Oral Bisphosphonates May Prevent Invasive Breast Cancer

Zosia Chustecka

December 11, 2009

December 11, 2009 (San Antonio, Texas) — Oral bisphosphonate drugs used for postmenopausal osteoporosis apparently offer protection against invasive breast cancer, according to 2 hypothesis-generating studies presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

A huge analysis of data from several Women's Health Initiative (WHI) studies, which together involved more than 150,000 generally healthy postmenopausal women, showed that those who were taking bisphosphonates to protect their bones had a 32% reduction in invasive breast cancer.

A smaller study from Israel, which involved 4575 postmenopausal women, found a 34% reduction in the relative risk for breast cancer.

Previous data suggesting that bisphosphonates have antitumor properties have come from trials in women who already had breast cancer, which showed a reduction in breast cancer recurrence, as previously reported by Medscape Oncology.

The new data in healthy women suggest a chemopreventive effect.

"The idea that bisphosphonates could reduce breast cancer incidence is very exciting . . . [because they] could easily be used to counteract both osteoporosis and breast cancer," said Rowan Chlebowski, MD, PhD, who presented the WHI data. Dr. Chlebowski is a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in California.

Osteoporosis and breast cancer are 2 common health problems in postmenopausal women, and "this cohort study indicates the possibility that a simple oral drug may prevent both of these common conditions," said Theresa Guise, MD, professor of medicine and oncology at the Indiana University School of Medicine in Indianapolis, who moderated the press conference. She said it was encouraging that a second study, which was conducted in a geographically different population, came up with a similar finding.

"This needs to be confirmed by controlled clinical trials, but it is a step forward," Dr. Guise said.

Huge WHI Analysis

The large analysis presented by Dr. Chlebowski was based on data from WHI studies of hormones, dietary intervention, and calcium/vitamin D supplementation. It analyzed data on 151,592 postmenopausal women, 2216 of whom used oral bisphosphonates when they began the study (90% alendronate, 10% etidronate). The majority of women were taking alendronate once daily, he added.

An important consideration in the analysis was the confounding factor that women who were prescribed bisphosphonates would have low bone mineral density (BMD), and would be at lower risk for breast cancer because of the cumulative effect of estrogen. To get around this "analytical problem," Dr. Chlebowski and colleagues used a 10-item hip fracture predictive score to measure BMD in all of the women, and compared these findings with those from 10,000 women who had had BMD measured by densitometry. The researchers correlated these findings to correct for any potential difference in BMD between women taking and not taking bisphosphonates.

Comparison of the 2 groups showed a significantly lower incidence rate of invasive breast cancer in women who were taking bisphosphonates (3.29/1000 person-years) than in those who were not (4.38/1000 person-years), which represents a reduction of 32% (hazard ratio, 0.68, 95% confidence interval, 0.52 - 0.89; P < .01).

Most of the breast cancers were estrogen-receptor positive, and the 30% difference between the 2 groups was statistically significant (P = .02). There were also numerically fewer cases of estrogen-receptor-negative cases, but this difference of 33% was not statistically significant because there were so few cases, Dr. Chlebowski explained.

However, there was an increase in ductal carcinoma in situ (DCIS) among the women who were taking bisphosphonates (1.53/1000 person-years), compared with those who were not taking these drugs (0.92/1000 person-years), with a hazard ratio of 1.53.

One physician in the audience asked about this "disconnect" between the reduction in invasive breast cancer and the increase in DCIS, and Dr. Chlebowski acknowledged that "this is a question that needs to be addressed." He noted that a similar finding was seen in the STAR trial of tamoxifen and raloxifene; however, the marginally statistically significant increase in DCIS that was seen in that trial "has not played out as an increase in invasive breast cancer."

Similar Finding in Second Study

The second study with a similar finding was presented at the SABCS meeting by Gar Rennert, MD, PhD, from the Carmel Medical Center of Clalit Health Services and the Technion-Israel Institute of Technology in Haifa, Israel.

This was a case–control study that matched 2368 cases of newly diagnosed breast cancer with a control group that was matched for age, ethnic background, and residential area. All of the women underwent an interview during which they were asked 400 questions about their medical and family history and medications taken. Although these data were self-reported, they were validated by pharmacy records, Dr. Rennert said.

Women who self-reported long-term use of bisphosphonates had a significantly lower rate of breast cancer incidence (2.5%) than those who did not (3.7%); the reduction of 34% was statistically significant.

Dr. Rennert and colleagues adjusted for a variety of risk factors, including age, consumption of fruit and vegetables, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplementation and hormone replacement therapy use, number of pregnancies, months of breast feeding, and age at first pregnancy. This lowered the figure for the reduction in the risk from breast cancer slightly, to 29%, but it remained statistically significant.

Dr. Rennert also noted that the breast cancer found in women who were taking bisphosphonates was more often estrogen-receptor positive and tended to be better differentiated, so these breast cancers "seem to have a better prognosis."

There was no difference in the incidence in DCIS in this study, he said.

The effect on breast cancer was seen after a year of taking bisphosphonate (but not earlier), and then remained stable even if the drug was taken for several more years, which "fits in with the pharmacokinetics of these drugs," he explained.

"The association between bisphosphonate use for a year or more and reduction in breast cancer was strong and robust," Dr. Rennert said. But he emphasized that it was an association, not proof, and said that randomized clinical trials are needed.

Questions following both presentations indicated that audience members were somewhat skeptical. One researcher asked about the confounding factor of low BMD, and appeared to be unconvinced by the measures that Dr. Chlebowski and colleagues applied to counter this, noting that Dr. Rennert's study did not control for this. Another researcher pointed out that lower BMD would indicate lower estrogen levels, and asked whether the effect seen was actually due to estrogen and not a drug effect of the bisphosphonates.

Countering that suggestion, Dr. Rennert pointed to the Austrian study (N Engl J Med. 2009;360:679-691) that showed a reduction in the incidence of contralateral breast cancer in patients who were taking bisphosphonates for another reason — to protect against bone loss induced by aromatase inhibitors that they were using for breast cancer recurrence risk reduction.

This bisphosphonate, zoledronic acid, was used intravenously, but it comes from the same class of drugs and, in this case, it shows a reduction in breast cancer incidence in a patient population that did not have low BMD.

"This suggests that it is an effect of the drug," Dr. Rennert said.

When asked why bisphosphonates, which were designed specifically to hone in on the bone, also have an antitumor effect, Dr. Chlebowski said that these drugs "reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators."

Dr. Guise added that bisphosphonates have been shown to have effects on cancer cell deaths and proliferation in vitro and in animal studies. In addition, recent human studies that analyzed cancer samples taken before and after bisphosphonate use showed that there was a reduction in prenylated proteins, which act to stabilize the membrane of cancer cells. This suggests that the drug is rendering the cancer cells less stable, she added.

Dr. Chlebowski reports serving as a consultant to Amgen, AstraZeneca, Lilly, Novartis, and Pfizer. Dr. Guise reports serving on the advisory boards of Amgen, Lilly, Novartis, and Roche. Dr. Rennert has disclosed no relevant financial relationships.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 21 and 27. Presented December 10, 2009.


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