Post-menopausal breast cancer patients who receive zoledronic acid in addition to chemotherapy have a significantly lower risk of cancer recurrence, researchers from Weston Park Hospital, Sheffield, England, reported at the European Multidisciplinary Cancer Congress 2011, Stockholm, Sweden. The presenters explained that their findings may provide a better understanding of the mechanisms behind breast cancer recurrence.

Zoledronic acid, also known as zoledronate is a bisphosphonate, a group of medications used for osteoporosis treatment. It is marketed by Novartis under the trade names, Zometa, Aclasta, Reclast, and Zomera. Zometa is currently used for some cancer patients to prevent skeletal fractures. It is also used for the treatment of hypercalcemia of malignancy and can help treat pain in patients with bone metastases.

The investigators wanted to determine whether zoledronic acid could be used for more than protection from the effects of secondary bone cancer. They explained that previous studies had suggested it might have anti-tumor effects, and could potentially enhance other chemotherapy treatments. So they set up the AZURE, multi-center trial to find out.

Professor Robert Coleman and team recruited 3,360 females with breast cancer from 174 centers. They all had Stages II and III breast cancer. They were randomly selected to received chemotherapy and/or endocrine therapy, with or without zoledronic acid. An interim analysis appeared to show no clinical benefits, so they released the data so that it could be scrutinized in more detail.

Further scrutiny confirmed that the drug seemed to have no impact, with the exception of a sub-set of females whose menopause had occurred at least five years previously. Among these women, survival rates averaged 85%, compared to 79% among those not receiving zoledronic acid. Even after ruling out such factors as tumor stage, estrogen receptor status, and lymph node involvement, the survival figures prevailed.

Professor Coleman explained:

“This is a small but significant increase. The finding is not sufficient to be taken up on its own but in the context of other studies and additional data anticipated later in the year, it is likely to change practice.

The effects on metastasis and recurrence outside bone suggests that the bone marrow is an important sanctuary for tumor cells which can be activated after, sometimes, many years of dormancy. With help from bone marrow stem cells, they may then spread via the blood stream to set up metastases at other sites.”

Even if it does occur in this way, the scientists cannot explain zoledronic acid’s beneficial effect. Perhaps the balance of cytokines, growth factors and other substances are altered – substances that control the bone marrow micro-environment. Perhaps in this altered state the cancer cells may become dependent on the presence of reproductive hormones to be able to move to move to other parts of the body.

Professor Coleman said:

“We plan to use new, more clinically relevant, animal models of metastasis to assess the early events in the spread of cancer and effects of treatments like zoledronic acid.”

This study is also published in NEJM (New England Journal of Medicine).

Professor Michael Baumann, president of ECCO (European CanCer Organization) said:

“It is important to note that so-called ‘negative trials’, that is trials that do not show the anticipated improvement in the endpoint selected, can yield very important information for further trials and also can feed important information back into preclinical research. Eventually negative trials, even if initially very disappointing for the investigators, can make important contributions to cancer research and to practice-changing new strategies relevant for cancer patients.”

ESMO (European Society for Medical Oncology) member, Professor Christoph Zielinski, from the Medical University of Vienna, commented:

“Whereas the earlier data from the AZURE trial did not show any influence of zoledronic acid upon outcomes in an unselected patient population, the present results show that post-menopausal patients do benefit from this treatment approach. These data are similar to the ABCSG 12 data reported earlier in which hormonal medication was given to premenopausal patients to induce premature menopause. Taken together, the two trials thus add up to a high level of evidence of a benefit of the addition of zoledronic acid to adjuvant therapy for early breast cancer in either naturally or medically induced postmenopausal women.”

Professor Zielinski was not involved in the study.

Written by Christian Nordqvist