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New Analysis of WHI Shows Bisphosphonates May Protect against Invasive Breast Cancer

Laino, Charlene

doi: 10.1097/01.COT.0000368894.52254.e1

A new analysis of data on more than 150,000 women in the Women's Health Initiative (WHI) suggests that use of oral bisphosphonates may protect against the development of invasive breast cancer.

Rowan T. Chlebowski, MD, PhD, Professor and Chief of the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, reported the results at the CTRC-AACR San Antonio Breast Cancer Symposium.

“The idea that bisphosphonates may protect against breast cancer incidence is very exciting because they could be used to counteract both osteoporosis and breast cancer,” he said.

In vitro and animal research suggest that the drugs may fight cancer in a variety of ways—by inducing apoptosis, by reducing angiogenesis, or by stimulating memory T cells, Dr. Chlebowski explained.

He noted that a recent study published in The New England Journal of Medicine showed that the addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival rates in premenopausal patients with estrogen-responsive early breast cancer (Gnant et al: NEJM 2009; 360:679–91).



Using WHI data, Dr. Chlebowski and colleagues compared the breast cancer rates in 2,816 women who reported using oral bisphosphonates at the start of the study with those of 151,952 women who reported that they did not take the drugs.

Ninety percent of the women using bisphosphonates were taking alendronate and 10% were taking etidronate.

Patients’ hip fractures scores were used to adjust for potential bone mineral density differences among bisphosphonate users and non-users. “Since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, it's important to correct for that,” Dr. Chlebowski said.

The hip fracture score, which provides a five-year probability of hip fracture, is a published, validated algorithm developed in the WHI cohort that takes into account 11 clinical factors that are available for all WHI participants.

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Bisphosphonate Users 31% Less Likely to Develop Cancer

Over the course of 7.8 years of follow-up, there were 4.38 cases of invasive breast cancer per 1,000 women not taking the drugs over the course of a year, compared with 3.29 cancers per 1,000 women taking the drugs.

In an age-adjusted analysis, this translated to a significant, 31% lower chance of developing breast cancer among bisphosphonate users, compared with women who said they did not take the drugs.

Women taking bisphosphonates were 30% less likely to develop ER-positive tumors and 32% less likely to develop ER-negative tumors, although the latter figure did not reach statistical significance due to the small number of cases, Dr. Chlebowski said.

GAD RENNERT, MD, PHD: “Breast tumors identified in bisphosphonates users were more often ER positive and less often poorly differentiated

GAD RENNERT, MD, PHD: “Breast tumors identified in bisphosphonates users were more often ER positive and less often poorly differentiated

He said there was one unexpected finding: Use of bisphosphonates was associated with an increased risk of ductal carcinoma in situ.

Possible explanations, he speculated, are that bisphosphonates prevent the progression of in situ cancer to invasive cancer or that they prevent invasive, but not in situ, breast cancer.

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Case-Control Study Shows Similar Findings

Also at the meeting, a case-control study, involving 4,039 postmenopausal women in Israel, showed that women who had breast cancer were significantly less likely to have taken oral bisphosphonates than women who did not have breast cancer.

In the Breast Cancer in Northern Israel Study, the self-reported use of bisphosphonates for at least five years prior to diagnosis was associated with a 34%, significantly reduced relative risk of breast cancer.

The association remained significant in a pharmacy records-based analysis after adjustment for age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body-mass index, use of calcium supplements, hormone-replacement therapy use, number of pregnancies, months of breast feeding, and age at first pregnancy, reported Gad Rennert, MD, PhD, of Technion-Israel Institute of Technology and Chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clatit Health Services in Haifa.

“Pharmacy records were used to validate self-reports, and concordance was high, at 96%. At the end of the game, the final multivariate analysis showed that women who used bisphosphonates for at least one year had a significant, 29% relative reduction in risk of breast cancer.”

In response to a question about whether the duration of bisphosphonate use affected the findings, Dr. Rennert said, “We didn't see an effect until after one year of use, and there was a dose response with increased duration of use, but the change from one year to the next was not dramatic. Five years of use was not much better than four.”



Breast tumors identified in bisphosphonates users were more often ER positive and less often poorly differentiated, Dr. Rennert added.

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Other Trials Ongoing

The fact that the two observational studies used different methodologies to arrive at the same basic result adds strength to the findings, commented Theresa A. Guise, MD, Professor of Medicine and Jerry W. and Peg S. Throgmartin Professor of Oncology at Indiana University, who was not involved with the work.

“This still needs to be confirmed in controlled trials, but is a step forward,” she said.

Several ongoing randomized clinical trials evaluating the impact of oral and intravenous bisphosphonates on the development of contralateral breast cancer may “provide confirmation of these observational cohort studies within a year or two,” Dr. Chlebowski said.

In addition, the pathways by which the drugs work would suggest that they may also protect against other types of cancer, and future research will also test that hypothesis, he added.

© 2010 Lippincott Williams & Wilkins, Inc.
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