Women's Health Initiative Randomized Research Articles

Estrogen Plus Progestin and Colorectal Cancer: Long-Term Findings From the Women's Health Initiative Randomized Clinical Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants (P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials

(Abstracted from JAMA 2020;324:369–380) Hormone therapy (HT) for menopausal symptoms and its risk-to-benefit ratio have been a controversial topic within the scientific community for several decades. The complicated benefits and potential adverse events associated with menopausal HT were first reported in 2002 by the Women's Health Initiative (WHI).

Menopausal Hormone Therapy and Risks of First Hospitalized Heart Failure and its Subtypes During the Intervention and Extended Postintervention Follow-up of the Women's Health Initiative Randomized Trials

BackgroundWe assessed whether postmenopausal hormone therapy (HT) was associated with incident heart failure (HF) and its subtypes and examined whether there was a modifying effect of age on the associations. Methods and ResultsPostmenopausal women aged 50–79 enrolled in the Women's Health Initiative HT trials were analyzed. The 16,486 women with a uterus were randomized to receive conjugated equine estrogens (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo, and 10,739 women with prior hysterectomy were randomized to receive CEE (0.625 mg/day) alone or placebo. Incident HF was defined as the first HF hospitalization. HF with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) was defined as EF < 50% or ≥ 50%. During the intervention phase, median follow-up was 5.6 years in the CEE-plus-MPA trial and 7.2 years in the CEE-alone trial. During the cumulative follow-up of 18.9 years, women randomized to HT vs placebo in the 2 combined trials had incidence rates of 3.90 vs 3.89 per 1000 person-years for total HF; 1.25 vs 1.40 per 1000 person-years for HFrEF, and 1.88 vs 1.79 per 1000 person-years for HFpEF, respectively. There were no significant effects of HT on the risk of total incident HF or its subtypes in either trial, and age at randomization did not significantly modify the results. ConclusionsPostmenopausal HT did not alter the risk of hospitalization for HF or its subtypes during the intervention or cumulative 18.9 years of follow-up, and results did not vary significantly by age at randomization. Trial Registrationclinicaltrials.gov Identifier: NCT0000611 https://clinicaltrials.gov/ct2/show/NCT00000611?cond=women%27s±health±initiative&rank=5

Abstract P6-13-04: Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials

Abstract OBJECTIVE: To quantitate breast cancer incidence (BrCa-I) and mortality (BrCa-M) outcome differences between the two Women's Health Initiative (WHI) HRT trials,1,2 the ratio of hazards was calculated for estrogen-alone based hormone replacement therapy (E-HRT) vs. placebo (P), and E + progestin Provera (ProgProv) combination HRT vs. P trials. METHODS: Hazard ratios (HR) of BrCa-I and BrCa-M and 95% confidence intervals (CI) were obtained from both WHI HRT trials. Subsequently, to compare BrCa outcomes between E-HRT vs. E + ProgProv, the ratios of HRs between the trials (HR1/HR2) were estimated separately for i. BrCa-I all women, ii. BrCa-I low Gail score (Gail score &amp;lt;1.75*), and iii. BrCa-M. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Outcome Comparison, the two WHI HRT randomized trials. Ratio of Hazards, BrCa Incidence and BrCa mortality E-HRT vs. P, HR1 (95% CI)E-HRT + ProgProv vs. P, HR2 (95% CI)HR1/HR2 (95% CI)pBrCa-I All Woman10.77 (0.62-0.95)1.25 (1.07-1.46)0.62 (0.47-0.80)0.0004BrCa-I Low Gail Score* (Gail score &amp;lt;1.75)10.65 (0.50-0.86)1.24 (1.01-1.51)0.53 (0.38-0.74)0.0002BrCa-M20.55 (0.33-0.92)1.44 (0.97-2.15)0.38 (0.20-0.75)0.004*Gail score &amp;lt;1.75; HRs calculated from Reference 1, Figure 3 CONCLUSIONS: Our calculations show that the different outcomes between the two WHI HRT trials, estimated as ratio of hazards, are highly significant on statistical basis, both for BrCa incidence and for BrCa mortality. These findings highlight the potential carcinogenic impact of ProgProv and the major public health benefits of HRT based on E alone. REFERENCES: 1. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. The Lancet Oncology 2012;13:476-86. 2. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. Citation Format: Ragaz J, Qian H, Wong H, Wilson KS, Shakeraneh S, Spinelli JJ. Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-04.

Abstract P6-13-06: Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm

Abstract OBJECTIVE: To compare, in the setting of breast cancer (BrCa) prevention, the impact of estrogen-based hormone replacement therapy (E-HRT) vs. tamoxifen (TAM) on breast cancer mortality (BrCa-M) and breast cancer case fatality ratio (BrCa-CFR), by analyzing data from the Women's Health Initiative Trial 2 (WHI HRT Trial 2, E-HRT vs. placebo [P])1 and the International Breast Cancer Intervention Study 1 (IBIS-1), TAM vs. P.2 METHODS: Hazard ratios (HR) and confidence intervals (CI) for BrCa incidence and mortality were extracted from the original WHI HRT Trial 2 and IBIS-1 trials.1,2 BrCa-CFRs were estimated by dividing the mortality HR by the incidence HR. Subsequently, to compare E-HRT vs. TAM outcomes, the ratios of HRs (HR1/HR2) between the two trials were estimated separately for BrCa-M and BrCa-CFR. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Mortality and Case Fatality Outcomes: Impact of E-HRT versus TAM, expressed as ratio of HRs E-HRT vs. Placebo, HR1TAM vs. Placebo, HR2HR1/HR2pMortality0.55 (0.33-0.92)1.19 (0.68-2.10)0.46 (0.22-0.99)0.046Case Fatality0.70 (0.40-1.20)1.68 (0.93-3.01)0.42 (0.18-0.94)0.040 CONCLUSIONS: While acknowledging between-trial comparisons including eligibility differences, E-HRT yields significant reductions in BrCa mortality and case fatality as compared with TAM (54% and 58% respectively). These unexpected breast cancer mortality reductions represent major public health gains, additional to the already known superiority of E-HRT over TAM in terms of skeletal fracture rates and Alzheimer's dementia mortality reduction, and, in women entering menopause, also of cardiac and all-cause mortality reductions. REFERENCES: 1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology 2015;16:67-75. Citation Format: Ragaz J, Shakeraneh S, Qian H, Wilson KS, Wong H, Spinelli JJ. Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-06.

Low-Fat Dietary Pattern and Health Outcomes in the Women's Health Initiative Randomized Clinical Trial

Background: Debate, stimulated recently by the Prospective Urban Rural Epidemiology study, concerns the preferred macronutrient dietary composition. Here we provide a comprehensive overview of health outcomes in the Women's Health Initiative Dietary Modification (DM) trial. Methods: The DM trial was a randomized, controlled trial conducted at 40 centres in the USA. 48,835 postmenopausal women, aged 50-79 years, with baseline intake of ≥32% energy from fat were randomly assigned by a computerized, stratified, permuted block algorithm to a low-fat dietary pattern intervention group (40%) or to a usual diet comparison group (60%) during 1993-8. Intervention goals were to reduce fat intake to 20% of total energy and increase vegetables, fruit, and grains. Invasive breast cancer and colorectal cancer were co-primary outcomes, and coronary heart disease was secondary, with other health outcomes also monitored. Findings: After the 8.5-year (mean) intervention period, intervention versus comparison group differences included lower fat by 8-10% of total energy and higher carbohydrate by 8-10% of total energy with increases in vegetables, fruit, and grains. Intervention and comparison group annual incidences were 0.42 and 0.46 (hazard ratio 0.92, 95% CI - 0.84 to 1.01) for invasive breast cancer, and 0.13 and 0.12 (HR, 1.07, 95% CI - 0.92 to 1.27) for colorectal cancer, with overall unchanged CHD incidence and total mortality. During 17.7-years (mean) cumulative follow-up, statistically significant reduction in deaths following breast cancer, diabetes requiring insulin, and CHD among women who were not hypertensive, emerged in intervention group, primarily among participants who were obese at enrollment. Interpretation: In postmenopausal women, reduction in total dietary fat with commensurate increase in carbohydrate did not increase all-cause mortality or have adverse health consequences, while having some health benefits. Clinical Trial Number: This study is registered with clinicaltrials.gov identifier: NC0611. Funding Statement: The development of this paper is partially supported by National Cancer Institute grants R01 CA119171 and R01 CA10921. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C, and these sources also partially support the development of this paper. Declaration of Interests: None of the authors report a conflict of interest related to this study. Ethics Approval Statement: Institutional review board approval was obtained at each individual center, and all participants provided written informed consent.

Estrogen Plus Progestin and Lung Cancer: Follow-up of the Women's Health Initiative Randomized Trial

IntroductionIn the Women's Health Initiative (WHI) estrogen plus progestin trial, after 5.6 years' intervention and 8 years' median follow-up, more women died from lung cancer in the hormone therapy group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.16-2.52; P = .01). Now after 14 years' median follow-up, we reexamined combined hormone therapy effects on lung cancer mortality. Patients and MethodsIn the WHI placebo-controlled trial, 16,608 postmenopausal women aged 50 to 79 years and with an intact uterus were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Incidence and mortality rates for lung cancer were assessed from multivariant proportional hazard models. ResultsAfter 14 years' cumulative follow-up, there were 219 lung cancers (0.19% per year) in the estrogen plus progestin group and 184 (0.17%) in the placebo group (HR, 1.12; 95% CI, 0.92-1.37; P = .24). While there were more deaths from lung cancer with combined hormone therapy (153 [0.13%] vs. 132 [0.12%], respectively), the difference was not statistically significant (HR, 1.09; 95% CI, 0.87-1.38; P = .45). The statistically significant increase in deaths from lung cancer observed during intervention in women assigned to estrogen plus progestin was attenuated after discontinuation of study pills (linear trend over time, P = .042). ConclusionThe increased risk of death from lung cancer observed during estrogen plus progestin use was attenuated after discontinuation of combined hormone therapy.

Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials.

The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use. To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women's Health Initiative (WHI) randomized clinical trials. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010. A total of 16,608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10,739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years. Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials. In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials. In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.

Will Extending the Women's Health Initiative Lead to Better Research and Policy?

Will Extending the Women's Health Initiative Lead to Better Research and Policy?

The Women’s Health Initiative Randomized Controlled Dietary Modification Trial: An inconvenient finding and the diet-heart hypothesis

One goal of the US$700 million Women's Health Initiative Randomized Controlled Dietary Modification Trial was to determine whether post-menopausal women who adopted what was regarded as a 'heart healthy' low-fat diet, high in vegetables, fruits and grains, reduced their risk of developing cardiovascular disease. The trial substantially favoured the outcome in the intervention group, who also received an intensive nutritional and behaviour education programme not offered to the control group. These studies neatly disprove the diet-heart hypothesis since adoption of 'heart healthy' eating not only failed to influence future cardiac events in the healthy but it increased such events in the unhealthy and worsened diabetic control in those with type 2 diabetes mellitus.

Low-Fat Diet and Skin Cancer Risk: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Large cohort studies have reported no relationship between dietary fat and nonmelanoma skin cancer (NMSC), although a low-fat diet intervention reduced NMSC risk in a small clinical trial. In animal studies, skin tumor development has been reduced by low-fat diet. We evaluated the effect of a low-fat dietary pattern on NMSC and melanoma in the Women's Health Initiative Dietary Modification trial. Postmenopausal women aged 50 to 79 years (n = 48,835) were randomly assigned to the low-fat dietary pattern intervention (n = 19,541) or comparison group (n = 29,294). The intervention goals included decreasing fat intake to 20% or less of calories, increasing vegetable and fruit intake, and increasing grain intake. Self-reported incident NMSC (n = 4,907) and physician-adjudicated incident melanoma (n = 279) were ascertained every 6 months. Over 8.1 years of follow-up, the low-fat diet intervention did not affect overall incidence of NMSC [HR 0.98; 95% confidence interval (CI), 0.92-1.04] or melanoma (HR, 1.04; 95% CI, 0.82-1.32). In subgroup analyses of melanoma risk, baseline fat intake interacted significantly with group assignment (Pinteraction = 0.006). Among women with higher baseline fat intake, the dietary intervention significantly increased risk (HR, 1.48; 95% CI, 1.06-2.07), whereas, among women with lower baseline fat intake, the intervention tended to reduce melanoma risk (HR, 0.72; 95% CI, 0.50-1.02). In this large randomized trial, a low-fat dietary pattern did not affect overall incidence of NMSC or melanoma. A low-fat diet does not reduce incidence of NMSC, but an interaction between baseline fat intake and dietary intervention on melanoma risk warrants further investigation.

Calcium Plus Vitamin D Supplementation and Joint Symptoms in Postmenopausal Women in the Women's Health Initiative Randomized Trial

BackgroundLow vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse. ObjectiveTo evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women’s Health Initiative randomized, placebo-controlled, clinical trial. DesignIn post hoc analyses, the results of the Women’s Health Initiative randomized clinical trial in which 36,282 postmenopausal women were randomized to receive calcium carbonate (1,000 mg as elemental calcium) with vitamin D-3 (400 IU) daily or placebo were examined in the 6% subgroup of 1,911 participants, oversampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups. ResultsAt baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared with 75.1% [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared with 32.4% [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using nonprotocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P=0.02). ConclusionsJoint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1,000 mg calcium carbonate and 400 IU vitamin D-3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.

Calcium Plus Vitamin D Supplementation and the Risk of Nonmelanoma and Melanoma Skin Cancer: Post Hoc Analyses of the Women's Health Initiative Randomized Controlled Trial

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC. Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

Placebo Adherence, Clinical Outcomes, and Mortality in the Women's Health Initiative Randomized Hormone Therapy Trials

Medication adherence may be a proxy for healthy behaviors and other factors that affect outcomes. Prior studies of the association between placebo adherence and health outcomes have been limited primarily to men enrolled in clinical trials and cardiovascular disease outcomes. We examined associations between adherence to placebo and the risk of fracture, coronary heart disease, cancer, and all-cause mortality in the 2 Women's Health Initiative hormone therapy randomized trials. Postmenopausal women randomized to placebo with adherence measured at least once were eligible for analysis. Time-varying adherence was assessed by dispensing history and pill counts. Outcome adjudication was based on physician review of medical records. Cox proportional hazards models evaluated the relation between high adherence (≥80%) to placebo and various outcomes, referent to low adherence (<80%). A total of 13,444 postmenopausal women were under observation for 106,066 person-years. High placebo adherence was inversely associated with most outcomes including hip fracture [hazard ratio (HR), 0.50; 95% confidence interval (CI), 0.33-0.78], myocardial infarction (HR, 0.69; 95% CI, 0.50-0.95), cancer death (HR, 0.60; 95% CI, 0.43-0.82), and all-cause mortality (HR, 0.64; 95% CI, 0.51-0.80) after adjustment for potential confounders. Women with low adherence to placebo were 20% more likely to have low adherence to statins and osteoporosis medications. In the Women's Health Initiative clinical trials, high adherence to placebo was associated with favorable clinical outcomes and mortality. Until the healthy behaviors and/or other factors for which high adherence is a proxy can be better elucidated, caution is warranted when interpreting the magnitude of benefit of medication adherence.

Cost-Effectiveness Analysis of a Low-Fat Diet in the Prevention of Breast and Ovarian Cancer

Background Results of the Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHI-DM) suggest that a low-fat diet may be associated with beneficial health outcomes for specific groups of women. Objective The objective is to assess how cost-effective the WHI-DM would be if implemented as a public health intervention and under the sponsorship of private health insurers and Medicare. Breast and ovarian cancers are the health outcomes of interest. Participants Two groups of WHI-DM participants form the target population for this analysis: participants consuming >36.8% of energy from fat at baseline, and participants at high risk for breast cancer with 32% or more of energy from fat at baseline. Methods This study uses Markov cohort modeling, following societal and health care payer perspectives, with Monte Carlo simulations and one-way sensitivity analyses. WHI-DM records, nationally representative prices, and published estimates of medical care costs were the sources of cost information. Simulations were performed for hypothetical cohorts of women aged 50, 55, 60, 65, or 70 years at the beginning of the intervention. Effectiveness was estimated by quality-adjusted life years (QALYs) and the main outcome measure was the incremental cost-effectiveness ratio (ICER). Results Following the societal perspective, the ICERs for the 50-year old cohort are $13,773/QALY (95% confidence interval $7,482 to $20,916) for women consuming >36.8% of energy from fat at baseline and $10,544/QALY ($2,096 to $23,673) for women at high risk for breast cancer. The comparable ICER from a private health care payer perspective is $66,059/QALY ($30,155 to $121,087) and from a Medicare perspective, it is $15,051/QALY ($6,565 to $25,105). Conclusions The WHI-DM is a cost-effective strategy for the prevention of breast and ovarian cancers in the target population, from both societal and Medicare perspectives. Private health care payers have a relative short timeframe to realize a return on investment, since after age 65 years the financial benefits associated with the prevention program would accrue to Medicare. For this reason, the intervention is not cost-effective from a private health care payer perspective.

Abstract S6-1: Menopausal Hormone Therapy Influence on Cancer Incidence and Related Cancer Mortality in the Women's Health Initiative Randomized Trials

Abstract The Women's Health Initiative (WHI) has conducted two phase III randomized placebo controlled trials evaluating menopausal hormone therapy. Conjugated equine estrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily (E+P) was evaluated in 16,608 postmenopausal women with no prior hysterectomy and conjugated equine estrogen alone 0.625 mg daily (E alone) was evaluated in 10,738 postmenopausal women with prior hysterectomy. Previous analyses suggested differences in E+P vs E alone influence on incidence and related mortality of several cancers. More recent analyses after additional follow-up clarify these issues and suggest a unifying hypothesis regarding hormone therapy influence on cancer. In cross study comparisons using multivariate Cox regression models statistically significant differences between the two WHI trials regarding E+P vs E alone influence on breast cancer incidence (P=0.01), colorectal cancer incidence (P=0.004) and deaths from non-small cell lung cancer (P=0.03) are seen. In addition, E+P, but not E alone, had a greater adverse influence on mortality attributed to breast cancer, colorectal cancer, and NSCLC then on the incidence of these cancers. Results are summarized below. Menopausal Hormone Therapy Influence on Incidence and Related Mortality of Selected Cancer Chlebowski JAMA 2003;289:3243, Chlebowski NEJM 2004;350:991, Stefanick JAMA 2006;242:1048, Ritenbaugh Cancer Epi Bio Prev 2008;17:2609, Prentice Cancer Epi Bio Prev 2009;18:1531, Chlebowski NEJM 2009;360:573, Chlebowski Gynecologic Oncology 2010;117:394; abst, Chlebowski Proc ASCO 2010;abst 1705 As estrogen plus progestin simulates angiogenesis, these findings suggest an hypothesis that, in addition to its influence on cancer incidence, combined E+P use, thru angiogenesis stimulation or other mechanisms, broadly enhances growth of already established cancers, differentially impacting cancer-related survival across several cancer categories. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-1.

Conjugated Equine Estrogen Influence on Mammographic Density in Postmenopausal Women in a Substudy of the Women's Health Initiative Randomized Trial

Increased mammographic density is associated with increased breast cancer risk and reduced sensitivity of screening mammography and is related to hormone exposure. However, the effects of conjugated equine estrogens (CEEs) alone on mammographic density in diverse racial/ethnic populations are not established. We examined the effect of CEE alone on mammographic density in a subsample of the Women's Health Initiative (WHI) clinical trial participants. In the WHI trial, women were randomly assigned to daily CEE 0.625 mg or placebo. The effect of CEE on mammographic percent density was determined over 1 and 2 years in a stratified random sample of 435 racially and ethnically diverse participants from 15 of 40 WHI clinics. Use of CEE resulted in mean increase in mammographic percent density of 1.6 percentage points (95% CI, 0.8 to 2.4) at year 1 compared with a mean decrease of 1.0 percentage point (95% CI, -1.7 to -0.4) in the placebo group (P < .001). The effect persisted for 2 years, with a mean increase of 1.7 percentage points (95% CI, 0.7 to 2.7) versus a mean decrease of 1.2 percentage points (95% CI, -1.8 to -0.5; P < .001) in the hormone and placebo groups, respectively. These effects were greater in women age 60 to 79 years (P = .03 for interaction across age). Use of CEE results in a modest but statistically significant increase in mammographic density that is sustained over at least a 2-year period. The clinical significance of the CEE effect on mammographic density remains to be determined.

Vasomotor Symptoms, Adoption of a Low-Fat Dietary Pattern, and Risk of Invasive Breast Cancer: A Secondary Analysis of the Women's Health Initiative Randomized Controlled Dietary Modification Trial

To assess whether the effect of a low-fat dietary pattern on breast cancer incidence varied by report of baseline vasomotor symptoms. Postmenopausal women age 50 to 79 years enrolled onto the Women's Health Initiative (WHI) Dietary Modification trial from 1993 to 1998 were randomly assigned to a low-fat dietary intervention (n = 19,541) or comparison (n = 29,294). Presence of vasomotor symptoms at baseline was ascertained from a 34-item self-report symptom inventory. Women were queried semi-annually for a new diagnosis of breast cancer. Each case report was verified by medical record and pathology report review by centrally trained WHI physician adjudicators. Among participants who reported hot flashes (HFs) at baseline (n = 3,375), those assigned to the low-fat diet had a breast cancer rate of 0.27 compared with their counterparts in the control group who had a rate of 0.41 (hazard ratio [HR] = 0.65; 95% CI, 0.42 to 1.01). Among women reporting no HFs (n = 45,160), the breast cancer rate was 0.42 in those assigned to the low-fat diet compared with 0.46 in the control group (HR = 0.93; 95% CI, 0.84 to 1.03; P for interaction = .12 by HF status). Furthermore, the dietary benefits observed seemed to be specific to estrogen receptor (ER) -positive/progesterone receptor (PR) -positive tumors (ER positive/PR positive v other, P for risk = .03). Although women with and without HFs differed with regard to breast cancer risk factors, the effect of the diet intervention on breast cancer incidence by HF status was consistent across risk factor strata. The results of this trial, which are hypothesis generating, suggest that HFs may identify a subgroup of postmenopausal women whose risk of invasive breast cancer might be reduced with the adoption of a low-fat eating pattern.

Conjugated Equine Estrogen Influence on Mammographic Density in Postmenopausal Women in a Substudy of the Women's Health Initiative Randomized Trial

Conjugated Equine Estrogen Influence on Mammographic Density in Postmenopausal Women in a Substudy of the Women's Health Initiative Randomized Trial

Low-Fat Dietary Pattern and Risk of Treated Diabetes Mellitus in Postmenopausal Women&lt;subtitle&gt;The Women's Health Initiative Randomized Controlled Dietary Modification Trial&lt;/subtitle&gt;

Decreased fat intake with weight loss and increased exercise may reduce the risk of diabetes mellitus in persons with impaired glucose tolerance. This study was undertaken to assess the effects of a low-fat dietary pattern on incidence of treated diabetes among generally healthy postmenopausal women. A randomized controlled trial was conducted at 40 US clinical centers from 1993 to 2005, including 48,835 postmenopausal women aged 50 to 79 years. Women were randomly assigned to a usual-diet comparison group (n = 29,294 [60.0%]) or an intervention group with a 20% low-fat dietary pattern with increased vegetables, fruits, and grains (n = 19,541 [40.0%]). Self-reported incident diabetes treated with oral agents or insulin was assessed. Incident treated diabetes was reported by 1303 intervention participants (7.1%) and 2039 comparison participants (7.4%) (hazard ratio, 0.96; 95% confidence interval, 0.90-1.03; P = .25). Weight loss occurred in the intervention group, with a difference between intervention and comparison groups of 1.9 kg after 7.5 years (P < .001). Subgroup analysis suggested that greater decreases in percentage of energy from total fat reduced diabetes risk (P for trend = .04), which was not statistically significant after adjusting for weight loss. A low-fat dietary pattern among generally healthy postmenopausal women showed no evidence of reducing diabetes risk after 8.1 years. Trends toward reduced incidence were greater with greater decreases in total fat intake and weight loss. Weight loss, rather than macronutrient composition, may be the dominant predictor of reduced risk of diabetes.