Michael F Gnant, MD
Professor of Surgery University of Vienna Vienna, Austria

Edited comments by Dr Gnant

ABCSG-12: Adjuvant anastrozole or tamoxifen in combination with goserelin (± zoledronic acid) for hormone receptor-positive, premenopausal breast cancer

Trial background and rationale

We have conducted trials with premenopausal breast cancer patients with endocrine-responsive disease for more than 10 years, attempting to optimize treatment, particularly without the use of cytotoxic chemotherapy. In ABCSG- 05, we showed that the chemical ovariectomy with goserelin plus tamoxifen was equivalent or actually better than the standard CMF. So, in Austria, we have come to a consensus that this hormonal therapy is appropriate for premenopausal women with low- and intermediate-risk, hormone-responsive breast cancer.

We feel the effect of cytotoxic chemotherapy in these patients is more an endocrine effect, and we can show that those patients who experience

amenorrhea during chemotherapy do much better than those that don’t. So at least part — maybe 70 or 80 percent — of the benefit of chemotherapy is actually an endocrine effect, rather than a direct cytotoxic effect.

This treatment approach is not as popular in the U.S. as it is in Europe, partially because the history of the endocrine treatment is not as extensive in the U.S. While medical oncologists in the U.S. are beginning to prescribe combinations of goserelin with other agents, cytotoxic chemotherapy remains the standard.

Given the results of ABCSG-05, the next logical step was to determine how to improve on the combination of goserelin/tamoxifen. It has been demonstrated several times that the aromatase inhibitors anastrozole and letrozole decrease serum estradiol levels in women even more effectively than tamoxifen, so ABCSG-12 was designed to compare the combination goserelin/tamoxifen to goserelin/anastrozole.

Trial design

The ABCSG-12 trial has four arms comparing goserelin/tamoxifen to goserelin/anastrozole with or without zoledronic acid. We included zoledronic acid because it’s the most potent bisphosphonate pharmacokinetically and we were concerned about the risk of osteoporosis with the aromatase inhibitors. Chemotherapy is only permitted as neoadjuvant therapy. No postoperative chemotherapy is allowed.

We did not include a tamoxifen-only arm because we tried to build upon our own results with goserelin/tamoxifen, which is now a national standard in Austria. I also believe tamoxifen-only treatment in premenopausal women is debatable because there is reasonable evidence you need to include some cytotoxic treatment.

Rationale and dosing for zoledronic acid

We still do not know whether bisphosphonates can impact survival, but the claim that they reduce bone metastasis is logical. If you can impact osteoclast function, then you might in some way delay or inhibit bone metastasis. In addition, zoledronic acid has exhibited antitumor functions, specifically antiangiogenic and apoptosis-inducing effects in animal models.

We began our trial with a dose of eight milligrams of the agent every month, higher than what is used in osteoporosis — hoping to see a survival benefit. However, alarming information about renal toxicity with the drug came out after the trial opened, so we decided to go back to the recommended antiosteoporosis dose.

Although safety is the most important directive you can use as a study group, this was probably a missed research opportunity. When we analyzed the serum creatinine levels of the 100 patients who received the higher dose — and we have more than a thousand such measurements — there was never even a slight increase in serum creatinine.

The alarming toxicity data came from heavily pre-treated myeloma patients — some of whom had impaired renal function before they ever began zoledronic acid. We are treating younger breast cancer patients who usually have perfect renal function, so I believe it would have been a safe approach. Clearly, we had to put safety first and reduce the dose to four milligrams every six months.

The dose of zoledronic acid used in animal models where antitumor mechanisms were seen would translate to a 32-milligram dose in humans, which is currently considered unsafe. However, I have heard that there are Phase I and II trials in myeloma patients with even higher doses administered more slowly. It’s believed that if you increase the infusion time to two or three hours, the kidneys are pharmacokinetically able to handle the higher doses, but I haven’t seen any written or published data on that.

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