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No Reduction in Breast Cancer Risk With Bisphosphonates
In recent years, several observational studies have suggested that the bone-targeting bisphosphonate drugs may also have a protective effect against breast cancer, but a new analysis of data from randomized clinical trials has found no such effect.
The new results, published online August 11 in JAMA Internal Medicine, suggesting there is no reduction in the risk for breast cancer, fly in the face of previous findings from observational studies, which suggest that bisphosphonates reduce the risk for breast cancer by around a third, leading some breast cancer experts to suggest that adjuvant bisphosphonates should be a “new addition” to the treatment of postmenopausal women with breast cancer.
However, there is a big difference in where these disparate findings have come from.
Many of the previous positive results showing a beneficial effect come from observational studies conducted in women who have already had breast cancer and were using an adjuvant bisphosphonate to protect their bones while on treatment to prevent breast cancer recurrences (aromatase inhibitors).
The new negative results showing no effect on the risk for invasive breast cancer come from randomized clinical trials conducted in postmenopausal women with osteoporosis who had not previously had breast cancer.
The researchers reporting the new finding of no effect, headed by Trisha Hue, PhD, MPH, from the Department of Epidemiology and Biostatistics at the University of California at San Francisco, emphasize the difference between the type of study (i.e., observational studies vs randomized controlled trials).
But researchers who had previously reported positive findings and were approached by Medscape Medical News emphasized the difference between the patient populations (i.e., postmenopausal women with breast cancer vs postmenopausal women with osteoporosis).
MIchael Gnant, MD, FACS, from the Comprehensive Cancer Center in Vienna, Austria, who was one of the first to report a positive effect of bisphosphonates on breast cancer risk reduction, commented to Medscape Medical News: “It is important to differentiate this research (in noncancer patients) from breast cancer bisphosphonate studies.”
“The overwhelming evidence of an (indirect?) anticancer effect of potent bisphosphonates in low-estrogen breast cancer patients is not contraindicated by the Hue et al report,” Dr. Gnant said. “We still don’t understand why these drugs work in breast cancer patients but apparently exert only doubtful preventive effects in nonbreast cancer patients.”
Rowan Chlebowski, MD, PhD, medical oncologist at the Los Angeles Biomedical Institute at Harbor-UCLA Medical Center, commented that these new findings “do not address the issue of bisphosphonates’ favorable effects on breast cancer recurrence risk.”
Plus, he argues that there are limitations from “forcing a breast cancer end point onto a fracture trial.”
He was referring to the 2 trials that were analyzed by Dr. Hue and colleagues: the Fracture Intervention Trial (FIT) with alendronate (Fosamax, Merck & Co.), with a median follow-up of 3.8 years; and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) with zoledronic acid (Zometa, Novartis) and a median follow-up of 2.8 years.
Both of these placebo-controlled trials were conducted in postmenopausal women with osteoporosis, and they showed that taking a bisphosphonate reduced the risk for a bone fracture (the primary end point of the studies, already published).
Dr. Hue and colleagues had been involved in these studies, and they had access to the data.
For the current study, they conducted a post hoc analysis to search the adverse-event database for any report of breast cancer.
They found no significant difference in the rate of invasive breast cancer between the bisphosphonate and placebo groups in either trial, nor in both trials combined.
The rate of invasive breast cancer was 1.5% with placebo vs 1.8% with alendronate in the FIT, and was 0.8% with placebo and 0.9% with zoledronic acid in the HORIZON-PFT; for the combined studies, the rate was 1.3% with bisphosphonates vs 1.1% with placebo.
“Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer,” Dr. Hue and colleagues conclude.
“The discrepancy between our results and the reports of associations in observational studies may be an example of indication bias,” the authors say.
Specifically, they highlight the fact that women with low bone density, fractures, and bone loss have substantially low levels of estradiol and high levels of sex hormone binding globulin, and both of these are strongly associated with a reduced risk for estrogen-receptor (ER)-positive breast cancer in postmenopausal women. “Thus, women with osteoporosis are likely to have a lower risk of ER-positive breast cancer,” they note.
Dr. Gnant told Medscape Medical News that he agrees with the authors’ conclusion that “the seemingly discrepant results of the impact of antiosteoporosis intervention on breast cancer prevalence may be an example of indication bias.”
He also noted that the bisphosphonates have been repeatedly demonstrated to have a beneficial effect on bone health, adding: “It would have been icing on the cake if they, in addition, prevented a malignant disease.”
Dr. Chlebowski also emphasized the fact that all the participants in these 2 trials had osteoporosis, and thus were a selected population at low risk for breast cancer. He suggested that the results may therefore not relate to a more general population. In fact, Dr. Chlebowski has previously reported an analysis of several Women’s Health Initiative (WHI) studies, which together involved more than 150,000 generally healthy postmenopausal women, and showed that those who were taking bisphosphonates to protect their bones had a 32% reduction in invasive breast cancer.
Limitations of Observational Studies
Dr. Hue and colleagues believe that their study “illustrates the limitation and hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done) and emphasizes the value of confirming such associations in randomized clinical trials.”
“This parallels the discrepancy in results seen in other research of treatment effects,” they continue, citing the about-face on the cardiovascular protective effects of hormone replacement therapy as another example. “The strong associations between estrogen and progestin use and the reduction in the risk of cardiovascular disease in well-conducted observational studies” was later contrasted with “the increased risk or lack of effect shown in randomized trials such as the Heart and Estrogen/Progestin Replacement Study (HERS) and WHI trials,” they note.
“Our finding reinforces the importance of testing the efficacy of treatments in randomized trials,” Dr. Hue and colleagues comment.
However, some of these conclusions were challenged by Dr. Chlebowski. He agrees with the authors’ comments about the limitations of observational studies to provide definitive evidence on causality. However, he takes issue with their claim that this post hoc analysis attempted to “confirm” the observational studies.
The 2 randomized trials had been conducted to investigate fracture risk, and there was no comprehensive assessment of breast cancer risk, and there was no mammography performed, either at baseline or during the trial. “Because breast cancer risk was not assessed, there was no stratification by breast cancer risk into the randomization groups. The analysis was clearly post hoc,” he said. To say that this post hoc analysis was an attempt to “confirm” observational study results “is not accurate,” he maintained.
JAMA Inter Med. Published online August 11, 2014.
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