Adjuvant study of LHRH agonist plus tamoxifen or anastrozole plus or minus zoledronic acid

At San Antonio, Dr Gnant's presentation of the Austrian study data -comparing an LHRH agonist with either tamoxifen or anastrozole with or without zoledronic acid - was very important in demonstrating that a bisphosphonate could ameliorate the decrease in bone density associated with hormonal therapy. Parenthetically, chemotherapy results in a sharp decline in the production of estrogen, also resulting in bone loss.

Clearly, we have to support our patients during treatment, just as we do with growth factors for neutropenic-related events or antiemetics for nausea. This is a very important issue for women with breast cancer. The issue is: How do we incorporate the data into clinical practice?

I assess bone density in postmenopausal patients receiving adjuvant anastrozole. These women are already in menopause, so we know the extent of their bone loss. The reduction in bone density from a chronic therapy, such as adjuvant anastrozole, is different than the acute bone loss from chemotherapy.

In a 60-year-old patient who has been in menopause for 10 years without significant bone loss, I'm not convinced anastrozole will produce a substantial decrease in bone density. On the other hand, in a patient who already has osteopenia or osteoporosis, anastrozole will likely exacerbate that.

You have to look at these patient populations differently. I assess bone density and, if it is normal, I repeat it one year later to determine whether or not to introduce a bisphosphonate; prophylactic zoledronic acid may not be necessary.

Positive findings have been published in the New England Journal of Medicine using intermittent zoledronic acid in patients with osteoporosis. The next step is to compare this approach to the conventional use of oral bisphosphonates in that setting. There are studies done in conjunction with the ATAC trial that will give us information about bone loss in patients on anastrozole versus tamoxifen.

Bisphosphonates for the prevention of metastatic disease

The limited data from trials of oral bisphosphonates are controversial. Unfortunately, we don't have information using the more potent, intravenous bisphosphonates. Randomized studies with zoledronic acid are being initiated, but it will be a substantial period of time before we have data.

Preclinical data support the use of bisphosphonates for the prevention of bone loss and bone metastases. Additionally, the landmark German study by Diel and colleagues suggests that bisphosphonates may also improve survival.

Increasingly, bisphosphonates are being utilized in women with early breast cancer because we're using aromatase inhibitors in that setting. How much secondary benefit these agents will provide for prevention of bone metastases will be of significant interest to physicians, and the best way to answer the question is with a large, prospective, randomized study.

The primary obstacle is that we aren't able to select which patients will have bone-only relapse. If we administer bisphosphonates to everybody without targeting the patients likely to benefit, it will be difficult to demonstrate a benefit. The absolute benefits we have seen through the years are small.

Similarly, the benefit seen with taxanes ranges from an absolute difference of one percent to eight percent. This means that the minority of our patients are benefiting from the therapy. Ideally, you'd like to look for this small percent of patients who benefit. We are trying to study this at MD Anderson, using gene profiling to try to prospectively confirm a specific gene profile to help decide which patients should and should not receive a specific therapy. This would allow us to spare toxicity and make therapies more effective by improving the tools to select patients for treatment. This is the direction the field is going, and it's very exciting.

Clinical advances with adjuvant taxanes

Several clinical trials have addressed the benefit of taxanes in the adjuvant setting. The results from CALGB trial 9344 have recently been published and demonstrate an improvement in disease-free and overall survival with the addition of paclitaxel to AC chemotherapy. BCIRG-001 - comparing TAC to FAC - also resulted in an improvement in disease-free survival. Most recently, CALGB-9741 documented an improvement in disease-free and overall survival with dose-dense AC and paclitaxel every two weeks with growth factor support.

Some physicians dismiss the findings from CALGB-9741, believing that there is minimal clinical application of the results. I disagree. Increasing the frequency of administration of AC and paclitaxel from every three weeks to every two weeks, with filgrastim support, clearly resulted in a substantial improvement in disease-free survival.

Interpretation of the results are controversial because CALGB-9741 was designed before the administration of weekly taxanes. Today studies such as the Intergroup study ECOG-N9831 - for patients with node-positive, HER2-positive disease - use weekly paclitaxel. So, there has been a shift in the administration schedule of paclitaxel, and some physicians question whether the improvement in disease-free survival was due to increasing the density of paclitaxel, of AC or of both. That issue remains unresolved, but a dose-dense approach is an acceptable option for women with node-positive early breast cancer.

Capecitabine/docetaxel (XT) in the treatment of breast cancer

Dr O'Shaughnessy's study of women with metastatic breast cancer demonstrated that the combination of capecitabine/docetaxel - compared to docetaxel alone - resulted in improved response rate, time to progression and survival.

The dosing and scheduling of the combination are controversial and remain to be defined. In the XT trial, the drugs were given simultaneously on day one. It's possible that upregulating TP with a taxane should be done before introducing capecitabine, and perhaps lower doses will result in the same benefit. If you want to utilize aggressive therapy, the combination in the XT trial was superior, and the quality of life wasn't impaired compared to the sequential approach.

We're evaluating capecitabine/docetaxel as neoadjuvant and adjuvant therapy. We're conducting a randomized study of weekly paclitaxel for 12 cycles followed by FAC for four versus docetaxel/capecitabine for four followed by FAC for four. If a patient with Stage II breast cancer (or greater) has an intact tumor, she will receive primary chemotherapy. If she has undergone locoregional therapy, she'll be randomized for adjuvant therapy.

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