F. Allan Hubbell

The women's health initiative recruitment methods and results

One of the most challenging aspects of the Women’s Health Initiative (WHI) was the recruitment of more than 161,000 women for this long-term prevention trial and observational study. The WHI had many enrollment goals that made recruitment efforts formidable (1). These included the recruitment of postmenopausal women, a group seldom targeted for clinical trials; enrolling minority groups in at least the same proportion as they existed in the general population; and enrolling women willing to participate in a long-term (8–12 year) study. The success of the WHI in meeting these goals can be attributed to several factors: the experience gained from prior studies, such as the National Cancer Institute (NCI)-sponsored Women’s Health Trial (2), the subsequent Women’s Health Trial Feasibility Study in Minority Populations (3), and the Postmenopausal Estrogen/Progestin Interventions Trial (4); detailed planning by the WHI investigators; the dedication of recruiters, staff, and investigators at the clinical centers; and, a social and political climate that enhanced women’s interest in health research. Prior to the WHI, few large-scale prevention or clinical trials focused on postmenopausal women. Indeed, until recently, relatively little emphasis was placed on the recruitment of women of any age into such studies (5). However, during the last decade, a number of forces have come together to change this situation. The stance that women

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS Postmenopausal women (N = 36 282) who were enrolled in a Womens Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

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

BACKGROUND By contrast with many observational studies, women in the Womens Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort. METHODS Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50-79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04). INTERPRETATION Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer. FUNDING US National Heart, Lung, and Blood Institute; Wyeth.

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

BACKGROUND In the post-intervention period of the Womens Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING National Heart, Lung and Blood Institute, National Institutes of Health.

Impact of U.S. Citizenship Status on Cancer Screening Among Immigrant Women

OBJECTIVE: We evaluated the relationship between U.S. citizenship status and the receipt of Pap smears and mammograms among immigrant women in California.DESIGN: Cross-sectional study using data from the 2001 California Health Interview Survey.PATIENTS/PARTICIPANTS: Noninstitutionalized, civilian women, aged 18 years and older living in California.MEASUREMENTS AND MAIN RESULTS: We analyzed data from the 2001 California Health Interview Survey and used logistic regression models to adjust for sociodemographic factors and for access and utilization of health services. After adjusting we found that U.S. citizen immigrants were significantly more likely to report receiving a Pap smear ever (adjusted prevalence ratio [aPR], 1.05; 95% confidence interval [CI], 1.01 to 1.08), a recent Pap smear (aPR, 1.07; 95% CI, 1.03 to 1.11), a mammogram ever (aPR, 1.17; 95% CI, 1.12 to 1.21), and a recent mammogram (aPR, 1.38; 95% CI, 1.26 to 1.49) as compared to immigrants who are not U.S. citizens. Also associated with receiving cancer screening were income, having a usual source of care, and having health insurance. Hispanic women were more likely to receive Pap smears as compared to whites and Asians.CONCLUSIONS: Not being a U.S. citizen is a barrier to receiving cervical and breast cancer screening. Additional research is needed to explore causal factors for differences in cancer screening rates between citizens and noncitizens.

Impact of English language proficiency on receipt of pap smears among Hispanics.

AbstractBACKGROUND: Compared to normal weight women, women with obesity have higher mortality from breast cancer but are less often screened. OBJECTIVES: To examine the relation between mammography use and weight category and to examine the influence of race, illness burden, and other factors on this relationship. DESIGN AND SETTING: The 1998 National Health Interview Survey, a U.S. civilian population-based survey. PARTICIPANTS: Five thousand, two hundred, and seventy-seven women ages 50 to 75 years who responded to the Sample Adult and Prevention questionnaires. MEASUREMENTS: Mammogram use in the preceding 2 years. RESULTS: Among 5,277 eligible women, 72% reported mammography use. The rate was 74% among white women and 70% among black women. Among white women, mammogram use was lowest in women with a body mass index (BMI) greater than 35 kg/m2 (64% to 67%). After adjusting for sociodemographic factors, health care access, medical conditions, hospitalizations, and mobility status, higher BMI was associated with lower screening among white women, P=.02 for trend; the relative risk (RR) for screening in moderately obese white women (BMI, 35 to 40 kg/m2) was 0.83 (95% confidence interval [CI], 0.68 to 0.96) compared to normal weight white women. Compared to normal weight black women, mammography use was similar or higher in overweight (BMI, 25 to 30 kg/m2; RR, 1.19; 95% CI, 1.01 to 1.32), mildly obese (BMI, 30 to 35 kg/m2; RR, 1.22; 95% CI, 0.98 to 1.39), and moderately obese black women (RR, 1.37; 95% CI, 1.37 to 1.50) after adjustment. The P value for the race-BMI interaction was .001. Results for white and black women were unchanged after additional adjustment for psychological functioning and health habits. CONCLUSION: Among white women, those with higher BMI were less likely to undergo breast cancer screening than normal weight women. This relationship was not seen in black women. Our findings were not explained by differences in sociodemographic factors, health care access, illness burden, or health habits. More research is needed to determine the reasons for these disparities so that appropriate efforts can be made to improve screening.

Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial

BACKGROUND In the Womens Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer. METHODS The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided. RESULTS After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79). CONCLUSION Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

Sex Hormone Levels and Risks of Estrogen Receptor–Negative and Estrogen Receptor–Positive Breast Cancers

BACKGROUND Endogenous sex hormone levels are associated with risks of breast cancer overall and estrogen receptor (ER)-positive breast tumors; however, their associations with ER-negative tumors remain unclear. METHODS In a case-cohort study within the Womens Health Initiative Observational Study among postmenopausal women aged 50-79 years, we examined associations between endogenous testosterone and estradiol levels and the risks of ER-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in 317 invasive breast cancer case subjects and in a subcohort of 594 women. Bioavailable sex hormone levels were calculated using the total hormone level and the sex hormone-binding globulin concentration (measured by radioimmunoassays and a chemiluminescent immunoassay, respectively). Cox proportional hazards regression was used for statistical analysis. All statistical tests were two-sided. RESULT The unadjusted absolute rates of ER-negative breast cancer for testosterone quartiles 1-4 were 0.34, 0.20, 0.23, and 0.21 per 10,000 person-years, respectively. Compared with women in the lowest quartile of testosterone level, those in quartile 2 had a 56% lower risk of ER-negative cancer (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.23 to 0.85), those in quartile 3 had a 45% lower risk (HR = 0.55, 95% CI = 0.30 to 1.01), and those in quartile 4 had a 49% lower risk (HR = 0.51, 95% CI = 0.28 to 0.94), independent of other risk factors. Estradiol level was not associated with ER-negative breast cancer. ER-positive breast cancer risk increased with higher testosterone levels (P(trend) = .04), but this trend was not statistically significant after adjustment for estradiol (P(trend) = .15). ER-positive cancer risk was approximately twofold higher in women with estradiol levels in quartiles 2-4 compared with women in quartile 1, independent of risk factors. CONCLUSION Higher serum levels of bioavailable testosterone are associated with lower risks of ER-negative breast cancer in postmenopausal women.

Improving Breast Cancer Control Among Latinas: Evaluation of a Theory-Based Educational Program

The study evaluated a theory-based breast cancer control program specially developed for less acculturated Latinas. The authors used a quasi-experimental design with random assignment of Latinas into experimental (n = 51) or control (n = 37) groups that completed one pretest and two posttest surveys. The experimental group received the educational program, which was based on Banduras self-efficacy theory and Freires empowerment pedagogy. Outcome measures included knowledge, perceived self-efficacy, attitudes, breast self-examination (BSE) skills, and mammogram use. At posttest 1, controlling for pretest scores, the experimental group was significantly more likely than the control group to have more medically recognized knowledge (sum of square [SS] = 17.0, F = 6.58, p < .01), have less medically recognized knowledge (SS = 128.8, F = 39.24, p < .001), greater sense of perceived self-efficacy (SS = 316.5, F = 9.63, p < .01), and greater adeptness in the conduct of BSE (SS = 234.8, F = 153.33,p < .001). Cancer control programs designed for less acculturated women should use informal and interactive educational methods that incorporate skill-enhancing and empowering techniques.

Estrogen Plus Progestin and Colorectal Cancer Incidence and Mortality

PURPOSE During the intervention phase in the Womens Health Initiative (WHI) clinical trial, use of estrogen plus progestin reduced the colorectal cancer diagnosis rate, but the cancers were found at a substantially higher stage. To assess the clinical relevance of the findings, analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up. PATIENTS AND METHODS The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were randomly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or matching placebo (n = 8,102). Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed. RESULTS After a mean of 5.6 years (standard deviation [SD], 1.03 years) of intervention and 11.6 years (SD, 3.1 years) of total follow-up, fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group (diagnoses/year, 0.12% v 0.16%; hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.94; P = .014). Bowel screening examinations were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (50.5% v 28.6%; P < .001) and were at higher stage (regional or distant, 68.8% v 51.4%; P = .003). Although not statistically significant, there was a higher number of colorectal cancer deaths in the combined hormone therapy group (37 v 27 deaths; 0.04% v 0.03%; HR, 1.29; 95% CI, 0.78 to 2.11; P = .320). CONCLUSION The findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.