Cancer In Postmenopausal Women Research Articles

Association of SNPs in CDKN2A (P14ARF) Tumour Suppressor Gene With Endometrial Cancer in Postmenopausal Women

This research was aimed to evaluate the association between three selected single nucleotide polymorphisms (SNPs) within the CDKN2A (P14ARF) tumour suppressor gene and the incidence of endometrial cancer (EC) in postmenopausal women. The study included 194 postmenopausal women; 144 with EC and 50 non-cancer controls. Genotypes in P14ARF rs3088440, rs3731217 and rs3731245 polymorphisms were assayed using PCR-RFLP and confirmed by sequencing. Regarding the rs3088440 polymorphism, CT, and CT-TT genotypes, were more prevalent among EC patients than in controls (OR=5.55, p=0.023, OR=5.29, p=0.027; and OR=2.92, p=0.023, respectively). The T allele within rs3088440 was more prevalent in EC females than in controls (χ2=4.7, p=0.030). Considering rs3731217, TG and TG-GG genotypes were less prevalent among EC (OR=0.34, p=0.024 or p=0.023; and OR=0.38, p=0.035, respectively). Polymorphisms in the CDKN2A gene are associated with EC in postmenopausal women.

The Impact of Hormonal Imbalances Associated with Obesity on the Incidence of Endometrial Cancer in Postmenopausal Women

Obesity has long been associated with endometrial cancer amongst postmenopausal women; in fact, obese women are more than twice as likely to develop endometrial cancer as women of normal weight. The risk of developing this type of cancer increases with weight gains in adulthood, especially among women who did not use hormonal therapy for menopause. Thus, with an association between menopause, obesity, and endometrial cancer established, it prompts the following question: what specific factors could cause higher risk levels for endometrial cancer in this cohort of women? In this paper, the factor of hormonal changes and imbalances associated with both obesity and menopause will be examined. The hormones that will be discussed are insulin and insulin-like factors, estrogen, and adipokines (specifically adiponectin, visfatin, and leptin).

Novel Melatonin, Estrogen, and Progesterone Hormone Therapy Demonstrates Anti-Cancer Actions in MCF-7 and MDA-MB-231 Breast Cancer Cells.

A novel melatonin, estrogen, and progesterone hormone therapy was developed as a safe bio-identical alternative hormone therapy for menopausal women based on the Women’s Health Initiative findings that PremPro™ increased breast cancer risk and mortality of all types of breast cancer in postmenopausal women. For HER2 breast cancer, melatonin, estrogen, and progesterone delayed tumor onset and reduced tumor incidence in neu female mice. For other breast cancers, its actions are unknown. In this study, melatonin, estrogen, and progesterone hormone therapy were assessed in human ER+ (MCF-7) and triple negative breast cancer (MDA-MB-231) cells, and found to decrease proliferation and migration of both breast cancer lines. Inhibition of MEK1/2 and 5 using PD98059 and BIX02189, respectively, inhibited proliferation and migration in MDA-MB-231 cells and proliferation in MCF-7 cells; however, when combined with melatonin, estrogen, and progesterone, BIX02189 blocked melatonin, estrogen, and progesterone–mediated inhibition of migration in MCF-7 cells and induced Elf-5. For MDA-MB-231 cells, BIX02189 combined with melatonin, estrogen, and progesterone inhibited proliferation and increased pERK1/2 and β1-INTEGRIN; levels of pERK5 remained low/nearly absent in both breast cancer lines. These findings demonstrate novel anti-cancer actions of melatonin, estrogen, and progesterone in ER+ and triple negative breast cancer cells through intricate MEK1/2- and MEK5-associated signaling cascades that favor anti-proliferation and anti-migration.

First-line fulvestrant plus anastrozole for hormone-receptor-positive metastatic breast cancer in postmenopausal women: a cost-effectiveness analysis.

In a recent randomized, open-label trial (S0226), the addition of fulvestrant to anastrozole therapy decreased the risk of progression and death in patients with hormone-receptor-positive metastatic breast cancer. However, the cost-effectiveness of incorporating fulvestrant into the first-line setting is unknown. We developed a Markov model to assess the costs and clinical outcomes of fulvestrant plus anastrozole compared with anastrozole as a first-line therapy in a cohort of patients with advanced hormone-receptor-positive breast cancer. The transition probabilities were estimated from the fitted survival curves in the S0226 trial. Health care costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for fulvestrant plus anastrozole compared with anastrozole from US payer's perspective. Fulvestrant plus anastrozole led to an improvement of 0.11 QALYs compared with treatment with anastrozole alone. However, incorporating fulvestrant into the first-line therapy produced significantly higher health care costs ($72,496 vs. $38,959 for all eligible patients, and $73,728 vs. $37,239 for patients with no previous hormonal adjuvant therapy), resulting in ICERs of $300,564 and $194,450/QALY, respectively. Two-way sensitivity analysis showed that when the cost of fulvestrant decreased to $1.5/mg for all eligible patients or $3.5/mg for patients with no previous hormonal adjuvant therapy, at the perfect health in progression-free status, the ICER became $141,320 and $145,543 per QALY. Substituting fulvestrant as a first-line therapy for hormone-receptor-positivemetastatic breast cancer is not cost-effective compared with anastrozole based on the willing-to-pay threshold of $150,000 per QALY.

Adherence to the low carbohydrate diet and the risk of breast Cancer in Iran

BackgroundPrevious studies on the link between macronutrients and breast cancer have mostly focused on individual macronutrients rather than their combination. This study investigates the association between adherence to a low carbohydrate diet and odds of breast cancer among women.MethodsThis hospital-based case-control study was carried out on 412 women with pathologically confirmed breast cancer within the past year and 456 apparently healthy controls that were matched in terms of age and residential place. Dietary data was collected using a 168-item validated FFQ. Participants were classified in terms of quintiles of percentages of energy intake from carbohydrates, proteins, and fats. Then, individuals in the highest quintile of fat and protein intake were given a score of 5 and those in the lowest quintile of these macronutrients were given a score of 1. Participants in the other quintiles of these macronutrients were given the corresponding score. In terms of carbohydrate intake, those in the highest quintile received a score of 1 and those in the lowest quintile received 5. The scores were then summed up to calculate the total low carbohydrate diet (LCD) score, which varied from 3 to 15. A higher score meant greater adherence to a low carbohydrate diet.ResultsThe mean age of study participants was 45.2 y and mean BMI was 28.4 kg/m2. Mean LCD score of participants was 8.9 ± 2.5 (8.9 ± 2.6 in cases and 9.0 ± 2.5 in controls). Although no significant association was observed between adherence to the LCD score and odds of breast cancer in the study population, a trend toward significant positive association was seen between consumption of LCD and odds of breast cancer in postmenopausal women; after controlling for several potential confounders, individuals in the third quartile of LCD score were 1.94 times more likely to have breast cancer than those in the lowest quartile (95% CI: 1.00, 3.76). This association strengthened after controlling for dietary variables (2.50; 1.18–5.32). Even after further adjustment for BMI, this association remained significant (2.64, 1.23–5.67). No significant relationship was observed in premenopausal women, either before or after controlling for confounders.ConclusionAdherence to LCD may be associated with increased odds of breast cancer in postmenopausal women. Prospective cohort studies are needed to confirm these findings.

Determinants of breast cancer in Saudi women from Makkah region: a case-control study (breast cancer risk factors among Saudi women)

BackgroundThere are various factors that play a major role in influencing the overall health conditions of women diagnosed with breast cancer. The population of women in Makkah region are diverse, therefore it is significant to highlight the possible determinants of breast cancer in this population. This is a case-control study that assessed determinants of breast cancer including socioeconomic factors, health-related characteristics, menstrual histories and breastfeeding among postmenopausal women in Makkah region in Saudi Arabia.MethodsA total of 432 female participants (214 cases and 218 controls) were recruited for this study. A validated questionnaire was completed by trained dietitians at King Abdullah Medical City Hospital in the Makkah region of Saudi Arabia.ResultsResults displayed that determinants of breast cancer were associated significantly (P < 0.05) with unemployment, large family size, lack of knowledge and awareness about breast cancer, obesity, sedentary lifestyle, smoking, starting menarche at an early age, as well as hormonal and non-hormonal contraceptive use. There was no effect of diabetes, hypertension, hyperlipidemia, and duration of breastfeeding on the incidence of breast cancer.ConclusionIn summary, the results of this study accentuate the possible effect of socioeconomic factors, health-related characteristics and menstrual history on the incidence of breast cancer in postmenopausal women in the Makkah region. Education programs should be applied to increase breast cancer awareness and possibly decrease its incidence.

Hormonal Therapy Resistance and Breast Cancer: Involvement of Adipocytes and Leptin.

Obesity, a recognized risk factor for breast cancer in postmenopausal women, is associated with higher mortality rates regardless of menopausal status, which could in part be explained by therapeutic escape. Indeed, adipose microenvironment has been described to influence the efficiency of chemo- and hormonal therapies. Residual cancer stem cells could also have a key role in this process. To understand the mechanisms involved in the reduced efficacy of hormonal therapy on breast cancer cells in the presence of adipose secretome, human adipose stem cells (hMAD cell line) differentiated into mature adipocytes were co-cultured with mammary breast cancer cells and treated with hormonal therapies (tamoxifen, fulvestrant). Proliferation and apoptosis were measured (fluorescence test, impedancemetry, cytometry) and the gene expression profile was evaluated. Cancer stem cells were isolated from mammospheres made from MCF-7. The impact of chemo- and hormonal therapies and leptin was evaluated in this population. hMAD-differentiated mature adipocytes and their secretions were able to increase mammary cancer cell proliferation and to suppress the antiproliferative effect of tamoxifen, confirming previous data and validating our model. Apoptosis and cell cycle did not seem to be involved in this process. The evaluation of gene expression profiles suggested that STAT3 could be a possible target. On the contrary, leptin did not seem to be involved. The study of isolated cancer stem cells revealed that their proliferation was stimulated in the presence of anticancer therapies (tamoxifen, fulvestrant, doxorubicine) and leptin. Our study confirmed the role of adipocytes and their secretome, but above all, the role of communication between adipose and cancer cells in interfering with the efficiency of hormonal therapy. Among the pathophysiological mechanisms involved, leptin does not seem to interfere with the estrogenic pathway but seems to promote the proliferation of cancer stem cells.

Risk Factor Analysis for Breast Cancer in Premenopausal and Postmenopausal Women of Punjab, India.

Objective:Amritsar, the second largest town of agrarian state of Punjab, India reports high number of breast cancer cases every year. The present study investigated the etiology of breast cancer using various obesity indices and other epidemiological factors among breast cancer patients residing in and around Amritsar city. Methods:In this case control study, risk factors for breast cancer were analyzed in 542 female subjects: 271 females with breast cancer patients and 271 unrelated healthy females matched for age as control females. Results:Bivariate analysis for risk factors in cases and controls showed a lower risk (OR=0.65, 95% CI 0.43-0.99, p=0.04) in obese cases with BMI≥25kg/m2 as compared to subjects with normal BMI. Risk factor analysis showed that parameter which provided risk for cancer in postmenopausal women was obesity and in premenopausal women was parity. Postmenopausal women with BMI (overweight: OR=0.39, 95% CI 0.17-0.92, p=0.03; obese: OR= 0.26, 95% CI 0.13-0.52, p=0.00), WC (OR=0.17, 95% CI 0.05-0.52, p=0.00) and WHtR (p=0.02) had highr risk. Premenopausal women with 3 or less than 3 children had a higher risk (OR=5.54, 95 % CI 2.75-11.19, p=0.00) than postmenopausal women when compared to women with more than 3 children. Binary logistic regression analysis revealed that low parity (≤3) substantially increased the risk for breast cancer (OR=4.80, 95% CI 2.34-9.85, p=0.00) in premenopausal women. Conclusion:Obesity, parity associated breast cancer risk and reduced breastfeeding cumulatively predispose the premenopausal women of this region to higher risk of breast cancer.

Influence of breast density on breast cancer risk: a case control study in Japanese women

Mammography is the standard examination for breast cancer screening of woman aged ≥ 40years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer. A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors. Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5kg/m2) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5kg/m2) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]). Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.

1961 Everolimus-Associated Gastric Antral Vascular Ectasia in a Patient With Advanced Breast Carcinoma

INTRODUCTION: Targeted cancer therapies have led to improvement in survival time and quality of life for patients with various cancer types, including advanced breast cancer. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for use in combination with exemestane for advanced hormone-receptor positive, HER2-negative breast cancer in post-menopausal women. While typically well-tolerated, a few cases of upper gastrointestinal bleeding from gastric antral vascular ectasia (GAVE) associated with everolimus have been described, primarily in oncology literature. In our patient, we present a case of gastrointestinal bleeding due to GAVE during treatment with everolimus. Given the clinical consequences of this adverse effect, gastroenterologists must maintain awareness of the associated risk of gastrointestinal hemorrhage and approach to treatment in patients treated with this agent. CASE DESCRIPTION/METHODS: Our patient is a 64-year-old female with stage III left breast invasive ductal carcinoma (HER2-negative, estrogen receptor positive, progesterone receptor positive). She underwent left lumpectomy, adjuvant doxorubicin and cyclophosphamide, paclitaxel, and radiation. Follow-up revealed bony metastases and right upper lobe pulmonary metastatic disease. She was initiated on exemestane and everolimus. Three weeks later, she presented with severe weakness and dyspnea. Rectal examination with dark hemoccult positive stools. Laboratory findings revealed Hgb of 6.0 g/dL. An upper endoscopy showed no source of bleeding. The patient responded to blood transfusions and Hgb stabilized. One month later, the patient represented with symptomatic anemia. A repeat upper endoscopy revealed blood with diffuse gastric antral oozing consistent with GAVE. She was treated with argon plasma coagulation (APC), and everolimus was discontinued. The patient stabilized after endoscopic therapy and was discharged after recovery. DISCUSSION: Gastrointestinal bleeding due to GAVE while undergoing treatment with everolimus is an uncommon event with an unknown mechanism. Review of current literature shows that few similar cases have been previously reported. Our patient responded well to therapy with APC. However, progression to life-threatening bleeding with poor response to endoscopic therapy has been described. As use of everolimus increases, we are more likely to encounter gastrointestinal bleeding due to GAVE. Clinicians should remain alert to the risk of severe bleeding and the utility of APC in these patients.

Association of single nucleotide polymorphisms of adiponectin and leptin genes with breast cancer.

Single nucleotide polymorphisms (SNPs) in adiponectin gene [rs1501299 (+276G/T) and rs266729 (-11377C/G)] and one SNP of leptin gene [rs7799039 (-2548G/A)] are known to influence plasma levels of adiponectin and leptin respectively. Literature is scarce on the association of adiponectin gene polymorphism rs266729 with breast cancer. The present study was taken up to study these polymorphisms and their association with breast cancer. Ninety-three patients diagnosed with malignant breast cancer were included as cases along with 186 age matched healthy controls. Adiponectin +276G/T, -11377C/G and leptin -2548G/A polymorphism were studied using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Adipokine levels in blood were measured using enzyme linked immunosorbent assay. Adiponectin +276G/T and leptin -2548G/A showed a significant increased risk for breast cancer even after adjusting for confounding variables like present age, age at menarche, age at first child birth and age at menopause. In the subset analysis, based on menopausal state, stronger association was observed between SNP in adiponectin gene +276G/T with the breast cancer in post-menopausal women after adjusting for all other variables. No association was found with adiponectin -11377C/G. No association of the gene polymorphisms with adipokine levels was observed. Also, no significant association was seen for the effect of gene-environment interaction i.e. presence of polymorphism with obesity and menopausal statefor any of the SNPs studied. Adiponectin +276G/T is strongly associated with breast cancer in postmenopausal women while leptin -2548G/A polymorphisms is significantly associated with breast cancer irrespective of the menopausal state in south Indian subjects.

Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update.

To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. An Expert Panel conducted targeted systematic literature reviews to identify new studies. A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor-positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines.

Visceral fat measured by computed tomography and the risk of breast cancer.

BackgroundObesity is a risk factor for the development of breast cancer, which can be examined to assess the association between abdominal fat distribution through computed tomography (CT) and risk of breast cancer by hormone receptor (HR) status in women.MethodsWe examined 234 cases of newly diagnosed breast cancer patients and 211 controls consisting of health examinees in the Republic of Korea. The abdominal body fat distribution was measured by CT scan. The subjects’ medical information, obtained from electronic medical records (EMR), were analyzed to verify the association between visceral fat and the type of breast cancer by HRs.ResultsWhile visceral obesity increased the risk of breast cancer in post-menopausal women by 1.50 (95% CI, 0.75–2.98), the effect was not observed in pre-menopausal women 0.86 (95% CI, 0.44–1.62). Also, histological grade was associated with visceral fat, which higher histological grade score (≥2) showed a slightly increased mortality rate (r=0.15, P=0.07). Patients with negative progesterone receptors tended to have a higher abdominal fat ratio than patients with positive progesterone receptors. Especially in pre-menopausal women, higher distribution of abdominal fat ratio in breast cancer patients had somewhat more of an effect on negative than positive HRs [estrogen receptor (ER), P=0.12; progesterone receptor (PR), P=0.06; human epidermal growth factor receptor 2 (HER2), P=0.43].ConclusionsOur results suggest that the clear association between breast cancer and distribution of abdominal fat, and the abdominal fat ratio, are useful indicators for risk factors for breast cancer as well as malignancy.

A novel GC-MS methodology to evaluate aromatase activity in human placental microsomes: a comparative study with the standard radiometric assay.

Estrogens are key factors in the development of the estrogen receptor-positive (ER+) breast cancer. Estrogens, estrone (E1), and estradiol (E2) production is achieved by aromatase, a cytochrome P450 enzyme that has androgens, androstenedione (AD), and testosterone (T) as substrates. Nowadays, third-generation aromatase inhibitors (AIs) are considered the gold-standard treatment for ER+ breast cancer in postmenopausal women as well as in premenopausal women with ovary ablation. Aromatase activity assessment still relies on radiometric assays that are expensive, hazardous, and non-environmentally friendly. Thus, in order to overcome these disadvantages, a new methodology was developed to evaluate aromatase activity, based on dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography-mass spectrometry (GC-MS). The enzymatic reaction was carried out in human placental microsomes, using AD as substrate, and the anti-aromatase activity was measured by determining the conversion percentage of AD into E1 (ratio E1/AD) using isotopic analogues as internal standards. The method showed good linearity (r2 = 0.9908 for AD and 0.9944 for E1), high accuracy (more than 74% for AD and more than 66% for E1), high extraction efficiency, and good intra-day and inter-day precision (below 14%, 4 levels). In this work, the IC50 valuesof the third-generation AIs, anastrozole, letrozole, and exemestane, obtained from theradiometric assay are also compared, and similar IC50 values are described. This method is a good alternative to the current radiometric assay, being fast and sensitive with a good extraction efficiency, accuracy, and recovery. In addition, it may be applied for the evaluation of the anti-aromatase activity of new potential AIs. Graphical abstract.

Aromatase (CYP19) inhibition by biflavonoids obtained from the branches of Garcinia gardneriana (Clusiaceae).

Overexpression of aromatase in breast cancer cells may substantially influence its progression and maintenance. In this sense, the inhibition of aromatase is a key target for the treatment of breast cancer in postmenopausal women. Although several flavonoids had already demonstrated the capacity of inhibiting aromatase activity, the role of biflavonoids as aromatase inhibitors is poorly studied. In this work, the biflavonoids isolated from Garcinia gardneriana, morelloflavone (1), Gb-2a (2) and Gb-2a-7-O-glucose (3) were submitted to in vitro assay to evaluate the aromatase modulatory effect. As results, it was demonstrated that all biflavonoids were able to inhibit the enzyme, with IC50 values ranging from 1.35 to 7.67 μM. This demonstrates that biflavonoids are an important source of scaffolds for the development of new aromatase inhibitors, focusing on the development of new anticancer agents.

A Spontaneous Aggressive ERα+ Mammary Tumor Model Is Driven by Kras Activation

The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors in nulliparous females, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole-genome and exome sequencing in a discovery cohort (n= 5) of end-stage tumors revealed canonical activating mutations and copy number amplifications of Kras. The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% of tumors (23 of 29). Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors compared with preneoplastic tissues; in cell-intrinsic processes associated with mitosis, cell adhesion, and invasion; as well as in the surrounding tumor environment. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors that may model a subset of aggressive clinical ER+ breast cancers.

Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses

BackgroundTransvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4.ObjectiveThe objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses.Study DesignThis was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared.ResultsOf 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers.ConclusionOur population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women.

Obesity and Breast Cancer: Role of Leptin.

Obesity-related breast cancer is an important threat that affects especially post-menopausal women. The link between obesity and breast cancer seems to be relying on the microenvironment generated at adipose tissue level, which includes inflammatory cytokines. In addition, its association with systemic endocrine changes, including hyperinsulinemia, increased estrogens levels, and hyperleptinemia may be key factors for tumor development. These factors may promote tumor initiation, tumor primary growth, tissue invasion, and metastatic progression. Although the relationship between obesity and breast cancer is already established, the different pathophysiological mechanisms involved are not clear. Obesity-related insulin resistance is a well-known risk factor for breast cancer development in post-menopausal women. However, the role of inflammation and other adipokines, especially leptin, is less studied. Leptin, like insulin, appears to be a growth factor for breast cancer cells. There exists a link between leptin and metabolism of estrogens and between leptin and other factors in a more complex network. As a result, obesity-associated hyperleptinemia has been suggested as an important mediator in the pathophysiology of breast cancer. On the other hand, recent data on the paradoxical effect of obesity on cancer immunotherapy efficacy has brought some controversy, since the proinflammatory effect of leptin may help the effect of immune checkpoint inhibitors. Therefore, a better knowledge of the molecular mechanisms that mediate leptin action may be helpful to understand the underlying processes which link obesity to breast cancer in post-menopausal women, as well as the possible role of leptin in the response to immunotherapy in obese patients.

The impact of bariatric surgery on qualitative and quantitative breast density.

Obesity and breast density are associated with breast cancer in postmenopausal women. Bariatric surgery effectively treats morbid obesity, with sustainable weight loss and reductions in cancer incidence. We evaluated changes in qualitative and quantitative density; hypothesizing breast density would increase following bariatric surgery. Women undergoing bariatric surgery from 1990 to 2015 were identified, excluding patients without a mammogram performed both before and after surgery. Changes in body mass index (BMI), time between mammograms and surgery, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) scores were assessed. VolparaDensity™ automated software calculated volumetric breast density (VBD), fibroglandular volume (FGV), and total breast volume for the 82 women with digital data available. Differences between pre- and postsurgery values were assessed. One hundred eighty women were included. Median age at surgery was 50.0years, with 8.8months between presurgery mammogram and surgery and 62.3months between surgery and postsurgery mammogram. Median BMI significantly decreased over the study period (46.0 vs 35.4kg/m2 ; P<0.001). No change in BI-RADS scores was seen between the pre- and postsurgery mammograms. Eighty-two women had VolparaDensity™ data available. While VBD increased in these patients, FGV and total breast volume both decreased following bariatric surgery. Increased VBD, decreased FGV, and decreased total breast volume were seen following bariatric surgery-induced weight loss. There was no difference in qualitative breast density, highlighting the discrepancy between BI-RADS and VolparaDensity™ measurements. Further investigation will be required to determine how differential changes in components of breast density may affect breast cancer risk.

Abstract 5256: Molecular signatures associated with obesity-related tumor growth in breast cancer women

Abstract Obesity has been widely associated with chronic diseases, including cancer. Obesity increases the risk of developing several types of cancer, both in women and men, especially breast cancer in postmenopausal women. However, the role of obesity after tumors is established and its potential mechanisms are unknown. Our study aims to determine the molecular signatures associated with obesity-related tumor growth in a cohort of breast cancer patients from a country with an obesity epidemic. We evaluated a cohort of patients with breast cancer (n=151) at diagnosis, including patients in all clinical stages and 78% of them showed overweight or obesity. We determined the role of body mass index (BMI) on clinical characteristics and, using RNA-seq analyses in biopsy samples at diagnosis, we determined potential genes associated. We found a positive correlation between BMI and tumor size at diagnosis (r = 0.147, p-value = 0.006) and age (r=0.116, p-value=0.03). Lower BMI was observed when the number of positive nodes increased (p-value = 0.015). In a random subset from these patients (n=12) and using robust linear models, we determined that 10 genes (GPRC5B, SLITRK6, KRT23, VTCN1, TNFRSF12, PTP4A2, BACE2, EPH8, CYP21A1P, and TMEM52) were positively associated with BMI. CSTA and IGKV1-16 showed a negative association with BMI. Gene ontology analyses revealed that VTCN1 and PTP4A3 were linked to increased proliferation and tumor progression. CSTA, a protease inhibitor, was also associated with poor prognosis. Our study suggested a deleterious effect of obesity on breast cancer patients, which could be caused by changes in cell expression on key genes in tumor cells. Citation Format: Diddier Prada, Cristian Arriaga-Canon, Jose Diaz-Chavez, Carlo Cortes, Marco Andonegui-Elguera, Pedro Perez-Collado, Rodolfo Muniz, David Cantu-de-Leon, Paula Cabrera-Galeana, Enrique Bargallo, Luis Herrera, Fernando Penaloza. Molecular signatures associated with obesity-related tumor growth in breast cancer women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5256.