Postmenopausal Breast Research Articles

Abstract 4136285: Large-Scale Proteomics Identifies Novel Shared Biomarkers of Heart Failure and Cancer: the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: There is a bidirectional relationship between cancer and cardiovascular disease risk. Identifying proteins associated with both cancer and heart failure (HF) may provide insight into common biological pathways underlying both conditions. Methods: Among 10,136 participants in the community-based ARIC cohort study who were free of HF and cancer at study visit 2 (1990-92) and had aptamer-based proteomics (SomaScan v4), we assessed the association of 4,955 plasma proteins with incident HF and with incident site-specific cancer ascertained by cancer registry linkage supplemented with medical records (lung, post-menopausal breast, prostate, colorectal, and hematologic) using multivariable Cox models adjusted for demographics, clinical characteristics, and social determinants of health. Two-sample cis-Mendelian randomization ( cis- MR) was performed to evaluate potential causal effects of proteins on HF, left ventricular (LV) function, and site-specific cancer. Results: Mean age at baseline was 56±6; 54% were female; and 24% reported black race. Over a median follow-up of 10 [IQR 10, 10] years, there were 604 incident HF events and 1,207 incident cancers (169 lung, 85 hematologic, 105 colorectal, 206 breast, 288 prostate). Using a Bonferroni significance threshold (p < 1.0x10 -5 ), 23 proteins were associated with both HF and lung cancer, 2 with HF and hematologic malignancy, 1 with HF and colorectal cancer, and none with HF and breast or prostate cancer. Six proteins remained significantly associated with both HF and lung cancer after further adjustment for pack-years of smoking (Figure). In cis- MR of these six proteins, ICAM5 and MMP12 showed potential causal effect on LV volume and lung adenocarcinoma, and PLAUR showed potential causal effect on HF and lung adenocarcinoma. Conclusion: Among various types of cancer, proteins associated with lung cancer showed the greatest overlap with proteins associated with HF, which was largely accounted for by smoking exposure. We uncovered a set of 6 plasma proteins associated with both incident HF and lung cancer after accounting for smoking. MR identified proteins with potential causal effects on both lung adenocarcinoma and LV size (ICAM5, MMP12) and HF (PLAUR).

Abstract 4135985: Association of Plasma Cystatin-C with Cancer Risk in Individuals with and without Cardiovascular and Chronic Kidney Disease: An Atherosclerosis Risk in Communities (ARIC) Study

Background: While previous studies suggested a relationship between circulating Cystatin-C (Cys-C), a cysteine protease inhibitor involved in regulating tissue inflammation and a renal filtration marker, and both cancer and CVD, they often lacked long-term follow-up or did not account for the impact of CVD on the relationship between Cys-C and cancer. Methods: We included participants from the Atherosclerosis Risk in Communities (ARIC) study followed from visit 2 (1990-1992) through 2015. Plasma Cys-C level was measured by SomaScan. Other renal filtration markers beta-2 microglobulin (B2M) and beta-trace protein (BTP) were used to compare their cancer association with Cys-C. Incident cancer was ascertained by state cancer registry linkage supplemented with medical records. After adjusting for age, sex, race, and study center, adjusted hazard ratios (aHR) of total and site-specific cancers were estimated using Cox proportional hazards regression stratified by baseline chronic kidney disease (CKD) and CVD status. Results: Among 10,869 individuals (median age of 56.9 years, 55% female, 25% Black, 74% White), 3352 incident cancers were ascertained over a median follow-up of 22.9 years. Among 9585 individuals with no history of CKD or CVD, higher Cys-C was significantly associated with a higher risk of total (aHR 1.22, 95%CI 1.02-1.46), bladder, lung, colorectal, and hematologic malignancies. Among 1,050 individuals with CVD, but not CKD, Cys-C level was not associated with total cancer (aHR 1.22, 95%CI 0.74-2.01), but was significantly inversely associated with colorectal (aHR 0.19, 95%CI 0.05-0.76) and positively associated with post-menopausal breast (aHR 4.52, 95%CI 1.05-19.40) cancer risk. In individuals with CKD but not CVD, Cys-C was negatively associated with bladder (HR 0.08, 95%CI 0.0-0.77) and lung (0.23, 95%CI 0.06-0.82) cancers. Lastly, those with both CKD and CVD showed higher hematopoietic and lymphatic cancer with higher Cys-C (HR 4.68, 95%CI 1.32-16.60). Similar patterns were observed for B2M and BTP proteins. Conclusions: Our study highlights the intricate relationship between various renal filtration markers and cancer risk. It suggests that they may play a significant role in cancer development among the general population and CVD patients but not CKD patients. Further research should explore the biological mechanism underlying these associations with even more CKD cases to refine risk estimates. Funding: NHLBI, NCI, NPCR

Cholesterol and Immune Microenvironment: Path Towards Tumorigenesis.

Since obesity is a major risk factor for many different types of cancer, examining one of the most closely associated comorbidities, such as hypercholesterolemia, is crucial to understanding how obesity causes cancer. Hypercholesterolemia is usually associated with many cardiovascular complications such as hypertension, angina, and atherosclerosis. In addition, cholesterol may be a major factor in increasing cancer risk. Cancer patients who received statins, an anti-hypercholesteremic medicine, demonstrated improved prognosis possibly through its effect on tumor proliferation, apoptosis, and oxidative stress.Cholesterol could also aid in tumor progression through reprogramming tumor immunological architecture and mediators. This review focuses on the immunomodulatory role of cholesterol on cellular and molecular levels, which may explain its oncogenic driving activity. We look at how cholesterol modulates tumor immune cells like dendritic cells, T cells, Tregs, and neutrophils. Further, this study sheds light on the modification of the expression pattern of the common cancer-related immune mediators in the tumor immune microenvironment, such as programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-β), interleukin 12 (IL-12), IL-23, and forkhead box protein P3 (FOXP3). We highlight relevant literature demonstrating cholesterol's immunosuppressive role, leading to a worse cancer prognosis. This review invites further research regarding the pathobiological role of cholesterol in many obesity-related cancers such as uterine fibroids, post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancers. This review suggests that targeting cholesterol synthesis may be a fruitful approach to cancer targeting, in addition to traditional chemotherapeutics.

Non-preventable cases of breast, prostate, lung, and colorectal cancer in 2050 in an elimination scenario of modifiable risk factors

Most Western countries have increasing number of new cancer cases per year. Cancer incidence is primarily influenced by basically avoidable risk factors and an aging population. Through hypothetical elimination scenarios of multiple major risk factors for cancer, we estimated the number of new cancer cases that are non-preventable in 2050. We compare numbers of new postmenopausal breast, prostate, lung, and colorectal cancer cases in 2021 to projected numbers of new cases in 2050 under prevention scenarios regarding smoking, overweight and obesity, and alcohol consumption: no intervention, 50%, and 100% instant reduction. Cancer incidence data were derived from NORDCAN, and risk factor prevalence data from the Danish National Health Survey. Cancer projections were calculated with the Prevent program. Hypothetical 100% instant elimination of major risk factors for cancer in Denmark in 2022 will result in unchanged numbers of new breast and colorectal cancers in 2050. The number of new prostate cancers will increase by 25% compared to 2021. Unchanged risk factor levels will result in noticeable increase in cancer burden. Increase in life expectancy and age will entail an increase in cancer incidence, despite maximum effect of preventive actions in the population. Our results are important when planning future health care.

A prospective cohort study of infertility and cancer incidence

To investigate the association between infertility and the incidence of invasive cancer. Prospective cohort study (1989-2015). Not applicable. A total of 103,080 women aged 25-42 years in the Nurses' Health Study II who were cancer-free at baseline (1989). The infertility status (failure to conceive after 1 year of regular, unprotected sex) and causes of infertility were self-reported at baseline and biennial follow-up questionnaires. Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian, and postmenopausal breast) or non-obesity-related (all other cancers). We fit the Cox proportional-hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between infertility and cancer incidence. During 2,149,385 person-years of follow-up, 26,208 women reported a history of infertility, and we documented 6,925 incident invasive cancer cases. After adjusting for body mass index and other risk factors, women who reported infertility had a higher risk of developing cancer than gravid women without a history of infertility (HR, 1.07; 95% CI, 1.02-1.13). This association was stronger among obesity-related cancers (HR, 1.13; 95% CI, 1.05-1.22; vs. non-obesity-related cancers, HR, 0.98; 95% CI, 0.91-1.06) and, in particular, obesity-related reproductive cancers (postmenopausal breast, endometrial, and ovarian cancers; HR, 1.17; 95% CI, 1.06-1.29) and was stronger among women who first reported infertility earlier in life (≤25 years, HR, 1.19; 95% CI, 1.07-1.33; 26-30 years, HR, 1.11; 95% CI, 0.99-1.25; >30 years, HR, 1.07; 95% CI, 0.94-1.22; P trend < .001). A history of infertility may be associated with the risk of developing obesity-related reproductive cancers; further study is needed to elucidate the underlying mechanisms.

Influence of excessive body weight on cancer development and prognosis

Introduction and purpose&#x0D; According to the WHO, overweight and obesity are defined as excessive or abnormal accumulation of adipose tissue, leading to deterioration of health. Excessive body weight is a constantly growing public health problem that has reached the scale of a pandemic. Currently, there is ample evidence that excess body weight increases the risk of developing cancer and worsens the prognosis. The aim of this review is to analyze the impact of overweight and obesity on cancer development and prognosis, and to elucidate pathogenesis.&#x0D; State of knowledge &#x0D; Based on the current state of knowledge in epidemiology, it is estimated that approximately 20% of all malignancies are related to excessive body weight. So far, there is sufficient evidence to support an association between excess body fat and 13 out of 24 cancer sites: esophagus, gastric cardia, colon, liver, gallbladder, pancreas, postmenopausal breast, endometrium, ovary, kidney, meningioma, thyroid and multiple myeloma. Adipose tissue cells produce growth factors, hormones and cytokines that can interfere with the regulation of cell growth and survival. Excess adipose tissue leads to systemic chronic inflammation, oxidative stress, insulin resistance, hyperinsulinemia, increase in sex hormones, increase in leptin levels and a decrease in adiponectin levels. This leads to DNA defects, stimulation of angiogenesis, cell proliferation and inhibition of apoptosis, and thus promotes the development of cancer. In addition, studies have estimated that excess body weight is responsible for 14% of cancer deaths in men and 20% in women.&#x0D; Conclusions&#x0D; Due to the increasing problem of obesity and cancer worldwide and the proven causal relationship between these diseases, it is necessary to intensify nutrition education and promote a healthy lifestyle in order to minimize excessive body weight, and thus reduce the incidence of cancer.

Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases.

Simple SummaryCancers and metabolic diseases represent a leading cause of death in both developing and developed countries. Thus, new diagnostic and prognostic targets are urgently required. NEU-1 is a sialidase which regulates many membrane receptors through desialylation which results in either the activation or inhibition of the receptors. At the plasma membrane, NEU-1 is the catalytic subunit of the elastin receptor complex. This sialidase is not only required for the biological effects that are mediated by the elastin-derived peptides on several metabolic disorders, but NEU-1 is also involved in the development of various cancers. The aim of this review is to describe the role of NEU-1 in several metabolic diseases and cancers and to show that this protein could be considered in some cases as a link between these two physiopathological contexts. Consequently, NEU-1 could represent a common pharmacological target to treat putative metabolic syndrome-associated cancers like colorectal, hepatocellular and postmenopausal breast cancer.Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells’ proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts.

The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer.

The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.

Obesity-related cancers disproportionately affect women compared to men in the United States (399)

<b>Objectives:</b> To determine the distribution of obesity-related cancers among women in the United States. <b>Methods:</b> Data were obtained from the United States Cancer Statistics database and the Behavioral Risk Factors Surveillance System (BRFSS) survey from 2001-2018. Obesity-related cancers as classified by the Centers for Disease Control and Prevention (CDC) were described using SEER*Stata. The average annual percent change (AAPC) was calculated using Joinpoint regression. Incidence rates and demographic factors, including age (divided into 5-10 year age groups), sex, and race (non-Hispanic White, Hispanic, non-Hispanic Black, and non-Hispanic Asian/Pacific Islander) were reported. <b>Results:</b> Between 2001 and 2018, obesity was related to 10,581,122 cancer cases. Although obesity affected more men than women (30.4% vs 28.33%), obesity-related cancers were twice as common in women compared to men (69.2% vs 30.8%). Obesity-related cancers were more common in the South (36.0%) compared to the Northwest (20.6%), West (20.7%), or Midwest (22.7%). Cancers of female-only origin accounted for 42.0% of all obesity-related cancers and 60.6% of obesity-related cancers in women (43.8% post-menopausal breast, 11.5% uterine, 5.3% ovarian). Thyroid cancer accounted for 6.7% of all obesity-related cancers and was three times more common in women compared to men (75.2% female, 24.8% male). While the incidence rates of the breast (AAPC -0.36, p<0.017) and ovarian (AAPC -2.03, p<0.000) cancer decreased in women, uterine and thyroid cancers increased (AAPC 3.07 and 0.71, respectively, p<0.000). <b>Conclusions:</b> Despite similar rates of obesity, obesity-related cancers affect more women than men and are more common in the South. Cancers of female-origin account for nearly two-thirds of obesity- related cancers in women.

The 2018 World Cancer Research Fund/American Institute for Cancer Research Score and Cancer Risk: A Longitudinal Analysis in the NIH-AARP Diet and Health Study.

We examined associations between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations using the standardized 2018 WCRF/AICR Score and cancer risk among older U.S. adults. Participants included 215,102 adults in the NIH-AARP Diet and Health Study followed between 2004 and 2011 (mean 7.0 person-years). Scores (range: 0-7 points) were calculated from self-reported weight, physical activity, and diet and alcohol intake measures. Outcomes included 17 cancers reviewed by WCRF/AICR (cases: male n = 11,066; female n = 8,865) and top three U.S. cancers in males (total n = 4,658; lung n = 2,211; prostate n = 920; colorectal n = 1,527) and females (total n = 5,957; lung n = 1,475; post-menopausal breast n = 3,546; colorectal n = 936). Cox proportional hazard ratios (HRs) were estimated for score and cancer risk associations, stratifying by sex and smoking status. Each one-point score increase was associated with 6% to 13% reduced cancer risk across combined outcomes, except for male never smokers' risk for top three cancers and male current smokers' risk for both combined cancer outcomes. Higher scores were associated with decreased lung cancer risk only among male former smokers (HR, 0.84; 95% CI, 0.79-0.89) and female current smokers (HR, 0.89; 95% CI, 0.82-0.96). Higher scores were associated with 7% to 19% decreased breast cancer risk across smoking strata and 10% to 14% decreased colorectal cancer risk among male and female never and former smokers. Greater recommendations adherence was associated with reduced cancer risk. Findings emphasize the importance of considering combined contributions of multiple lifestyle factors for cancer prevention among older adults and the potential modifying role of smoking history.

Metabolic dysfunction and obesity-related cancer: Beyond obesity and metabolic syndrome.

The metabolic dysfunction driven by obesity, including hyperglycemia and dyslipidemia, increases risk for developing at least 13 cancer types. The concept of "metabolic dysfunction" is often defined by meeting various combinations of criteria for metabolic syndrome. However, the lack of a unified definition of metabolic dysfunction makes it difficult to compare findings across studies. This review summarizes 129 studies that evaluated variable definitions of metabolic dysfunction in relation to obesity-related cancer risk and mortality after a cancer diagnosis. Strategies for metabolic dysfunction management are also discussed. A comprehensive search of relevant publications in MEDLINE (PubMed) and Google Scholar with review of references was conducted. Metabolic dysfunction, defined as metabolic syndrome diagnosis or any number of metabolic syndrome criteria out of clinical range, inflammatory biomarkers, or markers of metabolic organ function, has been associated with risk for, and mortality from, colorectal, pancreatic, postmenopausal breast, and bladder cancers. Metabolic dysfunction associations with breast and colorectal cancer risk have been observed independently of BMI, with increased risk in individuals with metabolically unhealthy normal weight or overweight/obesity compared with metabolically healthy normal weight. Metabolic dysfunction is a key risk factor for obesity-related cancer, regardless of obesity status. Nonetheless, a harmonized definition of metabolic dysfunction will further clarify the magnitude of the relationship across cancer types, enable better comparisons across studies, and further guide criteria for obesity-related cancer risk stratification.

Proton Pump Inhibitor Use and Obesity-Associated Cancers in the Women's Health Initiative

Purpose: Proton pump inhibitors (PPIs) inhibit fatty acid synthase (FAS), a critical enzyme in lipogenesis, energy balance, and cancer cell survival. We aimed to evaluate the association of PPI use with incidence of common obesity- related cancers in women: postmenopausal breast, colorectal, and endometrial cancers. Methods: Our study included 124,931 postmenopausal who were enrolled in the Women's Health Initiative (WHI) observational study and clinical trials, and had responded to a year 3 follow-up assessment. We examined prescription and over the counter use of PPI and/or histamine 2 receptor antagonists (H2RA) at baseline and year 3, to isolate potential effects of FAS inhibition by PPI rather than simply acid suppression. Incident cancer cases were physician-adjudicated. Cox proportional hazard regression models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for associations between PPI and/or H2RA use and cancer incidence after year 3. Results: There were 7956 PPI ever users (with or without H2RA use) and 9398 H2RA only users. PPI or H2RA use was not associated with risk of breast cancer (n=9186 cases), compared to women who did not use either agent (HR 1.01, 95% CI 0.93-1.10 and HR 0.95 95% CI 0.87-1.03, respectively). The incidence of colorectal cancer (n=2280) was significantly lower in PPI users (HR 0.75, 95% CI 0.61-0.92), but not in H2RA users (HR 1.13, 95% CI 0.97-1.31). This association was strengthened with increasing duration (p=0.006) and potency (p=0.005) of PPI use and held regardless of BMI or NSAID use. PPI or H2RA use was not associated with endometrial cancer (n=1231) (HR 0.81, 95% CI 0.61-1.07 and HR 1.13, 95% CI 0.91-1.40, respectively), but showed a trend in decreased risk with increasing PPI potency (P=0.048). Conclusions: Among postmenopausal women, PPI use, but not H2RA use, demonstrated an inverse, dose-responsive association with colorectal cancer incidence. This was consistent with preclinical data that FAS inhibition prevents colon cancer progression and supports further investigation of this commonly used medication as a cancer preventive agent. PPI use was not associated with incidence of breast or endometrial cancer.

Improved Fuzzy C-Means Clustering Algorithm-Based Dynamic Contrast-Enhanced Magnetic Resonance Imaging Features in the Diagnosis of Invasive Breast Carcinoma before and after Menopause.

The application effect of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on the improved fuzzy C-mean clustering (GA-PFCM) algorithm in analyzing premenopausal and postmenopausal invasive breast carcinoma was discussed. 159 patients with breast carcinoma were selected and divided into the postmenopausal group (71 patients) and the premenopausal group (88 patients) according to their menstrual status. The magnetic resonance images of the two groups were processed and analyzed using GA-PFCM algorithm, and the imaging characteristics and relevant parameters of DCE-MRI examination of the two groups were analyzed. Besides, the sensitivity, specificity, and accuracy of the diagnosis of invasive breast carcinoma by DCE-MRI examination were investigated. The results showed that the percentage of patients with lobulated lumps, patients with burrs on lesion edge, and patients with uniformly enhanced tumors in the premenopausal group was larger than that in the postmenopausal group (P < 0.05). In the postmenopausal group, TCI of 33 patients was shown as platform curves, and that of 34 patients was shown as outflow curves. In the premenopausal group, TCI of 39 patients was shown as platform curves, and that of 41 patients was shown as outflow curves with a high proportion. The number of patients with peak height time ranging between 130 s and 260 s and of patients with early signal enhancement rate ranging between 100% and 200% was large. In contrast, the number of patients with ADC value higher than 1.2 × 10−3 was the least. In this research, there were 128 patients with positive invasive breast carcinoma and 31 with negative invasive breast carcinoma by pathological examination. Based on DCE-MRI examination, there were 121 patients with positive invasive breast carcinoma and 38 with negative invasive breast carcinoma. The sensitivity, specificity, and accuracy of invasive breast carcinoma by DCE-MRI were 91.41%, 87.1%, and 90.57%, respectively. In addition, the positive and negative predictive values reached 96.69% and 71.05%, respectively. In summary, GA-PFCM algorithm can be applied in the processing and segmentation of DCE-MRI images, and DCE-MRI could better diagnose invasive breast carcinoma with positive guiding value.

Abstract 1627: Metabolic links between obesity and ferroptosis in a murine model of breast cancer

Abstract Background Obesity is an established risk factor for post-menopausal triple negative breast cancer (TNBC). Multiple aspects of fatty acid metabolism, including fatty acid synthesis, are upregulated in white adipose tissue during obesity development. The enzyme pyruvate carboxylase (PC), a supportive player in fatty acid synthesis, is relied upon for metastasis of murine TNBC particularly in models of obesity- further elucidating the importance of fatty acid metabolism to breast cancer progression in those with obesity. Ferroptosis, a method of cell death induced by peroxidation of phospholipid fatty acyl chains, is a recently discovered and rapidly developing mechanistic target in multiple cancer types. While several cancers, including breast cancer, are sensitive to ferroptosis induced by different mechanisms, the metabolic vulnerabilities and consequent therapeutic potential of ferroptosis are just beginning to be explored. This study aims to determine whether obesity-driven reprogramming of fatty acid metabolism exacerbates breast cancer progression via altered sensitivity to ferroptosis Methods The relationship between obesity, breast cancer and lipid peroxidation was investigated in vitro via proliferation assays, qPCR, Western blot and flow cytometry using multiple murine models of breast cancer treated with erastin and RSL3. PC was suppressed using shRNA introduced via lentiviral transduction. In vivo tumor growth in lean and obese mice was determined following treatment with erastin, RSL3, or a vehicle control. Results In vitro data reveals that TNBC cells are highly sensitive to treatment with the ferroptosis-inducing molecules erastin and RSL3. Erastin treatment transcriptionally induces PC expression in several murine models of TNBC in vitro. Suppression of PC at baseline (without ferroptosis induction) is sufficient to induce transcription of glutathione peroxidase-4 (a critical regulator of ferroptosis). While Affymetrix array data of untreated metastatic M-WntLung primary tumors showed a decrease in PC and associated genes in tumors from obese mice relative to lean mice, treatment with erastin increased PC expression specifically in tumors from obese mice. Tumors from obese mice relative to control mice have an altered response to treatment with the ferroptosis inducing molecules erastin and RSL3. Conclusion These data indicate that obesity-associated dysregulation of lipid metabolism and regulation of PC may be key determinants of sensitivity to induction of ferroptosis. Future work will delineate the relationship between breast cancer, ferroptosis, and fatty acid metabolism utilizing in vivo models to determine whether ferroptosis-specific mechanisms are exacerbated with PC suppression to further impede obesity-exacerbated tumor growth. Citation Format: Emily Devericks, Michael F. Coleman, Hannah Malian, Violet Kiesel, Dorothy Teegarden, Stephen D. Hursting. Metabolic links between obesity and ferroptosis in a murine model of 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 1627.

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

Adherence to adjuvant endocrine therapy assessed by data from prescription renewals and medical records from tamoxifen in Swedish patients with cytochrome P450 2D6 (CYP2D6) genotyped early breast cancer.

542 Background: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been suggested. The main aim of this study was to investigate the consistency between prescription refill data and reports from medical records on adherence to AET in early breast cancer. We also studied if there was an association between menopausal status, CYP2D6 activity, estimated risk for recurrence and adherence to AET. Methods: 1235 pre-and postmenopausal Swedish breast cancer patients operated 2006 – 2014, genotyped for CYP2D6, who initiated adjuvant tamoxifen treatment, were included in the study. Information on AET was retrospectively collected from both medical records and the Swedish Prescribed Drug Registry. Consistency was defined as dispensed doses of AET divided by AET intake documented in medical records. Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate (MPR) ≥ 80 %. Subgroup analyses were performed based on menopausal status, recurrence-risk and CYP2D6 activity. Results: In 84% of the patients the consistency of AET between the sources of information was within 80-125%. Consistency &lt; 80% was most frequent in premenopausal/high risk patients and CYP2D6 Poor Metabolizers (PM). Among 899 patients with at least 4.5 years follow up, adherence to tamoxifen was 72% according to prescription refill data, compared to 77% as reported by medical records. When including aromatase inhibitors adherence increased to 82% and 88%. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PM had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). Conclusions: Consistency between medical records and dispensing data on adherence was better than anticipated. Adherence to AET was good, 82% when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a reduced risk of side effects according to previous studies. Further work is needed to clarify the impact of CYP2D6 activity on adherence to tamoxifen.

Menstrual cycle characteristics and incident cancer: a prospective cohort study.

Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk? Irregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers. Long and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear. Prospective cohort study. Prospective follow-up of 78 943 women participating in the Nurses' Health Study II between 1989 and 2015. We followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14-17, 18-22 and 29-46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence. We documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29-46 years had an 11% (95% CI: 2-21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9-39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09-1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14-17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02-1.81). Our study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White. Women with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood. This work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare. N/A.

704The preventable future burden of cancer in Australia

Abstract Background Estimates of the future burden of invasive cancer attributable to current modifiable causal exposures can guide cancer prevention. Methods We linked pooled data from seven Australian cohort studies (N = 367,058) to national cancer and death registries, and estimated exposure-cancer and exposure-death associations using adjusted proportional hazards models. We estimated exposure prevalence from contemporary national health surveys and calculated population attributable fractions (PAFs) and 95% confidence intervals, using advanced methods accounting for competing risk of death. Results Current levels of past and current smoking explain 36.1% (95%CI 33.2%-38.9%), body fatness 13.6% (10.9%-16.2%) and alcohol consumption exceeding two drinks/day 2.3% (1.0%-3.6%) of cancers causally related to these exposures, corresponding to 210,000, 81,300 and 14,800 cancers in Australia in the next 10 years, respectively. Ever smoking is the leading modifiable cause of lung (82.1%), bladder (49.8%), oesophageal (42.8%), liver (39.8%), head and neck (35.6%), and pancreatic (21.3%) cancer burden. Body fatness is the leading modifiable cause of corpus uteri (42.5%), gastric cardia (33.6%), renal cell (29.1%), thyroid (20.1%), colorectal (12.6%) and postmenopausal breast (12.6%) cancer burden. The absolute numbers of cancers in the next 10 years attributable to smoking are highest for lung cancer (114,000). The numbers of cancers attributable to body fatness and alcohol are highest for colorectal cancer (23,000 and 9,900, respectively). Conclusions More reliable advanced methods demonstrate large proportions and numbers of cancers are preventable by modifying behaviours. Key messages Ever smoking and body fatness are the leading causes of preventable future burden of causally related cancers in Australia.

Postmenopausal estrogen receptor positive breast cancer and obesity associated gene variants.

Obesity is one of the most important health risks in postmenopausal women. Molecular pathways that are connected with obesity are believed to interact with the pathogenesis of breast cancer (BC). The aim of this research was to study the polymorphisms of two obesity-associated genes ADIPOQ and FTO that are also related to the pathogenesis of BC. Obesity-associated gene polymorphisms ADIPOQ rs1501299 and rs2241766, and FTO rs1477196, rs7206790, rs8047395, and rs9939609 were studied in 101 Turkish postmenopausal estrogen receptor-positive BC patients and 100 healthy control individuals. ADIPOQ rs1501299 was detected to be associated with protection against BC. The ADIPOQ rs1501299 TT genotype, the rs2241766 GT genotype and the G allele were found to be significantly higher in the control group. In addition, ADIPOQ rs1501299 polymorphism was protective in the recessive model and rs2241766 polymorphism was protective in the dominant model. While none of the FTO gene polymorphisms were found to be associated with BC, the frequencies of rs9939609 A allele and rs7206790 G allele were correlated with body mass index (BMI) in BC patients. ADIPOQ rs1501299 TT genotype, rs2241766 GT genotype, and G allele might be protective against BC in the Turkish population but this conclusion needs to be further verified.

Abstract 2566: The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast

Abstract Introduction: our purpose was to define if licorice and its main bioactive compounds can suppress aromatase expression/activity and Nrf2 dependent detoxification pathways in the postmenopausal breast. This chemopreventive potential has not previously been reported in preclinical models of high-risk postmenopausal breast. Methods: Inhibition of aromatase activity by three licorice extracts (Glycyrrhiza species), and their bioactive compounds, (liquiritigenin; LigF, isoliquiritigenin; LigC, 8-prenylapigenin; 8-PA, and licochalcone A; LicA) were evaluated fluorometrically, using aromatase supersomes. Computational docking was performed to assess the binding of the bioactive compounds to the binding pocket of aromatase crystal structure compared to the known aromatase inhibitors, letrozole (non-steroidal) and exemestane (steroidal). Using qPCR, the effects of treatments on the expression of aromatase (CYP19A1) mRNA and Nrf2 dependent detoxification enzyme NADPH:quinone oxidoreductase 1 (NQO1) in breast microstructures obtained from high risk postmenopausal women were evaluated. Results: Among the three medicinally used licorice species, Glycyrrhiza inflata (GI) showed the highest aromatase inhibitory potency (IC50 ≈ 1 µg/mL). Licorice phytoestrogens, LigF (400 nM or 0.1 µg/mL), and 8-PA (IC50 ≈ 590 nM or 0.2 µg/mL) exhibited the highest potency compared to the other tested licorice compounds. Computational docking suggested that these phytoestrogens bind to the aromatase binding pocket like the aromatase inhibitor, letrozole. This effect was not observed with non-estrogenic bioactive compounds of licorice, LigC and LicA (specific to GI). In breast microstructures obtained from high risk postmenopausal women, expression of aromatase mRNA was suppressed by GI (30%, P &amp;lt; 0.05), LigF (20%, P &amp;lt; 0.05), and LicA (45%, P &amp;lt; 0.05), while the expression of NQO1 mRNA was enhanced by LicA (200%, P &amp;lt; 0.0001). Conclusions: Licorice species, and their bioactive compounds inhibited aromatase activity in vitro. In the breast microstructures, GI, its compounds LigF and LicA suppressed aromatase expression, and LicA enhanced NQO1 induction, significantly. Further studies will further elucidate the potential of these natural products for promoting a breast tumor preventive environment in postmenopausal women. Citation Format: Atieh Hajirahimkhan, Caitlin Howell, Shao-Nong Chen, Susan E. Clare, Guido F. Pauli, Judy L. Bolton, Birgit M. Dietz, Seema A. Khan. The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2566.