Is there an adverse effect of adjuvant tamoxifen in premenopausal breast cancer?

This report appeared in the press two weeks ago. It was misquoted and has caused some alarm amongst patients with breast cancer. There is no need for doctors to change what they are doing based on this early research. Women should keep taking their tamoxifen as the clinical research supporting its benefit is overwhelming and is not changed by this early laboratory research.

Jirstrom K, Stendahl M, Ryden L, Kronblad A, Bendahl PO, Stal O, et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 2005;65(17):8009-16.

By
Dr CM McNeil
Department of Medical Oncology
Westmead Hospital
Date: 20 September 2005

Editors:

Dr M Brennan, Director of Education, Westmead Breast Cancer Institute
A/Prof John Boyages, Executive Director, Westmead Breast Cancer Institute

Introduction

There has been much media interest in the recent publication from Sweden. In the study 500 breast cancer specimens were looked at to determine if they carried the cyclin D1 gene (known as CCND1), and to see if they expressed product of this gene, a protein called cyclin D1(1).

What is cyclin D1?

• Cyclin D1 is a protein that is involved in the process of cell growth. In breast cancer cells that have receptors for oestrogen (ER positive), the female sex hormone oestrogen causes an increase in cyclin D1 leading to cell growth. Anti-oestrogens such as tamoxifen cause a decrease in cyclin D1 causing growth to stop. (2-6).
• In laboratory experiments it is possible to cause a short-circuit of this effect. This means cyclin D1 is artificially increased in breast cancer cells growing in the laboratory. This protects the cells from stopping growth after treatment with anti-oestrogen (5, 7).
• There is a theory that breast cancers that overexpress the cyclin D1 protein might be less responsive to tamoxifen treatment.

What does this study mean?

• A possible implication of this research is that cyclin D1 gene amplification does indeed lead to resistance to tamoxifen, and that this may lead to growth stimulation by tamoxifen.
• There are, however, other explanations for these findings on a detailed genetic level.
• There are a number of weaknesses in the study that should lead us to exercise caution in interpreting the results.
  • This is a retrospective study, which is generally considered to be a weaker study design than a prospective study.
  • A number of different subgroups were compared to one another, and in some of these groups there were only very small numbers of patients, and therefore this subgroup analysis may have led to inaccurate results.
  • The patients in this study were only treated with tamoxifen for 2 years, which we know is a suboptimal duration of therapy. Would the results have been different had the patients treated with tamoxifen had their treatment for 5 years instead of 2?
  • The success rate of the method of testing for cyclin D1 gene amplification was only 56%. This leads to many questions about how representative the analysed sample was and how clinically applicable the current gene amplification test is.

Should we change clinical practice?

• Certainly, this result would need to be repeated and shown to be accurate before clinical practice should be changed.
• It should be remembered that overall, tamoxifen halves the risk of recurrence from breast cancer, and has saved thousands of lives over the history of its use.
• Studies such this one are important in trying to identify those patients for whom tamoxifen does not help. Cyclin D1 gene amplification is seen in a only a very small number of breast cancers (ie: ~15%)
• If this proves to be relevant, based on this study, it will still only apply to a very small number of women- about one in eight women with breast cancer who have not gone through the menopause.
• This area is an important area for future research.
• This study does not negate the proven benefit of tamoxifen seen for the majority of ER +ve breast cancers.

References

1.Jirstrom K, Stendahl M, Ryden L, Kronblad A, Bendahl PO, Stal O, et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 2005;65(17):8009-16.

2.Musgrove EA, Hamilton JA, Lee CS, Sweeney KJ, Watts CK, Sutherland RL. Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol 1993;13(6):3577-87.

3.Altucci L, Addeo R, Cicatiello L, Dauvois S, Parker MG, Truss M, et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene 1996;12(11):2315-24.

4.Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 1997;272(16):10882-94.

5.Wilcken NR, Prall OW, Musgrove EA, Sutherland RL. Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. Clin Cancer Res 1997;3(6):849-54.

6.Watts CK, Sweeney KJ, Warlters A, Musgrove EA, Sutherland RL. Antiestrogen regulation of cell cycle progression and cyclin D1 gene expression in MCF-7 human breast cancer cells. Breast Cancer Res Treat 1994;31(1):95-105.

7.Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA, Sutherland RL. Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells. Cancer Res 2002;62(23):6916-23.