Frequency of bilateral prophylactic and contra-lateral risk-reducing mastectomies in women with germline PALB2 variants.

Postmastectomy breast reconstruction (PMBR) improves patients' quality of life, but patients often lack reliable, individualized information about complication risk. Machine learning (ML) can analyze complex clinical data to generate personalized risk estimates, facilitating shared decision-making. To develop and validate ML models trained on both structured data and manually abstracted variables from unstructured clinical notes to predict major complications after PMBR. This prognostic study used retrospective data from female patients aged 18 years or older who underwent unilateral or bilateral therapeutic mastectomy with immediate or delayed implant-based or autologous reconstruction at 2 academic centers in the US from 2012 to 2022. Demographic, treatment, and surgical variables were extracted from electronic health records with a 1-year postoperative follow-up period. Extreme gradient boosting (XGBoost) and random forest models were trained on 80% of the cohort (329 individuals) and tested on 20% of the cohort (82 individuals). Patients with bilateral prophylactic mastectomy, distant metastases, mixed autologous and implant-based reconstruction, or less than 12 months of follow-up were excluded. Of more than 4000 eligible patients, a random sample of 411 underwent manual health record review for variable abstraction. Data were analyzed from September through November 2024. PMBR. Outcomes of interest were major complications, defined as unplanned reoperations or rehospitalizations within 1 year of reconstruction. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). The sample included 411 female patients (667 breasts) receiving implant-based (290 individuals [70.6%]) or autologous (121 individuals [29.4%]) PMBR, with a median (IQR) age of 51.3 (44.0-58.3) years. The overall major complication rate was 25.8% (106 individuals). The XGBoost model outperformed the random forest model, achieving an AUROC of 0.83 (95% CI, 0.72-0.94) and an AUPRC of 0.62 (95% CI, 0.55-0.69; baseline: 0.26) on the test set, compared with 0.74 (95% CI, 0.66-0.82) and 0.56 (95% CI, 0.50-0.62), respectively, for the random forest model. Top predictors of major complications included smoking, adjuvant radiotherapy, body mass index, age, and diabetes. Model performance remained consistent across reconstructive modalities. In this prognostic study of PMBR outcomes, an internally validated ML model trained on both structured and unstructured clinical data was used to predict 1-year major complications. Such models support personalized risk assessment, inform decision-making, and provide a foundation for future externally validated and prospectively tested decision-support tools.

As the data on BRCA1/2-associated breast and ovarian cancer prevalence after prophylactic surgery has not been exhaustively investigated yet, we aimed to evaluate the cancer prevalence in a single center cohort of BRCA1 and BRCA2 carriers after conducting prophylactic mastectomy, as well as prophylactic bilateral salpingo-oophorectomy (PBSO) respectively. We included 875 women that were tested positive for a germline variant in the BRCA1/BRCA2 gene (gPV) between 2002 and 2022 at the Center of Hereditary Breast and Ovarian Cancer of the Technical University Munich Germany. Mean follow up was 7.2 years (range 0-44 years; 95% CI: 6.70 to 7.70). We differentiated breast and/or ovarian cancer diseased (n = 643) and non-diseased BRCA1/2 carriers (n = 232). Our analysis confirmed the effectiveness of prophylactic surgeries in genetically predisposed women with a gPV in the BRCA1/2 gene. We observed no breast cancer after prophylactic bilateral mastectomy, 2 contralateral breast cancer diseases after contralateral prophylactic mastectomy and 1 extraovarian serous adenocarcinoma after PBSO. Within the entire study collective, a total of 293 have undergone PBSO, with 6 women having an incidental finding of ovarian cancer and STIC respectively (=2.0%; 1.7% gBRCA1 and 0.3% gBRCA2). Our data suggests that, particularly regarding ipsilateral secondary cancer (ISC), higher oncological safety can be achieved through mastectomy rather than breast-conserving surgery (BCS). In the group of patients who had a second breast cancer and were treated with BCS during their first cancer, 18.3% showed an ISC. Within the patients who were first treated with a mastectomy, only 4.3% showed an ISC. Prophylactic surgeries demonstrate high oncological effectiveness in gPV BRCA1/2 carriers. In particular, mastectomy may provide greater protection against ISC compared with BCS. Further studies will have to be conducted to compare ipsilateral cancer prevalence after breast-sparing surgery and mastectomy.

Individual breast cancer risk can guide screening initiation, frequency, use of supplemental imaging, and preventive measures to improve breast cancer screening by shifting resources from low-risk women to high-risk women. To determine whether risk-based breast cancer screening is a feasible alternative to annual mammography. Parallel-group, pragmatic, multicenter randomized clinical trial comparing risk-based (n = 14 212) with annual (n = 14 160) breast cancer screening. Women aged 40 to 74 years without prior diagnoses of breast cancer or ductal carcinoma in situ, or prophylactic bilateral mastectomy, were recruited from all 50 US states from September 2016 to February 2023, with follow-up through September 5, 2025 (median follow-up, 5.1 years). Statistical analysis was conducted between July and November 2025. All study procedures were conducted via an online platform. Women who declined randomization were enrolled in an observational cohort. Risk assessment included sequencing of 9 susceptibility genes, polygenic risk score, and the Breast Cancer Surveillance Consortium version 2 model. The risk-based group received 1 of 4 recommendations: (1) highest risk (≥6% 5-year risk, high-penetrance pathogenic variant): alternating mammography and magnetic resonance imaging (MRI) every 6 months and counseling; (2) elevated risk (top 2.5 risk percentile by age): annual mammography and risk-reduction counseling; (3) average risk: biennial mammography; and (4) low risk (aged 40-49 years and <1.3% 5-year risk): no screening until risk is 1.3% or greater or age 50 years. The coprimary outcomes included noninferiority for stage ≥IIB cancers and superiority in reducing biopsy rates. Secondary outcomes included identification of stage ≥IIA cancers, mammogram rates, uptake of prevention strategies in higher risk cohorts, preference for screening group in the observational cohort, ductal carcinoma in situ, MRI, and stage-specific cancer rates. A total of 28 372 women were randomized. The mean (SD) age was 54 (9.6) years and the majority were non-Hispanic White (77%). The rate of stage ≥IIB cancers was noninferior in the risk-based compared with the annual group (risk-based: 30.0 [95% CI, 16.3-43.8] vs annual: 48.0 [95% CI, 30.1-65.5] per 100 000 person-years; rate difference, -18.0 per 100 000 person-years [95% CI, -40.2 to 4.1]). The rate of breast biopsies was not lower in the risk-based group (rate difference, 98.7 per 100 000 person-years [95% CI, -17.9 to 215.3]) despite fewer mammograms (rate difference, -3835.9 [95% CI, -4516.8 to -3154.9]). The cumulative incidence of cancer, biopsy, mammogram, and MRI increased as risk category increased. In the observational cohort, 89% of participants (15 980/18 031) chose risk based. Risk-based breast cancer screening that includes population-based genetic testing safely stratified risk and screening intensity, but did not reduce biopsy rates. ClinicalTrials.gov Identifier: NCT02620852.

The role of sentinel lymph node biopsy (SLNB) in prophylactic mastectomy remains controversial. We aimed to evaluate the diagnostic yield of SLNB and the incidence of occult malignancy in prophylactic nipple-sparing mastectomies (NSMs). We performed a review of a prospectively maintained NSM database at Massachusetts General Hospital (2007-2019). Patients undergoing bilateral prophylactic mastectomy (BPM) or contralateral prophylactic mastectomy (CPM) were included. Clinicopathologic features, BRCA status, magnetic resonance imaging findings, and SLNB results were analyzed. A total of 1624 prophylactic NSMs were performed in 1331 patients (36.1% BPM, 63.9% CPM). SLNB was performed in 53.4% of cases; three patients (0.4%) had positive nodes (two isolated tumor cells in the CPM cohort, one micrometastasis in the BPM cohort), and no macrometastatic disease was identified. Occult cancer was found in 91 cases (5.6%), more frequently in CPMs than in BPMs (6.9 vs. 3.2%, p=0.002). Most occult cancers were in situ (71.4%), and, among invasive cancers, 88.5% were luminal A subtype with a median size of 0.6 cm. Prior ipsilateral radiation and contralateral breast cancer also increased risk. On multivariable analysis, BRCA1/2 positivity was independently associated with a decreased risk of occult cancer (odds ratio 0.47; 95% confidence interval 0.23-0.92; p=0.034). Among patients with occult cancer who underwent preoperative magnetic resonance imaging, 55.3% had false-negative findings. Occult malignancy was uncommon, and SLNB positivity was exceedingly rare in prophylactic NSMs. Routine SLNB is not justified in this setting and should be reserved for select higher-risk scenarios. Personalized, risk-adapted approaches to axillary management and preoperative imaging are warranted.

Background/Objectives: Women who have genetic predisposition to breast cancer often opt for risk-reducing mastectomy with immediate reconstruction. Evaluating their satisfaction and quality of life is essential for guiding shared decision-making. Methods: This exploratory study assessed quality-of-life outcomes in two cohorts of patients undergoing bilateral prophylactic nipple-sparing mastectomy with immediate prepectoral implant-based reconstruction. Only patients without postoperative complications (necrosis, infection) were included. Each patient completed the BREAST-Q questionnaire both preoperatively (1–2 days before surgery) and postoperatively. Results: Postoperative BREAST-Q scores demonstrated significant improvement, with self-confidence increasing from 40.75 to 44.33, satisfaction with breast size and appearance from 50.42 to 58.50, and general esthetic/functional satisfaction from 26.92 to 33.17 (all p < 0.01). In contrast, physical comfort decreased from 48.00 to 32.42 (p < 0.001). Preoperative responses may have been influenced by anticipatory stress related to the imminent surgery and concern regarding the breast area to be operated. In contrast, postoperative results reflect psychological relief and satisfaction following a successful surgery, with no complications. Conclusions: Nipple-sparing mastectomy with immediate prepectoral reconstruction is associated with high patient-reported satisfaction and perceived improvements in quality of life, particularly regarding body image and emotional well-being. However, functional limitations such as reduced physical comfort should also be acknowledged. These findings further support evidence-based recommendations for prophylactic surgery in high-risk patients.

Background/Objectives: Breast cancer is the most common cancer among Spanish women. Carriers of certain genetic variants are at increased risk, which can significantly impact their quality of life. The main objective of the present research was to describe the health-related quality of life in women with breast cancer-associated genetic risk variants, distinguishing between those who had already developed cancer and those who did not. Additionally, we aimed to identify the variables influencing the decision to undergo risk-reducing surgery. Methods: Descriptive using the questionnaires BREAST-Q, SF-12 and DASS-21. Results: A total of 63 women participated, with a mean age of 43.38 years. In the 38.1% the genetic variant was identified during the diagnosis of breast cancer, while the rest did not have cancer. We found significantly lower scores for women with breast cancer in the BREAST-Q modules Satisfaction with breasts (p = 0.035) and Physical well-being: chest (p = 0.007), as well as in the physical component of SF-12 questionnaire (p = 0.005). Anxiety scores with DASS-21 were significantly higher in breast cancer patients (p = 0.017). A total of 55.6% of the patients decided to undergo bilateral prophylactic mastectomy, while 60.31% bilateral adnexectomy. These rates were significantly higher in breast cancer patients (p = 0.003), older women (p = 0.001), those with at least one child (p = 0.002) and those who were already menopausal (p = 0.0021). Women who underwent bilateral prophylactic mastectomy reported significantly lower scores in the BREAST-Q modules Satisfaction with breasts (p = 0.033) and Physical well-being: chest (p = 0.025), compared to the ones who decided to undergo a follow-up. Conclusions: Health-related quality of life is significantly lower in women with pathogenic genetic variants who have developed breast cancer. This may contribute to a higher rate of risk-reducing surgeries in this group.

Eligibility for bilateral prophylactic mastectomy: An expert opinion study in the Netherlands

ABSTRACT Background: Breast cancer (BC) is the most common cancer and the second leading cause of cancer-related death among women in Saudi Arabia. Its incidence has been steadily rising among Arab women over the past two decades. Bilateral prophylactic mastectomy (BPM) is a preventive option for high-risk individuals, yet public awareness remains limited. Aim: This study aimed to assess the awareness, attitudes, and acceptance of BPM as a preventive measure for BC among the general population in Makkah, Saudi Arabia. Materials and Methods: A cross-sectional survey was conducted in December 2024 among the residents of Makkah using a structured online questionnaire. Individuals of both genders were eligible to participate. Ethical approval was obtained from the Biomedical Ethics Committee at Umm Al-Qura University. Statistical Methods Used: Descriptive statistics were used to analyze the participants’ sociodemographic data, knowledge, and attitudes toward BPM. Results: Among 402 participants, 80.3% were aware of BC, but only 40.0% correctly identified BPM as the removal of both breasts for preventive purposes. While 79.9% correctly recognized that multiple methods are used for BC detection, significant misconceptions persisted regarding BPM. Conclusion: Despite the high overall awareness of BC, knowledge and acceptance of BPM remain limited. The findings underscore the need for culturally sensitive education campaigns to address misconceptions and improve understanding of BPM as a preventive strategy.

Neoadjuvant chemotherapy (NACT) is a critical component of breast cancer treatment, yet its impact on tissue expander (TE)-based breast reconstruction remains unclear. The purpose of this study was to examine the impact of NACT on complication rates after immediate TE-based breast reconstruction and on the commencement of adjuvant radiotherapy. Female patients who underwent immediate TE-based breast reconstruction between 2017 and 2022 were included. Inclusion criteria consisted of patients who completed NACT within 2 months of mastectomy and those who did not receive chemotherapy. Patients who underwent bilateral prophylactic mastectomy, delayed reconstruction, adjuvant chemotherapy, and neoadjuvant radiation therapy were excluded. A total of 2013 patients were included, of whom 1202 (59.7%) received NACT, and 811 (40.3%) did not receive chemotherapy. The rate of TE loss was significantly higher in the NACT cohort than in the control cohort (9.8% versus 3.9%; P < 0.001). Multivariable regression models showed that NACT significantly increases the rate of TE loss (OR, 2.39; 95% CI, 1.47 to 3.93; P < 0.001) but no other complications, including cellulitis. NACT did not delay the commencement to radiation therapy. However, patients who developed cellulitis started radiation therapy on average 17 days later than those who did not (95% CI, 3.5 to 31; P = 0.014). NACT is a significant predictor of TE loss but does not prolong the commencement to radiotherapy. The increased rate of TE loss among the NACT group may reflect a higher rate of adjuvant radiation treatment and the combination of the deleterious effects of NACT and radiation therapy on wound healing.

Abstract Background: The goal for the ATLAS study is to understand normal breast tissue. By identifying all cell types and cell states in collected disease-free breast tissue and establish an unbiased reference of normal breast cells that can be used to understand tumor growth in cancer patients. Previous studies have focused intensely on mammary epithelial cells however, there is a gap in knowledge concerning the non-epithelial cell types. Both cell types affect each other for normal breast development, lactation after pregnancy, and the more important focus on our protocol contribute to tumorigenesis. Excess tissue from healthy subjects as well as subjects who are at higher risk for developing breast cancer will be taken from women undergoing standard of care procedures such as reduction mammoplasties, prophylactic bilateral mastectomies and contralateral mastectomies from the unaffected breast. Factors such as ethnicity, age and menopause can be predictors in the breast cell type and cell state composition. Significant drawbacks that create bias could arise due to the lack of diversity in a study population. Any bias must be addressed to advance our understanding of diseased breast tissue. In this study we plan to collect clinical data from patients at the time of enrollment. Data such as participant’s parity, social and economic status, lactation history, known density of the breast, estrogen, progesterone and HER2 receptor status will help to provide specific answers to the correlation between underlying cell types and the patient’s association with the cancer and other genomic alteration. Methods: This is a trial in progress. Tissue has been collected prospectively from normal breast tissue removed during prophylactic mastectomy, reduction mammoplasty or delayed asymmetry correction. This study will collect contralateral and adjacent breast tissue from 150 patients along with clinical data. Once all planned tissue collections are completed, the patients will be taken off the study. Results: The site population has an accrual of 125 female patients. 65.6% African American, Caucasian (Non-Hispanic) 23.2%, Caucasian (Hispanic or Latino) 5.6%, Asian 1.6%, American Indian .8%, Arabic .8% and 2.4% declined to state their race. The ages range from 18-65, with most having an unknown BRCA status. Of the 125 participants only 11.5% have BRCA 1 or 2 mutation, PALB2 mutation or CDH1 positive. Gravida ranges from 0 to 10 and Parity ranges from 0 to 7. Conclusion: Instead of focusing on historical morphological features, the new data will perform unbiased single-cell RNA and epigenomic profiling to characterize these cell types which will serve as a reference ‘Human Breast Cell Atlas’ to study cell types in tumors, and how they contribute to tumor progression. While also allowing us to understand how we can improve the outcomes for women of all backgrounds. Citation Format: Nelly Hernandez, Ivan Marin, Margarita Riojas-Barrett, Jessica Montalvan, Bernardo Martinez-Leal, Chandandeep Nagi, Sebastian Winocour, Nicholas Navin, Alastair M. Thompson. Delineating The Role of Normal Cell Types In Breast Cancer (Breast Cell Atlas) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-19.

Breast cancer associated with pathogenic variants of BRCA1 and BRCA2 genes requires specific management. This review examines the prognostic benefits, prophylactic surgical strategies, and impact on quality of life of patients at very high risk of breast cancer. Breast surgical prophylaxis concerns women at high risk of breast cancer with a risk assessment based on their personal and family history, or by diagnosis of pathogenic variants in high-risk genes. Personalized management is based on enhanced clinical and radiological monitoring, the use of predictive tools such as BOADICEA, and surgical options such as prophylactic bilateral mastectomy, which can reduce the risk of cancer by over 90%. Although its impact on overall survival is still debated, advances in surgical techniques have significantly improved aesthetic results and patient satisfaction, thanks to modern reconstruction methods. The surgical strategy, whether primary or secondary, must be individualized, considering the patient's history, therapeutic needs, and preferences. Mastectomy with preservation of the skin envelope, often performed in one or two stages, offers significant psychosocial benefits, although radiotherapy may increase the risk of complications. Options include immediate reconstruction, by implant or autologous technique, adapted to the patient's morphology and any adjuvant treatments. Prophylactic bilateral mastectomy is an effective strategy for reducing the risk of breast cancer, particularly in patients with pathogenic BRCA gene variants. Personalized assessment, detailed information on risks and impacts, and the use of decision-support tools are essential to enable informed choices tailored to individual patient needs.

P134: Eligibility for bilateral prophylactic mastectomy: an expert opinion study in the Netherlands

The role that preoperative Satisfaction with Breast plays in a patient's postoperative course after postmastectomy breast reconstruction (PMBR) is not understood. The aim of this study is to understand the impact of the preoperative score on postoperative outcome as an independent variable. We examined patients who underwent PMBR between 2017 and 2021 and who completed the BREAST-Q Satisfaction with Breasts at 1year postoperatively. Two multiple linear regression models (Model 1 with the preoperative Satisfaction with Breasts score and Model 2 without the preoperative score), likelihood ratio tests, simple t-statistics, and sample patient dataset to predict the 1year score were performed. Multiple imputation was used to account for missing preoperative scores. Overall, 2324 patients were included. Model 1 showed that the preoperative score is significantly associated with the postoperative score (β = 0.09, 95% confidence interval 0.04-0.14; p < 0.001). Comparing Model 1 and Model 2 demonstrated that including preoperative Satisfaction with Breasts in a regression significantly improves model fit (test statistic = 10.04; p = 0.0021). Using the absolute value of the t-statistics as a measure of variable importance in linear regression, the importance of the preoperative score was quantified as 3.39-more important than neoadjuvant radiation, mastectomy weight, body mass index, bilateral prophylactic mastectomy, and race, but less than adjuvant radiation, reconstruction type, and psychiatric diagnoses. Preoperative Satisfaction with Breasts scores are an important independent predictor of postoperative satisfaction after PMBR. Just as vital sign and work-up are carefully documented before surgery, preoperative scores should be collected to pre-emptively gauge patients' satisfaction and optimize postoperative outcomes.

For women at increased risk of breast cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend clinical encounters every 6-12 months. While screening mammography has corresponded with a relative risk reduction in breast cancer mortality of approximately 20%, evidence validating clinical breast examination (CBE) as an efficacious screening modality is deficient. Our study aimed to assess the conventional merit of regular CBE for breast cancer detection among individuals at increased risk of breast cancer development. Women > 18 years with documented high-risk encounters at Corewell Health West from 1 January 2018 to 31 December 22 were retrospectively reviewed. High-risk criteria included genetic predisposition, 5-year (> 1.7%) or lifetime (> 20%) Tyrer-Cuzick and/or Gail Model risk estimations, thoracic radiotherapy before age 30 years, lobular carcinoma in-situ, or atypical hyperplasia. Patients with a history of breast cancer or bilateral prophylactic mastectomy prior to 2018 were excluded. Of the 9171 cumulative high-risk encounters among 2493 women, only one breast cancer was detected by CBE. CBE resulted in 1 (0.04%) cancer diagnosis compared with 30 (1.2%) detected on screening imaging and 10 (0.4%) self-reported. Of the 30 image-detected cancers, 28 (93.3%) had no detectable clinical findings at the time of preoperative consultation. Self-reported and CBE-detected cancers were more likely to be of higher clinical stage compared with imaging-detected malignancies. The role of routine CBE as a cancer detection modality in the high-risk patient population appears to be limited. Telemedicine can be offered to individuals who have completed screening imaging but are unable to commit and/or are inconvenienced by in-person high-risk breast cancer assessments.

Individual outcomes may not accurately reflect the quality of perioperative care. Textbook outcomes (TOs) are composite metrics that provide a comprehensive evaluation of hospital performance and surgical quality. This study aimed to investigate the prevalence and predictors of TOs in a multi-institutional cohort of patients who underwent breast reconstruction with deep inferior epigastric artery perforator flaps. For autologous reconstruction, a TO was previously defined as a procedure without intraoperative complications, reoperation, infection requiring intravenous antibiotics, readmission, mortality, systemic complications, operative duration ≤12 hours for bilateral and ≤10 hours for unilateral/stacked reconstruction, and length of stay (LOS) ≤5 days. We investigated associations between patient-level factors and achieving a TO using multivariable regression analysis. Of 1000 patients, most (73.2%) met a TO. The most common reasons for deviation from a TO were reoperation (9.6%), prolonged operative time (9.5%), and prolonged LOS (9.2%). On univariate analysis, tobacco use, obesity, widowed/divorced marital status, and contralateral prophylactic mastectomy or bilateral reconstruction were associated with a lower likelihood of TOs (P < 0.05). After adjustment, bilateral prophylactic mastectomy (odds ratio [OR], 5.71; P = 0.029) and hormonal therapy (OR, 1.53; P = 0.050) were associated with a higher likelihood of TOs; higher body mass index (OR, 0.91; P = <0.001) was associated with a lower likelihood. Approximately 30% of patients did not achieve a TO, and the likelihood of achieving a TO was influenced by patient and procedural factors. Future studies should investigate how this metric may be used to evaluate patient and hospital-level performance to improve the quality of care in reconstructive surgery.

Abstract Background: Women with germline BRCA1 mutations are at an increased risk for developing breast cancer in their lifetime, often at a young age with more aggressive tumors. At present, prophylactic bilateral mastectomy is the most effective strategy for reducing breast cancer risk. However, this invasive procedure is irreversible and associated with potential complications. We and others have found that PARP inhibitors can delay Brca1-mutant tumor formation in mice and could be beneficial for the prevention of breast cancer. However, currently available PARP inhibitors are associated with modest toxicities that may not be acceptable to women without cancer. Thus, there remains an urgent need for the development of safe and effective therapies for the prevention of breast cancer. Here, we present data demonstrating the activity of IRX4204, a minimally toxic and highly specific agonist of the nuclear retinoid X receptor (RXR), to delay the formation of mammary tumors in a Brca1-deficient mouse model. This inhibitory effect on tumor growth is due, in part, to the role of IRX4204 in stimulating the anti-tumor immune response. Methods: We used the established MMTV-Cre, conditional Brca1 gene knockout, p53 heterozygous loss mouse model (BRCA1co/co; MMTV-Cre+/+; p53+/-) and selected for mutant female pups using PCR genotyping. At 16 weeks of age, all mice were separated into 4 treatment groups (n=10 per group): (1) sesame oil control; (2) the novel RXR agonist, IRX-4204 (10mg/kg); (3) high-dose IRX4204 (20 mg/kg); and (4) the RXR agonist, 9-cis-UAB-30 (5 mg/kg). All treatments were given by oral gavage five days per week, and mice were observed daily for tumor formation and toxicity. At the study endpoint, tumors and normal mammary glands were collected for additional analyses. Immunohistochemical staining was used to quantify CD8a, Ki-67 and cleaved caspase 3 expression in Brca1-deficient tumors. Oil Red O staining was used to measure changes in lipid accumulation in Brca1-deficient cell lines treated with IRX4204. qPCR was used to quantify the changes in gene expression of lipid metabolism-associated genes upon treatment with IRX4204 in vitro. Results: Vehicle-treated Brca1-deficient mice had a median time-to-tumor formation (TTF) of 211 days, with 100% developing tumors by 330 days. Mice treated with UAB 5 mg/kg had an improved median TTF of 261 days, whereas mice treated with IRX4204 10mg/kg or 20mg/kg had a median TTF of 347 and 304 days, respectively (p &amp;lt; 0.01). In addition, 60% of mice treated with IRX4204 10 mg/kg remained tumor-free at 330 days. IRX4204-treated tumors showed an increased infiltration of CD8-positive T-cells over vehicle-treated tumors (p &amp;lt; 0.05). Treatment of Brca1-deficient cell lines with IRX4204 in vitro resulted in a significant increase in lipid accumulation accompanied by a 2-fold increase of Srebf1 expression (a key transcription factor that regulates lipid homeostasis) within 24 hours of treatment (p &amp;lt; 0.05). Conclusion: These data demonstrate a novel use of the RXR agonist, IRX4204, to delay the formation of Brca1-deficient mammary tumors. We have found that IRX4204 treatment modulates the tumor immune response through increased infiltration of cytotoxic CD8-positive T-cells in Brca1-deficient mammary tumors in vivo. We have also determined that IRX4204 modulates lipid metabolism in breast cancer cell lines in vitro. It is known that lipid-derived antigens can stimulate T-cell activity. Our findings suggest that RXR agonists may alter lipid antigen production to activate an anti-tumor response. Additional immune and lipidomic studies are on-going. This work was supported by NCI-PREVENT grant (to PB and AM HHSN26100008) and CFP Foundation (Odyssey Fellowship to CM). Citation Format: Cassandra Moyer, Darian Coleman, Jamal Hill, Lana A. Vornik, Michelle Savage, Martin Sanders, Sei Shizuko, Altaf Mohammed, Powel Brown, Abhijit Mazumdar. The RXR agonist, IRX4204, delays the formation of Brca1 mutant mammary tumors via modulation of the anti-tumor immune response [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 PS07-07.

Abstract Background Robot-assisted breast surgery was developed in 2014 for nipple-sparing mastectomy through a concealable lateral chest wall incision smaller. Although successful experiences have been reported using a multi-arm surgical robotic system, collisions between robotic arms and instruments often result in the discontinuation of console workflow and limit the performance of the surgical robot. Compared to multi-armed robot systems, the SP system is single-armed, equipped with flexible instruments containing multiple joints that may avoid instrument collision, a controllable camera reducing visual dead spots, and a designated non-third-party port that allows single-port entry and full deployment of the instrument. The RASPIM-01 trial (NCT05448963) is a single-armed pilot study assessing the feasibility of robot-assisted nipple-sparing mastectomy (NSM) using a new SP system. Method This study is a pilot trial conducted in a single-arm, non-randomized design with a recruitment of 30 participants. The SP surgical robot is used in NSM through the lateral chest wall incisions. The major inclusion criteria are 1) Breast cancer with preoperative clinical tumor sizes less than 5 cm, with an adequate tumor-skin distance of at least 3mm, and without nipple-areolar involvement in at least 1cm around the nipple by image, 2) Breast cancer up to clinical stage IIIA (T3, N1-2) showing adequate response to neoadjuvant therapy and meeting criteria 1), 3) Germline pathogenic/likely pathogenic BRCA1 or 2 variant carriers with or without a breast cancer diagnosis, requiring unilateral or bilateral therapeutic mastectomy or prophylactic mastectomy. Exclusion criteria include extensive breast skin or nipple involvement such as inflammatory breast cancer, Paget’s disease, nipple discharge associated with malignancy, image suggestive of cancer involvement of the nipple and subareolar tissue, and stage III breast cancer without response to neoadjuvant therapy, and previous radiotherapy of the surgical side breast. The endpoint measurements include Primary endpoint: The ability to complete nipple-sparing mastectomy with an SP system in the per-protocol population without additional assistant port or conversion to open surgery. Statistical analysis includes point estimation with a 95% confidence interval to analyze the mean or proportion of key performance parameters. No interim analysis will be performed due to the limited number intended to recruit. Results The study recruited 30 breast cancer patients and conducted 30 NSMs, while no prophylactic mastectomy case was recruited. The median age was 44 years old, BMI was 22.4 (18.9-30.0) kg/m2. Median tumor size was 3.0 (1.0-14.6) cm, and axillary lymph node metastases were present in 7 cases (23.3%). T2 (13 cases, 43.3%) tumors were the majority, followed by Tis (10 cases, 33.3%), T1 (5 cases, 16.7%), and T3 (2 cases, 6.7%). The anatomical stages of invasive cancer were Ia (16.7%), IIa (26.7%), IIb (16.7%), and IIIa (6.7%), among them 9 (30.3%) received neoadjuvant chemotherapy before surgery. All NSMs met the primary endpoint of successful completion using the SP robot system without conversion to open mastectomy or the addition of an assistant port. Median console time was 108.5 (73-285) min and docking time was 2.5 (1-9) min. Specimen weight was 311.6 (107-838) gm, while 2 (6.7%) cases had their nipple excised due to cancer-involved margin reported from the frozen section. Twenty-six (86.6%) cases received autologous free flap reconstruction, among which 25 (83.3%) cases received DIEP, and 1 (3.3%) received PAP reconstruction. Four cases received implant (2 cases, 6.7%) or tissue expander (3 cases, 6.7%). Conclusion This is the first NSM clinical trial operated with SP surgical robot system and met its primary endpoint showing the feasibility to conduct NSM. Secondary and exploratory endpoints data will be reported after the completion of clinical follow-ups. Citation Format: Wen-Ling Kuo, Chia-Huei Chu, Jung-ju Huang. Robot-assisted nipple-sparing mastectomy using da Vinci SP single-port system: primary results from the pilot trial RASPIM-01 [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 PO4-22-12.

Abstract Introduction: The amount and degree of the fibroglandular tissue (FGT) enhancement on breast MRI, known as background parenchymal enhancement (BPE), is an emerging marker of breast cancer risk. Higher qualitative and quantitative BPE levels have been shown to correlate with both future risk of initial breast cancer diagnosis and breast cancer recurrence after treatment. Furthermore, adjuvant and preventative therapies such as radiation and endocrine therapy have been shown to lower BPE in many women, potentially serving as a marker of treatment efficacy. However, the biological basis of BPE remains unclear and elucidation of this mechanism could identify novel targeted prevention strategies. The goal of this study was to assess the association of BPE levels with markers of inflammation, vascularity, proliferation, and estrogen sensitivity in a cohort of high-risk women. Materials and Methods: In this IRB-approved retrospective study, we identified asymptomatic high-risk women who underwent at least one dynamic contrast-enhanced (DCE) breast MRI within one year of prophylactic bilateral mastectomy. Qualitative BPE assessments were obtained from clinical reports. Quantitative BPE measures were obtained using in-house semi-automated software: whole breast FGT was first segmented on pre-contrast images, percent enhancement (PE) was calculated for each voxel as (S1-S0)/S0 × 100%, where S0 and S1 are pre- and early post-contrast signal intensity, respectively, and quantitative BPE was then defined as the mean PE of the FGT. Additionally, the BPE volume ratio was calculated as the fraction of FGT that had a PE &amp;gt;50%. Histopathology markers of inflammation (COX-2), vascularity (VEGF), proliferation (Ki-67), and estrogen receptor status (ER) were prospectively measured on archived mastectomy specimens of each breast. BPE metrics were correlated with histopathological markers using Spearman’s rank correlation, with and without adjustment by menopausal status of the patient. All tests were based on generalized estimating equations models to account for the non-independence of the two breasts per patient. A p-value &amp;lt; 0.05 was considered significant. Results: We identified 56 women (median age: 39; range: 26-63 years) for this study, of which 39% were post-menopausal (N=22). Distribution of qualitative BPE levels were 41% minimal (N=23), 29% mild (N=16), 18% moderate (N=10), and 12% marked (N=7). Qualitative BPE and quantitative BPE markers were moderately positively correlated (r=0.37-0.54, p&amp;lt; 0.01). Table 1 lists the correlations between BPE metrics and histopathology markers. After adjusting for menopausal status, qualitative BPE was positively associated with ER (r=0.27, p=0.02) and VEGF (r=0.24, p&amp;lt; 0.01; r=0.21, p=0.02 adjusted). Quantitative BPE and BPE volume ratio were both positively correlated with VEGF (p&amp;lt; 0.04) and negatively correlated with COX2 (p&amp;lt; 0.05). No significant associations were observed between BPE and Ki-67. Discussion: Our study suggests that increased BPE on MRI positively correlates with increased vascularity and higher estrogen receptor expression but not inflammation or proliferation within normal breast tissue in high-risk women. These findings, along with established associations between BPE and cancer risk, could be useful to select and assess efficacy of targeted preventative treatments. Table. Spearman rank correlations between BPE metrics and histopathological markers. Citation Format: Pegah Khoshpouri, Anum Kazerouni, Sana Parsian, Daniel Hippe, Olivia Walsh, Lisa Koch, Savannah Partridge, Habib Rahbar. The biological basis of breast MRI background parenchymal enhancement in women with high breast cancer risk [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 PO5-07-07.

Screening chest wall ultrasound in the mastectomy patient