Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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Tamoxifen is a nonsteroidal triphenylethylene derivative, which is generally classified as an antiestrogen with partial estrogen-agonist activity in some tissues. In fact, results from chemo-preventive and adjuvant trials suggest that treatment with tamoxifen is associated with an increase in bone mineral density and decreased serum cholesterol, particularly in postmeno-pausal women.91,92

More importantly, the use of adjuvant tamoxifen following primary surgery for estrogen-sensitive early breast cancer has been associated with prolonged disease-free survival and reduction in the risk of death by 20 to 30 percent. One of the major arguments in favor of the use of tamoxifen as a chemopreventive agent is derived from the observation of a significant reduction in the incidence of primary tumors in the contralateral breast in women treated with adjuvant tamoxifen.88,89,93,94

The National Surgical Adjuvant Breast and Bowel Project (NSABP) and other European studies showed a reduction between 40 and 50 percent in the incidence of primary tumors in the contralateral breast among women taking tamox-ifen as adjuvant therapy.88,91,92 Among the European trials, the Stockholm trial, designed to evaluate the efficacy and toxicity of adjuvant tamoxifen (40 mg daily) for 2 years in post-menopausal patients (23 percent older than 50 years) with unilateral breast cancer, deserves par ticular mention.90 This trial demonstrated a significant decrease in the incidence of contralateral breast cancer but also a six-fold increase in the incidence of endometrial cancer and an unexpected excess of gastrointestinal malignancies.

Of particular interest is the overview analysis of the major randomized trials of adjuvant tamoxifen among nearly 30,000 women with early breast cancer.95 A recent update of this analysis demonstrated a reduction in the incidence of contralateral breast cancer incidence of 47 percent with 5 years of treatment. The proportional reduction in contralateral breast cancer appeared to be unrelated to the estrogen receptor (ER) status of the original tumor. The treatment appeared to be associated with a significant increase in the incidence of endometrial cancer and a slight, not significant increase in colorec-tal cancer (larger with only 1 year of tamoxifen).

In 1986, a pilot study was started in the United Kingdom to test the feasibility and tox-icity associated with long-term tamoxifen treatment in women at high risk of breast cancer.93 Between October 1986 and June 1993, a total of 2,012 women were accrued and randomly assigned to tamoxifen (20 mg/day) or placebo for up to 8 years. A total of 265 women were on HRT at entry and 131 were randomized to tamoxifen treatment. With a median follow-up of 36 months and with a compliance of 77 percent of the women assigned to the treatment arm, no obvious effect on bone mineral density was observed and only marginal effects on clotting factors. Tamoxifen was associated with a significant reduction in the serum cholesterol level. More importantly, there was an increased incidence of uterine fibromata and benign ovarian cysts; however, no increase in endometrial cancer incidence was reported.

On the basis of these encouraging data, in 1992, a large, multicenter, randomized, doubleblind trial funded by the National Cancer Institute (NCI) was begun to test whether tamoxifen could prevent breast cancer in high-risk women.94 The population at risk was defined, taking into account the following risk factors, as indicated by the Gail model: age, age at menarche and at first live birth, number of first-degree relatives affected, and, finally, the number of previous breast biopsies and the presence or absence of atypical hyperplasia.

The Breast Cancer Prevention Trial (BCPT-P1) enrolled 13,388 women older than 35 years between April 1992 and September 1997. The research, coordinated by the NSABP, involved more than 300 centers across the United States and Canada. The study was closed and preliminary results released 14 months earlier than planned.94 In the median average follow-up time of 54.6 months, 89 cases of invasive breast cancer occurred in the group of women assigned to tamoxifen treatment (6,681 women) compared with 175 cases in the group assigned to placebo (6,707 women), corresponding to a 49 percent risk reduction. There was also a 50 percent reduction in the incidence of noninvasive breast cancer. Tamoxifen reduced the occurrence of ER-positive tumors by 69 percent, but no efficacy was seen in the prevention of ER-negative tumors. The risk reduction was not age dependent; the risk reduction in women aged 49 years or younger was 44 percent, and it was 55 percent in women older than 60 years. The NCI and the Endpoint Review, Safety Monitoring, and Advisory Committee agreed that the participants and their physicians should be told which treatment has been assigned because of the clear evidence that tamoxifen reduced breast cancer risk.

The Breast Cancer Prevention Trial was also designed to evaluate the possible benefit of tamoxifen in reducing cardiac events and osteoporosis-related complications. There was no difference between the tamoxifen group and the placebo group in the number of heart attacks, whereas there was a 19 percent reduction in the incidence of fractures of the hip, wrist, and spine (111 cases in the tamoxifen group versus 137 cases in the placebo group). Treatment with tamoxifen was associated with an increased incidence of endometrial cancer (33 cases versus 14 cases in the placebo group), in particular in women aged 50 years or older. A

slight increase in the incidence of deep vein thrombosis and pulmonary embolism in the tamoxifen group was also reported; all these events were more frequently observed in women older than 50 years of age. Because of these reported complications, the decision about whether to use tamoxifen as a chemopre-ventive agent must be carefully weighed for every patient on the basis of an accurate evaluation of the patient's age group, personal breast cancer risks, and comorbid conditions.

Similar trials of tamoxifen for chemopreven-tion have been conducted in Italy and the United Kingdom.96 The Italian study has completed accrual of 5,408 women who have had hysterectomy and have no factors associated with increased risk of breast cancer. Preliminary analysis at a median follow-up of 46 months did not show any difference in breast cancer incidence in the tamoxifen group compared with the placebo-control group.96 Differences in the study populations, age distributions, history of HRT, and family history may account for the inability of studies to confirm the effectiveness of tamoxifen for chemoprevention.

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