Breast cancer risk assessment continues to evolve as emerging knowledge of breast cancer risk drivers and modifiers enables better identification of high‐risk women who may benefit from increased screening or targeted risk‐reduction protocols. The ongoing development of breast cancer Risk Assessment and Management Programs (RAMPs) presents an opportunity to decrease breast cancer disease incidence with evidence‐based interventions. The goal of this review was to provide a practical guide for providers seeking to establish or update a breast cancer risk assessment and management program. We outline genetic/familial, personal, reproductive, and lifestyle‐related factors while discussing the incorporation of risk modeling for precise risk estimate personalization. We further describe the process for determining a risk management plan: information gathering, generation of a risk profile, and articulation and implementation of risk reduction. We also include an overview of clinical workflows in breast cancer management programs and underlines the logistics of establishing a program as well as general principles for guiding the formulation of an individualized risk management plan. We discuss practical considerations, such as clinic structure and operation, allocation of resources, and patient education. Other critical aspects of program design, including identification of the target population, delineation of the core components of the clinical experience, definition of provider roles, description of referral mechanisms, and the launching of a marketing plan are also addressed. The process of risk assessment is both anxiety‐provoking and empowering for women at increased risk. New knowledge has enabled strategies to both understand the risk and control it through evidence‐based risk management. These benefits can now be realized by an increasing number of unaffected, high‐risk patients collaborating with risk management practitioners. Continuation of these efforts will lead to further progress in both risk stratification and risk management of women at elevated breast cancer risk in the near future.

10602 Background: As the use of circulating tumor DNA (ctDNA) is more widely implemented, incidental identification of pathogenic variants reflecting germline alterations in cancer predisposition genes will occur more frequently. Such mutations are expected to have a high mutant allele frequency (MAF) or occur in genes typically associated with inherited syndromes. When a similar analysis was conducted by our group, we found that MAF of about 30% or greater in BRCA1/ 2 was associated with confirmed putative germline mutations in patients with breast cancer (Jacob et al & Davis et al, SABCS 2020). In this study, we extended this analysis to non-breast malignancies. Methods: Patients with non-breast solid malignancies and ctDNA testing between 2015-2020 were retrospectively identified from Northwestern Medicine. All ctDNA was analyzed using Guardant 360 (Guardant Health, Inc. Redwood City, Ca). Patients with ctDNA samples with mutations at high MAF (>30%) and those with BRCA1/2 mutations at any MAF were identified. We reviewed these charts for referral to genetic counselors and/or CLIA-approved germline testing. Descriptive analysis was reported for these findings. Genetic alterations were classified as pathogenic or of unknown significance based on OncoKB (Chakravarty et al, JCO PO 2017). Results: We identified ctDNA samples of 548 patients with non-breast solid malignancies, of whom 56 had gene mutations occurring at high MAF (>30%). Predominant cancer subtypes were lung (48%), colorectal (21%), pancreatic (7%), ovarian (3.5%), prostate (3.5%), and gastroesophageal (3.5%). The most common gene mutations identified were TP53 (46%), BRCA1/2 (18%), EGFR (18%), APC (13%), and KRAS (9%). 87.5% were pathogenic and 12.5% were of unknown significance. 11 patients (19.6%) had germline testing of whom 6 tested positive. These germline mutations were in BRCA2 (n = 3), EGFR, APC, and TP53. In addition to the 10 patients with BRCA1/2 mutations at high MAF (>30%), we identified 70 patients with BRCA1/2 mutations at low MAF ( < 30%). 54% were pathogenic and 46% were of unknown significance. 11 patients (14%) had germline testing of whom 3 tested positive for BRCA2, all at high MAF. 1 patient with a BRCA2 mutation at low MAF of 1.4% tested positive for a different germline BRCA2 variant. Conclusions: In patients with advanced cancers, ctDNA analysis can reveal variants with MAF >30% that are reflective of a germline mutation. Unfortunately the rate of genetic testing in these patients was low (20%). Future studies with germline testing in patients with high MAF variants would help understand the prevalence of germline variants. This can facilitate developing a more standardized approach for genetic counselor referral to identify families that may benefit from interventions for early detection or prevention of future cancers.

Background: Epidemiologic data have demonstrated an increased risk of breast cancer development following pregnancy which can last up to 10 years, particularly in women with older age at childbirth. The majority of women with parity associated breast cancer (PABC) undergo genetic testing based on their young age at onset, per current NCCN guidelines. Prior studies have evaluated the interaction of parity and germline BRCA1/2 mutation status, but these have not been extended to other pathogenic germline mutations in known breast cancer susceptibility genes (PALB2, TP53, PTEN, CDH1, CHEK2, ATM, and STK11). Our goal was to evaluate the prevalence of pathogenic germline mutations in a contemporary cohort of women less than 50 diagnosed with breast cancer in relation to their parity status and the time since their most recent pregnancy. Methods: The Northwestern Electronic Database Warehouse was queried for women diagnosed with a new breast cancer between 2010 - 2020 at the age of less than 50 and underwent genetic testing with results available. Patient demographic data, parity history, and genetic testing results were obtained from the structured electronic health records data as well as from semi-structured clinical notes using rule-based text mining methods. 929 women were identified with complete information on parity status, age at first birth, age at most recent birth, breastfeeding status, and germline mutation status. Statistical analyses included Pearson’s chi-square and logistic regression with adjustment for age at diagnosis. Results: 85 women (9.1%) had a germline genetic mutation, with the most prevalent mutations being BRCA1 (3.9%), BRCA2 (2.5%), CHEK2 (0.8%), PALB2 (0.6%) and ATM (0.5%). 90 women (9.7%) had a variant of uncertain significance (VUS) and were included in the no mutation group for analysis. There was no statistically significant difference between nulliparous and parous women in regard to likelihood of having a pathogenic germline genetic mutation (age-adjusted OR 0.85, CI 0.53 -1.29). Among parous women stratified by recency of pregnancy (&lt;5 years, 5-10 years, and &gt;10 years), there was an increased likelihood of having a germline genetic mutation with recency of pregnancy &lt; 5 years (age adjusted OR 2.2, CI 1.07-3.75) compared to women with &gt; 10 years since last pregnancy. Evaluation of each separate germline mutation demonstrated mixed results with CHEK2 mutations more likely with more recent pregnancy (age adjusted OR 3.58, CI 1.13 - 7.57), while PALB2 mutations were less likely with more recent pregnancy (age adjusted OR 0.72, CI 0.52-0.85). The remainder of the mutations were not statistically significantly different among nulliparous vs parous women or when stratified by recency of pregnancy. Conclusions: Nulliparous women with a new diagnosis of breast cancer under the age of 50 were equally as likely to have a germline genetic mutation compared to parous women. After adjusting for age, recency of pregnancy within 5 years of breast cancer diagnosis was associated with increased likelihood of having a germline genetic mutation. The influence of family history of cancer will be addressed in additional analyses. Our data suggest that these mutations may confer an increased risk of parity-associated breast cancer, but need confirmation in larger studies. Citation Format: Erica Wrubel, Saya Rene Dennis, Takahiro Tsukioki, Theresa Sciaraffa, Yuan Luo, Seema A Khan. Frequency of germline mutations in breast cancer susceptibility genes among women under age 50 presenting with parity associated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-15.