Breast Cancer In Premenopausal Women Research Articles

Effect and acceptability of jasmine compound essential oil for premenopausal breast cancer survivors suffering from genitourinary syndrome of menopause: A prospective interventional study.

1063 Background: Genitourinary syndrome of menopause (GSM) includes dyspareunia, vaginal dryness, vaginal burning, urinary urgency, and recurrent urinary tract infections. Breast cancer survivors (BCSs) exhibit more severe symptoms of GSM than healthy aging women, especially premenopausal BCSs in sexually active lifetime. GSM detrimentally impacts their quality of life and contributes to the premature cessation of endocrine therapy for breast disease. This study aims to explore the efficacy and safety of Jasmine compound essential oil in the treatment of GSM in premenopausal breast cancer women. Methods: Premenopausal sextually-active women with hormone receptor (HR) positive stage I to III BC taking ovarian function suppression (OFS) treatment and endocrine therapy with self-reported vaginal dryness, dyspareunia, or decreased libido were enrolled to the 12 weeks topically applied Jasmine compound essential oil trial. E2 and FSH was measured at baseline and weeks 12. A series of validated sexual quality-of-life questionnaires were completed at baseline, and subsequently at weeks 4, 8, and 12. The primary endpoint is the improvement in sexual pain evaluated based on the Female Sexual Function Index scale (FSFI). Acceptability was measured by patient preference and reported intention to continue using the products. Gynecologic examinations and metagenomic profiling of the vaginal microbiota were conducted at baseline and post-treatment for patients in an exploratory cohort. Results: Overall, 96 BCSs signed consent (mean [range] age, 45 [32-55] years) and 89 completed 12 weeks of treatment. E2 and FSH were maintained within the postmenopausal range without significant fluctuations during the treatment. Topically applied Jasmine compound essential oil resulted in significant improvements in dyspareunia, vaginal dryness, irritation and quality of life over time (all P< 0.001). Both BCSs and their sexual partners reported being satisfied with the essential oil treatment and the adherence rate reached 95% (SD 10). In the 20-patient exploratory cohort, there were improvements in vaginal pH (baseline mean 6.07 compared with 12-week mean 4.68[ P<.001]), and vaginal maturation index (45.3 compared with 52.1[ P<.001]). We also observed a positive influence on the vaginal microbiota after intervention. In patients with elevated baseline abundance of Lactobacillus in the vaginal microbiome, there was a more pronounced improvement in scale scores following essential oil access. Conversely, a high baseline abundance of Escherichia coli may be considered a detrimental factor associated with less benefit from essential oil. Conclusions: Jasmine compound essential oil could relieve vaginal symptoms and improve vaginal health in breast cancer survivors who have experienced menopause after cancer treatment.

Red Wine as an Aromatase Inhibitor: A Narrative Review.

As estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than serum estrogen, aromatase inhibitors for treating breast carcinomas in postmenopausal women have been developed. As the aromatase enzyme converts endogenous androgen to estrogenic compounds, its blockade lowers the in situ production of estrogen, demonstrated to encourage tumor proliferation. Red wine, but not white wine, may have aromatase-inhibiting properties that are being elucidated, although the exact mechanisms of action are not known. Polyphenols, tannins, and resveratrol have all been implicated as aromatase blockers, and there may also be synergistic interplay among selected constituents. The role of red wine would be in chemoprevention, the use of natural or synthetic substances to retard, block, or reverse cancer. One gene encodes aromatase, so aromatase inhibition would stop endogenous estrogen production. The role of aromatase inhibition in breast cancer in premenopausal women is not clear. While animal studies have demonstrated that red wine contains constituents that could block aromatase in vivo, the benefits also exist with nonalcoholic grape seed extract. Further investigation is needed but there are challenges in designing appropriate clinical trials for a substance as variable as red wine. While there is insufficient evidence to advocate for red wine as an aromatase inhibitor, there is sufficient evidence to warrant further investigation.

Abstract PO5-09-02: Breast Tissue Proteomic Profile of Breast Cancer in Premenopausal Women and Association with Mammographic Breast Density

Abstract Introduction: Breast cancer incidence is rising in premenopausal, hence, there is a critical need to understand factors underlying premenopausal breast cancer development in order to guide targeted prevention. Mammographic breast density is a strong risk factor for, as well as an intermediate phenotype for premenopausal breast cancer. Yet, the molecular mechanisms underlying the associations of dense breasts with breast cancer are not well understood. Our objectives in this study are to perform proteomic analysis in breast tissues to (i) identify proteins that are associated with breast cancer development in premenopausal women; (ii) determine which of these proteins are also associated with dense breasts. Methods: We performed proteomic analysis on tumor and adjacent normal tissues from 50 premenopausal women with breast cancer who had breast tissue samples archived at the St. Louis Breast Tumor Registry. Samples were analyzed on Orbitrap Eclipse Tribrid coupled with Vanquish Neo LC system (Thermo Fisher Scientific). Database search was performed using MaxQuant and MS1 LFQ intensities were used for further data analysis. We performed multiple imputation using Bayesian Principal Component Analysis and hierarchical clustering analysis using ‘ConsensusClusterPlus’ package in R. Pathway enrichment analysis was performed using Reactome Pathway database. 10 times repeated 5-fold cross validation using Logistic Regression (LR) was performed for model development. Top 10 proteins were selected by variable importance in logistic regression, and recursive feature elimination was performed for feature selection. We corrected for multiple testing by setting the false discovery rate, FDR, p-value < 0.05. Results: After imputing for missing values, we identified 3,571 proteins that were expressed in tumor and normal breast tissues. We selected 1,640 proteins for further analysis using median absolute deviation analysis. In multivariable-adjusted analysis, 451 proteins were up-regulated, and 180 proteins were down-regulated in tumor tissues compared to adjacent normal tissues (FDR < 0.05). 53 of the 451 proteins that were upregulated in tumor tissues were also upregulated in dense breasts. Some of the top proteins that were upregulated in both tumor tissues and dense breasts were AIMP2, ALDH18A1, BZW1, CKAP5, COPG1, ERGIC1, GSPT1, ILF2, IPO7, LRBA, and PSMD12. Mammographic breast density protein clusters were highly correlated with hormone receptor positivity clusters and were enriched in ESR-mediated signaling, IGF1R signaling, NOTCH4, PTEN regulation, and NFkB pathway. Discussion: Using untargeted proteomics, we identified proteomic signatures of breast cancer development in premenopausal women. We further identified protein biomarkers and pathways that are shared between breast tumors and dense breast tissues in premenopausal women. Our novel findings highlight mammographic breast density as a strong intermediate phenotype that can be targeted in breast cancer prevention in premenopausal women. Larger studies are needed to validate our findings. Citation Format: Shaili Tapiavala, Minsoo Son, Graham Colditz, Ah Young Goo, Adetunji Toriola. Breast Tissue Proteomic Profile of Breast Cancer in Premenopausal Women and Association with Mammographic Breast Density [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 PO5-09-02.

A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis

Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

Health-related quality of life of premenopausal young breast cancer survivors undergoing endocrine therapy

PurposeThe incidence of breast cancer in premenopausal women in South Korea is higher compared to the West. This study aimed to identify factors associated with the health-related quality of life (HRQoL) among survivors with premenopausal young breast cancer undergoing endocrine therapy by examining the effects of menopausal symptoms, social support, and resilience on HRQoL. MethodsCross-sectional study was used to select survivors with breast cancer undergoing endocrine therapy. The study instruments used included a basic information questionnaire, Menopause Rating Scale, Multidimensional Scale of Perceived Social Support, Connor–Davidson Resilience Scale, and Health-Related Quality of Life Instrument with 8 items. Researchers utilized independent t-tests, one-way analysis of variance, Pearson's correlation coefficients, and multiple linear regression to analyze the data. The data were collected from August to September 2021, and the questionnaire was administered via a link posted on a bulletin board of an online breast cancer survivors community. Finally, 133 questionnaires were included in the final analysis. ResultsAmong 150 participants, 133 completed the questionnaires. HRQoL was higher in the groups with a monthly income of ≥5 million KRW (β = 0.231, p = .011), fewer menopausal symptoms (β = −0.399, p < .001), and higher social support (β = 0.170, p = .038), and lower in the group receiving endocrine therapy and OFS (β = −0.192, p = .010). The explanatory power for HRQoL of premenopausal young breast cancer survivors undergoing endocrine therapy was 38.3% (F = 10.634, p < .001). ConclusionBreast cancer survivors should be supported to participate in economic activity, utilize rehabilitation and intervention programs to alleviate menopausal symptoms, and benefit from a social support network formed by the hospital, community, and government.

SY06-4 The sensitivity to chemotherapy for breast cancer in premenopausal women: Differences from postmenopausal women and reasons for the differences

SY06-4 The sensitivity to chemotherapy for breast cancer in premenopausal women: Differences from postmenopausal women and reasons for the differences

The relation between obesity and breast cancer risk in women by considering menstruation status and geographical variations: a systematic review and meta-analysis

Given the increase in the incidence of breast cancer during the past decades, several studies have investigated the effects of variables on breast cancer, especially obesity. This systematic review and meta-analysis aims to evaluate any effects of obesity on breast cancer risk in women, before and after menopause, and in different continents.All forms of relevant literature examining any association between obesity and breast cancer, including cohort, case–control, and cross-sectional studies, were identified in the PubMed, Scopus, EMBASE, and Web of Science databases from January 1, 1990 until January 13, 2023. Body mass index (BMI) > 30 was used to indicate obesity. Every type of breast cancer was examined as outcome factors. The quality of the papers was evaluated using the Newcastle–Ottawa scale checklist. The Egger and Begg test was used to evaluate publication bias. To assess any extra impact of each research on the final measurement, a sensitivity analysis was carried out.One hundred and two studies were included in this meta-analysis. Respectively, 48 and 67 studies reported associations between obesity and breast cancer in pre and post menopausal women. Combining all studies, the pooled OR of the association between obesity and breast cancer in pre-menopausal women was OR = 0.93 CI: (0.85–1.1), (I2 = 65.4%), and for post-menopausal woman, OR = 1.26 CI: (1.19–1.34), (I2 = 90.5%).Obesity has a protective role in breast cancer among pre-menopausal women, but this relationship is statistically significant only in European women. The chance of developing breast cancer increases in post-menopausal women who are obese. This relationship is significant among Asian, North American, African and European women.

The Molecular and Genetic Interactions between Obesity and Breast Cancer Risk.

Breast cancer (BC) is considered the leading cause of death among females worldwide. Various risk factors contribute to BC development, such as age, genetics, reproductive factors, obesity, alcohol intake, and lifestyle. Obesity is considered to be a pandemic health problem globally, affecting millions of people worldwide. Obesity has been associated with a high risk of BC development. Determining the impact of obesity on BC development risk in women by demonstrating the molecular and genetic association in pre- and post-menopause females and risk to BC initiation is crucial in order to improve the diagnosis and prognosis of BC disease. In epidemiological studies, BC in premenopausal women was shown to be protective in a certain pattern. These altered effects between the two phases could be due to various physiological changes, such as estrogen/progesterone fluctuating levels. In addition, the relationship between BC risk and obesity is indicated by different molecular alterations as metabolic pathways and genetic mutation or epigenetic DNA changes supporting a strong connection between obesity and BC risk. However, these molecular and genetic alteration remain incompletely understood. The aim of this review is to highlight and elucidate the different molecular mechanisms and genetic changes occurring in obese women and their association with BC risk and development.

Obesity and breast cancer in women under age 40.

10536 Background: Obesity is a well-established risk factor for postmenopausal hormone-receptor positive breast cancer (BC). The role of obesity in premenopausal BC, especially in women under the age of 40, is not well understood. Multiple studies have shown a decreased rate of premenopausal BC with increasing body mass index (BMI), notably for estrogen receptor positive tumors. Even though there is an inverse association between obesity and premenopausal BC, it has been suggested that obesity has a negative prognostic role in premenopausal BC. This may be explained if premenopausal obese women develop more aggressive tumors. Obesity is associated with triple negative and Luminal B cancers in premenopausal women. We sought to evaluate the relationship between premenopausal breast cancer and obesity in a diverse patient population. Methods: We assembled a 10-year database of women diagnosed with breast cancer before age 40 in a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, and stage at diagnosis. The control group was all women under the age of 40 presenting to our health system in the same time period. Stratification analysis was performed using Mantel-Haenszel Risk Estimation. Results: The risk ratio between the standardized estimates of BC patients under 40 with BMI ≤ 30 to BMI &gt; 30 is 0.7924, 95% CI (0.683 – 0.920), P = 0.0022. This implies that young BC patients are more likely to be obese than all young women presenting to our health system. There are more obese Black patients compared to White patients. The effect of obesity on BC diagnosis was more pronounced in Black patients, with a risk ratio of 0.59 compared to 0.96. Conclusions: The data presented here challenge previous research which had shown that obesity seemed to be protective against breast cancer in premenopausal women. Here, we see a statistically significant increase in obesity among young women &lt; 40 years presenting with breast cancer. The increased risk of breast cancer diagnosis was particularly pronounced in obese Black women. Previous studies have had a very low proportion of Black women represented, which may cause underestimation of risk in this patient population. These data suggest that obesity is a risk factor for breast cancer in young women, especially in Black patients. [Table: see text]

The Relationship Between High Folate Food Intake with Breast Cancer in Premenopausal Women and Views According to Islam

Breast cancer is a non-infectious malignancy that can attack ductal or lobular epithelial cells in the glandular tissue of the breast. Breast cancer is one of the most common types of cancer in Indonesia and the world. This study aims to determine the level of folate consumption in premenopausal women and its association with breast cancer. The research design used was case control. Premenopausal women's folate consumption levels from both groups were obtained using the Semi-quantitative Food Frequency Questionnaire. The results of the study were obtained from 76 respondents, the majority of respondents were &gt;41 years old when diagnosed with breast cancer (45.8%). Based on the results of the variable analysis, it was found that a total of 5 respondents smoked. Respondents who smoked were more in the control group with 4 respondents (80%) compared to the breast cancer group which only amounted to 1 respondent (20%). Based on the results of the analysis, it was found that only one respondent consumed alcohol and came from the breast cancer group. History of cancer in the family was found more in the breast cancer group, namely 17 respondents (73.9%). Based on these results, it can be concluded that a family history of cancer is a significant factor (p value &lt;0.05). Based on the results of an analysis of folic acid consumption by breast cancer and control groups, it was shown that in the breast cancer group, respondents with low consumption of folate were more, namely 22 respondents (55%), with a difference of 10%. Whereas in the control respondents, there were more respondents in the high consumption category, namely 16 respondents (44.4%) with a difference of 11.2%. In this study, it was found that there was no significant relationship between intake of foods high in folate and the incidence of breast cancer in premenopausal women (p value &gt; 0.05).

The Relationship Between High Folate Food Intake with Breast Cancer in Premenopausal Women and Views According to Islam

Breast cancer is a non-infectious malignancy that can attack ductal or lobular epithelial cells in the glandular tissue of the breast. Breast cancer is one of the most common types of cancer in Indonesia and the world. This study aims to determine the level of folate consumption in premenopausal women and its association with breast cancer. The research design used was case control. Premenopausal women's folate consumption levels from both groups were obtained using the Semi-quantitative Food Frequency Questionnaire. The results of the study were obtained from 76 respondents, the majority of respondents were &gt;41 years old when diagnosed with breast cancer (45.8%). Based on the results of the variable analysis, it was found that a total of 5 respondents smoked. Respondents who smoked were more in the control group with 4 respondents (80%) compared to the breast cancer group which only amounted to 1 respondent (20%). Based on the results of the analysis, it was found that only one respondent consumed alcohol and came from the breast cancer group. History of cancer in the family was found more in the breast cancer group, namely 17 respondents (73.9%). Based on these results, it can be concluded that a family history of cancer is a significant factor (p value &lt;0.05). Based on the results of an analysis of folic acid consumption by breast cancer and control groups, it was shown that in the breast cancer group, respondents with low consumption of folate were more, namely 22 respondents (55%), with a difference of 10%. Whereas in the control respondents, there were more respondents in the high consumption category, namely 16 respondents (44.4%) with a difference of 11.2%. In this study, it was found that there was no significant relationship between intake of foods high in folate and the incidence of breast cancer in premenopausal women (p value &gt; 0.05).

Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model.

Breast cancer (BC) is the most diagnosed cancer type, accounting for one in eight cancer diagnoses worldwide. Epidemiological studies have shown that obesity is associated with increased risk of BC in post-menopausal women, whereas adiposity reduces the risk of BC in premenopausal women. The mechanistic link between obesity and BC has been examined by combining murine BC models with high-fat diet (HFD) induced obesity. However, the effect of adiposity (not obesity) induced by a short period of HFD consumption on BC pathogenesis is not well understood. In the current study, we examined the effects of different diet compositions on BC pathogenesis using a young E0771 syngeneic BC mouse model fed on either an HFD or regular diet (RD: a low-fat high-carbohydrate diet) for a short period (4 weeks) before implanting mammary tumors in mice. We analyzed the effect of diet composition on the onset of tumor growth, metastasis, and metabolic and immune status in the tumor microenvironment (TME) using various methods including in vivo bioluminescence imaging and immunoblotting analyses. We showed for the first time that a short-term HFD delays the onset of tumorigenesis by altering the immune and metabolic signaling and energy mechanism in the TME. However, RD may increase the risk of tumorigenesis and metastasis by increasing pro-inflammatory factors in the TME in young mice. Our data suggest that diet composition, adipogenesis, and loss of body fat likely regulate the pathogenesis of BC in a manner that differs between young and post-menopausal subjects.

The impact of single nucleotide polymorphisms on return-to-work after taxane-based chemotherapy in breast cancer

PurposeBreast cancer treatment is associated with adverse effects, which may delay return-to-work. Single nucleotide polymorphisms (SNPs) may influence the risk and severity of treatment toxicities, which in turn could delay return-to-work. We examined the association of 26 SNPs with return-to-work in premenopausal women with breast cancer.MethodsUsing Danish registries, we identified premenopausal women diagnosed with non-distant metastatic breast cancer during 2007‒2011, assigned adjuvant combination chemotherapy including cyclophosphamide and docetaxel. We genotyped 26 SNPs in 20 genes (ABCB1, ABCC2, ABCG2, CYP1A1, CYP1B1, CYP3A, CYP3A4, CYP3A5, GSTP1, SLCO1B1, SLCO1B3, ARHGEF10, EPHA4, EPHA5, EPHA6, EPHA8, ERCC1, ERCC2, FGD4 and TRPV1) using TaqMan assays. We computed the cumulative incidence of return-to-work (defined as 4 consecutive weeks of work) up to 10 years after surgery, treating death and retirement as competing events and fitted cause-specific Cox regression models to estimate crude hazard ratios (HRs) and 95% confidence intervals (CIs) of return-to-work. We also examined stable labor market attachment (defined as 12 consecutive weeks of work).ResultsWe included 1,964 women. No associations were found for 25 SNPs. The cumulative incidence of return-to-work varied by CYP3A5 rs776746 genotype. From 6 months to 10 years after surgery, return-to-work increased from 25 to 94% in wildtypes (n = 1600), from 17 to 94% in heterozygotes (n = 249), and from 7 to 82% in homozygotes (n = 15). The HR showed delayed return-to-work in CYP3A5 rs776746 homozygotes throughout follow-up (0.48, 95% CI 0.26, 0.86), compared with wildtypes. Estimates were similar for stable labor market attachment.ConclusionOverall, the SNPs examined in the study did not influence return-to-work or stable labor market attachment after breast cancer in premenopausal women. Our findings did suggest that the outcomes were delayed in homozygote carriers of CYP3A5 rs776746, though the number of homozygotes was low.

44P Prognostic value of androgen receptor expression in premenopausal women with estrogen receptor-positive breast cancer

The prognosis of breast cancer in pre-menopausal women is very variable and dependent on the interactions of several biological factors. The androgen receptor (AR) could be among the prognostic variables related to survival although the data is scarce. The aim of the study was to examine the relationship between androgen receptor expression and survival outcomes in estrogen receptor (ER)-positive pre-menopausal invasive breast carcinoma patients.

Lipoprotein and metabolite associations to breast cancer risk in the HUNT2 study.

The aim of this study was to gain an increased understanding of the aetiology of breast cancer, by investigating possible associations between serum lipoprotein subfractions and metabolites and the long-term risk of developing the disease. From a cohort of 65,200 participants within the Trøndelag Health Study (HUNT study), we identified all women who developed breast cancer within a 22-year follow-up period. Using nuclear magnetic resonance (NMR) spectroscopy, 28 metabolites and 89 lipoprotein subfractions were quantified from prediagnostic serum samples of future breast cancer patients and matching controls (n = 1199 case-control pairs). Among premenopausal women (554 cases) 14 lipoprotein subfractions were associated with long-term breast cancer risk. In specific, different subfractions of VLDL particles (in particular VLDL-2, VLDL-3 and VLDL-4) were inversely associated with breast cancer. In addition, inverse associations were detected for total serum triglyceride levels and HDL-4 triglycerides. No significant association was found in postmenopausal women. We identified several associations between lipoprotein subfractions and long-term risk of breast cancer in premenopausal women. Inverse associations between several VLDL subfractions and breast cancer risk were found, revealing an altered metabolism in the endogenous lipid pathway many years prior to a breast cancer diagnosis.

Association between body mass index and incidence of breast cancer in premenopausal women: a Japanese nationwide database study.

The association between body mass index (BMI) and the incidence of premenopausal breast cancer in the Asian population remains unclear. We investigated this association using data from a Japanese nationwide administrative database. We retrospectively identified 785,703 females aged < 45years with available health checkup data on BMI from January 2005 and April 2020 from a Japanese nationwide database. Cox proportional hazards model was used to estimate hazard ratios for breast cancer (total breast cancer, breast cancer with hormonal drug and trastuzumab administration, and breast cancer by age ≤ 45years) associated with BMI recorded at the first health checkup. We conducted restricted cubic spline analysis without BMI categorization to investigate potential nonlinear associations with adjustment for backgrounds such as smoking and alcohol consumption. Overall, the median BMI was 20.5 (interquartile range [IQR], 18.9-22.7) kg/m2, and the median age was 37 (IQR, 29-41) years. Breast cancer occurred in 5597 participants (0.71%) at a median age of 44 (IQR, 42-46) years during a median follow-up of 1034 (IQR, 634-1779) days. A BMI of ≥ 22.0kg/m2 was significantly associated with lower incidences of total breast cancer, breast cancer with hormonal drug administration, and breast cancer by age ≤ 45years, whereas no significant associations were observed for breast cancer with trastuzumab administration. This study, which used a Japanese nationwide database, demonstrated that BMI was inversely associated with premenopausal breast cancer development in Japanese women, similar to that observed in Western women.

Abstract P1-10-02: Effect of metformin on metabolic markers associated with breast cancer risk in a phase II clinical trial in overweight/obese premenopausal women

Abstract Background: The increasing rate of obesity in the United States is accompanied by serious health concerns. Obesity increases breast cancer burden and is associated with increased risk of triple-negative breast cancer in premenopausal women and overall poor prognosis in breast cancer patients. There is a need for intervention strategies aiming to reduce obesity-associated dysregulation to attenuate breast cancer risk.Methods: We conducted a Phase II, double-blind, randomized, placebo-controlled clinical trial in overweight/obese premenopausal women with elements of metabolic syndrome to assess the potential of metformin to reduce obesity-associated breast cancer risk. Study participants received metformin (850 mg BID, n = 76) or placebo (n = 75) for 12 months. Fasting blood samples were collected at baseline, 6-months and 12-months from each participant. We analyzed the effects of metformin on circulating levels of insulin/IGF axis, adipokines, and neutrophil-to-lymphocyte ratio in samples collected from this trial. Serum concentrations of insulin, IGF-1, IGFBP-3, leptin and high-molecular weight adiponectin were measured using ELISA immunoassays. Results: The study population included 151 women and had a mean age of 39.5 years, mean body mass index (BMI) was 37.8 and study participants had a large waist and at least one other component of metabolic syndrome. Metformin treatment did not result in significant changes in members of the insulin/IGF axis compared to the placebo group, however, limiting the analysis to participants with detectable metformin in the blood serum resulted in favorable changes in insulin (p=0.0215), HOMA-IR (p&amp;lt;0.001) and a significant increase in IGFBP-3 (p=0.0176) in the metformin group after the intervention. We observed significant decreases in leptin (p=0.0018) and the leptin-to-adiponectin ratio (p=0.0036) in the metformin arm longitudinally. Additionally, we observed a significant reduction in the neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, in the metformin group compared to the placebo group (p=0.0170). Conclusions: We conclude that metformin led to favorable changes in metabolic markers associated with breast cancer risk in the metformin treated participants, however, the changes were not significantly different from the placebo group. The NLR was significantly reduced after metformin intervention compared to the placebo group. More research is needed to understand the effects of metformin on the insulin/IGF axis and adipokines in overweight/obese premenopausal women. Citation Format: Edgar Tapia, Diana Villa-Guilen, Pavani Chalasani, Sara Centuori, Denise J. Roe, Jose Guillen, Catherine Cordova, Liane Pinto, Sherry Chow. Effect of metformin on metabolic markers associated with breast cancer risk in a phase II clinical trial in overweight/obese premenopausal women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-02.

Insulin resistance and the development of breast cancer in premenopausal women: the Kangbuk Samsung Health Study.

Research on the role of insulin resistance (IR) in breast cancer risk in premenopausal women is scarce. We aimed to investigate the relationship between IR and the development of breast cancer in premenopausal women. We analyzed the prospective association of IR and incident breast cancer in premenopausal women without breast cancer at baseline using a subsample of the Kangbuk Samsung Health Study. Among 134,488 Korean premenopausal women, 696 women developed incident breast cancers during a median follow-up of 4.34years. After adjustment for dense breast and other potential confounders, HR (95% CI) for incident breast cancer comparing HOMA-IR quintiles 2, 3, 4, and 5 to the first quintile was 0.91 (0.71-1.17), 0.89 (0.69-1.15), 0.75 (0.57-0.98), and 0.87 (0.65-1.16), respectively (P for trend = 0.117), while HR (95% CI) comparing insulin quintiles 2, 3, 4, and 5 to the first quintile was 1.02 (0.80-1.30), 0.90 (0.69-1.16), 0.72 (0.54-0.96), and 0.96 (0.72-1.28), respectively (P for trend = 0.151). This pattern did not significantly differ by obesity. These results were attenuated and no longer significant in time-dependent analyses where updated status of insulin and other covariates over time were treated as time-varying covariates. Our findings do not support the positive relationship of IR with the development of breast cancer in premenopausal women, unlike in postmenopausal women. Thus, the role of IR as a risk factor for breast cancer may differ by menopausal status.

Urinary estrogen metabolites and breast cancer risk in Chinese population.

BackgroundIn China, the association between estrogen metabolism and breast cancer risk and the differences in metabolic pattern between breast cancer patients and controls are poorly understood.MethodsA total of 84 patients with invasive breast cancer and 47 controls with benign breast diseases were included in this study. Estrogen metabolites from their morning urine were determined by HPLC-MS/MS and evaluated in both groups, and the predictive value of each estrogen metabolite in the malignant group according to their menstrual status was analyzed.ResultsUrinary concentration of estrogen metabolites 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 4-methoxyestrone (4-MeOE1), and 16α-hydroxyestrone were lower in postmenopausal patients with breast cancer, compared with benign controls. In logistic regression model, breast cancer risk increased with the decline in the levels of 4-OHE2 and 4-MeOE1. In premenopausal patients, a difference in the level of 2-OHE2 was observed between both groups, and 2-OHE2 was found to have predictive value for breast cancer. Additionally, urinary 2-OHE2 level in premenopausal hormone receptor positive (HR+) patients was considerably higher compared with hormone receptor negative patients.ConclusionsWe found that lower urinary levels of 4-OHE2 and 4-MeOE1 had predictive value for breast cancer, and higher 2-OHE1 were associated with HR+ breast cancer in premenopausal women.

Lactate and pyruvate levels correlation with lactate dehydrogenase gene expression and glucose consumption in Tamoxifen-resistant MCF-7 cells using capillary electrophoresis with contactless conductivity detection (CE-C4 D).

Breast cancer is the second leading cause of cancer death in women after lung cancer. The first-line treatment of metastatic breast cancer in premenopausal women relies on tamoxifen. The development of tamoxifen resistance is not fully understood. In this study, capillary electrophoresis with capacitively coupled contactless conductivity detector was developed to monitor the changes in lactate and pyruvate levels in supernatant media of three models of developed MCF-7 tamoxifen-resistant cells and correlate these metabolites changes with lactate dehydrogenase genes expression and glucose consumption. The electrophoretic separation was achieved under reversed electroosmotic flow conditions. The linear ranges were 0.15-5 and 0.01-1mM with a correlation coefficient of 0.9966 and 0.9971 and the limits of detection were 0.01 and 0.02μM for lactate and pyruvate, respectively. Inter- and intrarun accuracy were in the range of 96.88-105.94% with precision (CV, %) of ≤7.35%. The method was completely validated and the results were in agreement with those obtained using the lactate and glucose assay kits. The results revealed a significant increase in both lactate and pyruvate production in the three tamoxifen-resistant MCF-7 cells models compared to control cells. This increase was correlated with the increase of lactate dehydrogenase genes expression and the increase of glucose consumption.