RATIONALE

When one looks at prevention, it’s clear that the key issue is reducing the estrogen stimulus to the breast. There are two complimentary strategies to do that; one is to block the receptor, which is the strategy with SERMs like tamoxifen. The other approach is to reduce the estrogen stimulus, and in our next round of trials, we’re essentially pursuing that strategy more actively. In premenopausal, high-risk women, we’re doing some pilot studies looking at the role of the LHRH agonists in very high-risk women, with an add-back such as a SERM or bisphosphonate.

In postmenopausal women, the analogous strategy is to look at the aromatase inhibitors. With the idea that it’s a good idea to base a prevention trial on a large-scale adjuvant trial, basically, we’ll be following the ATAC trial by about three years. There are some concerns about the effect of aromatase inhibitors on bone, but we believe we can simply monitor bone carefully and address it with a bisphosphonate, if necessary. At this point, there have been no reports from the ATAC data monitoring committee to suggest that bone is a particularly serious problem, and it’s helpful to know that every six months they’re looking at the ATAC data and will be reporting anything that’s serious.

Everything we know about breast cancer at the experimental level is that it’s the estrogen stimulus that causes the cells to divide and the cancers to be pushed forward. So, the rationale of IBIS 2 is quite simple. You lower the estrogen stimulus and hope that it’s below the threshold needed for cells to replicate.

—Jack Cuzick, PhD

PROTOCOL DESIGN

The latest version is without a combination arm, but we’re awaiting the results from the ATAC trial. If the combination arm in ATAC looks attractive for contralateral breast cancer, we may add that to IBIS 2. Aromatase inhibitors reduce endogenous estradiol levels to immeasurable levels. And if, as everyone believes, estrogens are the promoters of breast cancer — not inducers of the genetic instability — then, in theory, any environment that lowers estrogens should favor chemoprevention. Also, aromatase inhibitors are less likely or unlikely to have an agonist effect. So, endometrial problems are unlikely to be an issue. But against that, these agents are more likely to have a long-term effect on osteoporosis. So, like all these things, it’s going to be a balance.

—Michael Baum, ChM, FRCS

DESIGN PLACEBO ARM OF IBIS

The design of IBIS 2 is troublesome to me because of the placebo arm, although I can understand that if IBIS 1 is still incomplete and contains a placebo arm, it’s difficult to design a new trial in which there’s no placebo arm, because it implies that you know the end result. If IBIS 1 demonstrates that tamoxifen does convey a prevention advantage, they'll have to stop the placebo arm during the course of IBIS 2. 

—Richard Margolese, MD

An overview of the current available data leaves little doubt that tamoxifen will reduce the incidence of breast cancer. Even the negative results from the Italian and the Marsden trials aren’t strong enough to change that. But our view — and the view of the IBIS 1 Data Monitoring Committee — is that a trial shouldn’t be stopped until there is a clear indication of a clinical recommendation. And we feel that there are enough concerns about how durable this effect will be that the trial should continue. We’re beginning to see the long-term benefits now in the adjuvant studies, so we can be optimistic that five years of tamoxifen may give up to 10 years of protection. But if we really want to see that in prevention, we need to test it in prevention.

—Jack Cuzick, PhD

LOGISTICS

This will be an international trial, and we have two good models for big multi-national trials: the ATLAS trial of tamoxifen duration and the ATAC trial, which ran very similar treatment arms to IBIS 2. The entry criteria will be similar to IBIS 1, but restricted to postmenopausal women. We don’t use the Gail model. Family history is factored in, along with nulliparity and pathologic entities such as atypical hyperplasia and LCIS. We’re also adding a new category that potentially could be quite important — women who have mammographic dysplasia covering 50 percent or more of their breasts. That links it in nicely with screening, which to some extent, is really where prevention belongs. Screening programs should not only detect small cancers, but also identify women at high risk and offer them preventative strategies. IBIS 2 is also going to have a DCIS component. The trial will enter 12,000 high-risk women and another 4,000 patients with DCIS. We view DCIS patients as high-risk women, and preventing new tumors is as important as preventing recurrence of the old tumors.

—Jack Cuzick, PhD

SELECT PUBLICATIONS

Bogert S et al. Breast Cancer Risk Assesment in the Primary Care Setting: A Pilot Teleconference / E-mail Program Targeting Gynecologists, Nurse Practitioners and Physicians Assistants. Poster, 2001 Miami Breast Cancer Conference. Full-Text Cuzick J. Future possibilities in the prevention of breast cancer: Breast cancer prevention trials. Breast Cancer Res 2000;2(4):258-63. Abstract  Day R et al. Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-69. Abstract Powles T et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998; 352(9122):98-101. Abstract Veronesi U et al. Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352(9122):93-7. Abstract Vogel VG. Breast Cancer Prevention: A Review of Current Evidence. CA Cancer J Clin 2000;50:156-170. Full-Text

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Editor’s Note

Sentinel Node Dissection:
Implications to Medical Oncology

Postmastectomy Radiation
Therapy

Ductal Carcinoma In Situ

ER/PR Results and Endocrine
Therapy

Adjuvant Therapy for Low-risk
Invasive Tumors

ATAC Trial: Arimidex vs
Tamoxifen vs Combination

Bisphosphonates in Primary
Breast Cancer 

Adjuvant Taxanes: Surgical
Oncology Perspective

Proposed IBIS 2 Prevention Trial:
Arimidex vs Tamoxifen vs Placebo

Predictions of Future Trends
in Breast Cancer Research

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