed the online-based counseling tool iKNOW for women with a pathogenic germline variant in BRCA1/2 to improve risk understanding and quality of life. MethodsWith a randomized controlled trial, we investigated the efficacy of iKNOW with regard to risk understanding (primary endpoint), quality of life, risk perception, and anxiety (secondary endpoints). Self-report questionnaires were administered to N = 217 women with a pathogenic variant in BRCA1/2 before counseling (T0), immediately after (T1), 4 weeks after (T2), and 6 months after (T3). ResultDeviations between self-assessed and calculated cancer risks tended to be smaller in the intervention group than in the control group but no longer significantly after adjustment for multiple testing. In the intervention group, the proportion of women with a correct understanding of breast cancer risk at T3 was higher (30.7% vs 14.7%; P = .032). There were no differences in secondary endpoints. ConclusioniKNOW tends to positively influence the understanding of familial cancer risk. At the same time, it does not negatively influence any of the secondary endpoints. However, converging evidence suggests that iKNOW seems to affect the quality of counseling processes and can thus be used as a paradigm for reinventing the notion of efficient, digital care.

Polygenic Risk Score (PRS) Combined with NGS Panel Testing Increases Accuracy in Hereditary Breast Cancer Risk Estimation.

Breast cancer (BC) is the most prominent tumor type among women, accounting for 32% of newly diagnosed cancer cases. BC risk factors include inherited germline pathogenic gene variants and family history of disease. However, the etiology of the disease remains occult in most cases. Therefore, in the absence of high-risk factors, a polygenic basis has been suggested to contribute to susceptibility. This information is utilized to calculate the Polygenic Risk Score (PRS) which is indicative of BC risk. This study aimed to evaluate retrospectively the clinical usefulness of PRS integration in BC risk calculation, utilizing a group of patients who have already been diagnosed with BC. The study comprised 105 breast cancer patients with hereditary genetic analysis results obtained by NGS. The selection included all testing results: high-risk gene-positive, intermediate/low-risk gene-positive, and negative. PRS results were obtained from an external laboratory (Allelica). PRS-based BC risk was computed both with and without considering additional risk factors, including gene status and family history. A significantly different PRS percentile distribution consistent with higher BC risk was observed in our cohort compared to the general population. Higher PRS-based BC risks were detected in younger patients and in those with FH of cancers. Among patients with a pathogenic germline variant detected, reduced PRS values were observed, while the BC risk was mainly determined by a monogenic etiology. Upon comprehensive analysis encompassing FH, gene status, and PRS, it was determined that 41.90% (44/105) of the patients demonstrated an elevated susceptibility for BC. Moreover, 63.63% of the patients with FH of BC and without an inherited pathogenic genetic variant detected showed increased BC risk by incorporating the PRS result. Our results indicate a major utility of PRS calculation in women with FH in the absence of a monogenic etiology detected by NGS. By combining high-risk strategies, such as inherited disease analysis, with low-risk screening strategies, such as FH and PRS, breast cancer risk stratification can be improved. This would facilitate the development of more effective preventive measures and optimize the allocation of healthcare resources.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.

Abstract PO5-08-01: Investigating the Link between APC I1307K Mutation and Breast Cancer in Arab Population

Abstract Background: Identifying asymptomatic individuals with an increased risk of hereditary breast cancer may significantly enhance early detection and prevention strategies and may inform treatment decision of patients who carry such variants. The APC I1307K missense mutation is known to be unrelated to conditions such as familial adenomatous polyposis (FAP), attenuated FAP, or gastric adenocarcinoma. However, individuals of Ashkenazi Jewish ancestry who carry this variant, have increase risk of colon cancer compared to the general population. The association of this variant with other cancer types, such as breast cancer, and in individuals of other ancestries, like Arabs, remains unknown. In this study, we investigate the potential association between APC gene (I1307K variant) and breast cancer risk. Method: Over a course of 18 months, all newly diagnosed patients with solid tumors were offered to participate in a universal germline genetic screening study, utilizing a standard 21-gene or an investigational 84-gene panel testing. A retrospective analysis was conducted on the 153 patients within the study group who carry the APCI1307K missense variant irrespective of cancer type. Patients were classified as meeting the criteria or not meeting the criteria of the National Comprehensive Cancer Network (NCCN) v.1.2020. Data were extracted from electronic medical records and our institutional cancer registry. Descriptive statistics test was employed. Results: Among the screened cancer patients (n=3400), 153 (4.5%) were tested positive for the APC I1307K missense mutation are included in this analysis. Median age at cancer diagnosis was 52 (range,19-80) years, and 99 (64.7%) were female. Breast cancer was the most common primary tumor (n=67, 43.8%) followed by colorectal (n=38, 24.8%), lung (n=7, 4.6%) and pancreatic cancer (n=6,3.9%). Among the 67 breast cancer patients included, 16 (23.9%) were not eligible for genetic testing as per the NCCN guidelines, and were tested as part of the universal genetic testing study. Among the patients with breast cancer, 53 (79.1%) had screening colonoscopy and 9 (17.0%) were found to have polyps (range, 1-3); 8 (88.9%) were low-grade dysplasia, while the other 44 (83.0%) had completely normal colonoscopy. On the other hand, among the 38 patients with colorectal cancer, 21 (55.3%) had tumors presenting as polyps, or exhibited concomitant polyps (range, 1-3), or displayed abnormalities in the background that were polypoid in nature. Notably, 24 (63.2%) of patients with colorectal cancer, have a family history of breast cancer. Conclusions: APC I1307K variant is unexpectedly common among our cohort of Arab patients. Individuals who carry this variant may face an elevated risk of developing breast cancer; potentially contributing to hereditary and familial cases, and such patients are at higher risk for colorectal cancer, too. Citation Format: Baha' Sharaf, Hira Bani Hani, Anas Zayed, Maha Barbar, Ahmad Hushki, Rashid Abdel-Razeq, Mohammad Titi, Reem Al-Halalsheh, Suleiman Mahafdah, Hikmat Abdel-Razeq. Investigating the Link between APC I1307K Mutation and Breast Cancer in Arab Population [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 PO5-08-01.

Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health

BackgroundAdmixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage.MethodsBy comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations.ResultsThe Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese (https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/) and an open database named dbBRCA-Brazilian (https://genemutation.fhs.um.edu.mo/dbbrca-brazilian) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African.ConclusionOur study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.

Evaluating homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and olaparib sensitivity.

Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents. Previously, we developed an assay for site-specific HR activity (ASHRA) that can quantitatively evaluate HR activity and detect moderate HR deficiency. HR activity in cells measured by ASHRA correlates with sensitivity to the PARP inhibitor, olaparib. In this study, we applied ASHRA to lymphoblastoid cells and xenograft tumor tissues, which simulate peripheral blood lymphocytes and tumor tissues, respectively, as clinically available samples. We showed that ASHRA could be used to detect HR deficiency in lymphoblastoid cells derived from a BRCA1 pathogenic variant carrier. Furthermore, ASHRA could quantitatively measure the HR activity in xenograft tumor tissues with HR activity that was gradually suppressed by inducible BRCA1 knockdown. The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

Young Women's Perspectives on Being Screened for Hereditary Breast and Ovarian Cancer Risk During Routine Primary Care

PurposeThe U.S. Preventive Services Task Force recommends screening women to identify individuals eligible for genetic counseling based on a priori hereditary breast and ovarian cancer syndrome (HBOC) risk (i.e., risk assessment). However, risk assessment has not been widely integrated into primary care. This qualitative study explored young women's views on implementing routine HBOC risk assessment with a focus on equity and patient-centeredness. MethodsWe conducted group discussions with young women (aged 21–40 years) receiving care in an integrated health care system. Discussion groups occurred in two phases and used a modified deliberative approach that included a didactic component and prioritized developing consensus. Twenty women participated in one of three initial small group discussions (phase one). All 20 were invited to participate in a subsequent large group discussion (phase two), and 15 of them attended. FindingsKey themes and recommendations were as follows. Risk assessment should be accessible, contextualized, and destigmatized to encourage participation and reduce anxiety, particularly for women who do not know their family history. Providers conducting risk assessments must be equipped to address women's informational needs, relieve emotionality, and plan next steps after positive screens. Finally, to minimize differential screening uptake, health care systems must prioritize equity in program design and contribute to external educational and outreach efforts. ConclusionYoung women see pragmatic opportunities for health systems to optimize HBOC screening implementation.

Perceptions of surveillance with magnetic resonance imaging among women with a hereditary risk of breast cancer-A phenomenographic study.

To explore perceptions of annual surveillance with magnetic resonance imaging and perceptions of care during the examination among women with a hereditary risk of breast cancer. Phenomenography. Fourteen face-to-face interviews using a semi-structured interview guide were conducted among women undergoing surveillance in the southern region of Sweden. A seven-step phenomenographic analysis with investigator triangulation was performed. 'Considering own risk of developing breast cancer', 'Entrusting oneself to surveillance' and 'Living in a cycle' represented descriptive categories of perceptions. Family narratives introduced comprehension of own risk of breast cancer, followed by appraisal of own benefits of participating in surveillance. Entrusting oneself to surveillance included handing over management of diagnostic examinations and dealing with practical issues and diverse emotions related to surveillance. Planning life based around surveillance, struggling with fluctuating emotions, also between the examinations and questioning own identity implied the perception of living in a cycle. Surveillance for hereditary breast cancer implies living in a cycle of dealing with fluctuating emotions and planning life based around surveillance. Comprehension of one's own risk for breast cancer arises from awareness in the family. Women value the surveillance programme and trust the healthcare system. Knowledge of women's perceptions of the surveillance programme and care is vital for supporting women in their decision-making on attendance and providing person-centred care during surveillance. A gap in explorative studies from the perspective of the individual woman in the context of surveillance for breast cancer and care in magnetic resonance imaging in surveillance was addressed. 'Considering own risk of developing breast cancer', 'Entrusting oneself to surveillance' and 'Living in a cycle' represented women's perceptions of surveillance and care. The study results have implications for person-centred care among women in the surveillance programme. No patient or public contribution.

Increased risk of contralateral breast cancer for BRCA1/2 wild-type, high-risk Korean breast cancer patients: a retrospective cohort study

BackgroundThis study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients.MethodsWe conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service’s eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCAmutation group, the BRCAxgroup, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients.ResultsAmong 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11–13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76–4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted.ConclusionBreast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.

Harnessing BRCA Advances: Revolutionizing Breast Cancer Diagnosis and Treatment

Advancements in understanding BRCA gene mutations have reshaped breast cancer management, ushering in a new era of precision oncology. This review explores the transformative impact of BRCA research on breast cancer diagnosis and treatment strategies, emphasizing the pivotal role of genetic testing, targeted therapies, and personalized medicine approaches. Harnessing BRCA advances offers unprecedented opportunities for early detection, risk stratification, and tailored treatment modalities, fundamentally altering the landscape of breast cancer care. Central to harnessing BRCA advances is the widespread adoption of genetic testing for BRCA mutations, enabling the identification of individuals at heightened risk of hereditary breast cancer. Genetic testing informs risk stratification and facilitates personalized screening and preventive interventions, including risk-reducing surgeries and enhanced surveillance protocols. Moreover, genetic testing guide’s treatment decisionmaking by identifying candidates for targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors, which have demonstrated efficacy in BRCA-mutated breast cancers, offering new avenues for precision medicine in oncology. The integration of targeted therapies tailored to BRCA-related breast cancer subtypes represents a paradigm shift in treatment approaches, providing novel strategies to optimize patient outcomes. PARP inhibitors have emerged as a promising therapeutic option for BRCA-mutated breast cancers, leading to improved progression-free survival and overall survival in metastatic settings. On-going research endeavours aim to elucidate molecular mechanisms of treatment response and resistance, paving the way for the development of innovative therapeutic strategies to address unmet clinical needs and further enhance the efficacy of precision oncology in breast cancer management.

Use of a multi-phased approach to identify and address facilitators and barriers to the implementation of a population-wide genomic screening program

IntroductionPopulation-wide genomic screening for CDC Tier-1 conditions offers the ability to identify the 1–2% of the US population at increased risk for Hereditary Breast and Ovarian Cancer, Lynch Syndrome, and Familial Hypercholesterolemia. Implementation of population-wide screening programs is highly complex, requiring engagement of diverse collaborators and implementation teams. Implementation science offers tools to promote integration of these programs through the identification of determinants of success and strategies to address potential barriers.MethodsPrior to launching the program, we conducted a pre-implementation survey to assess anticipated barriers and facilitators to reach, effectiveness, adoption, implementation, and maintenance (RE-AIM), among 51 work group members (phase 1). During the first year of program implementation, we completed coding of 40 work group meetings guided by the Consolidated Framework for Implementation Research (CFIR) (phase 2). We matched the top barriers to implementation strategies identified during phase 2 using the CFIR-ERIC (Expert Recommendation for Implementing Change) matching tool.ResultsStaffing and workload concerns were listed as the top barrier in the pre-implementation phase of the program. Top barriers during implementation included adaptability (n = 8, 20%), complexity (n = 14, 35%), patient needs and resources (n = 9, 22.5%), compatibility (n = 11, 27.5%), and self-efficacy (n = 9, 22.5%). We identified 16 potential implementation strategies across six ERIC clusters to address these barriers and operationalized these strategies for our specific setting and program needs.ConclusionOur findings provide an example of successful use of the CFIR-ERIC tool to guide implementation of a population-wide genomic screening program.

Artificial intelligence-supported screen reading versus standard double reading in the Mammography Screening with Artificial Intelligence trial (MASAI): a clinical safety analysis of a randomised, controlled, non-inferiority, single-blinded, screening accuracy study

Retrospective studies have shown promising results using artificial intelligence (AI) to improve mammography screening accuracy and reduce screen-reading workload; however, to our knowledge, a randomised trial has not yet been conducted. We aimed to assess the clinical safety of an AI-supported screen-reading protocol compared with standard screen reading by radiologists following mammography. In this randomised, controlled, population-based trial, women aged 40-80 years eligible for mammography screening (including general screening with 1·5-2-year intervals and annual screening for those with moderate hereditary risk of breast cancer or a history of breast cancer) at four screening sites in Sweden were informed about the study as part of the screening invitation. Those who did not opt out were randomly allocated (1:1) to AI-supported screening (intervention group) or standard double reading without AI (control group). Screening examinations were automatically randomised by the Picture Archive and Communications System with a pseudo-random number generator after image acquisition. The participants and the radiographers acquiring the screening examinations, but not the radiologists reading the screening examinations, were masked to study group allocation. The AI system (Transpara version 1.7.0) provided an examination-based malignancy risk score on a 10-level scale that was used to triage screening examinations to single reading (score 1-9) or double reading (score 10), with AI risk scores (for all examinations) and computer-aided detection marks (for examinations with risk score 8-10) available to the radiologists doing the screen reading. Here we report the prespecified clinical safety analysis, to be done after 80 000 women were enrolled, to assess the secondary outcome measures of early screening performance (cancer detection rate, recall rate, false positive rate, positive predictive value [PPV] of recall, and type of cancer detected [invasive or in situ]) and screen-reading workload. Analyses were done in the modified intention-to-treat population (ie, all women randomly assigned to a group with one complete screening examination, excluding women recalled due to enlarged lymph nodes diagnosed with lymphoma). The lowest acceptable limit for safety in the intervention group was a cancer detection rate of more than 3 per 1000 participants screened. The trial is registered with ClinicalTrials.gov, NCT04838756, and is closed to accrual; follow-up is ongoing to assess the primary endpoint of the trial, interval cancer rate. Between April 12, 2021, and July 28, 2022, 80 033 women were randomly assigned to AI-supported screening (n=40 003) or double reading without AI (n=40 030). 13 women were excluded from the analysis. The median age was 54·0 years (IQR 46·7-63·9). Race and ethnicity data were not collected. AI-supported screening among 39 996 participants resulted in 244 screen-detected cancers, 861 recalls, and a total of 46 345 screen readings. Standard screening among 40 024 participants resulted in 203 screen-detected cancers, 817 recalls, and a total of 83 231 screen readings. Cancer detection rates were 6·1 (95% CI 5·4-6·9) per 1000 screened participants in the intervention group, above the lowest acceptable limit for safety, and 5·1 (4·4-5·8) per 1000 in the control group-a ratio of 1·2 (95% CI 1·0-1·5; p=0·052). Recall rates were 2·2% (95% CI 2·0-2·3) in the intervention group and 2·0% (1·9-2·2) in the control group. The false positive rate was 1·5% (95% CI 1·4-1·7) in both groups. The PPV of recall was 28·3% (95% CI 25·3-31·5) in the intervention group and 24·8% (21·9-28·0) in the control group. In the intervention group, 184 (75%) of 244 cancers detected were invasive and 60 (25%) were in situ; in the control group, 165 (81%) of 203 cancers were invasive and 38 (19%) were in situ. The screen-reading workload was reduced by 44·3% using AI. AI-supported mammography screening resulted in a similar cancer detection rate compared with standard double reading, with a substantially lower screen-reading workload, indicating that the use of AI in mammography screening is safe. The trial was thus not halted and the primary endpoint of interval cancer rate will be assessed in 100 000 enrolled participants after 2-years of follow up. Swedish Cancer Society, Confederation of Regional Cancer Centres, and the Swedish governmental funding for clinical research (ALF).

Prevalence of germline mutations in women with breast and/or ovarian cancer in a tertiary care center in Pune, India

In India, the incidence of breast cancer accounted for 1,78,361 cases, whereas ovarian cancer accounts for 45,701 cases, according to Globocan Report 2020. These cancers are known to have a hereditary basis, and &gt;10% of them are associated with pathogenic BRCA1 and BRCA2 mutations. The prevalence of BRCA1 and BRCA2 varies across various Indian studies and is reported to be 2.9–28%. However, gene mutations other than BRCA1 and BRCA2 which are shown to increase the risk of hereditary breast and ovarian cancer (HBOC) are underreported. Objectives: The objective of this study was to estimate the prevalence of deleterious germline mutations among women with breast and/or ovarian cancer. Material and Methods: A cross-sectional study was conducted in the department of oncology at a super specialty hospital. Patients were enrolled based on the current National Comprehensive Cancer Network guidelines for genetic risk and evaluation of HBOC. Demographic and clinical information was extracted from the electronic medical records of the hospitals from 2018 to 2021. Next-generation sequencing (NGS) was performed on the extracted DNA using a custom capture kit and classified based on the American College of Medical Genetics. Results: A total of 94 patients suspected of having HBOC were examined for deleterious germline mutations. The median age of the patient was 46 years (range: 38–57 years). Breast and ovarian cancer patients constituted 64.9% and 35.1%, respectively. The overall mutation detection rate was 25.5%. The positive mutation detection rate was 26.2% and 24.2% in breast and ovarian cancer, respectively, whereas the variant of uncertain significance rate was 18.03% and 24.2%, respectively. Among the pathogenic mutations, BRCA1 was the most common mutation in women with breast cancer (81.3%). In ovarian cancer, it was 50%. BRCA2 mutation was more prevalent in ovarian cancer (50%). Conclusion: Our study reports a higher prevalence of germline BRCA1 and BRCA2 mutations in breast and ovarian cancer as compared to other studies. Genetic testing can be offered to high-risk women regardless of family history. This will be useful during diagnosis and help physicians in planning subsequent treatment.

ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways—lessons from breast cancer patients

It has been well-established that mutations in BRCA1 and BRCA2, compromising functions in DNA double-strand break repair (DSBR), confer hereditary breast and ovarian cancer risk. Importantly, mutations in these genes explain only a minor fraction of the hereditary risk and of the subset of DSBR deficient tumors. Our screening efforts identified two truncating germline mutations in the gene encoding the BRCA1 complex partner ABRAXAS1 in German early-onset breast cancer patients. To unravel the molecular mechanisms triggering carcinogenesis in these carriers of heterozygous mutations, we examined DSBR functions in patient-derived lymphoblastoid cells (LCLs) and in genetically manipulated mammary epithelial cells. By use of these strategies we were able to demonstrate that these truncating ABRAXAS1 mutations exerted dominant effects on BRCA1 functions. Interestingly, we did not observe haploinsufficiency regarding homologous recombination (HR) proficiency (reporter assay, RAD51-foci, PARP-inhibitor sensitivity) in mutation carriers. However, the balance was shifted to use of mutagenic DSBR-pathways. The dominant effect of truncated ABRAXAS1 devoid of the C-terminal BRCA1 binding site can be explained by retention of the N-terminal interaction sites for other BRCA1-A complex partners like RAP80. In this case BRCA1 was channeled from the BRCA1-A to the BRCA1-C complex, which induced single-strand annealing (SSA). Further truncation, additionally deleting the coiled-coil region of ABRAXAS1, unleashed excessive DNA damage responses (DDRs) de-repressing multiple DSBR-pathways including SSA and non-homologous end-joining (NHEJ). Our data reveal de-repression of low-fidelity repair activities as a common feature of cells from patients with heterozygous mutations in genes encoding BRCA1 and its complex partners.

Advancing health equity: A qualitative study assessing barriers and facilitators of implementing hereditary breast and ovarian cancer risk screening tools in community-based organizations.

Genetic counseling and testing (GCT) inform cancer management for persons at risk for hereditary breast and ovarian cancer (HBOC). Community-based organizations (CBOs) may play a role in identifying at-risk Latinx individuals to connect them to GCT but data are lacking. Two academic centers and their four CBO partners planned to implement a validated questionnaire for HBOC risk screening ("HBOC risk screening tool"). This study aimed to assess CBO's preferences for HBOC risk screening tools, as well as the barriers and facilitators anticipated for future implementation. Pre-implementation focus groups were conducted with CBO's staff. Discussions centered on current practices to identify and refer at-risk patients. During the discussion, staff were asked to select one out of five validated HBOC risk screening tools to implement and to discuss anticipated barriers/facilitators for implementation. The four focus groups were coded and qualitative analyzed following the Consolidated Framework for Implementation Research (CFIR) and Health Equity domains. All CBOs chose the Family History Screen 7 (FHS-7). Participants (N = 35) highlighted how the FHS-7 was easy to adapt to better fit the target population and changing guidelines. They had positive attitudes toward implementing the screening tool, stressed how the culture of the organization positioned them to reach the target population, and noted barriers in different CFIR domains (e.g., low knowledge about HBOC and GCT referrals; scarce available resources). Participants pointed to barriers related to health equity domains including limited access to GCT and follow-up care for uninsured and underinsured populations, challenges obtaining accurate family history, and immigration-related barriers. CBOs highlighted the importance of partnering with other stakeholders to overcome barriers. Findings emphasize the need to develop multi-level implementation strategies to overcome barriers and leverage facilitators. This study can inform the development of implementation toolkits for CBOs to implement HBOC screening tools to advance health equity.

SA 4.1 Imaging, screening & surveillance for individuals with increased hereditary breast cancer risk

SA 4.1 Imaging, screening & surveillance for individuals with increased hereditary breast cancer risk

Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.

Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.

Abstract P6-02-03: Breast Health Assessment: A family health history tool using the electronic health record and clinical decision support to facilitate guidelines-driven hereditary breast cancer genetic testing at the time of screening mammogram

Abstract Background: Genetic testing (GT) is recommended for women who have a personal or family history of breast cancer and are at increased risk of carrying an inherited breast cancer risk gene pathogenic variant (PV) as defined by the National Comprehensive Cancer Network (NCCN) guidelines. Data shows that traditional GT workflows do not reach a large proportion of women eligible for GT. NorthShore University HealthSystem previously implemented the Genetic Wellness Assessment, a family health history (FHH) screening tool utilizing the electronic health record (EHR) and clinical decision support, to identify individual and familial risks to health conditions and personalize screening and prevention practices in primary care. To increase access to hereditary breast cancer GT, we implemented a similar FHH screening tool called the Breast Health Assessment (BHA) for patients completing routine screening mammogram. We describe uptake and results from implementation of the BHA in conjunction with routine screening mammogram. Methods: Patients scheduled for screening mammogram were assigned the BHA prior to their mammogram via the EHR portal. BHA questions addressed personal and family history of breast cancer and other cancer types associated with hereditary breast cancer syndromes. Upon completion of the BHA, patients who screened positive, i.e. identified as having a high-risk personal or family cancer history based on NCCN guidelines, were offered a comprehensive hereditary cancer panel (HCP). HCP included 38 genes associated with common cancer types, including all high and moderate risk breast cancer genes for which there are NCCN management guidelines. Individuals who were not identified as high-risk were offered a genetic health screen, which consisted of 148 genes associated with common cancer types, genetic forms of heart disease, medication response, and other health conditions. Saliva sample collection for GT occurred at the time of the patient’s screening mammogram appointment. Results: From August 2021 through May 2022, 32,438 patients were assigned the BHA prior to screening mammogram. Of these patients, 14,128/32,438 (44%) completed the BHA questionnaire. Based on BHA reponse, 3,490/14,128 (25%) screened positive and met NCCN criteria for GT for hereditary breast cancer risk genes and 529/3,490 (15%) completed GT. Additionally, 713/10,638 (7%) patients who screened negative on the BHA completed testing. In total, 1,242/14,128 patients (9%) completed GT and 78/1,242 (6%) were found to carry an inherited PV in a cancer risk gene, 35 of which were in an NCCN guidelines breast cancer risk gene. Of the 78 patients with a positive GT result, 57/78 (73%) had not been previously recommended for a genetics evaluation and/or received a genetics referral. Conclusion: The BHA is a novel FHH tool which increases access to hereditary breast cancer GT at the time of screening mammogram. Nearly half of women who completed screening mammogram completed the BHA and learned valuable information about their breast cancer risk and were invited to complete GT. Genetic testing completed through the BHA identified 78 patients with an actionable inherited PV in a cancer risk gene. This invaluable information will lead to potentially lifesaving personalized cancer screening and risk reduction and help identify additional at risk family members. Notably, 73% of patients who carried an inherited PV had not been previously recommended by their medical teams for genetic counseling and/or testing. The BHA has the potential to help close the care gap in GT for women at increased risk of breast cancer. Citation Format: Allison DePersia, Sarah Choi, Katharine Yao, Henry Dunnenberger, Peter Hulick. Breast Health Assessment: A family health history tool using the electronic health record and clinical decision support to facilitate guidelines-driven hereditary breast cancer genetic testing at the time of screening mammogram [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-03.