March 11, 2008 — Higher levels of serum estrogen contribute to the risk for disease recurrence in women previously treated for early-stage breast cancer, researchers report. According to the study results, which appear in the March issue of Cancer Epidemiology, Biomarkers and Prevention, patients with cancer recurrence had double the total estradiol levels of women who remained disease-free.

Although estrogenic stimulation seems to have a causal role in the pathogenesis of breast cancer, the relationship between estrogen and breast carcinogenesis is complex, write the researchers. A number of studies have linked higher levels of estrogens and androgens and a lower level of sex hormone–binding globulin (SHBG) with an increased risk for primary breast cancer in postmenopausal women.

Considering the growing body of data that supports an association between estrogen levels and an increased risk for breast cancer in postmenopausal women, the study results were not surprising, according to lead author Cheryl L. Rock, PhD, a professor in the Department of Family and Preventive Medicine at the University of California-San Diego, La Jolla. "This is just another link that needed to be established," she said.

Reducing estrogen stimulation has become a standard strategy in managing breast cancer, and antiestrogen therapy has developed into one of the most effective treatments for women with endocrine-responsive breast cancers. However, only a few studies have examined the relationship between breast cancer recurrence and circulating estrogen concentrations.

Dr. Rock and colleagues evaluated whether circulating concentrations of total, bioavailable, and free estradiol, and total, bioavailable, and free testosterone and SHBG were associated with a higher risk for breast cancer recurrence. The study was conducted in a nested case-control cohort of 306 women (153 case-control pairs) who participated in the Women's Healthy Eating and Living Study (WHEL).

The WHEL Study was a randomized dietary intervention trial that examined disease-free survival in a cohort of women previously diagnosed with early-stage breast cancer. Participants were recruited between 1995 and 2000, randomized for up to 4 years after diagnosis, and then followed up for an average of 7.3 years. The results of the trial were reported in the July 18, 2007, issue of the Journal of the American Medical Association and did not find that the WHEL Study diet intervention, which was high in vegetables, fruit, and fiber and low in fat, had an overall effect on recurrence or survival.

In the nested case-control design, the mean interval between diagnosis and recurrence was 5.6 years among the 153 cases. In each group, approximately 93% of the women were postmenopausal. The time between diagnosis and entry into the study was approximately 23.1 months for the patients, and 24.6 months among the control group.

The researchers found that, on average, women with breast cancer recurrence had an average total estradiol concentration that was double the average vs those who had no recurrence (22.7 vs 10.8pg/mL). The serum concentrations of total estradiol, bioavailable estradiol, and free estradiol were each associated with a risk for recurrence, and the risk increased by 41% per unit increase in log estradiol.

The levels of SHBG were not significantly higher, and total, bioavailable, and free testosterone concentrations were not significantly lower among the control group. A relationship between serum testosterone concentrations and the risk for recurrence was not observed, contrary to expectations. SHBG concentrations were also not independently associated with recurrence.

Chemotherapy and the use of tamoxifen were similar in both groups of women, thus suggesting that the effects of treatment were unlikely to bias the analysis. "This specific study was not designed to ask questions about the effect of tamoxifen, but it is well established that tamoxifen can affect the hormonal picture and risk for recurrence," Dr. Rock told Medscape Oncology. "So it was notable that the cases and recurrences had a similar percentage of tamoxifen users."

The researchers included intake of dietary fiber in the analysis because an inverse association between dietary fiber intake and serum estradiol concentration was previously observed in a subset of WHEL Study participants. The inverse association between fiber intake and serum estrogen concentrations has also been observed in other reports. However, in the current study, there seemed to be no difference in dietary fiber intake between patients and controls.

"There are numerous factors that may affect estrogen levels, including genetic polymorphisms," said Dr. Rock. "The women entered the WHEL study eating an average of over 7 servings of vegetables and fruit each day, so perhaps for the overall group, the effect of a further increase was not observed. Again, it was notable in this study that the cases and controls had similar fiber intakes, as otherwise, it could have explained differences in outcome and confused the interpretation."

Genetic and metabolic factors most likely modulate the relationship between circulating sex hormones and cancer risk, note the researchers, but the results from this study provide evidence that higher serum estrogen concentrations contributed to the risk for recurrence among women in this population.

"The appropriate take-home message is that lifestyle behaviors that may help to lower circulating estrogens, such as moderate to vigorous exercise and achieving and maintaining a healthy weight, should be encouraged, in addition to the use of antiestrogenic medications when they are appropriate and tolerated by the patient," said Dr. Rock.

The WHEL Study was initiated with the support of the Walton Family Foundation and continued with funding from a National Cancer Institute grant.

Cancer Epidemiol Biomarkers Prev. 2008;17:OF1-OF7.

Clinical Context

Study Highlights

• Included were women aged 18 to 70 years with a diagnosis of primary operable breast cancer stage I, II, IIIA, or IIIC by American Joint Committee on Cancer criteria within 4 years, who had been treated with axillary dissection and total mastectomy or lumpectomy followed by irradiation but not chemotherapy, with no other invasive cancer within 10 years.
• Patients were recruited from 7 clinical sites, and medical records were reviewed to confirm diagnosis.
• Clinic visits occurred at baseline, and specified intervals and blood samples were drawn.
• Women were randomized to the dietary intervention up to 4 years after initial diagnosis of breast cancer and were followed up for an average of 7.3 years.
• For this study, each woman with a recurrence was matched with another woman in the cohort who was cancer-free.
• Matching criteria were clinical site, cancer stage, age at diagnosis, and date of randomization.
• Most matches were within 12 months of each other.
• There were 153 patients and 153 controls.
• Women without baseline hormone concentrations were excluded from analysis.
• Covariates were dietary fiber intake by 24-hour recall, physical activity level, and the presence or absence of hot flashes, all of which had potential associations with estradiol and testosterone levels.
• Baseline blood samples measured estradiol (total, free, and bioavailable), testosterone, and SHBG levels with use of column chromatography.
• Mean age of participants was 55 years, 68.0% to 73.2% used tamoxifen at baseline, 83.7% to 88.9% were white, mean body mass index was 27.8 kg/m², two thirds had hot flashes at baseline, and 13.1% to 15.7% had a history of bilateral oophorectomy.
• 93.5% of patients and 92.8% of controls were postmenopausal.
• Mean interval between diagnosis and recurrence was 5.6 years in 153 cases (range, 1.6 - 12.0 years).
• Serum concentrations of total estradiol (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.01 - 1.97; P = .04), bioavailable estradiol (HR, 1.26; 95% CI, 1.03 - 1.53; P = .02), and free estradiol (HR, 1.31; 95% CI, 1.03 - 1.65; P = .03) were each significantly associated with the risk for recurrence.
• The risk for recurrence increased 41% per unit increase in log estradiol.
• Women with recurrence had an average estradiol concentration double that of women with no recurrence (22.7 vs 10.8 pg/mL; P = .05).
• SHBG and testosterone levels at baseline and ratio of testosterone to estradiol with use of total, bioavailable, or free estradiol levels were not associated with the risk for recurrence.
• Adjustment for menopausal status, hot flashes, ethnicity, fiber intake, and time between diagnosis and entry into study did not substantially change the association of recurrence with estradiol.
• The authors concluded that baseline estradiol, but not testosterone or SHBG, levels contributed to the risk for recurrence of breast cancer

Pearls for Practice

• Higher baseline estradiol levels at the time of initial diagnosis of early-stage breast cancer are associated with a higher risk for recurrence of breast cancer.
• Baseline SHBG and testosterone levels are not associated with a subsequent risk for recurrence of breast cancer.

CME Test