Prior Hormone-Replacement Therapy Linked to Reduced Risk of Metastasis to Bone, Lung, Liver

HEIDELBERG, Germany—Breast cancer patients who have received prior hormone-replacement therapy (HRT) have a significantly reduced risk of metastasis to bone, lung, and liver, according to a study reported by Ingo J. Diel, MD, of the Institute for Gynecological Oncology in Mannheim Germany. Dr. Diel was previously affiliated with the Department of Obstetrics and Gynecology at University Hospital in Heidelberg, Germany. The German study supports previous reports of improved outcome for breast cancer patients who have used HRT.

"We know very well that we have a moderate but significant increased risk for breast cancer in HRT users," Dr. Diel said. "But we know that for HRT and breast cancer mortality it is a different story. Several, but not all, studies on this topic show an improvement in overall survival in breast cancer patients with a history of preoperative HRT use. They conclude that there is reduced aggressiveness—by better grading of the tumor—slow-growing tumors, and smaller tumor size."

Most Were Postmenopausal

The Heidelberg group performed a retrospective study involving 1,160 patients who underwent breast cancer surgery at University Hospital between 1990 and 2000. The age range was 45 to 70. Most of the women were postmenopausal—847 compared to 313 women who were premenopausal.

Patients designated as HRT users had taken hormones for at least 1 year prior to diagnosis (mean, 60 months). In the study population, 343 patients were considered to be HRT users, and 504 patients were designated as nonusers. Among the HRT users, 63.8% had used cyclic estrogen and progesterone.

The investigators’ analyses confirmed previous findings that HRT users have an advantage in terms of tumor size and tumor grade. Moreover, the group of patients who had not taken HRT had the highest death rates, and mortality was greatly reduced in the postmenopausal HRT users. No significant differences were found between HRT users and nonusers in terms of nodal status, hormone receptor status, and S-phase fraction.

Completely New Finding

Multivariate analysis showed that HRT was an independent prognostic factor—a completely new finding, according to Dr. Diel. Patients who had not used HRT had a significantly increased incidence of bone metastases (14% vs 3% in HRT users), lung metastases (9% vs 3%), and liver metastases (9% vs 4%). Dr. Diel said that metastases were present at the time of surgery in 16 patients who had not used HRT, whereas these "primary" metastases were present in only two women who were HRT users.

Dr. Diel noted that smaller, less aggressive tumors could not entirely explain the survival advantage conferred by HRT use. In turn, he proposed several hypotheses to explain the lower risk of metastases in HRT users.

"Bone marrow is a pool for disseminated hematogenous tumor cells and the bone matrix is full of previously stored growth factors, which could have an effect on tumor cells if they are released. These growth factors could be very important for the settlement and proliferation of tumor cells in the bone marrow," Dr. Diel explained.

"Our hypothesis is that HRT normalizes activated bone turnover until the day of diagnosis or the day of removal of the primary tumor."

Familiar ‘Vicious Cycle’

Dr. Diel outlined the familiar "vicious cycle" between metastatic cells and bone.

"We know that if a bone metastasis grows, it releases osteolytic factors, and these osteolytic factors activate osteoclasts," he said, "[through bone destruction], previously stored growth factors could be released and may have a proliferative effect on metastases."

With HRT, as with other osteoprotective treatments like bisphosphonates, he added, "we treat the soil for tumor-seeding cells." Clodronate, for example, has been shown to reduce the number of subsequent metastases and to prolong overall survival, a property recently confirmed (Diel et al: N Engl J Med 339:357-363, 1998; Powles et al: J Clin Oncol 20: 3219-3224, 2002).

Dr. Diel noted that in Heidelberg study population, premenopausal or perimenopausal patients had a higher incidence of bone metastasis—a finding that might be explained by the rapid bone turnover that takes place between the ages of 45 and 55. During this time of activated osteoclast bone turnover, some women may be at very high risk not only of developing osteoporosis but also of hosting tumor cells if they have breast cancer.

"Healthy bone is an infertile soil for tumor-seeding cells," Dr. Diel said. "It seems to be important to avoid activated bone metabolism due to cancer treatment. Cancer treatment-induced osteoporosis is an important issue, and we are responsible for this long-term side effect."

"It’s important that we perform studies in which we use osteoprotective substances to avoid this long-term side effect," he continued. "Osteoprotective substances, like estrogen, clodronate and other bisphosphonates, maybe the selective estrogen receptor modulators (SERMs), or other substances, could be useful in the prophylaxis of tumor therapy-induced osteoporosis and maybe for bone metastasis as well."