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Solid Tumors
ISSUE: FEBRUARY 2014 | VOLUME: 09:02

SABCS 2013
A Conclusion to the Bisphosphonate
Controversy?
San AntonioA large meta-analysis presented at the recent San Antonio Breast Cancer
Symposium (SABCS) has tried to end the long-standing controversy over whether adjuvant
bisphosphonates can act as an anticancer therapy in women with breast cancer. The study
concluded that bisphosphonates are capable of reducing bone recurrence by 34% and breast
cancer death by 17%, but only in postmenopausal women and those who have
chemotherapy-induced menopause.
The involvement of the 20,000 patients in these trials has not been in vain. We have finally
defined a new addition to standard treatment, said Robert Coleman, MBBS, MD, a professor
of medical oncology at the University of Sheffield in Sheffield, England, who presented the
study (S4-07). The incremental benefit is at least as large as we have seen with most of the
agents we use at the moment, aromatase inhibitors, taxanes, et cetera.
He recommended use of either zoledronic acid at least every six months or, in countries where
available, daily oral clodronate. He pointed out that there is no data with the weekly dose of
oral bisphosphonates used to treat osteoporosis, so these drugs and schedules cannot be
recommended.
For the past 15 years, various studies have investigated whether bisphosphonates can exert
an anticancer effect in patients with breast cancer. Some studies showed a clear benefit.
Others did not, but hinted at a benefit in subsets of patients. A number of hypotheses,
however, emerged: Bisphosphonates might only exert anticancer benefits in women with low
levels of estrogen, and only on distant metastases rather than local recurrences or
contralateral disease. The scientific rationale for bisphosphonates as an anticancer agent lies
in the fact that osteoclasts and osteoblasts are critical to the development of metastases
(Figure).

The Vicious Cycle of Bone Destruction

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Bisphosphonates Embed in Bone and Interrupt the Cycle

Figure. The scientific rationale for bisphosphonates as an anticancer agent lies in the fact that osteoclasts
and osteoblasts are critical to the development of metastases. Tumor cells secrete factors that stimulate
osteoclast differentiation and maturation, and cancer cells directly interact with osteoclast precursors. Tumor
cells also secrete various growth factors that increase bone cell function and, through the release of RANK
ligand, both enhance bone destruction and the release of bone-derived factors that can stimulate tumor
growth. Bone resorption agents can inhibit osteoclasts and block the release of growth factors and cytokines
from bone that create the fertile environment for cancer growth.
BMP, bone morphogenetic protein; Ca, calcium; FGF, fibroblast grow th factor; IGF, insulin-like grow th factor; IL,
interleukin; PDGF, platelet-derived grow th factor;

In the SABCS study, the Early Breast Cancer Trialists Collaborative Group conducted a metaanalysis of data from all randomized trials comparing the use of bisphosphonates in the
adjuvant setting of breast cancer versus no bisphosphonate or placebo. The meta-analysis
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included 36 trials involving roughly 20,000 patients. Subgroup analyses included outcomes by
site of recurrence, site of first distant metastasis (bone vs. not bone), menopausal status (pre, peri- and postmenopausal), type of bisphosphonate (aminobisphosphonate or clodronate),
and drug schedule (advanced cancer or bone protection). Aminobisphosphonates included
mainly zoledronic acid (65%), some oral ibandronate (24%) and oral pamidronate (8%), and a
few oral residronate and oral alendronate.
In postmenopausal women, adjuvant bisphosphonates reduced the risk for bone recurrence
by 34% (P=0.00001) and reduced the risk for breast cancer death by 17% (P=0.004). The
effect was somewhat more pronounced in patients receiving an anticancer dose of the drug,
rather than just an osteoporosis dose. The benefit was seen in patients regardless of
estrogen-receptor status, node status or whether the patients also were receiving
chemotherapy. In postmenopausal women, bisphosphonates had no effect on deaths not
related to breast cancer, contralateral breast cancer or locoregional recurrence. In
premenopausal women, the drugs had no significant effect on any disease outcomes.
The cumulative data are becoming more and more convincing, said Kent Osborne, MD, the
director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at
Baylor College of Medicine in Houston. He suspected the study would change practice at his
center.
Hope Rugo, MD, the director of the Breast Oncology Clinical Trials Program at the University
of California, San Francisco, said clinicians are still questioning whether or not to change their
practice based on the data.
I think we have quite a bit of background data that suggests that at least for a subset of
patients, bisphosphonates play a role in reducing or delaying the risk for metastases, said
Dr. Rugo. The meta-analysis was very, very useful and really gives us an idea that there is a
group of patients who are in menopause where bone turnover is a really big deal, and you
can possibly reduce the incidence of bone metastases with bisphosphonates.
My take on it, she continued, is that I use it in patients in menopause who are having bone
loss, because that is what the approved indication is. I think if you had a patient who was
identical to the ABCSG-12 trial populationyoung, on ovarian suppression, hormone therapy
and no chemothen I would use a bisphosphonate. Outside of that, it is really hard to know.
However, based on this data, I would consider adjuvant bisphosphonates for women with
higher-risk disease.
Kate ORourke
Dr. Coleman has received speaker fees from Bayer and research funding from Novartis. Dr. Osb orne has
b een a consultant/advisor for AstraZeneca, Genentech and Novartis. Dr. Rugo disclosed research funding
from AstraZeneca and Novartis.

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