Bilateral Prophylactic Mastectomy Research Articles

Abstract PS07-07: The RXR agonist, IRX4204, delays the formation of Brca1 mutant mammary tumors via modulation of the anti-tumor immune response

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 < 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 < 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 < 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 PO4-22-12: Robot-assisted nipple-sparing mastectomy using da Vinci SP single-port system: primary results from the pilot trial RASPIM-01

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 PO5-07-07: The biological basis of breast MRI background parenchymal enhancement in women with high breast cancer risk

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 >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 < 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< 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< 0.01; r=0.21, p=0.02 adjusted). Quantitative BPE and BPE volume ratio were both positively correlated with VEGF (p< 0.04) and negatively correlated with COX2 (p< 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

BackgroundWhile there are clear guidelines regarding chest wall ultrasound in the symptomatic patient, there is conflicting evidence regarding the use of ultrasound in the screening of women post-mastectomy. ObjectiveTo assess the utility of screening chest wall ultrasound after mastectomy and to assess features of detected malignancies. MethodsThis IRB approved, retrospective study evaluates screening US examinations of the chest wall after mastectomy. Asymptomatic women presenting for screening chest wall ultrasound from January 2016 through May 2017 were included. Cases of known active malignancy were excluded. All patients had at least one year of clinical or imaging follow-up. 43 exams (8.5 %) were performed with a history of contralateral malignancy, 465 exams (91.3 %) were performed with a history of ipsilateral malignancy, and one exam (0.2 %) was performed in a patient with bilateral prophylactic mastectomy. ResultsDuring the 17-month period, there were 509 screening US in 389 mastectomy patients. 504 (99.0 %) exams were negative/benign. Five exams (1.0 %) were considered suspicious, with recommendation for biopsy, which was performed. Out of 509 exams, 3 (0.6 %) yielded benign results, while 2 (0.39 %) revealed recurrent malignancy, with a 95 % confidence interval (exact binomial) of 0.05 % to 1.41 % for screening ultrasound. Both patients who recurred had previously recurred, and both had initial cancer of lobular histology. ConclusionOf 509 chest wall screening US exams performed in mastectomy, 2 malignancies were detected, and each patient had history of invasive lobular carcinoma and at least one prior recurrence prior to this study, suggesting benefit of screening ultrasound in these populations.

Fear of cancer recurrence in breast cancer survivors carrying a BRCA1/2 mutation: A qualitative study.

There is preliminary evidence suggesting that FCR is a major problem for breast cancer survivors carrying a BRCA1/2 mutation. The goal of this qualitative study, conducted among women who were treated for breast cancer, was to provide a deeper understanding of how FCR is experienced in the context of a genetic predisposition to breast cancer. Three focus groups (90-110 min) were conducted with 19 breast cancer survivors carrying a BRCA1/2 mutation. The semistructured interview probed FCR level and impact, the role FCR played in the decision to have a prophylactic bilateral mastectomy and/or salpingo-oophorectomy, the effect that surgery had on FCR, and the relevance of offering a psychological intervention targeting FCR to this population. Findings indicated that FCR was a significant issue in these women, even though a majority had undergone a prophylactic surgery. Patients strongly affirmed the need to develop and provide access to FCR interventions that are specifically adapted to the needs of this group. These results suggest that, although being the most effective medical option to reduce the actual risk of local recurrence (or second breast cancer), prophylactic surgery only partially reduces FCR. A psychological intervention targeting specifically FCR would be an appropriate complement to preventive surgery.

Spectrum of histopathologic findings in risk-reducing bilateral prophylactic mastectomy in patients with and without BRCA mutations

Many germline mutations have been implicated in breast cancer pathogenesis and despite several studies on occult atypical lesions in prophylactic mastectomy specimens from patients with BRCA1/2 mutations, there are very limited data on other genes associated with increased breast cancer risk and the distribution of lesions in patients with hereditary breast cancer. We identified 207 patients who underwent bilateral prophylactic mastectomy due to germline mutations in BRCA1/2, PALB2, CHEK2, ATM, CDH1, PTEN, BARD1, or strong family history between 2015 and 2023. Patients with biopsy-proven past or current invasive breast carcinoma or carcinoma in-situ preoperatively were excluded. In addition to multiple benign lesions, the following atypical lesions were identified: flat epithelial atypia (16.9%), atypical ductal hyperplasia (14.0%), lobular neoplasia (14.0%), ductal carcinoma in-situ (4.3%), invasive ductal carcinoma (0.4%). Both low-grade and high-grade pathway lesions were identified in this cohort, and in a subset of patients, they co-occurred. The frequency of atypical lesions identified in patients with strong family history were comparable to those with proven germline mutation. PTEN immunohistochemistry showed loss of expression in ductal carcinoma in-situ and tubular adenomas in PTEN-mutant patients. Overall, findings from this cohort support the benefit of prophylactic mastectomy in patients with germline mutations and/or strong family history. Additionally, this is the first demonstration that PTEN immunohistochemistry may be helpful in identifying germline mutations in patients with atypical or neoplastic proliferations.

Bilateral Free Deep Inferior Epigastric Artery Perforator Flaps for Reconstruction following Mastectomy in Poland Syndrome Patients.

Poland syndrome is classically described as symbrachydactyly, with hypoplasia of the pectoralis major and other upper thoracic musculoskeletal structures. It is thought to be caused by intrauterine interruption in subclavian arterial flow and often includes breast hypoplasia. Affected vasculature can pose a challenge for reconstruction with free flaps because inflow may not be reliable in this patient population. We present the rare case of a 28-year-old woman with left-sided Poland syndrome, significant family history of breast cancer, and BRCA1+ mutation who underwent bilateral prophylactic nipple-sparing mastectomies with successful immediate bilateral deep inferior epigastric artery perforator free flap reconstruction. The surgical literature in this clinical scenario is also reviewed. Preoperative computed tomography angiography of the chest successfully demonstrated the patency and quantified the caliber of the internal mammary vessels to support free flap breast reconstruction. Free tissue transfer is a viable option for breast reconstruction in patients with Poland syndrome undergoing mastectomy guided by preoperative computed tomography angiography to characterize the internal mammary vasculature.

Impact of non-BRCA genes in the indication of risk-reducing surgery in hereditary breast and ovarian cancer syndrome (HBOC)

Hereditary breast and ovarian cancer syndrome (HBOC) is associated with other genes beyond BRCA. The performance of prophylactic bilateral mastectomy (PBM) and risk-reducing salpingo-oophorectomy (RRSO) are primary prevention measures that can be recommended depending on the type of pathogenic/likely pathogenic (P/LP) variant detected or family history. Descriptive, retrospective, and observational audit. Between the years 2015 to May 2023, a total of 288 families were studied by a multigene panel using NGS. Statistical analysis was performed using IBM SPSS Statistics 22. Non-BRCA P/LP variants were detected in 38 families (84.2% females and 15.8% males); 18 in ATM (44.7 %), 7 in CHEK2 (18.4%), 5 in TP53 (13.2%), 2 in PTEN (5.3%), 2 in PALB2 (5.3%), 1 in RAD51C (2.6%), 1 in BRIP1 (2.6%), 1 in CDH1 (2.6%) and 1 in RAD51D (2.6%). Risk-reducing surgery was recommended in 18 patients (PBM in 18 [46.2 %] and RRSO in 5 [13.2%]). Given the results of our study, we support the recommendations of the guidelines on the use of multigene panels in the study of HBOC. Knowing P/LP variants beyond BRCA1 and 2 has an impact on the follow-up and primary and secondary prevention of affected families.

Complication Rates in Therapeutic Versus Prophylactic Bilateral Mastectomies: Insights From a National Database.

The "Jolie effect" and other media focus on prophylactic treatments have resulted in unilateral breast cancer patients increasingly undergoing contralateral prophylactic mastectomy. Little is known, however, regarding outcomes following therapeutic versus prophylactic mastectomy. In this study, we compared complication rates of unilateral breast cancer patients undergoing contralateral prophylactic mastectomy (BM-TP) to patients undergoing bilateral prophylactic mastectomy (BM-P). The BM-TP and BM-P patients from 2015 to 2019 were identified in Optum Clinformatics DataMart. Six-month outcomes were assessed and included wound complications, infection, hematoma/seroma, breast pain, fat necrosis, flap failure, implant failure/removal, other flap/implant complications, and other complications. Multivariable regression models adjusted for age, residence, insurance, race, and Charlson Comorbidity Index score. Of 9319 women, 7114 (76.3%) underwent BM-TP, and 2205 (23.7%) underwent BM-P. In multivariable analysis, BM-TP had higher odds of overall complications (adjusted odds ratio [aOR], 1.35; P < 0.0001), but no difference was observed among patients who had autologous ( P = 0.1448) or no breast reconstruction ( P = 0.1530). Higher odds of overall complications persisted even after controlling for radiation therapy (aOR, 1.25; P = 0.0048) and chemotherapy (aOR, 1.28; P = 0.0047), but not after controlling for lymph node surgery ( P = 0.7765). The BM-TP (vs BM-P) patients face higher odds of overall complications but without any difference in certain reconstructive modalities or after controlling for lymph node surgery.

Decision-analytic evaluation of the comparative effectiveness and cost-effectiveness of strategies to prevent breast and ovarian cancer in German women with BRCA-1/2 mutations

BackgroundWomen with inherited mutations in the BRCA1 or BRCA2 genes have increased lifetime risks for developing breast and/or ovarian cancer and may develop these cancers around the age of 30 years. Therefore, prevention of breast and ovarian cancer in these women may need to start relatively early in life. In this study we systematically evaluate the long-term effectiveness and cost effectiveness of different prevention strategies for breast and ovarian cancer in women with BRCA-1/2 mutation in Germany.MethodsA decision-analytic Markov model simulating lifetime breast and ovarian cancer development in BRCA-1/2 carriers was developed. Different strategies including intensified surveillance (IS), prophylactic bilateral mastectomy (PBM), and prophylactic bilateral salpingo-oophorectomy (PBSO) alone or in combination at different ages were evaluated. German clinical, epidemiological, and economic (in 2022 Euro) data were used. Outcomes included cancer incidences, mortality, life years (LYs), quality-adjusted life years (QALYs), and discounted incremental cost-effectiveness ratios (ICER). We adopted the German health-care system perspective and discounted costs and health effects with 3% annually.ResultsAll intervention strategies are more effective and less costly than IS alone. Prevention with PBM plus PBSO at age 30 maximizes life expectancy with 6.3 LYs gained, whereas PBM at age 30 with delayed PBSO at age 35 improves quality of life with 11.1 QALYs gained, when compared to IS alone. A further delay of PBSO was associated with lower effectiveness. Both strategies are cost effective with ICERs significantly below 10,000 EUR/LYG or QALY.ConclusionBased on our results, PBM at age 30 plus PBSO between age 30 and 40 prolongs life and is cost effective in women with BRCA-1/2 mutations in Germany. Serial preventive surgeries with delayed PBSO potentially improve quality of life for women. However, delaying PBM and/or PBSO further may lead to increased mortality and reduced QALYs.

Nipple margin assessment at the time of nipple-sparing mastectomy.

Documenting negative margins at the nipple-areolar complex (NAC) during nipple-sparing mastectomy (NSM) remains the standard, but how to achieve this and how to manage a positive margin is debated. We sought to review nipple margin assessments at our institution and to analyze the risk factors of a positive margin and rate of local recurrence. Patients who underwent NSM between 2012 and 2018 were reviewed and divided into 3 groups based on indication - cancer, contralateral prophylactic mastectomy (CPM) and bilateral prophylactic mastectomy (BPM). Nipple-sparing mastectomies were performed on 337 patients; 72% for cancer, 20% for CPMs and 8% for BPMs. Nipple margin assessments were performed in 87.8% of patients; 10 patients (3.4%) had a positive margin, 7 of whom underwent NAC excision and 3 were managed with observation. As indications for NSM increase, assessment of nipple margin provides valuable information to manage the NAC in patients with cancer. The routine use of nipple margin biopsies in patients undergoing CPM and BPM may no longer be required, as rates of occult malignant disease are low with no positive biopsies. Further studies with larger sample sizes are needed.

Incidence of Cancer and Role of Sentinel Lymph Node Biopsy in BRCA Mutation Carriers Undergoing Prophylactic Mastectomies.

Breast surveillance in patients with BRCA mutations include mammography (MMG) and MRI. Patients may elect to undergo risk-reducing bilateral prophylactic mastectomies (BPM). Sentinel lymph node biopsies (SLNB) are frequently performed and associated with increased morbidity. This study sought to determine the correlation between preoperative imaging and the final pathology and evaluate the role of SLNB in these high-risk patients. A prospective database identified BRCA patients who underwent BPM between 2006 and 2022. Imaging, pathology, and operative reports were reviewed. 170 patients with BRCA 1/2 mutations were identified. 162 (95.3%) had imaging within one year of BPM. Of these, 28 (17.3%) patients had a MMG/ultrasound, 53 (32.7%) had an MRI, and 81 (50%) had both; 21/162 (13.0%) patients had abnormal imaging. Bilateral SLNB were performed in 31 (18.2%) patients, of which 7 had abnormal imaging; unilateral SLNB were performed in 4 (2.4%) patients, of which 3 had abnormal imaging. 11/170 (6.4%) patients had a malignancy and only one (9%) of these patients had imaging abnormalities. 1/170 (0.6%) patient had an invasive carcinoma requiring an axillary lymph node dissection (ALND), and 10/170 (5.9%) patients had ductal carcinoma in situ (DCIS). 25/170 (14.7%) had ADH/ALH. Only 7/170 (4.1%) patients had imaging abnormalities and abnormal pathology. All SLNB and ALND performed demonstrated no metastatic disease. There is a high rate of discordance between preoperative imaging prior to surgery in BRCA patients undergoing prophylactic mastectomies and final pathology. This study does not support routine SLNB at the time of BPM.

Psychosexual responses to BRCA gene mutations in women of childbearing age.

Diagnosis of a BRCA gene mutation presents a dilemma because life-changing medical decisions must be made to prevent breast and ovarian cancer. There is minimal evidence regarding how psychosexual functioning, psychological well-being with regard to body image and sexuality, affects the decision to have prophylactic treatment in women of childbearing age (WCBA; 18-49 years) with a BRCA gene mutation. To explore, describe, and interpret the experience of women with a BRCA mutation during the treatment and decision-making process. A qualitative descriptive design was used to recruit participants online through social media postings and from national and local BRCA support groups. Participants participated in semistructured interviews exploring their experience after BRCA diagnosis. Interpretive descriptive analysis was used to identify themes. The purposive sample comprised 18 women aged 21-49 years. Four major themes, such as body image, sexuality, femininity, and childbearing/childrearing, were identified that influenced decisions related to the diagnosis and management of a BRCA mutation. All participants voiced that concerns regarding body image and sexuality caused hesitancy in their decision to have prophylactic surgery. Women who had undergone bilateral prophylactic mastectomy were concerned about the impact of the surgery, scarring, breast disfigurement, and the lack of sensation resulting from surgical intervention. Psychosexual concerns arise from internal and external influences that significantly affect the decision to undergo prophylactic measures. Therefore, body image, sexuality, and sexual orientation should all be addressed during the decision-making process. Provider communication and preparation for realistic surgical outcomes can be improved to assist WCBA throughout the decision-making process and enhance psychosexual functioning.

Psychological distress and decision-making factors for prophylactic bilateral mastectomy in cancer-unaffected BRCA1/2 pathogenic variant carriers.

Women carrying a BRCA1/2 pathogenic variant have an increased risk for breast cancer and may opt for risk-reducing bilateral mastectomy. In this study, we examine which demographic, psychosocial, and personality factors are associated with their decision to undergo risk-reducing bilateral mastectomy. Cancer-unaffected women with a pathogenic variant in BRCA1 or BRCA2 were recruited before receiving their genetic test result and completed follow-up including decision to undergo mastectomy over 6-8months after genetic test result disclosure. Anxiety, depression, breast cancer worry, personality and sociodemographic data were assessed. A total of 125 cancer-unaffected women were included in the analysis. Participants were found to have higher anxiety levels than the general female population regardless of mastectomy decision. Breast cancer worry was higher among women who opted for risk-reducing mastectomy and did not decrease over time. By contrast, women who did not opt for surgery experienced decreasing levels of breast cancer worry. Regression analysis found that women with a pathogenic variant in BRCA1, younger women and women with higher breast cancer worry were more likely to opt for surgery. Our study provides valuable insights into the factors that influence women with a BRCA1/2 pathogenic variant to undergo risk-reducing mastectomy. These findings may be helpful in understanding individual differences in decision-making concerning preventive options and show the need to address negative anticipatory feelings associated with carrying a pathogenic variant in a high breast cancer risk gene in clinical care.

Abstract OT3-21-01: A pilot study of robot-assisted nipple-sparing mastectomy followed by immediate breast reconstruction using da Vinci SP ® single-port system

Abstract Introduction- Robotic mastectomy is a novel breast surgery approach accessed from a concealable anterior axillary incision showing better cosmetic outcomes with a scarless front view. The oncological safety awaits further follow-up from clinical trials or registered studies to mature. Compared to older da Vinci systems with multiple arms, the new SP system is single-armed, equipped with flexible instruments and a camera that may avoid instrument collision and dead spots in the surgical field. This trial (NCT05448963) is not only the leading SP mastectomy trial in Asia but also the first one that incorporates autologous flap reconstruction. Methods- -Objectives: To determine the performance, technical algorithm, safety data, and patient-reported outcomes in single-port-accessed nipple-sparing mastectomy using da Vinci SP® system. -Study design: This study is a pilot clinical study conducted in a single-arm, non-randomized design with a goal to recruit 30 participants. The da Vinci SP ® surgical robot is applied in the nipple-sparing mastectomy and axillary lymph node dissection (if indicated) of each enrolled patient in Chang Gung Memorial Hospital Linkou Medical Center. The post-mastectomy reconstructive method may use autologous flaps or implants depending on the type of build, technical feasibility, and flap site availability of the patient. The eligibility criteria include: I. Meet at least one of the following indications of NSM for breast cancer: 1. Preoperative clinical tumor sizes less than 5 cm, with an adequate tumor-skin distance of at least 3mm and above, and without nipple-areolar involvement in at least 1cm around the nipple by image 2. Breast cancer up to stage IIIa (T3, N1-2) as the initial clinical stage showing adequate response to neoadjuvant therapy and meeting criteria 1. 3. Germline pathogenic/likely pathogenic BRCA1 or 2 mutation carriers (actionable mutations including pathogenic and likely pathogenic mutations) with a breast cancer diagnosis or requiring unilateral or bilateral prophylactic mastectomy as a risk reduction procedure II. Age equal to or above 20 years III. ECOG (Eastern Cooperative Oncology Group) performance score 0-1 IV. ASA anesthesia risk class 1~2, and with adequate organ functions Endpoint measures: -Primary endpoint: Ability to complete nipple-sparing mastectomy with da Vinci SP system in the per-protocol population. -Secondary endpoints: Safety measured by adverse events through 30-day post-operative follow up -Exploratory endpoints: Surgical time, blood loss, hospital stay, breast specimen weight, cancer resection margin, nipple-preservation rate morbidity and mortality rate within 30 days of operation, and reoperation within 30 days post-surgery -Statistical analysis: Point estimation with a 95% confidence interval will be used to analyze the mean or proportion of key performance parameters. No interim analysis will be performed due to the limited number intended to recruit. -Trial status: Active recruitment Conclusion: The single-port robotic system features single port access with multi-jointed instruments which is particularly designed for narrow surgical spaces such as mastectomy. The feasibility of applying da Vinci SP systems to robotic nipple-sparing mastectomy and robiotic axillary lymph node dissection will be demonstrated in this study. Citation Format: Wen-Ling Kuo, Chia-Huei Chu, Jung-ju Huang. A pilot study of robot-assisted nipple-sparing mastectomy followed by immediate breast reconstruction using da Vinci SP ® single-port system [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 OT3-21-01.

Effectiveness of Prophylactic Mastectomy

Introduction: The growing incidence and recurrence rate of breast cancer has influenced multiple strategies such as surgical interventions that serve as preventive measures for women at high risk. Prophylactic mastectomy seems to be the most effective tool in the primary prevention of breast cancer, but opinions are not uniform, especially among specialists. The goal of this presentation is to examine the effect of risk-reducing mastectomy, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes in cohort of patients who underwent prophylactic mastectomy. Materials and Methods: We retrospectively reviewed the outcomes of 20 years of experience with prophylactic mastectomies performed at the department from 1999 to 2019. In this study were included patients who underwent bilateral prophylactic mastectomy with no breast cancer, and patients with breast cancer, if they underwent contralateral risk-reducing mastectomy, however, only the prophylactic side was considered in the analysis. Patients with bilateral breast cancer were excluded. Results: A total of 749 risk-reducing prophylactic mastectomy in 545 patients were performed at our department from 1999 to 2019. Bilateral prophylactic mastectomies were performed in 204 patients (37,4%), and 341 (62,6%) underwent a unilateral risk-reducing mastectomy secondary to cancer in the contralateral breast. Overall, 243 patients with BRCA1 mutations and 113 with BRCA2 mutations were included. Conclusion: Prophylactic mastectomy is highly preventive against breast cancer. Although further clinical studies are needed to determine the effectiveness of prophylactic mastectomies in individual indications. With the effectiveness of prophylactic mastectomy should also be taken into consideration the quality of life after the immediate breast reconstruction, and the associated complications.

Abstract OT2-10-02: Phase I trial of an alpha-lactalbumin vaccine in patients with operable triple-negative breast cancer (TNBC)

Abstract Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 as well as other genes. Alpha-lactalbumin (aLA) is a milk protein expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA inhibits the growth of established breast tumors and provides potent protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). Specific Aims: We are conducting a Phase I trial of vaccination with an aLA vaccine in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a relevant immunologic response to aLA. Trial Design: Patients are being entered into a Phase I trial of alpha-lactalbumin with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive a total of 3 vaccinations administered once every 2 weeks. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested in the current protocol are alpha-lactalbumin/zymosan 0.01/0.01, 0.1/0.01, 0.5/0.01, 0.5/0.03, and 0.5 mg/0.06 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). Eligibility Criteria: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage II-III or who had residual disease after standard pre-operative systemic therapy. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Dose Selection: Doses are being escalated using a 3+3 trial design to determine the maximum tolerated dose, the lowest immunologic dose and the optimal immunologic dose Present Accrual and Target Accrual: Dependent on toxicity, 18-30 patients will be treated. Future Plans and Contact Information: After identification of the maximum tolerated dose and expansion of the dose levels associated with effective tumor immunity we plan to enroll 2 additional cohorts of patients: 1) patients who have completed pre-operative chemo-immunotherapy and are receiving pembrolizumab as standard of care therapy, and 2) patients without cancer planning to undergo prophylactic bilateral mastectomy. Interested parties may contact Dr. Budd at buddg@ccf.org. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Citation Format: George Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Megan L. Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Vincent K. Tuohy. Phase I trial of an alpha-lactalbumin vaccine in patients with operable triple-negative breast cancer (TNBC) [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 OT2-10-02.

Diagnosis, Management, and Surveillance for Patients With PALB2, CHEK2, and ATM Gene Mutations

BackgroundThis study aims to capture clinical and surgical practice patterns of patients with deleterious mutations in partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2) and ataxia telangiesctasia mutated (ATM) genes. Materials and MethodsThis study is a retrospective chart review of patients with PALB2, CHEK2 or ATM mutations. Patient demographics, testing indications, management decisions, and surveillance strategies were recorded. ResultsSixty-two patients were found to have deleterious mutations: 14 (23%) with a PALB2 mutation, 30 (48%) with a CHEK2 mutation, and 18 (29%) patients with an ATM mutation.Thirty-one (50%) patients have a history of breast cancer. Twenty-three patients were diagnosed and treated prior to genetic testing while 8 patients learned of their mutation status and breast cancer diagnosis simultaneously. Of these 8 patients, 4 sought treatment at our institution, 3 underwent bilateral mastectomy, and 1 patient opted for lumpectomy and surveillance.Thirty-one patients had no history of breast cancer. After genetic diagnosis, 3 of the 9 patients who continued clinical follow-up proceeded with bilateral prophylactic mastectomy within 2 years. Clinical surveillance continued for 23 months on average. ConclusionMost patients who learned of their genetic and breast cancer diagnoses simultaneously underwent bilateral mastectomy, whereas only a third of patients without cancer opted for bilateral prophylactic mastectomy.

Bilateral prophylactic mastectomy: should we preserve the pectoral fascia? Protocol of a Dutch double blinded, prospective, randomised controlled pilot study with a within-subject design (PROFAS)

IntroductionBilateral prophylactic mastectomy (BPM) in women with a high risk of developing breast cancer has shown to provide the greatest risk reduction. Many surgical guidelines recommend the removal of the...

Abstract P037: Association between circulating osteoprotegerin levels and estimated risk of BRCA1-associated breast cancer

Abstract Purpose: Dysregulation of the receptor activator of nuclear factor κB (RANK) pathway may contribute to the pathogenesis of BRCA1-associated breast cancer. Specifically, lower levels of osteoprotegerin (OPG), an endogenous inhibitor of RANK-ligand (RANKL) that competes with RANK for RANKL binding, have been reported among women with pathogenic or likely pathogenic variant (mutation) in the BRCA1 gene. It has been suggested that lower OPG levels may be associated with an increased risk of breast cancer, proposing that OPG may serve as a biomarker for breast cancer risk. Whether OPG is associated with estimated breast cancer risk remains unknown. The goal of this study was to evaluate the relationship between OPG and the estimated risk of breast cancer in women with a BRCA1 mutation. Methods: Women were eligible for inclusion if they had a BRCA1 mutation, were between ages 18 and 79, had a pedigree, had no prior history of cancer, had not undergone prophylactic bilateral mastectomy and provided a blood sample available for OPG analysis. Detailed information on various risk factors (i.e., reproductive, hormonal, family history) was collected using biennial questionnaires. An enzyme-linked immunosorbent assay was used to quantify serum OPG levels (pg/mL). Risk of breast cancer was estimated using Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 6 incorporated in the CanRisk tool. The relationship between OPG and estimated lifetime (up to age 80) and ten-year (age 40–50) risks of breast cancer was evaluated using quantile regression analyses. Analyses were further stratified by age (≤50 vs &amp;gt;50 years). Results: A total of 539 women were included in the analysis. The median age at blood collection was 39 years (18–77 years). For lifetime breast cancer risk, a 1 standard deviation (SD; 38.40 pg/ml) increase in OPG level was associated with a 5.4% lower risk at the 25th percentile (P ≤ 0.001), a 4.2% lower risk at the 50th percentile (P ≤ 0.001), and a 1.5% lower risk at the 75th percentile (P ≤ 0.001). For ten-year breast cancer risk, a 1 SD increase in OPG level was associated with a 1.2% lower risk at the 25th percentile (P ≤ 0.001), a 0.8% lower risk at the 50th percentile (P ≤ 0.001), and a 0.8% lower risk at the 75th percentile (P = 0.005). The association between OPG and both estimated risks did not vary in the analysis stratified by age (≤50 vs &amp;gt;50 years). Conclusion: Higher circulating OPG levels were associated with significantly lower estimated lifetime and ten-year risks of BRCA1-associated breast cancer. These associations were stronger for women at a lower risk of developing lifetime breast cancer. Further research is needed to determine whether integrating circulating OPG levels can improve existing risk prediction models. These data contribute to ongoing interest in the role of RANK signaling in mammary tumorigenesis. Inhibiting RANK signaling may therefore be a potential target for breast cancer prevention in women with a BRCA1 mutation and other high-risk populations. Citation Format: Sarah S. Park, Tasnim Zaman, Shana J. Kim, Jennifer D. Brooks, Andy K. O. Wong, Jan Lubiński, Steven A. Narod, Leonardo Salmena, Joanne Kotsopoulos. Association between circulating osteoprotegerin levels and estimated risk of BRCA1-associated breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P037.