What is the optimal management of women at high risk for breast cancer, including the role of chemoprevention?

OVERVIEW: The publication of NSABP P-1 brought the issue of chemoprevention in high-risk women to the forefront of attention in both the press and the medical literature. While tamoxifen was found clearly to reduce the incidence of breast cancer in high-risk women by 50%, NSABP P-2 (the STAR trial) is underway evaluating the SERM, raloxifene, in this setting. The recent presentation of the ATAC trial — demonstrating an advantage to anastrozole over tamoxifen in contralateral cancers — hints towards future trials of the aromatase inhibitors in the chemoprevention setting. Ultimately, with multiple effective agents, issues of toxicity and side-effects will be paramount.

Approximately how many women have you evaluated, in your practice in the last year, that were high enough risk to consider some type of intervention (not including women with a personal history of breast cancer)?

What do you believe the results would be of a randomized clinical trial comparing tamoxifen to anastrozole in high-risk postmenopausal women?

What type of research data would you require to use anatrozole or another aromatase inhibitor in a postmenopausal high-risk woman?

IMPLICATIONS OF ATAC CONTRALATERAL DATA FOR PREVENTION

The odds ratio for the reduction of contralateral breast cancer favoring anastrozole over tamoxifen is .42, and the difference emerges within one year. So, there is a staggering 58% reduction over tamoxifen. Tamoxifen can produce a 50% reduction long term. If these findings hold up, we can add another 60% reduction on top of the 50%, and this starts translating into potentially very significant chemoprevention of breast cancer.

—Michael Baum, MD, FRCS

It’s very, very exciting. We’re talking about a 60% reduction of contralateral tumors from the rate that tamoxifen was achieving – which itself is a 50% reduction from no treatment at all. If this actually pans out, we’re talking about a potential 80% reduction in new cancers. This is a very serious prospect for prevention. This is very important for the IBIS II prevention trial. The ATAC data, particularly on the safety profile, was necessary before the final approval. Now that the data is available, I’m confident that we will be able to proceed rather rapidly with the trial, comparing anastrozole to tamoxifen to placebo in high-risk women and those with DCIS.

—Jack Cuzick, PhD

From the ATAC data we’ve seen, we would expect that anastrozole will dramatically decrease the number of breast cancers and should be superior to tamoxifen in the prevention setting. In addition, in terms of toxicity — although the DVT, pulmonary embolus and stroke risk associated with tamoxifen were just seen in postmenopausal women, anastrozole doesn’t result in these conditions, which can cause death. We also see virtually no vaginal discharge with the aromatase inhibitors in either the metastatic or adjuvant settings, and hot flashes are much less of a problem than they are with tamoxifen.

—J Michael Dixon, MD, FRCS

This has tremendous implications for prevention — the IBIS II trial is planned to evaluate anastrozole in this setting and in DCIS. We need to explore this further in the United States with definitive studies in postmenopausal high-risk women — in this subgroup, the toxicity of tamoxifen is substantial.

The main safety concerns with tamoxifen are the agonist effects (i.e., risks of thromboembolic complications and small risk of endometrial cancer). Even women with just vaginal bleeding without endometrial cancer still have to go through a number of tests and procedures before we know that she doesn’t have the problem. There’s no question that the safety profile of anastrozole is much better than tamoxifen. Anastrozole is an agent with almost nonexistent side effects — at least in the preliminary analysis of the data — making it a very attractive agent to be evaluated in the prevention setting.

—Aman Buzdar, MD

NSABP P-2: THE STAR TRIAL

There is a great deal of enthusiasm for this trial, and an enormous amount of credit has to go to the NSABP members who are c o m m i t t e d to moving the state-of-the-art forward. That's their primary commitment, and it was the primary commitment of the 13,388 selfless and courageous women who entered the P-1 trial. I believe that there will be 22,000 more women out there who will enter P-2.

—Norman Wolmark, MD

RALOXIFENE

Raloxifene has been studied in a completely different population, namely older postmenopausal women selected for osteoporosis risk, and some data suggest that women with decreased bone density have a decreased breast cancer risk. The raloxifene data on breast cancer risk reduction is promising, but right now for postmenopausal women who are at increased risk, tamoxifen is clearly the drug of choice outside of a clinical trial. Also, raloxifene is only for postmenopausal women; there are no safety data in premenopausal women.

—Monica Morrow, MD

NSABP P-1: RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL TO DETERMINE THE WORTH OF TAMOXIFEN FOR PREVENTING BREAST CANCER CLOSED PROTOCOL

Fisher et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90(18):1371-88. Abstract

NSABP P-2: STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) FOR THE PREVENTION OF BREAST CANCER OPEN PROTOCOL

PROJECTED ACCRUAL: Approximately 22,000 patients will be accrued to this trial.

Quality of life assessed at baseline and six-month intervals to five years then annually thereafter.

STUDY CONTACT Norman Wolmark, Chair, Ph: 412-359-3336 National Surgical Adjuvant Breast and Bowel Project Allegheny General Hospital, Pennsylvania

PROPOSED IBIS 2 TRIAL: INTERNATIONAL BREAST INTERVENTION STUDY 2

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