Bisphosphonates and Beyond: Managing Bone Density and Reducing Breast Cancer

Released: 3-Dec-2009 1:00 PM EST
Embargo expired: 10-Dec-2009 1:30 PM EST
Source Newsroom: American Association for Cancer Research (AACR)
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Newswise — Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggests that these agents may play a role in reducing recurrent breast cancer as well.

Theresa Guise, M.D., professor of medicine and Jerry W. and Peg S. Throgmartin professor of oncology in the Division of Endocrinology at the Indiana University School of Medicine, will moderate a press conference on this new data at the CTRC-AACR San Antonio Breast Cancer Symposium.

The press conference will take place on Thursday, Dec. 10, 2009, at 12:30 p.m. CT, in room 217C of the Henry B. Gonzales Convention Center. Reporters who cannot attend in person can participate by using the following information:

• U.S. & Canada: (888) 282-7404
• International: (706) 679-5207
• Access Code: 39115588
• Topic: AACR

The following abstracts will be presented at this press conference:

4083. The Effect of Zoledronic Acid on Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: The Z-FAST Study 5-Year Final Follow-Up

Zoledronic acid is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

“Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option,” said Adam Brufsky, M.D., Ph.D., associate professor of medicine, associate chief of hematolgy-oncology, and associate director for clinical investigation, University of Pittsburgh Cancer Institute.

Brufsky estimates that between 20,000 to 30,000 women a year will benefit from this therapy and that number is growing. Anastrozole, currently sold as Arimidex by AstraZeneca, is scheduled to go off patent within the next few years.

“Women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection,” said Brufsky.

Beyond the aging population, use of zoledronic acid could increase even further if the signs that it prevents breast cancer recurrence continue in larger studies.

Brufsky’s study, Z-FAST (Zometa-Femara Adjuvant Synergy Trial), focused on 602 postmenopausal women with stage I to IIIa estrogen or progesterone receptor-positive breast cancer. The researchers randomized patients to immediate zoledronic acid or delayed zoledronic acid. The delayed group received it only if the T-score dropped below two or a clinical fracture occurred.

After five years, patients in the immediate treatment arm had a bone mineral density increase of 6.2 percent in their lumbar spine area, while those in the delayed arm had a decrease of 2.4 percent. In the hip area, the increase was 2.6 percent with immediate treatment compared with a 4.1 percent decrease with delayed treatment.

Fractures occurred in 10.7 percent of the patients treated immediately and 12.4 percent of the patients who received delayed treatment.

There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated.

21. Oral Bisphosphonate and Breast Cancer: Prospective Results from the Women's Health Initiative (WHI)

Results of a new analysis of data from the Women’s Health Initiative (WHI) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. These findings were presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

In the 150,000-plus cohort of generally healthy postmenopausal women, the researchers found that women who used bisphosphonates, mostly alendronate, which is sold as Fosamax by Merck, had 32 percent fewer cases of invasive breast cancer compared to women who did not use such drugs.

“The idea that bisphosphonates could reduce breast cancer incidence is very exciting because there are about 30 million prescriptions for these agents written annually in the United States targeting bone health, and more could easily be used to counteract both osteoporosis and breast cancer,” said the study’s lead investigator, Rowan Chlebowski, M.D., Ph.D., medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center.

The concept arose from findings in a report on an adjuvant breast cancer trial where use of the bisphosphonate zoledronic acid given intravenously every six months resulted in fewer contralateral breast cancers.

“It appeared to make bone less hospitable to breast cancer,” Chlebowski said.

However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed.

Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users. Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the researchers found that only 64 women developed breast cancer, and most of those cases (50) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.

“Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators,” Chlebowski said. “This association needs to be studied further.Wwhile we currently have several options for reducing receptor-positive breast cancers, none are available for receptor-negative cancers.”

Several ongoing adjuvant breast cancer trials evaluating oral and intravenous bisphosphonate will be available in the near future to provide randomized clinical trial evidence regarding their influence on new contralateral breast cancer risk, Chlebowski said

27. Use of Bisphosphonates and Risk of Postmenopausal Breast Cancer

The use of bisphosphonates for more than one year was associated with a 29 percent reduction in the risk of postmenopausal breast cancer, according to results presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Lead researcher Gad Rennert, M.D., Ph.D., chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clalit Health Services and a faculty member at the Technion-Israel Institute of Technology in Israel, said these data help shed light on a possible new pathway for breast cancer prevention.

“We have identified a new class of drugs that is associated with a reduced risk of breast cancer, and if proven in randomized trials, we may be able to recommend it to postmenopausal women for this purpose,” said Rennert.

Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview.

The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34 percent.

This reduction remained significant, at 29 percent, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.

Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.

“These tumors are the type that are associated with a better prognosis,” said Rennert.

22. AA Comparison of Denosumab Versus Zoledronic Acid on the Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.

“Denosumab prevented more events, was better tolerated and is more convenient for patients,” said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center.

Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with subcutaneous denosumab or intravenous zoledronic acid every four weeks.

Denosumab works by inhibiting RANKL, which regulates osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Full data will be presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

2009. Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer

Preoperative combination therapy with letrozole and zoledronic acid is safe and effective, but more research is needed to verify the impact on overall survival or reduced morbidity.

Nigel J. Bundred, M.D., professor in surgical oncology at the University Hospital of South Manchester and the University of Manchester, United Kingdom, and colleagues conducted this study to determine whether the addition of the bisphosphonate zoledronic acid to treatment with letrozole increased cell death or lowered proliferation.

Letrozole is an oral, non-steroidal aromatase inhibitor used for treatment of local or metastatic breast cancer that is hormone receptor-positive. Zoledronic acid, also known as zoledronate, is used to prevent bone fractures in patients with cancers like prostate cancer and multiple myeloma, or for treatment of bone metastases.

Researchers conducted the study in 109 postmenopausal women with early, invasive hormone receptor-positive breast cancer. Patients were randomized and treated for 14 days with placebo, letrozole 2.5 mg per day, or to letrozole with adjuvant use of zoledronic acid 4 mg intravenously two to four days before surgery.

While the addition of zoledronic acid was safe, results showed no other benefits compared with letrozole use alone.

“Letrozole significantly lowered proliferation,” said Bundred. “A combination of letrozole and a bisphosphonate, while lowering proliferation, did not do significantly greater than letrozole on its own.”

The mission of the CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for breast cancer patients. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor, and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. The 32nd annual symposium is expected to draw more than 8,500 participants from more than 90 countries.


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