Obese Breast Cancer Patients Research Articles

Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer

As two diseases with rapidly increasing incidence, the molecular linkages between obesity and breast cancer (BC) are intriguing. Overall, obesity may be a negative prognostic factor for BC. Single-cell RNA-sequencing (scRNA-seq) was performed on tumor tissues from 6 obese and non-obese BC patients. With 48,033 cells analyzed, we found heterogeneous tumor epithelium and microenvironment in these obese and lean BC patients. Interestingly, the obesity-associated epithelial cells exhibited specific expression signatures which linked tumor growth and hormone metabolism in BC. Notably, one population of obesity-specific macrophage up-regulated the nuclear receptor subfamily 1 group H member 3 (NR1H3), which acted a transcription factor and regulated FABP4 expression through its interaction with the DNA of SREBP1, and further increased the proliferation of tumor cells in BC. Using single-cell signatures, our study illustrate cell diversity and transcriptomic differences in tumors from obese and non-obese BC patients, and sheds light on potential molecular link between lipid metabolism and BC.

Obesity in breast cancer patients after oncological treatment. How to conduct a nutritional intervention?

Obesity in breast cancer patients after oncological treatment. How to conduct a nutritional intervention?

Clinical Performance Evaluation of Ambu AuraGain versus I-gel in Obese Female Patients Undergoing Short-duration Surgeries for Breast Cancer: A Randomised Controlled Trial

Background and Aims: Supraglottic airway devices (SADs) secure and maintain airways in patients undergoing breast cancer surgery. I-gel and Ambu AuraGain (AAG) are two common second-generation SADs used. However, data comparing their efficacy are limited in adult obese breast cancer patients. This study was planned with the primary objective of comparing the oropharyngeal leak pressure (OLP) of these two SADs at 1 min after insertion. Methods: A total of 80 patients scheduled for breast cancer surgery were recruited and randomised into two groups: Group A (AAG) and Group I (I-gel). The insertion time of the SADs, the number of insertion attempts, the OLP at 1 min after insertion, the ease of insertion, the fibre-optic bronchoscopy view (FOB), the ease of suction catheter placement, additional manipulation during insertion and maintenance, the OLP at 30 min after insertion and complications, etc., were assessed. Results: OLP was significantly higher (P < 0.05) in Group I compared to Group A at 1 min and 30 min after the SAD placement. Ease of insertion and FOB view score were significantly better in Group I than in Group A (P < 0.05). Moreover, patients in Group A reported a higher incidence of sore throat compared to Group I patients (P < 0.05). Conclusion: The I-gel demonstrated superior sealing pressures and mitigated sore throat significantly compared to the AAG in obese female patients undergoing breast cancer surgery. Furthermore, as confirmed by FOB, its enhanced perilaryngeal positioning underscores its efficacy over the AAG in this patient demographic.

Reviewing the recurrence rates in stage I-III HR or ER positive breast cancer in obese patients given multi-modal weight loss plan post-treatment with aromatase inhibitors.

15 Background: Aromatase inhibitors (AIs) in the treatment of endocrine recepter positive breast cancer stages I-III, poses significant challenges in the management of obesity. Obesity is not only associated with an increased risk of breast cancer incidence but also with higher rates of cancer recurrence and poorer treatment outcomes. Moreover, the use of AIs, while effective in reducing estrogen levels and preventing ER or HR positive breast cancer recurrence, may exacerbate weight gain and metabolic disturbances in obese individuals. Weight management strategies have experienced increased attention in breast cancer survivors in recent years, especially overweight or obese individuals. Novel data makes it possible to infer that obesity management activities and multimodal programs that incorporate dietary counseling and physical activity can reduce recurrence rates. Methods: Participants in this study were individuals with Stage I-III endocrine receptor positive breast cancer who had completed adjuvant therapy and had a BMI in the 40s or 50s, increasing risk of recurrence. Eligible patients were identified based on the start date for endocrine therapy. High-risk patients were then assigned to either the intervention or control group. Those in the intervention group received access to a dietician, along with informational pamphlets on physiology and weight loss strategies. Additionally, they were offered discounts to certain gyms or provided free access to fitness facilities. Both intervention and control groups were briefed about the study, with those in the intervention group encouraged to utilize the provided resources for weight management. Results: The evidence from our study will underscore the potential benefits of multimodal weight loss interventions in overweight or obese breast cancer survivors, particularly in improving anthropometric outcomes and enhancing overall quality of life. Conclusions: While the studies included in our analysis demonstrated reductions in body weight, BMI, and waist circumference, as well as improvements in quality of life measures, there remains a notable gap in understanding the impact of these interventions on breast cancer recurrence rates, especially in the context of endocrine-positive breast cancer treated with Aromatase Inhibitors (AIs).

Abstract PO5-28-01: Dynamics of Adipocyte Progenitors in the Mammary Gland during Obesity

Abstract Being overweight or obese is associated with a higher risk of breast cancer (BC) and worse disease-free and overall survival compared to normal-weight BC patients. The underlying biological basis for this association is attributed to alterations in the endocrine and inflammatory milieu of adipose tissue. However, existing chemotherapy and endocrine therapy are not effective in obese BC patients. There is a critical need to pin down adipose tissue cell types that may govern increased BC risk and adverse outcome in obesity. Adipocyte progenitors are immature mesenchymal cells in adipose tissue that have adipocyte differentiation potential and reported to be dysfunctional in obesity. In previous research, we first reported mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFRα) in the stromal microenvironment that transition into epithelial lineages during expansion of the murine mammary epithelium. The contribution of MAPs to shaping a pro-tumorigenic mammary tissue milieu in obesity is not known. Here, using diet-induced obesity MAP reporter and lineage tracing mouse models combined with single-cell RNA sequencing, we reveal elevated PDGFRα+ MAPs in the local mammary stroma in obesity. MAPs in the obese mammary gland manifest alterations in proliferation, cell state and molecular mechanisms, generating an inflammatory, cancer-prone tissue microenvironment. Our findings uncover the MAP lineage as a key contributor to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell population for eradicating BC risk related to augmented adiposity. Citation Format: Sharon Kwende, Prashant Nuthalapati, Dun Ning, Jacqulene Sunder Singh, Purna Joshi. Dynamics of Adipocyte Progenitors in the Mammary Gland during Obesity [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 PO5-28-01.

Abstract PO1-25-07: Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment

Abstract Objective: Breast cancer is the most frequently diagnosed cancer and a common cause of cancer related death in women. The breast cancer microenvironment (TME) is mainly composed of adipose tissue, consisting of adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells. Interestingly, it is well recognized that obesity, as indicated by increased body mass index (BMI≥30), is associated with an enhanced risk of more aggressive breast cancer (BC) as well as reduced patient survival. Therefore, we asked how BC affects the biological functionality of bASC, how obesity fuels this process, and on the other hand how these cells influence BC cells. Methods: Multiple molecular biological approaches as transcriptomic profiling and diverse functional assays were conducted to characterize at least 5 lean and obese patients derived bASCs samples near the TME (lean/obese-aT) or distant (lean/obese-dT). Afterwards, these cells were used to investigate the interaction with BC cells in 2-dimensional and 3-dimensional cell culture experiments. Moreover, immunohistological analyses were conducted in 16 lean and 16 obese breast cancer patients (grade 3-4). Results: The TME shifts bASCs towards cancer supporting phenotypes into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype with a significant deregulated gene expression, cytokine/chemokine secretion, and reduced differentiation capacity. In corroberation, these BMI dependent de-differentiation processes could be confirmed in breast cancer tissue. Moreover, the cell-cell interaction of BC cells with aT-bASCs increased their proliferation, motility, and chemoresistance. Conclusions: The study found multiple pathways deregulated in bASCs associated with tumor promoting effects. Additionally, it revealed the role of aT-bASCs in promoting breast cancer progression on a functional and molecular level. Citation Format: Andreas Ritter, Christine Solbach, Juping Yuan. Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment [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 PO1-25-07.

Downregulation of the circadian clock gene period 2 aggravates prognosis in breast cancer patients with obesity

Abstract Background Obese individuals diagnosed with breast cancer often experience a less favorable prognosis; however, the underlying mechanisms linking obesity to breast cancer outcomes remain elusive. This study aimed to identify and validate novel prognostic markers associated with breast cancer in patients with obesity. Methods We conducted a reanalysis of gene expression profiles from normal-weight, overweight, and obese breast cancer patients to identify candidate genes. Subsequently, we validated the protein levels of these candidates using immunohistochemistry. Finally, we investigated the association between candidate genes and breast cancer prognosis at Tongji Hospital, utilizing data from an 8-year follow-up through the Kaplan-Meier method and univariate and multivariate Cox regression models. Results The fold change of the circadian clock gene period 2 (PER2), which exhibited a declining trend with increasing body mass index, was 0.76 in obese patients compared with normal-weight patients. The expression rates of PER2 protein were 44.7%, 51.5%, and 61.3% in normal-weight, overweight, and obese patients, respectively. The 8-year recurrence-free survival rates were 75.9%, 69.6%, and 64.1%, whereas the 8-year overall survival rates were 86.8%, 83.0%, and 76.1% in normal-weight, overweight, and obese patients, respectively (P < 0.05). Furthermore, the 8-year recurrence-free survival rates were 66.2% and 76.4%, and the 8-year overall survival rates were 79.9% and 86.3% in the low and high PER2 expression groups, respectively (P < 0.05). The unadjusted hazard ratio for PER2 was 1.550 (95% confidence interval, 1.029–2.335), and the adjusted hazard ratio was 3.003 (95% confidence interval, 1.838–4.907). Conclusions Our findings indicate that low PER2 expression serves as an independent risk factor for breast cancer prognosis and may contribute to the unfavorable outcomes observed in obese patients.

The impact of BMI on breast cancer - an updated systematic review and meta-analysis.

Breast cancer is the most frequent form of cancer in women all over the world. It is the main cause of cancer death and the most often diagnosed cancer in women in 140 of the world's 184 countries. The link between breast cancer risk and body mass index (BMI) has gotten increasing attention in recent years, although the results are still debatable. Therefore, the current systematic review and meta-analysis evaluate the impact of BMI on breast cancer. The current study was carried out as a systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched Cochrane, Google Scholar, PubMed, EMBASE and Scopus databases to identify eligible articles impact of BMI on breast cancer with the appropriate Medical Subject Headings (MeSH). The Newcastle-Ottawa checklist was used for the risk of assessment for the included studies. Meta-analysis was performed using Review Manager 5.3 software. Forty-six studies were included in the current review, which met the selection criteria of the current review. Among included 46 studies in this review, 50% (n = 23) of the studies found the HER2 type of breast cancer followed by triple-negative and HR-positive. The obesity was significantly higher in the case group compared with the control group (P < .001). Heterogeneity between the 14 studies is medium (I2 = 72%). In this review, there was no significant relation between overweight and breast cancer in women (P > .05). Heterogenecity between the 14 studies is medium (I2 = 89%). However, after removing the publication bias a significant relation between overweightness and breast cancer in women (P = .0005) was observed. Obese breast cancer patients are a specific type of patient. They are more likely to develop cancer. Their need to surgery and radiation may cause greater difficulties. Obesity and overweight in women greatly increase the risk of breast cancer, according to the findings of the current meta-analysis. To confirm these findings and understand the pathogenic pathways, more research is required.

Towards Understanding the Development of Breast Cancer: The Role of RhoJ in the Obesity Microenvironment.

Obesity is a growing pandemic with an increasing risk of inducing different cancer types, including breast cancer. Adipose tissue is proposed to be a major player in the initiation and progression of breast cancer in obese people. However, the mechanistic link between adipogenicity and tumorigenicity in breast tissues is poorly understood. We used in vitro and in vivo approaches to investigate the mechanistic relationship between obesity and the onset and progression of breast cancer. In obesity, adipose tissue expansion and remodeling are associated with increased inflammatory mediator's release and anti-inflammatory mediators' reduction.. In order to mimic the obesity micro-environment, we cultured cells in an enriched pro-inflammatory cytokine medium to which we added a low concentration of beneficial adipokines. Epithelial cells exposed to the obesity micro-environment were phenotypically transformed into mesenchymal-like cells, characterized by an increase in different mesenchymal markers and the acquisition of the major hallmarks of cancerous cells; these include sustained DNA damage, the activation of the ATR-Chk2 pathway, an increase in proliferation rate, cell invasion, and resistance to conventional chemotherapy. Transcriptomic analysis revealed that several genes, including RhoJ, CCL7, and MMP9, acted as potential major players in the observed phenomenon. The transcriptomics findings were confirmed in vitro using qRT-PCR and in vivo using high-fat-diet-fed mice. Our data suggests RhoJ as a potential novel molecular driver of tumor development in breast tissues and a mediator of cell resistance to conventional chemotherapy through PAK1 activation. These data propose that RhoJ is a potential target for therapeutic interventions in obese breast cancer patients.

Does Haematological Toxicity Increase with the Use of Lipophilic Chemotherapeutic Agents in Obese Breast Cancer Patients?

Does Haematological Toxicity Increase with the Use of Lipophilic Chemotherapeutic Agents in Obese Breast Cancer Patients?

Nonmetastatic Axillary Lymph Nodes Have Distinct Morphology and Immunophenotype in Obese Patients with Breast Cancer at Risk for Metastasis

Obese breast cancer patients have worse outcomes than their normal weight counterparts, with a 50% to 80% increased rate of axillary nodal metastasis. Recent studies suggest a link between increased lymph node adipose tissue and breast cancer nodal metastasis. Further investigation into potential mechanisms underlying this link may reveal potential prognostic utility of fat-enlarged lymph nodes in breast cancer patients. This study uses a deep learning model to identify morphological differences in non-metastatic axillary nodes between obese, node-positive and node-negative breast cancer patients. The model was developed using nested cross-validation on 180 cases and achieved an AUC of 0.67 in differentiating patients using hematoxylin and eosin stained whole-slide images. The top predictive patches from the slides according to the model were reviewed by a pathologist and their morphological differences were quantified. This analysis showed an increased average adipocyte size (p-value=0.004), increased white space between lymphocytes (p-value<0.0001), and increased red blood cells (p-value<0.001) in non-metastatic lymph nodes of node-positive patients. Preliminary immunohistochemistry analysis on a subset of 30 patients showed a trend of decreased CD3 expression and increased leptin expression in fat-replaced axillary lymph nodes of obese, node-positive patients. These findings suggest a novel direction to further investigate the interaction between lymph node adiposity, lymphatic dysfunction, and breast cancer nodal metastases, highlighting a possible prognostic tool for obese breast cancer patients.

The impact of low muscle mass and strength on chemotherapy toxicity in women with early breast cancer.

9 Background: Systemic anticancer therapy is indicated in particular patients with early breast cancer (EBC) before or after surgery to eradicate micrometastatic spread and reducing the risk of recurrence. Muscle mass and strength were related to chemotherapy toxicity in cachexia patients. However, there is limited data about the impact of low muscle mass and strength in normal or obese breast cancer patients on chemotherapy toxicity. Methods: A prospective cohort study of women with EBC in whom adjuvant or neo-adjuvant chemotherapy was planned. The subjects were evaluated the muscle mass using bioelectrical impedance analysis, muscle strength using JAMAR hand grips strength, and body mass Index (BMI). The validated cut off of low muscle mass and strength were derived from Indonesian healthy population aged 20-40 years old. The outcome is to know chemotherapy toxicity in the first 3 cycles of chemotherapy, evaluated using National cancer Institute (NCI) common terminology criteria for adverse events version 5.0. The performance status, comorbidity, menopause status, chemotherapy regiment, diet intake, and physical activity were also evaluated to adjust the relationship using logistic regression multivariate analysis. Results: A total of 72 EBC patients were who come to secondary referral cancer center were included. Median of age was 47(25- 59) year old. Most subjects were in normal weight criteria, 26(36.1%) were in obese criteria. The mean of BMI, muscle mass, and muscle strength were 23.73+4.02, 5.61+1.23, 15,32+6.16, respectively. Low muscle mass and strength were observed in 34(55.7%) and 24(39.3%), respectively. Low muscle mass was only associated with chemotherapy toxicity after 3rd cycles of chemotherapy with relative risk (RR) 2.667(1.235-5.757). Low muscle strength was only associated with chemotherapy toxicity after 3rd cycles of chemotherapy with RR 4.206(1.168-15.143). After adjusted with performance status, comorbidity, menopause status, chemotherapy regiment, diet intake, and physical activity, low muscle mass and strength were associated with chemotherapy toxicity after 3rd cycles of chemotherapy with odds ratio 11(1.730-69.956) and 14.625(2.191-97.612), respectively. Conclusions: Low muscle mass and strength were associated with chemotherapy toxicity after three cycles of chemotherapy in women with EBC.

Prevalence and influence of overweight and obesity on clinical and epidemiological profile of breast cancer patients in the North of Mato Grosso, Brazil: a retrospective cross-sectional study

Obesity is one of the main preventable risk factors in post-menopausal breast cancer. This retrospective cross-sectional study aimed to demonstrate the clinical and epidemiological profile of breast cancer patients diagnosed in the period from 2013 to 2018 in the North of Mato Grosso, Brazil and to verify the prevalence and influence of overweight and obesity in these patients. Data were collected from patient’s medical records who were diagnosed with breast carcinoma in the Department of Oncology of Santo Antônio’s Hospital, in Sinop-MT. 196 patients were included. 99.5% were women. The majority were married, ≥50 years old (57.7%) and overweight or obese. In the overweight and obesity group the percentage of patients with invasive breast carcinoma were significantly higher when compared with eutrophic group (p=0.03). In all groups the profile of estrogen and progesterone receptors positive and HER-2 negative were more prevalent, however, the frequency of triple negative profile was higher in the overweight (7.1%) and obesity (6.3%) group when compared with control (4.3%) group, as well as the presence of hypertension and diabetes. In conclusion, it was observed a high prevalence of overweight and obesity in breast cancer patients, which contributed to modify the histological type of breast cancer (high prevalence of invasive and lobular carcinomas), increase the frequency of patients in stages 3 and 4, the percentage of triple negative profile and the frequency of other comorbidities, as hypertension and diabetes. Furthermore, metformin, an antidiabetic drug, seems to be contributing to reduce tumor development and improve the clinical profile and prognosis in diabetic breast cancer patients.

Abstract 5916: Weight loss intervention triggered gut microbiota modulation can positively impact obesity associated endocrine therapy resistance

Abstract Background: 41.9% of adult US population is obese and every 5-unit BMI increase is associated with 12 percent increase in breast cancer risk; it is an independent predictor of poor outcomes in breast cancer. Microbiome has emerged as a central regulator of obesity and we recently discovered that microbes can not only potentiate breast cancer growth and metastasis but also affect therapeutic response. We showed weight-loss by Diet/Exercise/Behavioral intervention (POWER-remote trial) exerts favorable effects. Here, we examine molecular underpinnings of poor therapy response in obese state and explore the gut microbiome to mitigate the same. Methods: We co-implanted lineage determined human White preAdipocytes (hWAT) with MCF7 breast cancer cells in the mammary glands of mice. Changes in tumor microenvironment and tumor cells were evaluated ex situ by RNA sequencing, flow cytometry, Raman spectroscopy, Quantitative phase microscopy, PCR, immunoblotting and functional assays. To inspect the gut microbiome, 16 obese breast cancer patients were subjected to weight loss intervention over 14 weeks. Gut microbiome was analyzed at baseline and post-intervention by microbial shotgun sequencing. Patients were divided into responders and non-responders based on % weight-loss. Results: We found that human breast cancer cells co-implanted with hWAT formed more aggressive tumors compared to controls. RNA sequencing revealed significant upregulation of multiple oncogenic pathways along with robust innate immune response. Tumor dissociated cells from hWAT-MCF7 tumors showed extensive molecular reprogramming rendering them more proliferative, motile and stem-like along with dramatic physiological changes like increased intercellular lipid accumulation. hWAT-MCF7 cells attained resistance to multiple drugs including Tamoxifen, Fulvestrant, Letrozole and Palbociclib. Simultaneous targeting of multiple signaling pathways using pharmacological inhibitors is infeasible in clinical setting hence we explored the obesity-microbiome axis. Obese breast cancer patients underwent POWER-remote intervention and their gut microbiome analysis showed significant differential expression of many microbes. Based on abundance and metabolite profile, F. prausnitzii was selected as the candidate of interest. On treatment with F. prausnitzii growth media, acquired multi-drug resistance in hWAT-MCF7 cells could be reversed suggesting that increase in gut population of the bacterium could be helpful in sensitizing patients unresponsive to therapy. Conclusion: Direct interaction between breast cancer cells and WAT rendered them resistant to multiple drugs. Metabolites produced by weight-loss-associated bacterium F. prausnitzii reversed adiposity-induced multi-drug resistance, hence, can potentially have therapeutic benefits in obese breast cancer patients. Citation Format: Sheetal Parida, Sumit Siddharth, Nethaji Muniraj, Zhenhui Liu, Ishan Barman, Michael Smith, Jenni Sheng, Vered Stearns, Janelle W. Coughlin, Dipali Sharma. Weight loss intervention triggered gut microbiota modulation can positively impact obesity associated endocrine therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5916.

Does body mass index influence surgical options and overall survival in breast cancer patients?

Obesity is a relevant risk factor in breast cancer (BC), but little is known about the effects of overweight and obesity in surgical outcomes of BC patients. The aim of this study is to analyse surgical options and associated overall survival (OS) in overweight and obese women with BC. In this study, 2143 women diagnosed between 2012 and 2016 at the Portuguese Oncology Institute of Porto (IPO-Porto) were included, and the clinicopathological information was retrieved from the institutional database. Patients were stratified by body mass index (BMI). Statistical analysis included Pearson's chi-squared test with statistical significance set at p < 0.05. Multinomial, binary logistic regression and cox proportional-hazards model were also performed to calculate odd ratios and hazard ratios with 95% confidence intervals for adjusted and non-adjusted models. The results revealed no statistical difference in histological type, topographic localization, tumour stage and receptor status and in the number of surgical interventions. Overweight women have increased probability to be subjected to sentinel node biopsy. Obese and overweight women are more likely to be submitted to conservative surgery and contrariwise, less likely to undergo total mastectomy. Patients submitted to conservative surgery and not submitted to total mastectomy had a favourable OS although without statistical significance. No significant differences were observed in OS when stratified by BMI. Our results revealed significant variations regarding the surgical options in overweight and obese patients, but these were not translated in OS difference. More research is recommended to better address treatment options in overweight and obese BC patients.

Obesity and breast cancer

The paper presents an analysis of the latest literature data on the problem of obesity and breast cancer (BC). This review presents modern approaches to the diagnosis of BC in obese patients, new molecular methods of breast imaging, analyzes the features of the course of BC with obesity depending on menstrual status, molecular biological subtypes of the tumor, the mechanisms of the development of BC against the background of obesity.

Mitigating Breast Cancer Disparities by Addressing the Obesity Epidemic.

Purpose of ReviewObese breast cancer patients have poorer outcomes compared to non-obese patients. The intent of this review is to discuss recent studies and analyses regarding the status of the obesity epidemic and its effect on breast cancer incidence and outcomes. Subsequently, we will introduce a program implemented at a New York City hospital to reduce the morbidity and mortality of breast cancer patients with obesity.Recent FindingsThe prevalence of obesity among adult Americans is 42%, spanning all racial and socioeconomic groups. Importantly, obesity is associated with multiple chronic diseases including cancer. Among breast cancer patients, obesity is linked to higher mortality and poorer clinical outcomes, including but not limited to distant recurrence and secondary malignancies.SummaryCurrent treatment of breast cancer patients does not address the link between obesity and poorer prognosis. Here, we present a general strategy for reducing the morbidity and mortality of obese breast cancer patients by addressing the obesity epidemic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12609-022-00460-4.

Effects of Single Nucleotide Polymorphisms and Mediterranean Diet in Overweight or Obese Postmenopausal Women With Breast Cancer Receiving Adjuvant Hormone Therapy: A Pilot Randomized Controlled Trial.

Background and AimsWeight management is recommended in overweight or obese breast cancer patients, as they have an increased risk of cancer recurrence and poor prognosis. Furthermore, identifying the relationships between genetic factors and nutrition could help suggest possible individualized nutritional solutions in weight management. The objective of this pilot randomized controlled trial was to investigate the influence of two obesity-associated single nucleotide polymorphisms and the Mediterranean diet intervention on weight loss and modification of nutrient intake and metabolic parameters in overweight or obese, postmenopausal, breast cancer patients receiving adjuvant hormone therapy.MethodsSeventy-eight breast cancer patients were randomly assigned to the Mediterranean diet (MeDiet) group or control group, and seventy-one were finally analyzed. Body composition, nutrient intake, and metabolic parameters were assessed at baseline and after the 8-week intervention. Fat mass and obesity-associated (FTO) rs7185735 and melanocortin-4 receptor (MC4R) rs476828 variants were genotyped.ResultsWe found that both variants did not influence weight loss or improvement of metabolic parameters within the Mediterranean diet intervention. Intake of saturated fatty acid (SFA) and trans fat was significantly increased in C carriers compared with the TT genotype of MC4R rs476828 only in the control group (p = 0.002 for SFA; p = 0.016 for trans fat), whereas no significant difference was observed between genotypes in the MeDiet group. There were statistically significant interactions between MC4R rs476828 and dietary intervention for changes in SFA intake (p = 0.009) and trans fat intake (p = 0.049).ConclusionOur data suggest that considering the effects of genotype may be more necessary when the Mediterranean diet is not followed and that this diet may have a protective role against the effects of certain genotypes. Further studies are required to determine the potential mechanism of the observed gene-diet interaction.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT04045392].

Abstract 724: Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis

Abstract Obesity significantly increases risk of breast cancer development, and following diagnosis, obese breast cancer patients have an overall worsened prognosis. The complex relationship of obesity to breast cancer growth and aggressiveness must continue to be examined. Within breast adipose tissue, obesity causes a state of chronic, macrophage-driven inflammation. Chronic inflammation is associated with increased extracellular matrix (ECM) deposition. Increased collagen within the mammary microenvironment is a risk factor for tumor formation, as well as more aggressive tumors, in mouse models. In breast tumors from obese patients, tumor desmoplasia is also found to be increased. To better understand how obesity affects mammary tumor growth, inflammation, and fibrosis, we used a diet-induced obesity mouse model paired with the estrogen receptor alpha (ERα)+ TC2 mammary tumor cell line in female FVB mice. We observed that TC2 mammary tumors grew significantly faster in obese mice compared to lean mice and had significantly more macrophage infiltration. TC2 tumors from obese mice also had significantly more collagen deposition than TC2 tumors from lean mice, indicating that obesity leads to more fibrotic tumors. To identify how weight loss alters the mammary gland and mammary tumor microenvironments, obese mice were switched from a high-fat diet to a low-fat diet for six weeks, to induce weight loss. In non-tumor-bearing mammary glands, weight loss led to a significantly decreased number of crown-like structures, a marker of adipose tissue inflammation, similar to observations in human adipose tissue. TC2 mammary tumors grew at an intermediate rate between tumors from lean and obese mice, indicating that weight loss may be a viable option to reduce tumor aggressiveness, particularly for obese patients with other breast cancer risk factors. Understanding these weight-related changes in the mammary gland and mammary tumor microenvironments will provide greater insight into possible interventions for obese breast cancer patients. Citation Format: Genevra M. Kuziel, Lisa M. Arendt. Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 724.

Abstract 3200: Examining the role of obesity and leptin signaling in triple negative breast cancer

Abstract Individuals with a high body mass index (BMI) have an increased risk of developing many adult cancers, including breast cancer. In triple negative breast cancer (TNBC), a clinically aggressive subtype of breast cancer, increased BMI is associated with more aggressive tumor types and a higher risk of recurrence. The differences in outcomes between obese and non-obese breast cancer patients is a consequence of the complex interplay between social, environmental, and physiological factors that contribute to the etiology of breast cancer. Therefore, understanding the complex signaling events in the obese tumor microenvironment is essential. Adipose stem cells (ASCs) are a component of the breast microenvironment, and are a subset of mesenchymal stem cells. ASCs from obese patients (obASCs) secrete higher levels various cytokines and adipokines that induce a more invasive phenotype in triple negative breast cancer cells compared to ASCs from lean individuals. Leptin, an adipokine that is expressed proportionally to fat mass, has been implicated in many cancers. Increased leptin and leptin receptor expression is associated with worse prognosis. This study seeks to examine the role of leptin signaling in triple negative breast cancer. Previous work in conjunction with a collaborating lab has shown that leptin signaling promotes metastasis and increased expression of epithelial-mesenchymal transition (EMT) markers in triple negative breast cancer. This project expands upon this work through using both patient-derived cell lines and and patient-derived xenografts (PDX), and examines the role of leptin signaling both in vitro and in vivo. To determine the effects of obesity upon a PDX model, a high fat diet was used to induce obesity in vivo. Exposure to conditioned media harvested from obASCs increased the percentage of TNBC cells that expressed cancer stem cell markers, whereas exposure to a small peptide antagonist of the leptin receptor decreased the percentage of cells with CSC markers. PDX tumors implanted into diet-induced obesity mice had an increased volume compared to tumors implanted into lean controls. Conclusions: These molecular differences may contribute to the differences in cancer outcomes between obese and lean individuals with breast cancer, and further study of the crosstalk between obASCs and TNBC is critical. Citation Format: Courtney Brock, Maryl Wright, Khoa Nguyen, Katherine Hebert, Madlin Alzoubi, Thomas Cheng, Bridgette Collins-Burow, Matthew Burow. Examining the role of obesity and leptin signaling in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3200.