Bisphosphonates as adjuvant treatment for breast cancer

Bisphosphonates are potent inhibitors of the osteoclastic bone resorption that is associated with skeletal metastases, with proved efficacy in reducing skeletal complications in metastatic cancer. Randomised clinical trials investigating the adjuvant use of bisphosphonates to prevent bone metastases in patients with breast cancer have yielded intriguing yet conflicting results. Defining the potential role of these agents in the treatment of breast cancer is of great clinical relevance.

The skeleton is the first site of recurrence in 25-40% of patients with metastatic breast cancer. The development of bone metastases entails complex interactions between cancer cells and the microenvironment of bones. In the early establishment of metastases, bone is destroyed by the osteoclast, which is activated by a variety of cytokines produced directly or indirectly by the tumour cell. As bone matrix is broken down, a rich supply of mitogenic factors is released, which in turn can lead to increased proliferation of cancer cells.

Bisphosphonates are effective in treating conditions in which excessive bone resorption and osteoclast activity prevail, including osteoporosis and Paget's disease of bone. Several randomised clinical trials in patients with breast cancer with bone metastases have shown the ability of bisphosphonates to reduce skeletal related events and symptoms, including pathological fractures, surgery, radiation, compression of the spinal cord, hypercalcaemia, and pain, although they have not shown improved survival.^1–6 Clodronate and pamidronate have been evaluated extensively in patients with metastatic cancer and are widely used in oncology.^1–3 Zoledronic acid and ibandronic acid represent highly potent, newer generation bisphosphonates with recently shown benefit in reducing skeletal related events.^4–6

Preclinical studies show that bisphosphonates might also be capable of preventing the development of bone metastases. Laboratory data show that bisphosphonates can inhibit adherence of breast cancer cells to the bone matrix, inhibit release of growth factors stored in the bone matrix, and enhance the sensitivity of osteoclasts, macrophages, and tumour cells to apoptosis.

Three randomised clinical trials of the oral bisphosphonate clodronate as adjuvant treatment in breast cancer have yielded conflicting results. A German trial of 302 patients with primary breast cancer with immunocytochemical evidence of cancer cells in a bone marrow aspirate randomised patients to two years of clodronate or control. At almost five years of follow up, a reduction in the recurrence of bone metastases, a trend towards reduction in visceral metastases, and an increase in overall survival were seen in the clodronate group.⁷,⁸ The effect of clodronate as an adjuvant seemed weakened with longer follow up.

A Finnish trial including 299 women with lymph node positive breast cancer randomised to three years of clodronate as an adjuvant showed virtually the opposite result, with no effect on the rate of bone metastasis and a deleterious effect on relapse rates of non-bone metastasis as well as survival.⁹ After five years of follow up, bone metastases were detected equally in the clodronate and placebo groups, and non-skeletal metastases were significantly more common in the clodronate group. Overall survival was significantly worse in the clodronate group.

Most recently a randomised multicentre trial including 1079 patients with operable breast cancer evaluating two years of clodronate as an adjuvant reported a benefit in overall survival.¹⁰ In the two years of treatment with clodronate, occurrence of bone metastases was significantly lower in the group receiving clodronate compared with placebo; but at five years of follow up it was no longer significantly different between the two treatment arms. No effect was observed on visceral sites of metastases, although reassuringly no trend toward an increase was identified. Overall survival was significantly improved in the clodronate arm.

The intriguing but contradictory results of these studies highlight the need for further studies to determine whether bisphosphonates can influence the development of bone metastases and improve survival in early stage breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is conducting an ongoing multicentre confirmatory trial. NSABP B34 is evaluating oral clodronate for three years versus placebo in 2200 patients with stage I or II breast cancer. Additionally, the North American Intergroup has proposed an adjuvant trial with bisphosphonates, comparing newer, more potent bisphosphonate agents with clodronate.

If bisphosphonates are found to have benefit as an adjuvant it will be important to address carefully the optimal agent, dose, schedule, and duration of treatment. Whether doses used in metastatic disease are required for prevention or whether lower doses would suffice is unknown. It is unclear whether adjuvant bisphosphonates should be given continuously and orally, or whether intermittent intravenous treatment would be preferable. The optimal duration of treatment is also unknown, with the studies presented to date implying that two years is an insufficient duration of treatment. Long term follow up will be needed to determine if bisphosphonates are actually able to prevent or merely delay bone lesions. Ultimately we hope to determine which patients with breast cancer might benefit most from treatment with bisphosphonates by evaluating the characteristics of the tumour and the patients that predict who is at highest risk for occurrence of bone metastases. Irrespective of inhibition of bone metastases, all patients with postmenopausal breast cancer in the early stage can potentially benefit from bisphosphonates because they help to preserve bone density. This issue could become tremendously important with the increasing use of aromatase inhibitors instead of selective oestrogen receptor inhibitors as adjuvant hormonal treatment. The effect on bone density needs to be evaluated in the risk:benefit analysis of bisphosphonate use.

The true efficacy of bisphosphonates in reducing the incidence of bone metastases in women with early stage breast cancer remains an open question. Until this is resolved, the use of bisphosphonates to reduce recurrence of breast cancer outside a clinical trial is not recommended.¹¹,¹² Studies reported to date provide a strong impetus for continued clinical and laboratory research. We need to show unequivocally that these agents can reduce the rate of bone recurrence and that this translates into an improvement in survival, or an improvement in quality of life through reduced skeletal events, in order to justify the costs that would be associated with their widespread use. Bisphosphonates, with an established track record in reducing skeletal complications in metastatic disease, offer promise in the prevention of bone as a site of recurrence in breast cancer.