'Mounting Evidence' for Bone Drugs as Adjuvant Breast Cancer Tx

Low Estrogen Is Needed for Effect

Nick Mulcahy

December 13, 2011

December 13, 2011 (San Antonio, Texas) — There is "mounting evidence" suggesting that bisphosphonates will eventually become "established as efficacious" in the adjuvant treatment of postmenopausal women with early breast cancer, according to an expert here at the 34th Annual San Antonio Breast Cancer Symposium (SABCS).

However, the evidence in postmenopausal women is still "insufficient" because it comes from unplanned analyses of clinical trials of the bone drugs, said James Ingle, MD, from the Mayo Clinic in Rochester, Minnesota.

Dr. Ingle served as a discussant for the session in which data were presented from 2 trials on the use of the intravenous bisphosphonate zoledronic acid (Zometa, Novartis) in hormone-sensitive early breast cancer.

Results from one of the studies, the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, in premenopausal women have already been reported by Medscape Medical News. In the other study, the Zometa-Femara Adjuvant Synergy Trial (ZO-FAST), postmenopausal women with early breast cancer were treated with letrozole (Femara, Novartis) and zoledronic acid.

New 5-Year ZO-FAST Results Are Final

The ZO-FAST trial was designed to explore the addition of zoledronic acid to adjuvant endocrine therapy to reduce the bone mineral density loss seen with aromatase inhibitors. Bone loss was, at the time of study enrollment in 2003/04, a "big concern," said lead author Richard de Boer, MD, from the Royal Melbourne Hospital in Victoria, Australia. The study met this primary end point, he reported.

Dr. de Boer and his coinvestigators also looked at disease-free survival, even though the study was not designed to detect a difference in breast events.

Post hoc analyses showed that immediate (as opposed to delayed) use of zoledronic acid led to a 34% improvement in disease-free survival at 5 years (hazard ratio, 0.66; P = .0375). There was a 3.6 absolute difference in disease-free survival between immediate and delayed use (91.9% vs 88.3%).

This benefit is similar to that seen in ABCSG-12 and another trial of zoledronic acid — the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial.

Results of Trials of Zoledronic Acid in Breast Cancer

Trial Increase in Disease-Free Survival
ZO-FAST 3.6% at 5 years
ABCSG-12 4.0% at 7 years
AZURE 7.1% at 5 years (subset of patients)

Dr. Ingle noted that the magnitude of benefit from adjuvant endocrine therapy, such as tamoxifen, was in the same ballpark as that seen with zoledronic acid in select patient populations. For instance, the National Cancer Institute of Canada Clinical Trials Group MA.17 trial indicated a 4.6% increase in disease-free survival at 4 years with endocrine therapy (tamoxifen followed by letrozole) in postmenopausal women.

How do the results of ZO-FAST and AZURE, both in postmenopausal women, jive with results of ABCSG-12, which is in premenopausal women? The answer seems to lie in the fact that the women who experienced a benefit all had a "low estrogen environment." (The premenopausal women in ABCSG-12 received ovarian function suppression with goserelin for 3 years.)

Dr. Ingle explained that the ZO-FAST findings, as unplanned analyses, do not support zoledronic acid as a standard of care in postmenopausal women. However, the results are "consistent with this developing theme that bisphosphonates are of value in women with a low estrogenic environment."

The final word is not in.

Dr. Ingle said that he would not start using bisphosphonates in his practice in postmenopausal women with hormone-sensitive early breast cancer on the basis of these trials. "The final word is not in," he told journalists at a press conference.

Additional studies are needed to fully define the breast cancer populations most likely to benefit from adjuvant zoledronic acid, added Dr. de Boer.

In the meantime, "patients with hormone-receptor-positive breast cancer who are postmenopausal and about to commence letrozole have the option of considering the addition of zoledronic acid — primarily to maintain bone mineral density, but also with the aim of reducing the risk for disease recurrence," Dr. de Boer said in a press statement.

However, at last year's SABCS, Medscape Medical News found clinicians who were, on the basis of earlier data from letrozole–zoledronic acid studies, as well as from AZURE, using zoledronic acid in this setting.

For instance, Rowan Chlebowski, MD, PhD, from the University of California at Los Angeles, told Medscape Medical News that he would use zoledronic acid in postmenopausal women with breast cancer to reduce their risk for recurrence. "Many states cover use of zoledronic acid to prevent bone loss in the patient population, so I prescribe it for that," he said.

More ZO-FAST Details

In ZO-FAST, 1064 postmenopausal women with early breast cancer receiving letrozole (2.5 mg/day for 5 years) were randomly assigned to immediate zoledronic acid (4 mg injected every 6 months) or delayed zoledronic acid (initiated only for fracture or for high risk for fracture).

About half of the women received adjuvant chemotherapy and about half did not.

The 2 treatment groups were well balanced in terms of age, disease stage, and bone mineral density scores. Three patients developed osteonecrosis of the jaw, but there was no increase in serious renal events.

ZO-FAST was funded by Novartis, the manufacturer of zoledronic acid and letrozole. Dr. Ingle has disclosed no relevant financial relationships. Dr. de Boer reports being on the speakers' bureau for Novartis.

34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-2. Presented December 7, 2011.


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