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Addition of ibandronate to adjuvant hormonal therapy shows no benefit in early breast cancer
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SAN ANTONIO — The addition of ibandronate to adjuvant hormonal therapy demonstrated no proof of benefit for postmenopausal women with early hormone receptor–positive breast cancer, according to results of the TEAM IIb trial presented at San Antonio Breast Cancer Symposium.
However, the ibandronate regimen showed a trend toward longer DFS and less bone metastases.
“It might be that this analysis was done too early, especially for this type of breast cancer,” Sabine Linn, MD, PhD, medical oncologist in the department of molecular pathology at Netherlands Cancer Institute, said during a press conference. “For luminal A breast cancer, once might need a more mature follow-up to see the true effect of the addition of ibandronate. The other question is whether this study was underpowered.”
Prior research established a clear interaction between tumor cells and bone. Osteoclasts are involved in bone breakdown. When they are active, they release several growth factors from bone that help tumor cells to grow and proliferate. In turn, tumor cells release growth factors that further stimulate osteoclasts to become more active.
Bisphosphonates can block the activity of osteoclasts, breaking this vicious cycle.
The TEAM IIb trial included 1,116 postmenopausal women with early-stage breast cancer treated at one of 37 hospitals in the Netherlands.
All women received 5 years of hormonal therapy with tamoxifen followed by exemestane, or exemestane without a switch. Linn and colleagues randomly assigned half the women to also receive 3 years of treatment with the bisphosphonate ibandronate (Boniva, Genentech), administered in 50-mg daily doses.
DFS at 3 years served as the primary endpoint. Safety, OS, time to bone metastasis and other sites of recurrence served as secondary endpoints.
Trial protocol established a 10-year follow-up. Linn presented initial data based on median follow-up of 4.6 years.
During that time, 149 DFS events occurred. Researchers reported 95 deaths during follow-up (ibandronate, n = 48; control, n = 47). Seventeen deaths (35.4%) in the ibandronate group and 29 deaths (61.7%) in the control group were due to breast cancer; 14 patients (29.2%) assigned ibandronate and nine (19.1%) assigned the control regimen died of secondary malignancy.
At 3 years, researchers reported a higher DFS rate (94.3% vs. 90.8%; HR = 0.8; 95% CI, 0.58-1.1) and reduced incidence of bone metastasis (1.6% vs. 4.7%; HR = 0.65; 95% CI, 0.38-1.11) in the ibandronate group. However, the differences did not reach statistical significance.
Incidence of stomach- or reflux-related symptoms was higher in the ibandronate group (8.3% vs. 2.2%). Twenty percent of patients assigned the experimental regimen discontinued treatment due to side effects, but not all were related to ibandronate.
Four patients (0.7%) developed osteonecrosis of the jaw, but all cases resolved after treatment ended.
Renal function appeared stable during ibandronate treatment. Two patients developed renal failure, but the condition may not have been related to treatment, Linn said.
“If the results from this trial are considered along with the results from the EBCTCG trial, in which a modest benefit of OS was observed for postmenopausal women by adding a bisphosphonate to standard adjuvant systemic therapy, the evidence to treat postmenopausal women with early breast cancer with adjuvant bisphosphonate increases,” Linn said in a press release. “Patients should discuss this adjuvant treatment with their physicians to outweigh the possible side effects from the possible gain in survival.” – by Mark Leiser
Reference:
Linn S, et al. Abstract 6-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio.
Disclosure: The study was funded by unrestricted research grants from Roche Netherlands and Pfizer Netherlands. Linn reports research grants from Roche Netherlands and an advisory board role with Roche.
Perspective
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Adam M. Brufsky, MD, PhD, FACP
Several large randomized trials have shown substantial benefits in DFS and OS in postmenopausal women who receive adjuvant treatment with bisphosphonates. Based on meta-analyses, we know there is a roughly 3.3% improvement in OS at 10 years for postmenopausal women who receive at least 2 years of adjuvant bisphosphonates. It is important to understand, though, that there is no benefit in premenopausal women. Also, it appears the benefit is due to a reduction in the number of or the presence of bone metastases.
In this study, DFS was 94.3% in the ibandronate arm and 90.8% in the control arm. The rate of bone metastases in the ibandronate arm also was lower (1.6% vs. 4.7%).
There was no additional toxicity with ibandronate. Incidence of osteonecrosis of the jaw was about 0.7%. That’s four patients out of approximately 500 randomly assigned to the regimen. There was a little more stomach and gastrointestinal upset with ibandronate, but otherwise it was very well tolerated.
There are two important issues. It looks like the trend in this study is consistent with other trials that showed small but clinically significant — even if not statistically significant — improvements in these women on ibandronate adjuvant therapy. More important, I think results of this trial were released a little too early. With 73 patients not even finishing ibandronate therapy, it’s a little too soon to know what is going on here. Also, I think this trial may have been a little underpowered for what the researchers are trying to see.
The data appears at least numerically to be consistent with other data that suggest adjuvant bisphosphonate therapy likely does provide a small but statistically significant benefit in ER–positive breast cancer at least in reducing bone recurrence. This is a continuing theme — one that a lot of us still don’t accept yet because we don’t quite know the mechanism behind it.
In an era in which we’re going to have a lot more luminal A breast cancer — with more interest in subtyping and more genomic assays being used — we will be looking for ways to improve DFS, and this may be one of them. However, at this time, these data do not suggest to use ibandronate as a bisphosphonate for adjuvant therapy.
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Amy H. Comander, MD
The results that have been presented thus far, with median follow-up of 4.6 years, show there does not seem to be difference in DFS between women who took ibandronate vs. those who did not take the bisphosphonate. However, we will need to have longer-term follow-up to further assess whether there is a benefit in terms of DFS and other endpoints for women who took the bisphosphonate medication. Researchers plan to follow these patients for up to 10 years. It is possible that, with longer follow-up, this result will indeed be statistically significant.
There is significant interest in the use of bisphosphonate therapy for our patients with estrogen-sensitive breast cancer — particularly those women who take aromatase inhibitors, which is a mainstay of endocrine therapy for women with breast cancer. The main concern is that, with administration of aromatase inhibitor therapy, there is the concern for accelerated bone loss. Bisphosphonates help strengthen bone and decrease bone loss. There also has been significant interest in whether bisphosphonate therapy can result in a lower risk for recurrence in the bone and possibly in other sites.
It is important to put this study in context of other studies that have evaluated the role of bisphosphonate therapy for both pre- and postmenopausal women with estrogen-sensitive breast cancer. There are data from studies of other bisphosphonates that show there may indeed be a benefit for bisphosphonate use as part of adjuvant therapy for women with estrogen-sensitive breast cancer. This study, perhaps with longer-term follow-up, may also show a similar benefit.
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