Undergoing Reduction Mammoplasty Research Articles

Predicting Reduction Mammaplasty Total Resection Weight With Machine Learning.

Machine learning (ML) is a form of artificial intelligence that has been used to create better predictive models in medicine. Using ML algorithms, we sought to create a predictive model for breast resection weight based on anthropometric measurements. We analyzed 237 patients (474 individual breasts) who underwent reduction mammoplasty at our institution. Anthropometric variables included body surface area (BSA), body mass index, sternal notch-to-nipple (SN-N), and nipple-to-inframammary fold values. Four different ML algorithms (linear regression, ridge regression, support vector regression, and random forest regression) either including or excluding the Schnur Scale prediction for the same data were trained and tested on their ability to recognize the relationship between the anthropometric variables and total resection weights. Resection weight prediction accuracy for each model and the Schnur scale alone were evaluated based on using mean absolute error (MAE). In our cohort, mean age was 40.36 years. Most patients (71.61%) were African American. Mean BSA was 2.0 m2, mean body mass index was 33.045 kg/m2, mean SN-N was 35.0 cm, and mean nipple-to-inframammary fold was 16.0 cm. Mean SN-N was found to have the greatest variable importance. All 4 models made resection weight predictions with MAE lower than that of the Schnur Scale alone in both the training and testing datasets. Overall, the random forest regression model without Schnur scale weight had the lowest MAE at 186.20. Our ML resection weight prediction model represents an accurate and promising alternative to the Schnur Scale in the setting of reduction mammaplasty consultations.

Abstract 780: Normal breast tissues harbor rare populations of aneuploid epithelial cells

Abstract Although aneuploidy is a hallmark of invasive breast cancers, the presence of aneuploid cells in breast tissues of disease-free women is poorly understood. Furthermore, the expansion of aneuploid cells and the specific copy number events that they harbor, as well as their relationship to invasive breast cancers has not been characterized in large cohorts of women. In this study, we obtained viable cell suspensions from 31 disease-free women that underwent reduction mammoplasty surgeries and fresh tissue collection in the HBCA project along with the collection of clinical metadata. The viable cell suspensions from 31 women were enriched for epithelial cells and used to perform high-thoughput nanowell scDNA-seq. In total, 55,321 cells were analyzed. The normal breast tissue samples were also embedded into OCT and frozen to perform Spatial Transcriptomics (Visium 10X Genomics) profiling and embedded into FFPE to perform histopathological analysis. Our data shows that all women harbored rare populations of aneuploid epithelial cells (mean 4.3%) that increased in frequency and their number of copy number aberrations with age. Many aneuploid epithelial cells (mean 79%) in normal breast tissues underwent clonal expansions of their genomes and harbored chromosomal aberrations detected in invasive breast cancers (gain of 1q and loss of 7q, 10q, 16q). Spatial mapping showed that aneuploid cells are localized in focal regions of ductal and lobular epithelial structures with normal histopathological features. Collectively, these data show that aneuploid epithelial cells exist in the normal breast tissues of disease-free women and increase with age. In many women, the aneuploid cells expand and harbor CNA events associated with invasive breast cancer. Citation Format: Yiyun Lin, Junke Wang, Kaile Wang, Shanshan Bai, Aatish Thennavan, Runmin Wei, Yun Yan, Jianzhuo Li, Heba Elgamal, Emi Sei, Anna Casasent, Mitchell Rao, Chenling Tang, Jessica Montalvan, Chandandeep Nagi, Sebastrian Winocour, Bora Lim, Alastair Thompson, Nicholas Navin. Normal breast tissues harbor rare populations of aneuploid epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 780.

Efficacy of Serratus Posterior Superior Intercostal Plane Block on Postoperative Pain and Total Analgesic Consumption in Patients Undergoing Reduction Mammoplasty Surgery: An Evidence Based Report.

Serratus posterior superior intercostal plane block (SPSIPB) is a novel technique that provides analgesia in shoulder, hemithorax and in the back of the neck. In this study, the efficacy of this block on postoperative pain and quality of recovery is reported in ten consecutive patients who had undergone reduction mammoplasty. Blocks were performed bilaterally with 30 ml 0.25 % bupivacaine for each side, at the end of surgery. Cumulative tramadol consumption and numerical rating scale (NRS) scores during rest (static) and coughing (dynamic) were assessed within the first postoperative 24 hours. Mean total tramadol consumption was 39 ±9.94 mg. NRS scores above 4 were observed in 5 patients in the dynamic NRS assessment at the postoperative 1st hour, while static and dynamic NRS scores were ≤4 at other durations. SPSIPB may play a part in postoperative multimodal analgesia following mammoplasty in the future and may reduce total analgesic consumption. Key Words: Serratus posterior superior intercostal plane block, Reduction mammoplasty, Breast surgery, Postoperative analgesia.

Clinical and quality of life outcomes following reduction mammoplasty for symptomatic macromastia among Sri Lankan women: A prospective observational study

Background: The impact of macromastia is unfortunately underestimated among developing South Asian countries. However, it remains a common cause of physical and emotional suffering among women. Aims and Objectives: We aimed to evaluate the efficacy of reduction mammoplasty in alleviating symptoms of macromastia and its impact on quality of life (QOL) among Sri Lanka females. Materials and Methods: A prospective study was conducted among 48 patients who underwent reduction mammoplasty in a surgical unit in Sri Lanka. SF-36 questionnaire and a Visual Analog Scale were used to assess QOL and pain. The outcomes were assessed 1 week prior and at 2 weeks and 6 months after surgery. Results: Median age was 43 years and the median body mass index was 26.8 kg/m2. The average duration of symptoms was 2 years. All patients initially were reluctant to seek medical advice. Only 10.4% of patients were aware of the availability of treatment. Wise-pattern reduction mammoplasty was performed in 79.2%. There was a significant reduction in pain following surgery. There was also an improvement in all domains of the QOL following surgery, especially in general health, pain, and physical functions. Conclusion: Reduction of mammoplasty caused a significant improvement in the overall QOL with the reduction in pain for patients suffering from macromastia. Creating more awareness among the public to encourage women to discuss breast-related symptoms and to overcome sociocultural taboos is a timely necessity.

Evaluation of nipple vascularity using superb microvascular imaging in patients with reduction mammoplasty.

We aimed to investigate the effect of the chosen pedicle on nipple vascularity by evaluating changes in the microvascular circulation of the nipples in patients undergoing reduction mammoplasty through superb microvascular imaging study (SMI). 70 nipples were included in this retrospective study. There were 15 patients (30 nipples) in Group A using the inferior pedicle and 20 patients (40 nipples) in Group B using the superomedial pedicle. The vascular index (VI) of each nipple were evaluated preoperatively and at the third postoperative month using SMI. The mean VI in Group A was 1.25 (0.5-3.6) preoperatively and 1.3 (0.4-3.2) at the third postoperative month (P > .05). The mean VI in Group B was 1.65 (0.7/2.9) preoperatively and 1.15 (0.2/1.9) at the third postoperative month (P < .05). While the VI increased by 11.3% in Group A, it decreased by 30.6% in Group B (P < .001). The changing of the VI was analyzed between comparable groups, and decreasing microvascular circulation of the nipple with use of the superomedial pedicle was detected by quantitative values, which can be useful in at-risk patient groups, the planning of surgical procedures, and early revisions at postoperative month 3.

Using Laser-Assisted Indocyanine Green Angiography to Assess Nipple-Areolar Complex Survival During Reduction Mammoplasty.

In reduction mammoplasty, preserving an appropriate skin flap is crucial to achieve a favorable postoperative appearance and prevent blood supply disorders in the nipple-areolar complex (NAC). Previous studies have indicated that a thinner or narrower flap is more favorable for breast shaping, but also increases the risk of blood supply disorders. Accessing the blood perfusion of the NAC and determining the critical threshold for NAC viability are essential aspects of reduction mammoplasty. The aim of this study was to utilize indocyanine green (ICG) angiography to assess NAC perfusion during reduction mammoplasty. It also sought to identify critical thresholds of various indicators affecting NAC survival and provide guidance for skin flap trimming. Thirty-eight patients who underwent reduction mammoplasty were included. Each patient received ICG angiography before and after skin flap trimming. Data on NAC perfusion, skin flap length, width, thickness, and other relevant indicators were collected. Among the patients, 5 experienced NAC blood supply disorders. Multiple linear regression analysis demonstrated that the NAC blood supply had a significant correlation with the tissue thickness at the pedicle base (P < .001) and with the length-to-width ratio across the nipple (P < .05). To optimize NAC survival and achieve favorable breast shaping, cutoff points for the thickness at the pedicle base and the length-to-width ratio across the nipple of 1.15 cm and 1.71, respectively, were established. ICG angiography provides an effective means to assess NAC blood supply and postoperative survival. The cutoff points established in this study help to predict the survival of the NAC and guide flap trimming.

Repigmentation of the Nipple-Areolar Complex Following Free Nipple Grafting.

Free nipple grafting (FNG) is a technique historically used during breast reduction and gender dysphoria top surgery to minimize nipple areolar complex (NAC) hypoperfusion and subsequent loss. One drawback of this approach is NAC hypopigmentation. This study seeks to quantify long-term pigmentation changes in the NAC following FNG. A retrospective review of patients who underwent reduction mammoplasty or simple mastectomy with FNG from 2000-2020 at our institution was conducted. Patients were included if they had pre-operative, early, and late post-operative images. Images were analyzed using NIH Image J software for pigmentation changes over time. Of the 151 patients identified, 56 patients (111 breasts) had complete imaging (macromastia n=47; oncologic n=4; gender dysphoria n=5). All patients had NAC hypopigmentation on early imaging, with 25.5% (SD 18.1%) of the NAC affected. On late imaging, 83 NAC (74.7%) experienced repigmentation with only 8.7% (SD 7.3%) of the NAC area remaining hypopigmented. This represents a 67.2% resolution of pigmentation (p<0.001). 10 NAC (9.0%) had progression of hypopigmentation, and 17 NAC (15.3%) had no change. In a subset analysis by race, Caucasian patients had significantly greater area of NAC hypopigmentation on early post-operative imaging (Caucasian, 29.3% (SD 18.8%) vs Black, 18.3% (SD 14.0%), p<0.01). However, resolution of hypopigmentation was similar between both. While partial hypopigmentation of the NAC is nearly universal following FNG, a majority of patients experience repigmentation with low residual hypopigmentation at 1 year. These findings are useful for counseling patients with early pigmentation changes in addition to guiding surgical decisions about breast surgery with FNG.

Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.

In estrogen receptor-positive (ER+)/HER2- breast cancer, multiple measures of intratumor heterogeneity are associated with a worse response to endocrine therapy. We sought to develop a novel experimental model to measure heterogeneity in response to tamoxifen treatment in primary breast tumors. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live normal breast specimens and human tumors immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. Live primary cell suspensions were treated ex vivo with tamoxifen (10 μmol/L) or control media for 12 hours, and single-cell RNA libraries were generated using the 10X Genomics droplet-based kit. In total, we obtained and processed normal breast tissue from two women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2- invasive breast carcinoma. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from resistant subpopulations predict poor outcomes in two large cohorts of ER+ breast cancer patients and are enriched in endocrine therapy-resistant tumors. This novel ex vivo model system now provides the foundation to define responsive and resistant subpopulations within heterogeneous human tumors, which can be used to develop precise single cell-based predictors of response to therapy and to identify genes and pathways driving therapeutic resistance.

Breast Cancer After Reduction Mammoplasty: A Population-Based Analysis of Incidence, Treatment and Screening Patterns.

The risk of breast cancer may be decreased in women who undergo reduction mammoplasty. The purpose of this study was to describe the incidence and treatment of breast cancer after reduction mammoplasty and to better understand the use of breast cancer screening modalities in these patients. This population-based retrospective analysis utilized the Discharge Abstract Database held by the Canadian Institute for Health Information and the National Ambulatory Care Reporting System to identify all women aged 20 years or older who underwent reduction mammoplasty in Alberta, Canada. The incidence and treatment of breast cancer were compared among patients who underwent reduction mammoplasty and age-sex-matched controls. Imaging utilization, including the use of mammography, ultrasound, and breast biopsy, was also compared. Between 2003 and 2007, 8021 patients over 20 years old underwent reduction mammoplasty in Alberta. Patients were followed for an average of 12.6 years. Eighty-nine (1.1%) patients who underwent reduction mammoplasty developed breast cancer after surgery, compared to 453 (1.9%) controls (P < 0.0001). Among patients diagnosed with breast cancer, there was no difference in patient and tumor characteristics. Women who underwent reduction mammoplasty were more likely to undergo mastectomy for cancer (41.6% vs 1.5%; P < 0.0001) and were more likely to undergo mammography (66.7% vs 58.7%; P < 0.0001), ultrasound (29.2% vs 26.2%; P < 0.0001) and biopsy for benign disease (7.2% vs 6%, P < 0.0001) compared to controls. Despite an increased frequency of breast cancer screening, the incidence of breast cancer is lower after reduction mammoplasty compared with women who did not undergo breast reduction. After a diagnosis of breast cancer, surgical treatment patterns differ between groups, whereby mastectomy is more common after reduction mammoplasty.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

SP05. A Novel, Patient-specific, Organotypic 3D Platform for Modeling Cell Behavior in the Setting of Malignancy

PURPOSE: With the advent of personalized cancer treatments, patient-specific in vitro models of the breast malignancies are critical for modeling the complex in vivo milieu and to better assess therapeutic efficacy. A primary challenge to developing such platforms is isolating and successfully co-culturing the many primary cell types that constitute the tumor microenvironment. In addition, optimizing for cost-effectiveness of such platforms is critical to making the technology translational. Using patient-derived cells and machine learning-based image analysis, we have developed a low-cost 3D biomimetic platform that allows for the study of cell behavior in a highly organotypic model of breast malignancy. METHODS: Stromal vascular fraction, organoids and mature adipocytes were isolated from breast tissue obtained from healthy female patients undergoing reduction mammoplasty. Isolated cells were embedded in non-ribosylated collagen, creating a biomimetic milieu that approximates the patient-specific in vivo cellular environment (“biomimetic collagen”). 3D collagen constructs consisting of a bottom layer of plain collagen or collagen embedded with RFP-tagged MDA-231 tumor cells followed by a layer of plain or biomimetic collagen were built in a 96-well plate. GFP-tagged human umbilical vascular endothelial (HUVEC) cells were plated in a monolayer layer on top of the collagen to mimic the endothelial barrier. Constructs were imaged with confocal microscopy on days 0 and 7 to assess for endothelial cell organization and migration. Image analysis was completed in Imaris. ANOVA tests for statistical significance were completed in R Studio. RESULTS: Confocal microscopy at day 0 revealed ~800μm thick constructs with distinct tumor and non-tumor collagen layers and a robust HUVEC top monolayer. Confocal images at day 7 were notable organization of the HUVEC layer into 2D tubular networks with some HUVEC below the top monolater indicating migration through the collagen matrix. Our machine-learning based approach was able to reliably and reproducibly parse HUVEC cells from the surrounding cells and collagen, allowing for quantification of cell migration in the Z-axis. Statistical analysis revealed a significant difference in migration across treatment groups (p < 0.01), with endothelial cells in the tumor and biomimetic collagen platform migrating 20-40 microns further than endothelial cells in the other construct designs, a finding retained on intergroup pairwise comparison (p < 0.01). CONCLUSION: This biomimetic platform design and image analysis allows for reliable, reproducible study of discrete endothelial cell interactions with the tumor microenvironment. The finding of enhanced HUVEC migration in the platform with both tumor and biomimetic cells is consistent with the hypothesis that stromal cells, adipocytes and malignant cells enhance the angiogenic capacity of endothelial cells. Importantly, this utilization of patient-derived stromal vascular fraction and mature adipocytes in this platform makes it inherently personalized, a vital component of any future clinically-relevant in vitro cancer platform.

Abstract P4-08-03: Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant TNBC

Abstract Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant TNBC Background and Premise: Triple-negative breast cancer (TNBC) is an aggressive, metastatic disease with high mortality. The standard-of-care neoadjuvant chemotherapy (NACT) in TNBC shows an initial response but followed by an increase in tumor relapse and distant metastases. Furthermore, metastatic TNBC (mTNBC) patients often develop resistance to NACT and targeted therapies. Immunotherapy with therapeutic antibodies such as anti-programmed death ligand-1 (PD-L1) has shown efficacy in treating a subset of TNBC patients, but currently only 20% of patients qualify for that treatment. Hence, there is an unmet need for developing a precision approach against novel actionable targets along with immunotherapy to treat mTNBC. Eukaryotic initiation factor 4A1 (eIF4A1) is an integral part of the translational machinery for many oncogenic mRNAs including survivin, c-MYC, Rho kinase1, and Cyclins D1 and D3, which all require the helicase activity of eIF4A1 for their translation. Our lab previously established that the eIF4A1 is a vulnerable target in breast cancer stem-like cells (BCSCs) and bulk tumor cells. We further demonstrated a key role for eIF4A1 in cancer stemness and drug resistance. Interestingly, we also observed a reduction in levels of PD-L1 when eIF4A1 is pharmacologically inhibited or genetically ablated. Many downstream effectors of eIF4A1 such as c-MYC, STAT1 and ARF6 (involved in recycling of PD-L1 back to the plasma membrane) are indeed upstream regulators of PD-L1 gene expression and cell surface expression of PD-L1. In this study, we examine human TNBC biospecimens for total eIF4A1 level, levels of STAT1, c-MYC, ARF6 and PD-L1. This will help establish the differential operation of the eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant primary and mTNBC. Approach: Human biospecimens were obtained from CHTN NIH repositories and now we have a collection of more than 100 TNBC tumor samples as well as some lymph node, lung and brain metastases and one sample of male breast primary tumor. These specimens are analyzed for role of eIF4A1 in translation of oncogenic mRNAs that contribute to the gene expression of immune checkpoint PD-L1 and other emerging immune checkpoint markers such as VISTA, TIGIT, and LAG3. To mimic the inclusion criteria for current PD-L1 monoclonal antibody treatment, TNBC tumors are examined for PD-L1 expression via immunohistochemistry after subjecting the samples to deglycosylation for effective detection and also by immunoblotting. Results: The levels of total eIF4A1 from 16 matched, therapy naive TNBC tissue were compared to adjacent normal breast tissue from the same patient via immunoblotting. Total eIF4A1 levels were found to be significantly elevated in TNBC compared to adjacent normal tissue. The downstream effectors of eIF4A1 such as STAT1 and ARF6 were also significantly elevated indicating a robust helicase activity of eIF4A1 in tumor samples. Importantly, PD-L1 levels was found to be elevated. Additionally, the total eIF4A1 level from tumor lysates from TNBC patients that had received a variety of NACT (i.e., patients with demonstrated drug resistance) were compared against normal untreated breast tissue from volunteers who underwent reduction mammoplasty by immunoblotting. The total eIF4A1 was found to be elevated in drug-resistant TNBC specimens compared to control, therapy-naïve TNBC samples. Conclusion: The eIF4A1-STAT1-PD-L1 axis is highly active in TNBC especially in drug-resistant situations. Currently, we are evaluating emerging immune checkpoints such as VISTA, TIGIT, and LAG3. Citation Format: Andrew Boring, Dharmindra Dulal, Dayanidhi Raman. Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant 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 P4-08-03.

Menstrual Phase and Menopausal Status Classification of Benign Breast Tissue Using Hormone-Regulated Gene Expression and Histomorphology: A Validation Study.

The validation of breast cancer risk biomarkers in benign breast samples (BBS) is a long-sought goal, hampered by the fluctuation of gene and protein expression with menstrual phase (MP) and menopausal status (MS). Previously, we identified hormone-related gene expression and histomorphology parameters to classify BBS by MS/MP. We now evaluate both together, to validate our prior results. BBS were obtained from consenting women (86 premenopausal, 55 postmenopausal) undergoing reduction mammoplasty (RM) or contralateral unaffected breast (CUB) mastectomy. MP/MS was defined using classical criteria for menstrual dates and hormone levels on the day of surgery. BBS gene expression was measured with reverse transcription quantitative polymerase chain reaction (RT-qPCR) for three luteal phase (LP) genes (TNFSF11, DIO2, MYBPC1) and four menopausal genes (PGR, GREB1, TIFF1, CCND1). Premenopausal samples were classified into LP or non-LP, using published histomorphology parameters. Logistic regression and receiver-operator curve analysis was performed to assess area under the curve (AUC) for prediction of MP/MS. In all 131 women, menopausal genes plus age>50 years predicted true MS [AUC 0.93, 95% confidence interval (CI) 0.89, 0.97]. Among premenopausal women, high TNFSF11 expression distinguished non-LP from LP samples (AUC 0.80, 95% CI 0.70, 0.91); the addition of histomorphology improved the prediction nonsignificantly (AUC 0.87, 95% CI 0.78, 0.96). In premenopausal subsets, addition of histomorphology improved LP prediction in RM (AUC 0.95, 95% CI 0.87, 1.0), but not in CUB (0.84, 95% CI 0.72, 0.96). Expression of five-gene set accurately predicts menopausal status and menstrual phase in BBS, facilitating the development of breast cancer risk biomarkers using large, archived sample repositories.

Abstract PD4-08: PD4-08 A Novel Single Cell Model of Tamoxifen Response in Primary Human Breast Tumors

Abstract A Novel Single Cell Model of Tamoxifen Response in Primary Human Breast Tumors Austin Whitman, Hyunsoo Kim, Kamila Wisniewska, Rasha Kakati, Susana Garcia Recio, Hector Franco, Charles Perou, Philip Spanheimer Background: Resistance to endocrine therapy is a primary cause of treatment failure and death in patients with estrogen receptor (ER)-positive breast cancer. Intratumor heterogeneity is associated with resistance to therapy across tumors, and specifically in ER+/HER2- breast cancer, heterogeneity in ER and PR expression is associated with a worse response to endocrine therapy. We hypothesize that subpopulations within and across ER+/HER2- human breast tumors have distinct responses to tamoxifen and that discerning heterogeneity in response will improve understanding of inherent and emerging resistance to endocrine therapy. Methods: We developed an operating room-to-laboratory pipeline immediately after surgical resection for studies using alive tissue. Tissue samples were obtained and single cell suspensions created using physical and enzymatic dissociation. Cells were treated with tamoxifen (10 M) or control media for 12 hours in suspension and single cell RNA libraries generated using the 10X Genomics droplet-based kit and sequenced using the Illumina NextSeq2000. Results: We obtained normal breast tissue from 2 women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2- invasive breast carcinoma. In tamoxifen treated and control matched pairs, a total of 22,195 cells from normal breast and 94,558 cells from tumor samples were sequenced. Computational analysis using consensus clustering was performed and cell types assigned using canonical correlation. Both tumor and normal samples identified clustering by cell type and not by patient revealing significant variability in cell type abundance between samples. In the normal breast samples, we performed differentially expressed genes (DEG) analysis comparing tamoxifen treatment to control for each cell type (Immune cells, fibroblasts, basal epithelial cells, luminal progenitor cells, and mature luminal cells) and enrichment analysis of up- and down-regulated genes performed. Strong depletion of estrogen induced genes was observed in tamoxifen-treated normal luminal progenitor and mature luminal cells, but not in basal epithelial cells or fibroblasts, demonstrating distinct, subpopulation-specific response to tamoxifen. In the 10 tumor matched pairs, 4 had a high epithelial proportion and tumor cells identified using inferred copy number variation. Tumor cells in 3 of these 4 samples showed significant down regulation of estrogen response genes with tamoxifen treatment. Using scBCSubtype to assign PAM50 subtype to individual tumor cells, the 3 responsive tumors were comprised primarily of LumA cells while the unresponsive tumor was predominantly LumB. Finally, we developed a novel score to quantify responsiveness at the single cell level based on downregulation of estrogen response genes with tamoxifen treatment relative to matched cluster-specific untreated expression. This analysis demonstrated heterogeneity in response to tamoxifen in tumor cells and identified distinct subpopulations of responsive and unresponsive tumor cells to tamoxifen treatment. Conclusion: We developed a novel ex vivo model to determine heterogeneity in therapeutic response to tamoxifen in normal human breast tissue and primary human breast tumors. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within human tumors. This provides a foundation to define features of responsive and resistant populations on the individual cell and specimen basis, and should allow us to develop precise, single cell-based predictors of response to endocrine therapy, and to identify genes and pathways driving resistance to therapy. Citation Format: Hyunsoo Kim, Austin Whitman, Kamila Wisniewska, Susana Garcia-Recio, Rasha Kakati, Hector L. Franco, Charles M. Perou, Philip Spanheimer. PD4-08 A Novel Single Cell Model of Tamoxifen Response in Primary Human Breast Tumors [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 PD4-08.

A Systematic Review of the Impact of Patient Factors on BREAST-Q Outcomes After Reduction Mammoplasty.

As reduction mammoplasty rises in popularity, it will become increasingly important to understand the patient-reported outcome measurements associated with a successful operation. There has been a growing body of literature on BREAST-Q outcomes for patients undergoing reduction mammoplasty, but meta-analyses of patient factors and BREAST-Q Reduction Module scores are lacking. This study sought to ascertain which patient factors were associated with improvements in BREAST-Q scores compared with preoperative levels. A literature review through August 6, 2021, was conducted using the PubMed database to select publications using the BREAST-Q questionnaire to evaluate outcomes after reduction mammoplasty. Studies examining breast reconstruction, breast augmentation, oncoplastic reduction, or breast cancer patients were excluded. BREAST-Q data were stratified by comorbidities, age, body mass index (BMI), complication rate, and resection weight. Among 14 articles and 1816 patients, the mean age ranged from 15.8 to 55 years, mean BMI ranged from 22.5 to 32.4 kg/m2, and bilateral mean resected weight ranged from 323 to 1845.96 g. Overall complication rate was 19.9%. On average, satisfaction with breasts improved by 52.1 ± 0.9 points (P < 0.0001), psychosocial well-being improved by 43.0 ± 1.0 points (P < 0.0001), sexual well-being improved by 38.2 ± 1.2 points (P < 0.0001), and physical well-being improved by 27.9 ± 0.8 points (P < 0.0001). The mean age was positively correlated with preoperative sexual well-being (Spearman rank correlation coefficient [SRCC]: 0.61, P < 0.05). Body mass index was negatively correlated with preoperative physical well-being (SRCC: -0.78, P < 0.01) and positively correlated with postoperative satisfaction with breasts (SRCC: 0.53, P < 0.05). The mean bilateral resected weight was significantly positively correlated with postoperative satisfaction with breasts (SRCC: 0.61, P < 0.05). No significant correlations were observed between complication rate and preoperative, postoperative, or mean change in BREAST-Q scores. Reduction mammoplasty improves patient satisfaction and quality of life as reflected by the BREAST-Q. Although preoperative or postoperative BREAST-Q scores may be individually influenced by age and BMI, these variables demonstrated no statistically significant effect on the average change between these scores. This literature review suggests that reduction mammoplasty delivers high satisfaction across a diverse range of patient populations, and additional prospective cohort or comparative studies gathering robust data on other patient factors would benefit this area of research.

Expanding Candidacy for Nipple-sparing Mastectomy in Women with Large or Ptotic Breasts: Staged Reconstruction Outcomes.

We performed a retrospective chart review of all patients who underwent reduction mammoplasty followed by NSM at our institution between January 2014 and September 2020. Clinical and surgical characteristics were collected. All surgical complications, including NAC loss rates, were analyzed. Forty-one patients (74 breasts) underwent staged NSM during the defined time period. The average time between breast reduction mammoplasty and NSM was 213 days. Overall, 94.6% of NSM resulted in successful nipple preservation. There was no significant difference in the time interval from breast reduction mammoplasty to NSM between patients who had NAC loss (208 days) and those who did not (213 days, P = 0.87). Increasing age was significantly associated with risk of NAC loss (P = 0.002) in our cohort. In women with breast ptosis (which precludes safe NSM), it is possible to first offer reduction mammoplasty to preserve the NAC for future NSM. Our data suggest that 3 months between staged procedures is a safe time frame.

Reduction Mammoplasty in the Pediatric Population: An Analysis of Pediatric NSQIP Data From 2012 to 2019

Introduction: Reduction mammoplasty is becoming more commonly performed in the pediatric population yet the risk factors for complications have not been well-studied. The purpose of this study was to assess the relationship between preoperative patient characteristics and postoperative complications in a large population of pediatric patients undergoing reduction mammoplasty. Methods: Pediatric patients undergoing reduction mammoplasty were identified within the 2012 to 2019 National Surgical Quality Improvement Program database for cross-sectional study. The predictor variables were age, body mass index (BMI), diabetes, chronic steroid use, time under anesthesia, and operative time, and the primary outcome was a 30-day postoperative surgical site-related complication. Multivariate logistic regression was performed to identify a relationship between predictor variable and primary outcome. Results: A total of 1216 pediatric patients were identified with a mean age of 16.6 years and mean BMI of 30.8 kg/m2. The incidence of overall postoperative complications was 4.6%. Superficial surgical site infection (SSI) was the most common complication (29/1216; 2.4%). BMI was significantly associated with superficial SSI (odds ratio: 1.03, 95% confidence interval: 1.00-1.05, P = .02) . Sixteen patients (1.32%) underwent a second operation, most commonly to address hematoma/seroma (7/16; 43.8%). Conclusion: In a large series of patients, pediatric reduction mammoplasty is a safe procedure with a low complication rate. BMI was significantly associated with the incidence of superficial SSIs with the most common cause for reoperation being a hematoma/seroma. This study can help guide the discussion between physicians and patients regarding potential risks associated with pediatric reduction mammoplasty.

Improving symmetry of nipple–areola complex (NAC) position in reduction mammoplasty using laser level projection

Symmetrical height of the nipple-areola complex (NAC) is a key factor in the perception of breast symmetry. For preoperative markings, we mainly rely on conventional anthropometric measurements of distances in correlation to anatomical landmarks. In this study, we evaluated whether the use of a class 2 laser projection water level would lead to better symmetry of nipple height in reduction mammoplasty procedures when used for preoperative planning. We analysed 100 patients undergoing reduction mammoplasty with a supero-medial pedicle and wise-pattern skin resection. We compared the bilateral differences in nipple height of the last 50 reduction mammoplasty procedures before using the laser projection water level (group A; no laser) with the first 50 reduction mammoplasties after implementation of this device (group B; laser). The follow-up period was 12 months. A total of 48 patients were included in group A and 44 patients in group B. Patient demographics, mean resection weight and complications did not differ statistically significantly. Nipple height differences were significantly lower in group B (laser), measuring 0.22±0.20cm (0-0.9; n=44), than those in group A (no laser; p < 0.001), measuring 0.61±0.28cm (0.2-1.2; n=49). Using laser level projection helped improve nipple height symmetry in reduction mammoplasty. We consider a difference of more than 1 cm in nipple height to be unacceptable in aesthetic reduction mammoplasty. This simple tool facilitates preoperative markings, and we find it to be safe, quick to install and very helpful in daily practice.

Outcomes of Extended Pedicle Technique vs Free Nipple Graft Reduction Mammoplasty for Patients With Gigantomastia.

Optimal reduction mammoplasty techniques to treat patients with gigantomastia have been debated and can involve extended pedicles (EP) or free nipple grafts (FNG). The authors compared clinical, patient-reported, and aesthetic outcomes associated with reduction mammoplasty employing EP vs FNG. A multi-institutional, retrospective study of adult patients with gigantomastia who underwent reduction mammoplasty at 2 tertiary care centers from 2017 to 2020 was performed. Gigantomastia was defined as reduction weight >1500 g per breast or sternal notch-to-nipple distance ≥40 cm. Surgeons at 1 institution employed the EP technique, whereas those at the other utilized FNG. Baseline characteristics, preoperative and postoperative BREAST-Q, and clinical outcomes were collected. Aesthetic outcomes were assessed in 1:1 propensity score-matched cases across techniques. Preoperative and postoperative photographs were provided to reviewers across the academic plastic surgery continuum (students to faculty) and non-medical individuals to evaluate aesthetic outcomes. Fifty-two patients met the inclusion criteria (21 FNG, 31 EP). FNG patients had a higher incidence of postoperative cellulitis (23% vs 0%, P < 0.05) but no other differences in surgical or medical complications. Baseline BREAST-Q scores did not differ between groups. Postoperative BREAST-Q scores revealed greater satisfaction with the EP technique (P < 0.01). The aesthetic assessment of outcomes in 14 matched pairs of patients found significantly better aesthetic outcomes in all domains with the EP procedure (P < 0.05), independent of institution or surgical experience. This multi-institutional study suggests that, compared with FNG, the EP technique for reduction mammoplasty provides superior clinical, patient-reported, and aesthetic outcomes for patients with gigantomastia.

Predictive risk factors of complications in reduction mammoplasty-analysis of three different pedicles.

BackgroundReduction mammoplasty can be performed in several different techniques. Understanding the complication profile and risk factors in different reduction methods can help in choosing a technique, which serves the patient best. The authors present their experience of three different reduction techniques [superomedial pedicle (SMP), superior pedicle (SP) and inferior pedicle (IP)] with an emphasis on predictors of complications.MethodsA retrospective review of a prospectively maintained database of breast reductions between 2014 and 2020 was performed. Patient’s demographics [age, body mass index (BMI), comorbidities, smoking, nipple to sternal notch distance (N-SN)], operative details (pedicle, tissue resected, drains, operating surgeon) and complications according to Clavien-Dindo classification were assessed. Study variables were compared against overall complication rates for the three techniques.ResultsIn total, 760 patients underwent reduction mammoplasty, including 578 (76%) bilateral and 182 (24%) unilateral operations. Of patients, 477 (63%) were operated with SMP, 201 (26%) with IP and 82 (11%) with SP. An average weight of resected tissue per breast was 460 g. Overall complication rate was 38%. The rate was higher in IP group (50%) compared to SMP (36%) and SP (22%) groups (P<0.001). Complications were mainly minor and related to delayed wound healing. The rate for major complications was 4%. Multivariable analysis showed that complications were associated independently with IP [odds ratio (OR) 1.89, 95% confidence interval (CI): 1.33–2.69], age <50 years (OR 1.87, 95% CI: 1.32–2.65), bilateral operation (OR 1.67, 95% CI: 1.00–2.76) and resected tissue weight ≥650 g per breast (OR 2.02, 95% CI: 1.36–2.99). Each factor contributed 1 point in the creation of a risk-scoring system. The overall complication rate was increased as the presence of statistically significant risk factors (IP, age <50, bilateral operation and/or resected tissue ≥650 g per breast) increased (31%, 38%, 59% and 90% for number of 1, 2, 3 and 4 risk factors respectively, P<0.001).ConclusionsThe rate of complication can be predicted by a risk-scoring system. In increasing variety of patients undergoing reduction mammoplasty, careful consideration of the best operation technique is important to prevent complications and costs.