Bisphosphonates May Lower Breast Cancer Risk

(MedPage Today) -- The risk of invasive breast cancer declined 30% to 40% among postmenopausal women using bone-preserving bisphosphonate drugs, two large cohort studies have found.

Bisphosphonate users in the Women's Health Initiative (WHI) had a 32% reduction in breast cancer risk during almost eight years of follow-up, while an Israeli study showed a 39% reduction in relative risk among women who took bisphosphonates for at least a year. Moreover, breast cancers among women taking bisphosphonates tended to have favorable prognostic characteristics. The two studies were published online in the Journal of Clinical Oncology.

"As oral bisphosphonates are in widespread and increasing using in clinical practice, these findings have public health implications," Rowan T. Chlebowski, MD, of Harbor-UCLA Medical Center in Torrance, Calif., and co-authors reported. "The influence of bisphosphonates in ongoing randomized, adjuvant therapy trials in women with early-stage breast cancer addressing outcomes including contralateral breast cancer will help clarify the clinical significance of the current findings."

Authors of the Israeli study called for prospective chemoprevention trials to assess the effects of bisphosphonates on breast cancer risk.

The two articles expand on findings initially reported last year at the San Antonio Breast Cancer Symposium.

Evidence from several sources has suggested that bisphosphonates may reduce breast cancer recurrence, Chlebowski and co-authors noted. Low bone-mineral density (BMD), a principal indication for bisphosphonates, is associated with a reduced risk of breast cancer, a potential confounding factor that might have discouraged evaluation of the drugs' chemopreventive potential in prior observational studies.

Potential mechanisms for the chemopreventive effects of bisphosphonates (seen in preclinical and emerging clinical evidence) include blocking release of factors that foster tumor growth and angiogenesis inhibition, according to background information provided by Chlebowski and co-authors.

The WHI afforded an opportunity to adjust for potential confounding between bisphosphonate users and nonusers. Of the 154,768 participants in observational and randomized clinical trials, 2,816 were users of oral bisphosphonate at baseline. A calculated hip fracture risk score was significantly associated with BMD and breast cancer incidence. The risk score was incorporated into regression analyses to adjust for BMD difference between bisphosphonate users and nonusers.

After a mean follow-up of 7.8 years, bisphosphonate users had a 32% lower incidence of invasive breast cancer compared with nonusers (P<0.01). The incidence of estrogen receptor-positive breast cancer was reduced by 30% in bisphosphonate users (P=0.02) and the incidence of ER-negative breast cancer by 34% (P=0.27). Bisphosphonate users had a higher incidence of ductal carcinoma in situ (HR 1.58, P=0.02).

The Israeli study involved 4,039 postmenopausal patients and controls, identified by pharmacy records. The records showed that 14.8% of controls and 10.5% of patients filled at least three prescriptions for bisphosphonates. Further analysis showed that use of a bisphosphonate for at least a year reduced the risk of invasive breast cancer by 39% (range 24% to 50%). Use for a shorter duration did not reduce the risk, Gad Rennert, MD, of Carmel Medical Center in Haifa, and co-authors reported.

In an analysis adjusted for multiple factors, use of bisphosphonates for at least a year reduced breast cancer risk by 28% (range 10% to 43%). Increasing duration of bisphosphonate use beyond one year did not lead to further reductions in breast cancer risk.

In contrast to the WHI study, the Israeli study found a significantly higher number of estrogen-receptor positive tumors among bisphosphonate users.

The statistically significant reductions in breast cancer risk associated with bisphosphonate use "are profound and intriguing, because they suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing breast cancer," Michael Gnant, MD, of the medical University of Vienna in Austria, wrote in an editorial.

Nonetheless, the results warrant cautious interpretation, he continued.

"In the absence of a prospective randomized study, the analyses should be viewed as hypothesis generating and not practice changing at this time," Gnant wrote.

Chlebowski disclosed relationships with AstraZeneca, Novartis, Pfizer, Amgen, and Eli Lilly. Co-author Jane A. Cauley disclosed relationships with Novartis. Co-author Anne McTiernan disclosed relationships with Merck. Co-author Robert B. Wallace disclosed a relationship with Merck.

Rennart and co-authors reported no disclosures.

Gnant disclosed relationships with AstraZeneca, Novartis, Pfizer, Roche, and sanofi-aventis.

Primary source: Journal of Clinical Oncology Source reference: Chlebowski RT, et al "Oral bisphosphonate use and breast cancer incidence in postmenopausal women" J Clin Oncol 2010; DOI: 10.1200/JCO.2010.28.2095.Additional source: Journal of Clinical OncologySource reference: Rennart G, et al "Use of bisphosphonates and risk of postmenopausal breast cancer" J Clin Oncol 2010; DOI: 10.1200/JCO.2010.28.1113.Additional source: Gnant M "Can oral bisphosphonates really reduce the risk of breast cancer in healthy women?" J Clin Oncol 2010; DOI: 10.1200/JCO.2010.29.6327. Source reference: Gnant M "Can oral bisphosphonates really reduce the risk of breast cancer in healthy women?" J Clin Oncol 2010; DOI: 10.1200/JCO.2010.29.6327.