Women's Health Initiative Report Research Articles

Abstract 3700: Incidence trends of breast, endometrial, and ovarian cancer among US women in relation to changing patterns of menopausal hormone therapy

Abstract Background: Menopausal hormone therapy (MHT) increases risk of breast, endometrial, and ovarian cancer. Following the Women's Health Initiative (WHI) report in 2002 linking MHT to increased breast cancer risk, both MHT use and breast cancer rates declined sharply in the US. Subsequently, we reported an accelerated decline in ovarian cancer rates after 2002 using age-period-cohort (APC) modeling to estimate period changes independent of age and birth cohort effects. Given links between MHT and risks for breast, ovarian and endometrial cancer, we compared changes in rates of these tumors following the WHI announcement in 2002 by applying a comparative APC modeling approach. Methods: Using the North American Association of Central Cancer Registries (NAACCR) database (1995-2010), we created three analytic files for women ages 50 to 84 years (surrogate for menopause): breast (ICD-0-3 codes C500-509; n = 1,597,409), endometrial (C540-549, C559; 340,498), and ovarian (C569; 174,755) cancers. We applied standard (SEER*STAT, joinpoint regression) and APC models to estimate cancer incidence rate changes pre- (1995-2002) and post- (2003-2010) WHI report, to assess temporal changes associated with the decline in MHT prescriptions. Results: Although age-standardized breast cancer incidence was heterogeneous before and after WHI-report, APC models demonstrated a decline in rates after 2002. Age-standardized endometrial cancer rates declined 0.82%/year (95% CI: -1.44 to -0.19%/year) pre-WHI, after which the rates increased 1.03%/year (95% CI: 0.59 to 1.47%/year). APC models confirmed the increase for endometrial cancer post-WHI. Age-standardized ovarian cancer incidence declined 1.02%/year (95% CI: -1.55 to -0.48%/year) pre-WHI, after which the rates declined 2.36%/year (95% CI: -3.00 to -1.70%/year). APC models showed an accelerated decline in ovarian cancer incidence post-WHI. Conclusion: Following a marked reduction in MHT use circa 2002, incidence rate trends changed somewhat differently for breast, endometrial and ovarian cancer. Specifically, rising breast cancer rates fell, decreasing endometrial cancer rates increased, and decreasing ovarian cancer rates fell more rapidly. Further analysis by age, race and histological subtype may provide insights into complex etiological differences between these hormone-related tumors. Citation Format: Hannah P. Yang, William F. Anderson, Britton Trabert, Philip S. Rosenberg, Gretchen L. Gierach, Clara Bodelon, Nicolas Wentzensen, Kathleen A. Cronin, Mark E. Sherman. Incidence trends of breast, endometrial, and ovarian cancer among US women in relation to changing patterns of menopausal hormone therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3700. doi:10.1158/1538-7445.AM2015-3700

Ovarian Cancer Incidence Trends in Relation to Changing Patterns of Menopausal Hormone Therapy Use in the United States

After a report from the Women's Health Initiative (WHI) in 2002, a precipitous decline in menopausal hormonal therapy (MHT) use in the United States was linked to a decline in breast cancer incidence rates. Given that MHT use is also associated with increased ovarian cancer risk, we tested whether ovarian cancer incidence rates changed after 2002. Using the North American Association of Central Cancer Registries database (1995 to 2008; N = 171,142 incident ovarian cancers), we applied standard analytic approaches and age-period-cohort (APC) models to estimate ovarian cancer incidence rate changes before (1995 to 2002) and after (2003 to 2008) the WHI report. Among women age ≥ 50 years, age-standardized ovarian cancer incidence declined by 0.8% per year (95% CI, -1.8% to -0.5% per year) before the WHI announcement; after the WHI report, the rate declined by 2.4% per year (95% CI, -2.5% to -2.2% per year). APC models confirmed an accelerated decline in ovarian cancer incidence after the WHI report, adjusted for age and birth cohort effects. This sudden change was notable among women most likely to have used MHT (ie, women age 50 to 69 years, white women, and residents of regions with highest MHT prescription frequency). The largest changes were found for the endometrioid histologic subtype. After a marked reduction in MHT use around 2002, ovarian cancer incidence rates demonstrated an accelerated decline, with the largest changes for endometrioid carcinomas. This strong temporal association, although not proving a causal role of hormones in ovarian carcinogenesis, suggests that future analytic research supporting cancer control efforts should clarify the role of hormonal exposures on the development and behavior of subtypes of ovarian cancer.

Risk of noncompliance due to patient discomfort during screening mammogram

1522 Background: There is enough evidence supporting the benefits of screening mammograms than any other screening procedure for the early detection of malignancy. Compliance to the screening method is very important to achieve this purpose. There is some concern about future trends in breast cancer mortality as a decline in rates of mammogram screening has been noticed. Pain during mammography has been recognized as a significant deterrent to breast screening. Hence this study was done to evaluate compliance in screening mammogram and to analyze major reasons for noncompliance. Methods: Randomly selected patients visiting the doctor's office for various reasons were asked about mammogram and their experience. Their responses were tabulated and analyzed statistically. Results: Out of 160 people questioned, 155 patients had mammogram regularly at 1–2 year interval and five patients did not. 50% of respondents were 51–70 years of age, 15% were 50 years or under, and 31% were over 70 years. Ninety patients (58%) reported their mammogram experience was unpleasant, causing pain and bruising. In spite of the discomforts reported, 132 (82.5%) patients said they would continue the screening as recommended. However, 28 patients (17.5%) indicated their intention not to get further mammograms based on their painful experience, unless the screening technology was improved. Conclusions: Breast cancer incidence after peaking in 1998 has decreased 9.8% since then with a 12% decline in women aged 50–60. The sharpest decline was noted from 2003 that could be due to the decrease in the hormone replacement therapy after the Women's Health Initiative report. However, it may also reflect some reduction in screening mammograms from 70% (in 2000) to 66% (in 2005) as estimated by National Health Interview Survey. Various causes were attributed for the decline in screening mammogram rate including the discomfort and pain caused by compression during film mammography. More than 1 in 6 patients refusing to undergo further screening is definitely a sign of concern. Better screening methods like patient controlled compression mammogram reported by Duke University Medical Center or other methods are worth investigating, to improve the compliance of the one of the effective preventive measures. No significant financial relationships to disclose.

Use of total abdominal hysterectomy and hormone replacement therapy in BRCA1 and BRCA2 mutation carriers undergoing risk-reducing salpingo-oophorectomy

Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of developing ovarian and breast cancer in BRCA 1 and BRCA 2 (BRCA1/2) mutation carriers. The short-term use of hormone replacement therapy (HRT) after RRSO may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction gained by RRSO. Multiple factors may influence decisions regarding whether or not total abdominal hysterectomy (TAH) is done at the time of RRSO, whether HRT is elected after surgery, and if so, which type of HRT is selected. Our investigation has been to examine factors associated with TAH and HRT use and to determine if the choice of TAH at the time of RRSO and the type of HRT that was chosen has changed since the report of data from the Women's Health Initiative (WHI) in 2002, which showed that the relative risk for breast cancer is higher in subjects who used combined estrogen-progestin HRT compared with those who used estrogen alone. We identified 73 female BRCA1/2 mutation carriers who were known to have undergone RRSO between 1/1972 and 11/2005 who had no history of breast or ovarian cancer at the time of the surgery. Information regarding whether or not TAH was done in addition to RRSO, the type of HRT, and the subsequent diagnosis of breast cancer was collected. Of 73 unaffected BRCA1/2 carriers known to have had RRSO, 40 (40/73, 55%) also underwent TAH. Thirty-three of 73 (33/73, 45%) began HRT following RRSO. Of 33 HRT users, 17 (17/33, 52%) used estrogen only and 14 (14/33, 42%) used combined hormonal therapy. There was no difference in use of HRT in women with TAH (17/40, 43%) vs. those without (16/33, 48%) (P = 0.6). There was no difference in the proportion of women who underwent TAH before and after the WHI report in 2002. Use of HRT, most notably combined estrogen-progestin HRT, appears to have declined since 2002, although this result did not reach statistical significance. In this single institution study, the majority of BRCA1/2 mutation carriers undergoing RRSO also underwent TAH, and a substantial number took HRT. TAH did not increase the likelihood of taking HRT compared to RRSO alone.

Changes of the prescription of hormone therapy in menopausal women: An observational study in Taiwan

BackgroundTo evaluate the impact of the 2002 Women's Health Initiative (WHI) study results on the prescription of menopausal hormone therapy (MHT) to treat menopause-related symptoms in Taiwan.MethodsThis retrospective study participant data collected from women interviewed in 2001 Taiwan's National Health Interview Survey (NHIS) and the National Health Insurance (NHI) outpatient claims for women being treated for menopause-related symptoms. We compared prescriptions made for MHI to women seeking outpatient treatment for menopause-related symptoms before and after the publication of the 2002 WHI to study its effect of prescription behavior in Taiwan. There was one dichotomous outcome variable, which was whether MHT was prescribed or not in an outpatient visit to treat menopause-related symptoms.ResultsOur study included 504 women 45 years old or above whose outpatient visits for menopause-related symptoms were covered by National Health Insurance in 2002. In total, these 504 women made 2549 outpatient visits to be treated for these symptoms. The proportion of outpatient visits in which MHT was prescribed dropped from 83.0% (n = 1,155) before WHI to 73.0% (n = 844) after WHI. We found a decrease in likelihood that women would be prescribed MHT for menopause-related symptoms after the release of the WHI report (OR = 0.36, 95%CI = 0.25 to 0.52, p < 0.05). Gynecologists and obstetricians are more likely to prescribe MHT than physicians with other medical specialties (5.34; 95%CI = 3.45 to 8.26, p < 0.05). Women with college level educations or higher became less likely to be prescribed MHT (Model 2; OR 0.30; 95% CI 0.11–0.83), and academic medical centers became less likely to prescribe MHT than other medical care institutions (Model 3; OR 0.15; 95% CI 0.34–0.63).ConclusionThe WHI report caused a substantial decline in the use of MHT to treat menopause-related symptoms in Taiwan. It was found to exert most of its influence in patients with higher educations, physicians with specialties other than gynecologists and obstetricians, and academic medical centers.

Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757

Objectives At present the Women's Health Initiative trial is the only reported randomised controlled trial studying the effects of hormone therapy among healthy postmenopausal women. The Women's Health Initiative reports have been criticized for lacking in generalisability, due to the characteristics of the trial population. We aimed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women. Methods Eligible women were randomised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment. One thousand seven hundred and seventy-eight postmenopausal women aged 50–64 at the time of sampling were recruited in 1999–2001 at three clinical centers in Estonia. Participants received conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 5 mg/d, if less than 3 years had passed since menopause at recruitment, or matched placebo or non-treatment. Trial treatment was stopped gradually from 1 January 2004 to 31 May 2004. Results After a follow-up period from 2.0 to 5.0 years the combined hazard ratio, stratified by blinding and adjusted for age at recruitment and former oral contraceptive use was 1.12 (95% confidence interval [CI]: 0.90–1.40) for coronary heart disease, 1.24 (95% CI: 0.85–1.82) for cerebrovascular disease, 1.36 (95% CI: 0.73–2.52) for total cancer, and 0.61 (95% CI: 0.42 to 0.89) for bone fractures. Conclusions The results from the Estonian Postmenopausal Hormone Therapy randomised trial are consistent with the Women's Health Initiative findings.

Moderate dosage estrogen–androgen therapy improves continuation rates in postmenopausal women: impact of the WHI reports

Objective The purpose of this report is not to provide descriptive data for practice recommendations but to point the way to more liberal thinking than the conservatism of today. The patients in this historical practice, where moderate dosages of estrogen are used, with androgens added when indicated, continue hormone replacement therapy (HRT) for many years. These women were audited to determine the reasons for continuance.Design During the 3 years from 1996 to 1999, 814 women have been followed prospectively, the date of this first visit recorded, as well as the date last seen, the years of hormone use, and their current hormone replacement, so that continuation rates could be determined. The records of the patients were reviewed in January 2005 to determine the impact of the Women's Health Initiative (WHI).Results Of the 814 patients, there were 573 surgically menopausal women with a mean age of 61.8±3.25 years and 241 naturally menopausal women with a mean age of 58.6±3.08 years. During the 3 years of observation, 692 women continued HRT while 122 discontinued their therapy. Of those continuing therapy, 606 were treated with the implantation of various combinations of estradiol and testosterone pellets, while 86 used injectables, patches or oral hormones. Continuation rates for pellet patients were 96.7% for 10 years, 88.8% for 20 years, and 21.9% for 40 or more years. Continuation rates for the other hormone users were 53.5% for 10 years and 20.9% for 20 years. Eighty-one percent of the patients were prescribed progestogens, and 18 different progestogens or dosages or regimens were used to individualize therapy and provide as side-effect-free a regimen as possible. Continuation rates in the 692 remaining patients declined to 66.7% during the next 5 years.Conclusions Moderate dosages of estrogens, with androgens added when indicated, improve continuation rates. Therapy must be individualized so that not only are menopausal symptoms relieved but also side-effects are minimal and women continue to feel good. The implantation of estradiol and testosterone pellets is not necessary for even the majority of postmenopausal women. However, estrogen dosages must be adequate to provide a sense of well-being. After the WHI reports, continuation rates declined more rapidly.

Attitudes of Korean clinicians to postmenopausal hormone therapy after the Women's Health Initiative study

To assess the attitudes of Korean physicians toward hormone therapy (HT) after publication of the Women's Health Initiative (WHI) study. Self-administered questionnaires, consisting of 22 items, were sent by mail to the members of the Korean Society of Menopause. More than 95% of Korean physicians were aware of the WHI study. The HT prescription rate decreased by 16% after publication of the WHI report; approximately half of the physicians who continued prescribing HT changed their prescriptions. The largest decreases occurred in regimens using conjugated equine estrogens and medroxyprogesterone acetate, for which prescriptions of sequential and continuous-combined regimens decreased by 20.7% and 22.7%, respectively. In contrast, the prescription rate for tibolone increased by 3.6%. Approximately 30% of physicians changed from standard to low doses, and 67.8% shortened the duration of HT. After publication of the WHI report, the main reasons for not prescribing or discontinuing HT were patient refusal and increased risk of cardiovascular disease, rather than breast cancer risk. After publication of the WHI report, the number of physicians who prescribed alternative or complementary medicines increased, the rate of HT prescription for the prevention of osteoporosis decreased, and the number of postmenopausal outpatients decreased. Despite the results of the WHI report, most Korean physicians who participated in this study continued prescribing HT; however, approximately half of those who continued prescribing HT changed their prescriptions. The greatest change occurred in regimens using conjugated equine estrogens and medroxyprogesterone acetate.

A significant change in Norwegian gynecologist's attitude to hormone therapy is observed after the results of the Women's Health Initiative Study

In Norway about 40% of climacteric women have been on hormone therapy (HT). The women usually seek advice from their doctor concerning HT. The attitude of the medical profession thus has great impact on the decision to use or to restrain from use of HT. We, therefore, in 1997 (1) and in 2002 conducted a survey among all Norwegian gynecologists to investigate the attitude and prescribing practice concerning HT. The 2002 survey was carried out in April to June 2002, immediately before the results of the Women's Health Initiative (WHI) (2) and the Heart and Estrogen/progestin Replacement Study (HERS) II (3) were published. It offered us an opportunity to investigate if remarkable publications had an immediate impact on the opinion concerning HT. In 1997 80.4% of Norwegian gynecologists (382 of 475) answered a written questionnaire, in 2002 66.8 (397 of 594) responded. Selected questions that might be influenced by the WHI and HERS II were repeated in November 2002. This latter questionnaire was addressed to colleagues having responded to the previous inquiry but was not sent to retired gynecologists or those living abroad. The survey was anonymous and no reminder was sent. The response rate was 69.9 (244 of 349). The WHI report was known to 93.4% of the respondents. Thirty four percent had read the original article itself, whereas the others had information about the results from other sources such as medical journals, media or information from colleagues or from pharmaceutical companies. The percentage of gynecologists answering positive to selected questions is seen in Table I. There was a significant change in attitude from being liberal to be more reluctant concerning prescribing HT after the two publications came out. An increasing awareness of HT as a risk factor for breast cancer was seen through the three inquiries. In 1997 more than one third regarded HT to protect against thrombosis, but this assumption almost disappeared in the two 2002 surveys. In the first study, 77% of doctors considered HT to give protection for ischemic heart disease (primary prevention), in spring 2002 still 32% shared this opinion, but in autumn 2002 the number dropped to 7%. Concerning angina pectoris and recurrent heart attack, HT was in 1997 considered indicated for secondary prevention, but this attitude had changed in 2002 after the HERS I study (4) and almost had disappeared in the last investigation after the HERS II study (3). Knowledge about HT being protective against colon cancer was observed in less than 50% of the gynecologists during the spring of 2002, but in the autumn more than 80% were aware of this fact. In our 1997 survey (5) we asked about the female gynecologists or the partners of the male gynecologists personal use of HT, 78 and 77%, respectively, used HT. These figures were almost unaltered in the investigation performed during the spring 2002 where 74 and 75%, respectively, were HT users. In the last inquiry it turned out that none of them had stopped the treatment due to the results of the WHI study. It was evident that newly-published studies were quickly picked up by the gynecologists. Further, their views were adapted according to the new information, but their personal attitude to their own or their spouses use of HT was not affected. This is in contrast to Norwegian statistics showing an almost 40% drop in sales of HT since the summer of 2002 when the WHI study was published, a trend that also has been observed in US (6). We do, however, not know if the decrease in the use of HT and the changed attitude towards HT will be permanent.