Breast Cancer Rates Have Dropped Since WHI of 2002

Pharmacology Watch

Several important papers have been published in the last 2 months, none more important than the realization that breast cancer rates have dropped precipitously since the publication of the Women's Health Initiative (WHI) in 2002. The issue of estrogen-alone (not in combination with a progestin) and the risk of breast cancer is addressed in a new paper, as is the use of herbal supplements to treat postmenopausal vasomotor symptoms in women who have stopped HRT. Finally the duration of treatment of bisphosphonates for osteoporosis gains some clarity with publication of new data from the Fracture Intervention Trial.

The WHI study of combined estrogen and progesterone was halted in 2002 when it was found that women on the drug combination were at increased risk of breast cancer. Prior to the publication of the study, it was estimated that 30% of American women over the age of 50 were taking HRT. Within 6 months of the publication of WHI, half of those women had discontinued HRT. Now preliminary data suggests that breast cancer rates dropped precipitously in 2003 compared to 2002. The decline was most pronounced in women over the age of 50, and the biggest decline was in estrogen-receptor-positive breast cancer. Breast cancer rates had been rising steadily in this country at an average of 1.7% per year until 1998 when the rate began declining at 1% per year. The 7% drop seen in 2003 was the largest single decrease ever seen within a single year. The data was presented at the 29th Annual San Antonio Breast Cancer Symposium by researchers from MD Anderson. In a separate study, researchers from Northern California presented their own data that showed a decrease in hormone use of 68% between 2001 and 2003, and a decrease in breast cancer rates of 10-11%, which was sustained to 2004 (J Clin Oncology 2006;24:e49-50). The implication is that the sudden decrease in HRT use is responsible for the decrease rate of breast cancer, a conclusion supported by the dramatic decrease in ER positive cancers in postmenopausal women.

In contrast to the findings of the estrogens/progesterone wing of the Women's Health Initiative, the estrogen-only wing showed no increased risk of breast cancer (JAMA. 2004;291:1701-12). This was in contrast to several European studies, including the Million Woman Study, which showed an increased rate of breast cancer with unopposed estrogen (Lancet. 2003;362:419-427). Now a new study also suggests that estrogen-only is associated with a slightly increased risk of breast cancer. The study from Finland looked at nearly 85,000 women using oral or transdermal estradiol, 8,000 women using oral estriol (widely used in Europe but uncommonly used in the United States), and 18,000 women using vaginal estrogens for least 6 months were followed from 1994 through 2001. There was no increase risk for breast cancer for estradiol use of less than 5 years. Women who used estradiol for more than 5 years had a relative risk of breast cancer of 1.44 (1.29-1.59). Oral and transdermal estradiol conveyed similar risk. Oral estriol and vaginal estrogens did not increase breast cancer risk. The authors conclude that the use of estradiol for more than 5 years is associated with a increased risk of breast cancer (Obstet and Gynecol. 2006;108:1354-1360).

Herbal Supplements to Treat Vasomotor Symptoms

Many women who have stopped HRT have tried herbal supplements to treat vasomotor symptoms. A new study compares the effectiveness of black cohosh, multibotanicals, and soy with HRT and placebo. Researchers from the University of Washington enrolled 351 women who were in menopausal transition or were postmenopausal. They were given black cohosh 160 mg daily, multibotanical with black cohosh 200 mg plus 9 other ingredients, multibotanical plus dietary soy counseling, HRT with conjugated equine estrogen 0.625 mg daily with or without medroxyprogesterone 2.5 mg daily, or placebo. There was no difference in vasomotor symptoms between the herbal interventions and placebo at 3, 6, or 12 months or for the average over-all follow-up time points (P > 0.05 for all comparisons), with the exception that symptom intensity was significantly worse with the multibotanical plus soy compared with placebo (P = 0.016). Hormone therapy was effective at reducing vasomotor symptoms (P < 0.001). The authors conclude that black cohosh alone or as part of a multibotanical regimen was ineffective at treating menopausal vasomotor symptoms (Ann Int Med. 2006; 145: 869-879). As pointed out in an accompanying editorial, even though herbal supplements were found to be ineffective, the good news is that women in the placebo group had a 30% reduction in the severity and frequency of vasomotor symptoms during the 12-month follow up, a number that probably reflects the natural history of postmenopausal symptoms (Ann Int Med. 2006;145:924-925).

Bisphosphonates to Treat LBD, After 5 Years?

Since WHI, bisphosphonates have become the drugs of choice for many women with low bone density. Treatment with bisphosphonates for 5 years is safe and effective; however, treatment beyond 5 years has been debated with some experts recommending a "drug holiday" after 5 years because of a concern about diminished bone strength and microfractures. A new study suggests that there is no harm in extending treatment beyond 5 years, although there is minimal benefit. In the Fracture Intervention Trial (FIT), 1,099 postmenopausal women who had used alendronate for 5 years were randomized to 5 more years of alendronate 5 mg per day, 10 mg per day, or placebo. Outcomes were hip bone mineral density (BMD) with an exploratory outcome measure of fracture incidence. Compared to women who continued alendronate, those who were switched to placebo at 5 years had declines in BMD at the total hip (-2.4%; 95% CI, -2.9% to -1.8%; P < 0.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P < 0.001). Still, despite discontinuing alendronate, BMD remained at levels above pretreatment levels 10 years earlier. The cumulative risk for non-vertebral fractures was not significantly different between those continuing or discontinuing alendronate (19% vs 18.9%). Those who continued alendronate had significant lower risk of clinically recognized vertebral fractures, however, (5.3% placebo vs 2.4% alendronate) but no significant reduction in morphometric vertebral fractures. Of the women continuing alendronate, 18 underwent bone biopsies and none showed any qualitative abnormalities. The authors conclude that discontinuing alendronate after 5 years results in a moderate decline in BMD, a gradual rise in biochemical markers, but no higher fracture risk other than for clinical vertebral fractures compared to women who continued alendronate. The data also suggests that stopping alendronate at 5 years is safe, although the authors suggest that high-risk women may want to continue beyond 5 years (JAMA. 2006;296:2947-2953). Interestingly, no cases of osteonecrosis of the jaw were reported in women who took alendronate for 10 years.

FDA Actions

The FDA has approved a new estradiol gel for the treatment of moderate to severe vasomotor symptoms assisted with menopause. The gel, which is applied daily, supplies the lowest dose of estradiol approved by the FDA for this indication. Estradiol gel will be marketed as "Elestrin" by Kenwood Therapeutics.

The FDA has approved Novartis' combination antihypertensive "Exforge." The drug combines valsartan and amlodipine in one pill that is dosed once daily. It is expected to be marketed by September 2007.

The FDA has approved the first generic ondansetron injection (Zofran) for the prophylaxis of postoperative nausea and vomiting, and nausea and vomiting associated with cancer chemotherapy. The generic is manufactured by Teva pharmaceuticals.

The FDA has also approved generic oxybutynin extended release tablets (Ditropan XL). 'The new generics will be available in 5 mg and 10 mg extended-release tablets made by Mylan, and 50 mg extended-release tablets manufactured by Impax Laboratories. Oxybutynin is indicated for once daily treatment of overactive bladder in patients with urge incontinence, urgency, and frequency.

A generic bupropion extended-release tablet has been approved by the FDA. The generic version of Wellbutrin XL for the treatment of depression will be available in 150 mg and 300 mg tablets. The new generic is manufactured by Anchen Pharmaceuticals.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. 'In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5431. E-mail: