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History of HRT benefits breast cancer patients. (Lower Incidence of Bone Metastases).

SAN ANTONIO -- Women who have been on hormone replacement therapy before being diagnosed with breast cancer have a significantly reduced incidence of bone metastases, Dr. Ingo J. Diel said at a breast cancer symposium sponsored by the San Antonio Cancer Institute.

"Our hypothesis is that healthy bone with normal bone turnover provides an infertile soil for tumor-seeding cells," said Dr. Diel, an ob.gyn. at the University of Heidelberg (Germany).

"We believe that with HRT, like other osteoprotective therapies, we treat the soil for seeding tumor cells," Dr. Diel explained.

He retrospectively reviewed 1,160 patients in whom breast cancer was diagnosed at age 45-70 years. A total of 504 patients were postmenopausal with no history of HRT use, 343 were postmenopausal with at least 1 year and a mean of 5 years of HRT use, and 313 were pre- or perimenopausal at diagnosis.

During a median follow-up period of 70 months following breast cancer surgery, the postmenopausal HRT users had the lowest incidence of death and bone metastases. (See table.)

Particularly noteworthy was the finding that 16 women in the postmenopausal/no-HRT group had primary bone metastases at the time of breast surgery, compared with just 2 postmenopausal women with a history of HRT use, he said.

There also were fewer metastases to the liver and lungs among the HRT users than among the never-users, Dr. Diel reported.

In a multivariate logistic regression analysis, HRT use emerged as an independent prognostic marker for metastasis-free survival. A history of HRT use was associated with a 39% reduction in the risk of death or metastasis, the analysis showed.

The finding that prior use of HRT was independently associated with a reduced risk of bone metastasis has not been reported previously. But other investigators have determined that HRT is associated with smaller, lower-grade breast cancers and with a lower frequency of positive axillary lymph nodes. This was also true in Dr. Diel's study.

The finding that bone metastases were most frequent in pre- and perimenopausal women may strike many physicians as surprising. This pattern raises the question of why these patients were not protected from bone metastasis by their endogenous estrogen.

The answer, according to Dr. Diel, is that the period of greatest bone turnover in a woman's life does not occur postmenopausally, as is widely supposed, but in fact occurs at age 45-55 years. This time of activated bone turnover as a result of osteoclastic activity is a very high-risk period for bone metastases in women who have breast cancer, he said.

When breast cancer occurs, the bone marrow offers a potential pool for disseminated tumor cells. The adjacent bone matrix is loaded with growth factors. If these stored growth factors are released--as occurs during the perimenopausal period of high bone turnover or due to osteoporosis-promoting adjuvant breast cancer therapy--that could promote tumor cell proliferation in bone marrow and subsequent bony metastases.

Dr. Diel described a vicious cycle in which metastatic cells within the bone marrow obtain a foothold in bone and then release osteolytic factors that trigger osteoclastic activity. That results in the release of stored growth factors, which in turn encourage further metastatic growth.

The ob.gyn. noted that he and other investigators have previously shown that giving adjuvant bisphosphonates to breast cancer patients reduces metastases and prolongs overall survival.

Dr. Diel called for additional trials using osteoprotective agents such as selective estrogen receptor modulators, estrogen, and bisphosphonates for prophylaxis against cancer therapy-induced osteoporosis as well as against metastases.

"It seems to be important to avoid activated bone turnover in cancer therapy Cancer treatment--induced osteoporosis is an important issue. We are responsible for this long-term side effect," he said.
Incidence of Death, Bone Metastases by HRT Status at Diagnosis

 Postmenopausal Postmenopausal
 And No History of And at Least 1 Premenopausal or
 HRT Use Year of HRT Use Perimenopausal
 (n=504) (n=343) (n=313)

Death 21% 8% 14%
Bone Metastases 14% 6% 16%

Note: Data from a 70-month follow-up of 1,160 patients after breast
cancer surgery.

Source: Dr. Ingo J. Diel
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Title Annotation:hormone replacement therapy
Author:Jancin, Bruce
Publication:Internal Medicine News
Date:Mar 1, 2003
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