Effect Of Raloxifene After Tamoxifen On Breast And Endometrial Cancer Growth
Heather Jones, MD
University of Pennsylvania Cancer
Last Modified: May 15, 2001
Presenter: Ruth M. O'Regan
Affiliation: Northwestern University, Chicago, IL
After the completion of 5 years of tamoxifen therapy, breast cancer patients are still at risk for osteoporosis and breast cancer recurrence. Raloxifene (RAL) is a selective estrogen receptor modulator, approved for the prevention of osteoporosis in postmenopausal women. RAL appears to have antiestrogenic effects on the breast and is not associated with thickening of the endometrium. Currently, there is no clinical data on the effects of RAL on breast and endometrium following treatment with tamoxifen (TAM). This is an animal model study that evaluates the use of RAL after TAM.
Materials and Methods:
This study examined the effects of RAL in 3 breast cancer (BC) models grown in athymic mice (AM):
- A TAM-sensitive model (MCF7);
- A TAM-resistant model, which has been exposed to short-term (ST) TAM for 1 year (MCF7TAMST) and is stimulated by TAM and estrogen (E2);
- A second TAM-resistant model, which has been exposed to long-term (LT) TAM for greater than 5 years (MCF7TAMLT) and is stimulated by TAM but inhibited by E2.
- Additionally, they examined RAL in 2 endometrial cancer (EC) AM models: a TAM-naïve model (ECC-1) and a TAM-exposed model (EnCa101TAM), which has been exposed to TAM for greater than 5 years.
- In all cases, AM were bitransplanted with BC on one side and EC on the other and treated with TAM 0.5mg, RAL 0.5mg or 1.5mg daily by mouth, with and without postmenopausal levels of E2
In the TAM sensitive model
Neither TAM nor RAL significantly stimulated growth of the MCF7 (TAM-sensitive) BC tumors or EC tumors in the (TAM-naïve) ECC-1 model.
In the short-term TAM resistant model
In the MCF7TAMST (short-term TAM-resistant) BC tumors postmenopausal levels of E2 significantly stimulated growth; although both RAL and TAM, with and without E2, stimulated MCF7TAMST tumor growth, there was no significant difference between the antiestrogens (AE).
In the long-term TAM resistant model
In the MCF7TAMLT (long-term TAM-resistant) BC model, there was no significant difference between TAM or RAL, in combination with E2 on tumor growth. Both E2 and the AE significantly stimulated growth of the EnCa101TAM (TAM-exposed) EC tumors, but there was no significant difference in the effects of TAM alone and RAL alone, or TAM with E2 and RAL with E2 on tumor growth.
These results suggest that if RAL is used for osteoporosis prevention after 5 years of TAM, it could result in the growth of occult breast cancer or endometrial cancer. The two agents TAM and RAL appears cross-resistant in the TAM- resistant breast cancer model, supporting the clinical finding that it is not of value in the treatment of advanced TAM-refractory breast cancer.
This study highlights the cross-resistance that occurs with tamoxifen and raloxifene, two agents that are similar in structure. Thus, patients resistant to tamoxifen should be offered placement on the appropriate clinical trial evaluating aromatase inhibitors.
OncoLink ASCO 2001 coverage is provided by an unrestricted educational grant from Amgen