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What are the guidelines for screening in postmenopausal women? Who should be given chemopreventive agents? Does HRT increase breast cancer risk? Find answers to these questions as well as how to care for survivors of breast cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe long-term mortality trends by ethnicity, sex, and age for selected cancers and to assess the effect of age-adjustment using different standard populations on rate ratios and rate differences comparing black to white cancer mortality. DESIGN: Mortality rates for selected cancers were obtained from published reports of the Vital Statistics of the United States (1950-1992). All ethnic- and sex-specific cancer rates were directly age-adjusted to the total 1970 US standard population and to a subset of the 1970 US standard population 40 years and older. RESULTS: Over a 42-year period, lung cancer mortality increased in all population subgroups. Colorectal cancer mortality declined in whites, but increased in blacks. Prostate cancer mortality increased slightly in white men, but dramatically increased in black men. Breast cancer mortality stabilized in white women, but increased markedly in black women. Uterine cancer mortality declined for both ethnicities, while ovarian cancer mortality rates increased for both ethnicities. As expected, the ratios of the age-adjusted cancer mortality rates comparing blacks to whites were the same regardless of the age structure used as the standard population. In contrast, the differences in the age-adjusted rates between blacks and whites were greater when the age-truncated standard population was used. CONCLUSIONS: There are unexplained ethnic differences in the long-term mortality trends of selected cancers. Of particular concern are the increasing death rates in black individuals from colorectal, prostate, breast, and ovarian cancers. Since almost all deaths from these cancers occur in persons over 40, age-adjustment using an age-truncated standard population that includes only those age groups at risk should be considered, particularly when the question to be addressed is one dealing with the impact of a characteristic, such as ethnicity or sex, on mortality risk. [ABSTRACT FROM AUTHOR]

Yes and no. Now with an indication for breast cancer prevention, tamoxifen offers new hope--but not for all, and with some risk. Other possibly safer agents are becoming available. [ABSTRACT FROM AUTHOR]

Yes and no. Now with an indication for breast cancer prevention, tamoxifen offers new hope-but not for all, and with some risk. Other, possibly safer, agents are becoming available. [ABSTRACT FROM AUTHOR]

We review herein the evidence that estrogen is protective against the development of cardiovascular disease in women. To our knowledge, no studies in women have looked at endogenous estrogen levels as predictors of cardiovascular disease. Studies of surrogate measures of endogenous estrogen such as parity, age at menarche, and age at menopause have provided inconsistent results. Current use of oral contraceptives increases risk in older women who smoke cigarettes, but most studies of past use show no increased risk. Most, but not all, studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen. These important observations need to be confirmed in a double-blind, randomized clinical trial, since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded. [ABSTRACT FROM AUTHOR]

Recent data indicate that hormone replacement therapy reduces the risk of heart disease and can be taken safely by an increasing number of women. Is it time you took a fresh look at HRT? [ABSTRACT FROM AUTHOR]

We report on agreement in interpreting endometrial biopsy specimens between the local and central pathologists of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. This trial was a 3-year, multicenter, randomized, double-masked, placebo-controlled trial of four groups taking estrogen or estrogen/progestin combinations. A total of 1804 follow-up biopsies were performed in 596 subjects. Relative sensitivity and relative specificity using the diagnosis from the central pathologist as the gold standard and overall agreement are presented. Almost 90% of the diagnoses were reported normal by both readers. There were significant differences in agreement among clinics and treatment arms (p < 0.0001). The visit at which the biopsy specimen was obtained, age at baseline, prior postmenopausal estrogen use, parity, and drug adherence were not associated with agreement between the two readers. Higher proportions of disagreement were seen in two clinics (13% and 11%) compared with the other five clinics (2%-5%). Biopsy specimens from participants who were taking conjugated equine estrogens (CEE) only were more likely to be diagnosed differently by both readers (11%) than biopsy specimens from women taking a placebo (2%) or CEE combined with progestins (5%). Relative specificity varied from 86.4% to 98.9% among the clinics (p < 0.0001). Relative sensitivity was based on a small number of diagnoses, as few biopsy specimens were classified abnormal by the central pathologist. In patients assigned to CEE combined with progestin, 5 of the 7 biopsy specimens that were recorded abnormal by the central pathologist received a normal diagnosis locally. Our findings show that sample size requirements for study designs in which a central reader is used can be at least threefold lower than the requirements for designs relying on local diagnoses. Centralized protocols for endometrial histopathology reading and staff training are highly desirable in multicenter trials. [ABSTRACT FROM AUTHOR]

What are the guidelines for screening in postmenopausal women? Are mammograms passe? Who should be given chemopreventive agents? Does ERT/HRT increase breast cancer risk? Find answers to these and other important questions in this latest update. [ABSTRACT FROM AUTHOR]

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics., (©2021 American Association for Cancer Research.)

Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.

Background: The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and -B expression and kinase activity is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models., Methods: In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours., Results: Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ≤ 0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues., Conclusion: Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.

Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F(11); parental), MDA-MB-231 (F(11)) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F(11)) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F(11)) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors., (©2013 AACR.)

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series., (Copyright © 2012. Published by Elsevier Ltd.)

mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

Background: Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST)., Methods: This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays., Results: Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Delta552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays., Conclusions: In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.

In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line-specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis.

Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations., Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided., Results: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk., Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Objective: Black women are more likely to be diagnosed at a more advanced stage of breast cancer than are white women. Traditionally, this has been attributed in part to social or cultural factors. Given that black women are more likely to be obese than white women and that being obese is associated with a more advanced stage at diagnosis, this study aims to assess to what extent the racial difference in stage at diagnosis can be explained by racial differences in obesity., Methods: Incident cases of breast cancer between 1991 and 1997 (white, n = 585; black, n = 381) were identified from hospitals in the Baltimore metropolitan area. Information, including age, race, weight, height, and pathology reports, was obtained from hospital medical records., Results: Black women were more likely than white women to be diagnosed with breast cancer at tumor-node-metastasis (TNM) stage II or greater (age-adjusted odds ratio [OR] = 1.51, 95% confidence interval [CI] 1.15-1.99). Further, black women were more likely than white women to be overweight or obese. A high body mass index (BMI) was significantly associated with an advanced stage of breast cancer at diagnosis. Adjustment for the higher prevalence of obesity in black women attenuated the risk estimate of more advanced stage of breast cancer at diagnosis in black women compared with white women by approximately 30%., Conclusions: Our results suggest that the higher prevalence of obesity among black women plays an important role in explaining their relative disadvantage in stage at diagnosis of breast cancer. Nonetheless, a racial difference in stage of breast cancer at diagnosis persists after adjustment for obesity.

Obesity is a well-known risk factor for postmenopausal breast cancer. In contrast, the relationship between obesity and stage of breast cancer at diagnosis is less clear. We hypothesized that increased breast size in obese women may delay discovery of breast tumors. Thus, the purpose of our study was to examine whether there is an association between body mass and stage of breast cancer at diagnosis using hospital medical records. Newly diagnosed breast cancer cases (n = 966) in the Baltimore metropolitan area from 1991 to 1997 were included in our study. Patient information including age, ethnicity, weight, height and pathology data were obtained from hospital medical records. High body mass was significantly associated with late stage of breast cancer at diagnosis. Women who were obese (body mass index [BMI] > or = 27.3) were more likely to be at an advanced stage at diagnosis compared with women with a BMI of < 27.3 (multivariate-adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.15-2.14). The association between body mass and stage at diagnosis was stronger among women younger than 50 years (OR 2.34, 95% CI 1.34-4.08) compared with women 50 years or older (OR 1.30, 95% CI 0.89-1.91). Our study suggests that higher body mass is associated with advanced stage of breast cancer at diagnosis. This finding may be of considerable concern, given the increasing prevalence of obesity in women in the United States and the poor prognosis associated with late-stage tumors., (Copyright 2001 Wiley‐Liss, Inc.)

Many studies have investigated the role of estrogen during menopause; however, less attention has been paid to the role of androgen. Given the possible opposite effects of estrogen and androgen on cardiovascular disease risk, it is suggested that relative androgen excess may better predict the increased risk of cardiovascular disease in women over the age of 50 years than estrogen levels alone. Three phases of hormonal milieu changes are hypothesized as a better way to identify the hormone-cardiovascular disease risk association. A first phase, prepause, occurs before estrogen levels decline (approximately 2 years before menopause). A second phase, interpause, occurs from the end of prepause until approximately age 55. A third phase, postpause, occurs after interpause. The duration of the interpause phase, characterized by relative androgen excess, may be an independent risk factor of cardiovascular disease. This hypothesis could provide a basis for further clinical and epidemiologic research, and it could have important implications for establishing the initiation and duration of estrogen replacement therapy use as a means to prevent cardiovascular disease.

Media coverage of scientific research plays a major role in shaping public opinion and influencing medical practice. When an association is controversial, such as with hormone replacement therapy (HRT) and breast cancer, it is important that a balanced picture of the scientific literature be reported. The objective of this study was to assess whether scientific publications that do and do not support an HRT/breast cancer association were cited in the media in proportions similar to those with which they appear in the scientific literature. Scientific publications reporting on the HRT/breast cancer association published from January 1, 1995, to June 30, 2000, were identified through a systematic Medline search. Media reports from newspapers, magazines, television, and radio that reported on HRT and breast cancer were retrieved from an online database. Investigators independently recorded characteristics of the scientific publications and media reports. A total of 32 scientific publications were identified: 20 (62.5%) concluded there was an increased risk of breast cancer associated with HRT (positive publications), and 12 (37.5%) concluded there was no evidence for an association (null publications). Nearly half (47%) of the scientific publications were not cited by the media. There were 203 media citations of scientific publications: 82% were of positive publications and 18% were of null publications, representing a significant excess of citations of positive publications (p < 0.01). Media coverage of this controversial issue is based on a limited sample of the scientific publications. Moreover, the excess of media citations for positive scientific publications suggests a bias against null scientific publications.

Background: Non-high-density lipoprotein cholesterol (non-HDL-C) contains all known and potential atherogenic lipid particles. Therefore, non-HDL-C level may be as good a potential predictor of risk for cardiovascular disease (CVD) as low-density lipoprotein cholesterol (LDL-C)., Objectives: To determine whether non-HDL-C level could be useful in predicting CVD mortality and to compare the predictive value of non-HDL-C and LDL-C levels., Methods: Data are from the Lipid Research Clinics Program Follow-up Study, a mortality study with baseline data gathered from 1972 through 1976, and mortality ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64 years at entry were observed for an average of 19 years, with CVD death as the main outcome measure., Results: A total of 234 CVD deaths in men and 113 CVD deaths in women occurred during follow-up. Levels of HDL-C and non-HDL-C at baseline were significant and strong predictors of CVD death in both sexes. In contrast, LDL-C level was a somewhat weaker predictor of CVD death in both. Differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 19% and 15%, respectively, in men. In women, differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 11% and 8%, respectively., Conclusions: Non-HDL-C level is a somewhat better predictor of CVD mortality than LDL-C level. Screening for non-HDL-C level may be useful for CVD risk assessment.

The beneficial effects of SERMs, specifically tamoxifen in the treatment and prevention of breast cancer and raloxifene in the prevention of osteoporosis, are well established. In addition, numerous groups of investigators have reported that these agents have a positive impact on cardiovascular health, possibly as a result of their cholesterol-lowering and anticoagulation actions. Although studies clearly showed that tamoxifen therapy improved the levels of some types of lipids, the changes did not appear to translate into a decreased risk of cardiovascular disease. However, the risk of thromboembolic events (as well as endometrial cancer) was increased with the use of tamoxifen, which is often prescribed for breast cancer prevention in healthy women. Similarly, raloxifene treatment had modest positive effects on cardiovascular risk factors but was associated with an increased risk of thromboembolism. When viewed as a whole, study results dictate that the benefits of SERM use for the prevention of cardiovascular disease be carefully weighed against the potential risks.

Background: Tamoxifen-treated breast carcinoma survivors are at elevated risk of endometrial carcinoma. Whether to recommend annual surveillance for uterine abnormalities in this population is currently under debate., Methods: This study was a cross-sectional, community-based investigation of tamoxifen use and the frequency of surveillance for endometrial carcinomas in 541 women with breast carcinoma. Study participants whose breast carcinoma was diagnosed in 1994 were interviewed in 1998. Data were collected from a telephone interview and from a cancer registry record. Tests for uterine abnormalities, based on participant reports of endometrial biopsy and transvaginal ultrasound, were categorized according to frequency. Testing for uterine abnormalities was defined as irregular if women reported tests once every 3 years, on average, and as regular, if they reported annual tests., Results: Forty-nine percent of respondents were current tamoxifen users, 12% were former tamoxifen users, and 39% reported never taking tamoxifen. Of respondents with a uterus (n = 385), 19% reported irregular and 30% regular testing for uterine abnormalities after their breast carcinoma diagnosis. Respondents more frequently reported transvaginal ultrasound (37%) than endometrial biopsy (29%). Women 65 years of age and older were significantly less likely to report regular surveillance for uterine abnormalities (16%) than those younger than 65 years (35%). Current tamoxifen users more frequently reported regular surveillance (43%) than either former (35%) or never tamoxifen users (15%). Multivariable analyses showed tamoxifen users were more likely to have regular (odds ratio [OR], 9.8; 95% confidence interval [CI], 4.4-21.8) or to have irregular testing for uterine abnormalities (OR, 3.9; 95% CI, 1.9-8.1) compared with women who never used tamoxifen, after adjustment for age, number of recent gynecologic visits, and gynecologic symptoms., Conclusions: The results of the current study indicate that half of the breast carcinoma survivors in this population were tested for uterine abnormalities. Although at increased risk, 38% of tamoxifen users never had a test. Clear guidelines need to be established for the type and frequency of testing for uterine abnormalities among tamoxifen-treated breast carcinoma patients., (Copyright 2000 American Cancer Society.)

In the premenopausal period, the risk of heart disease is considerably lower in women than in men; however, in the postmenopausal period, when estrogen levels are considerably lower, women's risk of heart disease increases dramatically and approaches that of men. Numerous animal studies, using a variety of models, also confirm estrogen's cardioprotective effect. Although the results of numerous population-based, observational studies have demonstrated a lower risk of heart disease in women who receive estrogen replacement therapy, evidence from prospective, randomized clinical trials is scant. The Postmenopausal Estrogen/Progestin Intervention (PEPI) trial evaluated cardiovascular risk factors, not events, in a large, prospective, randomized trial and found that estrogen improved lipid profiles and other known risk factors. In addition, the PEPI trial compared several estrogen/progestogen treatment regimens, including both medroxyprogesterone acetate (MPA) and micronized progesterone (MP), and found that combined hormone replacement therapy regimens including MP attenuated the beneficial effects of estrogen less than those containing MPA. In the Heart and Estrogen/Progestin Replacement Study (HERS), however, which prospectively evaluated whether estrogen and MPA use reduced the number of nonfatal myocardial infarctions and cardiovascular events, no effect was seen. Although HERS was a null trial, the vast literature base showing a cardioprotective effect should not be discounted. Further research will be required before blanket recommendations on the cardioprotective effects of hormone therapy can be made.

Several studies have reported an association between hormone replacement therapy (HRT) in postmenopausal women and increased risk of idiopathic venous thromboembolic events (VTEs). Given the widespread use of HRT, it is important to identify factors that may predispose women on HRT to VTEs. To address this concern, we examined potential risk factors for VTEs in women assigned to HRT in the Postmenopausal Estrogen/Progestin Interventions (PEPI) study, a three-year, double-blinded, placebo-controlled trial of 875 postmenopausal women designed to assess the effects of HRT on heart disease risk factors (HDL cholesterol, fibrinogen, blood pressure, and insulin). Women with a history of estrogen-associated VTEs were excluded from the trial. Ten women, all assigned to HRT, had a VTE during PEPI. Only baseline fibrinogen varied significantly between those who did (mean = 249.0 mg/dl) and did not (mean = 280.8 mg/dl) have a VTE while assigned to HRT (P < 0.03). Adjusting for covariates including age, smoking, body mass index, lipid levels, blood pressure, alcohol, exercise, and prior HRT or oral contraceptive use did not affect this finding. The significantly lower fibrinogen levels seen among women subsequently reporting VTEs may be a marker for a specific, but as yet undefined, coagulopathy that is magnified in the presence of exogenous hormones. However, larger studies are needed to confirm this finding., (Copyright 1999 Wiley-Liss, Inc.)

There are limited data on the factors associated with menopausal hot flashes, a common and potentially morbid condition. The objective of this study was to identify predictors of menopausal hot flashes. To meet this objective, 233 naturally perimenopausal or post-menopausal women (ages 45-65) attending a large urban hospital center primary care clinic, mammography unit, or women's health practice were enrolled. The women responded to a self-administered questionnaire assessing selected demographic factors, reproductive history, and behavioral factors. Sixty-seven percent of respondents experienced hot flashes, with 63% reporting frequent hot flashes (at least one hot flash per day) and 60% with hot flashes describing the hot flashes as severe. Women with hot flashes were significantly more likely to have mothers who experienced hot flashes (OR = 4.4, CI = 2.0-10.0) or to be smokers (OR = 2.0, CI = 1.2-3.5). There were no statistically significant associations between hot flashes and other selected demographic, reproductive, or behavior characteristics. These results reveal that menopausal hot flashes are associated with a maternal history of hot flashes as well as with cigarette smoking. These results may help physicians to counsel their patients about smoking cessation.

To examine racial/ethnic differences in breast cancer mortality over time by menopausal status, data from published U.S. Vital Statistics tables (1950-1992) and the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (1973-1991) were used to calculate age-adjusted breast cancer mortality and incidence rates. Overall, breast cancer mortality rates for white women were relatively stable from 1950 to 1992. In contrast, breast cancer mortality rates for black women increased during this period. Among premenopausal women there was no difference in breast cancer mortality between black and white women from 1950 to about 1975. However, after 1975, mortality rates in black premenopausal women increased, whereas those in white women decreased. Among postmenopausal women, breast cancer mortality was substantially lower in blacks than in whites in 1950. Between 1950 and 1992, rates in blacks increased and eventually exceeded rates in whites, which remained stable during this period. This excess in breast cancer mortality in black women is not explained by changes in breast cancer incidence rates. There is an unexplained epidemic of breast cancer mortality in black women that appears to differ somewhat by menopausal status. Reasons for temporal increases in breast cancer mortality seen only among black women need to be identified, as do reasons for the heterogeneity of trends by menopausal status.

Background: Although widely believed that co-occurring chronic diseases in elderly persons do not act independently in causing death, there has been little empirical research assessing prognostic interrelationships between comorbidities., Methods: Nonconcurrent prospective follow-up of 3,549 Virginia-resident elderly women diagnosed with a first breast cancer and 2,114 elderly women with no breast cancer history admitted to Virginia hospitals with principal diagnoses of genital prolapse during 1986-1988 was conducted through linkage of cancer registry and Medicare administrative records. Aggregate comorbidity was measured from Medicare claims via the Charlson comorbidity index (CCI). Mortality rates and relative risks were estimated for the breast cancer and non-breast-cancer groups stratified by the presence and level of comorbidity. Proportional hazards models were used to estimate Rothman's synergy index (S) measure of additive interaction., Results: Over full follow-up, the excess mortality rate for women with breast cancer and other comorbidity was 17% greater than expected under the null hypothesis that risks were additive and independent (S = 1.17, p = .12). Stratified analyses revealed a pattern of S estimates across cancer stage subgroups that was biologically sensible, but this pattern was not supported by strong statistical evidence., Conclusions: This study provides the first empirical estimates of statistical interaction between breast cancer and other chronic comorbidity. S index values tended to be small, but these small effects would translate into substantial numbers of deaths attributable to interaction between cancer and comorbidity. Interactions between breast cancer and comorbid disease should be explored further in large studies that can estimate these effects with increased precision.

The risk of dying from breast cancer differs between racial groups, and the reason for this racial difference is unknown. In this paper, we hypothesize that racial differences in breast cancer mortality may be due to racial differences in the metabolism of drugs used to treat women with breast cancer. Racial differences in the metabolism and effectiveness of other commonly used drugs have been described, and these differences are thought to result from genetic differences in the cytochrome P450 enzyme system. Tamoxifen, widely used for breast cancer treatment, is metabolized by the cytochrome P450 system. Preliminary evidence from human studies suggests that this agent is less effective in non-whites than whites; however, more definitive studies are needed. A better understanding of racial differences in cytochrome P450 drug metabolism and subsequent effectiveness will lead to better breast cancer treatment for all women.

Background: Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy., Methods and Result: The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use., Conclusions: Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.