Interim bone mineral density results

The early results of ABCSG-12 demonstrate that the combination of goserelin/anastrozole, and goserelin/tamoxifen to a lesser degree, leads to significant deterioration in bone mineral density in premenopausal women and that this can be completely counteracted by zoledronic acid. Even though tamoxifen has an agonistic effect on bone, when combined with the more potent agent, goserelin, it results in a net reduction in bone density. The bone deterioration is more pronounced with anastrozole/goserelin, but there is not a significant difference at this time. The main message is that zoledronic acid was able to completely prevent bone loss, regardless of which hormone combination the patients received.

While the trial is ongoing, we decided we needed to present the bone mineral density results after the interim analysis. We wanted to inform physicians and patients about the effects on bone and give them the opportunity to do something to counteract these, if necessary.

The decrease in bone mineral density is about 10 percent — osteopenic rather than osteoporotic — so treatment is not mandatory. However, patients can take precautions such as exercise and vitamin substitution.

Also, we are observing a strong correlation between age, baseline bone mineral density and changes in bone mineral density. In younger patients, if you decrease the estradiol with goserelin/anastrozole to almost undetectable levels, they suffer a more pronounced deterioration in bone mineral density than the perimenopausal patients. Younger patients on anastrozole or tamoxifen may be at higher risk, although we have never seen a patient with a T-score change of more than minus 2.5, in whom bisphosphonate treatment would be mandatory.

Anticipated long-term results

One problem with this study is that the event rate is lower than we expected. In 15 years of designing and conducting clinical trials, it has always been my experience that we overestimate the event rate. This is good for patients, but not for the trial. I expect that next year we’ll have to consider increasing the sample size, basing it on the actual event rate in the first two years, rather than on our pretrial projections.

I suspect that we will not see a survival benefit for the bisphosphonates at our current dose of zoledronic acid; however, we may see a slight survival advantage for the anastrozole combination, based on the ATAC data. Goserelin renders all the patients postmenopausal, and I don’t know of any reason women who become postmenopausal as a result of therapy would respond differently than those who become postmenopausal naturally.

Breast-conserving surgery

At our institution, we have a 75 to 80 percent breast conservation rate. In reviewing six of our clinical trials, we found the rate was as high as 82 percent in premenopausal patients with T1 tumors. With extensive use of preoperative chemotherapy and improved operative techniques, I believe mastectomy should become an obsolete surgical procedure.

Significant variance exists in breast conservation rates from country to country. Some of that is a cultural difference in the surgeon’s approach to patients, and some of that variance has to do with the availability of radiotherapy resources. In countries outside the western world, this is a major problem.

From the patient’s point of view, it is very important that we have the resources available to facilitate breast conservation everywhere in the world. In the year 2003, I feel it’s unacceptable for any patient not to be offered a reasonable choice of organ conservation in all surgical oncology indications, whether it's breast, rectal or other cancers.

Neoadjuvant hormonal therapy and disease progression

I do not routinely use preoperative hormonal therapy outside of clinical trials. To me, the problem with the neoadjuvant endocrine treatment is that you have a certain rate of nonresponders, which we don’t have with cytotoxic chemotherapy. For example, in our neoadjuvant trial, ABCSG-14, comparing three versus six cycles of epirubicin and docetaxel, we have a 70 to 80 percent response rate, probably a 15 to 25 percent complete pathological remission rate, and no progressive disease.

Disease progression during neoadjuvant therapy is a big problem. Patients are eager to have their lump removed, and while they may be willing to undergo neoadjuvant therapy to increase their likelihood of breast conservation, if you use endocrine therapy you have to tell them there’s a 10 percent chance the lump will actually grow. I believe we should continue to test this therapy in clinical trials on cohorts of patients not suitable for cytotoxic chemotherapy.

Sentinel node: A standard of practice

We are not involved in sentinel node trials because this procedure is already the standard of care in Austria. One of the advantages of being in a small country with a well-functioning network of breast centers is that you can quickly translate an experimental procedure into daily practice. A set of guidelines was established, teaching courses were offered, institutions exchanged surgeons and sentinel node biopsy became a standard in the country.

Research in radiotherapy

We are conducting a trial randomizing patients with low risk after breast conservation to radiation or no radiation. Patients must be over age 60, nodenegative, on endocrine therapy and have a tumor size less than 3 centimeters. We have shown in retrospective studies that these patients have a local recurrence rate of only about two percent, so we need to determine if there’s a subset of patients who do not need adjuvant radiation after breast conservation. This study will require a large number of patients and a long follow-up to determine equivalence of these two approaches.

We also have two Austrian institutions exploring intraoperative radiotherapy (IRT). It’s very compelling to substitute this for five weeks of treatment, but from what I know about the concept of fractions, the rationale for this approach may be debatable. Also, in all the trials that I’m aware of, IRT is being used in patients at very low risk, and these are patients who probably do not need radiation whatsoever.

Future of research in breast cancer treatment and prevention

I believe future research will focus on defining subgroups of women with lowand intermediate-risk disease and finding appropriate treatments. One of the problems at this point is that progress may be made in smaller increments and may cost more. It may be easier and cheaper to increase an effect from 50 to 70 percent, than to increase it from 70 to 75 percent.

In the population at high risk, efforts to maximize dosing and then rescue patients, as with stem cell transplantation, have failed overall. It's probably a qualitative effect, rather than a quantitative effect, in that tumor cells vary in their response to different treatments. I believe researching areas such as growth factors and tyrosine kinase treatment will be important.

Apromising trend in research is the emerging chip technology. This allows researchers to target specific mutations present in each cancer, which will hopefully lead to the development of tailored, more effective treatments, especially in the population at high risk. Chip technology may also be used in prevention by helping us understand the transition from atypical ductal hyperplasia to cancer, how invasion occurs and determining which women — other than BRCA carriers — are at high-risk for developing breast cancer. Once we identify these patients, we can intervene with endocrine treatment for prevention.

Patient benefits from participation in clinical trials

We have demonstrated that patients gain individual benefits from participating in clinical research trials. We did a retrospective analysis, presented at ASCO in 2000, comparing 5,700 patients in clinical trials with 2,000 patients with similar risk treated by a so-called standard treatment. These were all primary breast cancer patients and there was almost a 10 percent survival difference in favor of the patients on trials.

Clearly there is a problem with the standard of treatment patients receive outside clinical trials. In our analysis, we were able to look at the treatment received by the patients not in trials, and about 90 percent of these patients received therapies we would consider suboptimal. Clinical trials are designed to ensure that patients receive optimal therapy. I see 500 breast cancer patients a year, and by treating patients within a clinical trial, I have all kinds of assistance — checklists, monitors, data verifications — to prevent me from forgetting something.

An additional explanation for the survival benefit of clinical trial participation is that, through required visits and tests, we pick up other medical problems that can be remedied. While a patient’s risk reduction is about 40 percent after ten years, only 20 percent comes from breast cancer-related survival. The other 20 percent is related to other causes of death. I know a prospective randomized comparison of regular follow-up versus symptom-oriented follow-up doesn’t show any survival difference, but personally I don’t agree with that data.

When we treat patients within clinical trials, we not only help that individual patient, but we also help the next generation of patients and I believe that this is the most important task right now.

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