Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer.

PURPOSE: To determine biologic differences, if any, between presurgical endocrine treatment with an aromatase inhibitor (vorozole) and tamoxifen in patients with postmenopausal primary breast cancer. PATIENTS AND METHODS: Randomization was to 12 weeks of 2.5 mg of vorozole per day or 20 mg of tamoxifen per day, both orally. Clinical response was assessed monthly together with serum sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens (E1, E2, and E1S), lipids, insulin-like growth factor-1 (IGF-1), and bone metabolites (CrossLaps CTx). Tissue samples for Ki67, apoptotic index (AI), estrogen receptor, and progesterone receptor were collected at 0, 2, and 12 weeks. RESULTS: Ki67 fell by 58% and 43% (means) at 2 weeks in the vorozole and tamoxifen patients, respectively (P =.13). In the vorozole group, the correlations of proportional changes in Ki67 at 2 weeks with tumor volume changes and clinical response at 12 weeks were not significant (P =.09) and marginally significant (P =.04), respectively. Serum lipids did not differ between groups. Serum levels of EI, E2, and E1S were suppressed markedly by vorozole, whereas levels of SHBG increased and LH and FSH fell significantly with tamoxifen. IGF-1 levels fell significantly with tamoxifen (P =.001) compared with the nonsignificant rise with vorozole. Twelve-week CTx values fell by 19% with tamoxifen (P =.006) and rose by 11% with vorozole (P =.15). CONCLUSION: The correlation with vorozole of Ki67 with volume and clinical response supports this as an intermediate marker. The nonsignificant effects on bone and lipid metabolism by the aromatase inhibitor may be important to consider for adjuvant and potential prevention strategies.

Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer.

PURPOSE: Cyclooxygenase (COX)-2 is overexpressed in breast cancer and may have a role in regulating tumor growth via effects on angiogenesis, cell proliferation, or apoptosis. This study aimed to derive data from human breast carcinomas to help substantiate or refute these relationships. EXPERIMENTAL DESIGN: We performed immunohistochemical analysis of a set of 86 breast tumors for COX-2, estrogen receptor (ER), progesterone receptor (PGR), HER-2, Ki67 (a marker of proliferation), and CD31 (an endothelial cell marker of angiogenesis). RESULTS: COX-2 protein expression was detected in 79% of all tumors studied, ER was detected in 79% of all tumors studied, PGR was detected in 73% of all tumors studied, and HER-2 was detected in 16% of all tumors studied. COX-2 protein expression did not significantly correlate with tumor size, grade, axillary lymph node status, or the presence of vascular invasion. A significant negative correlation (P < 0.001) was observed between ER and Ki67. COX-2 expression showed a significant linear correlation with CD31 staining (P < 0.001). No significant correlations were observed between COX-2 and ER, PGR, or HER-2. CONCLUSIONS: This study demonstrates a novel relationship between COX-2 expression and the neovasculature of human breast adenocarcinomas. If this is a functional relationship, it provides support for a potential therapeutic role of COX-2 inhibitors in human breast cancer tissue via their antiangiogenic properties.

Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention.

The aromatase enzyme converts androgens to estrogens and is the therapeutic target for aromatase inhibitors in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Third-generation inhibitors such as letrozole are being considered as potential prophylactic agents for breast cancer. The rationale for their preventive application would be aided by knowledge of their effects on the normal breast and on other estrogen-dependent processes such as bone and lipid metabolism. Thirty-two women without active breast disease were recruited to 3-month treatment with letrozole (2.5 mg/day). Core-cut biopsies from the breast and blood samples were collected before and at the end of treatment. Plasma estradiol levels were markedly suppressed in all but two patients, who were excluded from the efficacy assessment. There was no significant change in the proliferation marker Ki67 (mean change, -23%; 95% confidence interval, -50% to +23%) or estrogen receptor in breast epithelial cells with treatment. Similarly, there were no significant changes in plasma levels of insulin-like growth factor I or lipid profiles. However, there was a significant increase (25%) in the levels of the bone resorption marker C-telopeptide crosslinks (CTx). We conclude that any prophylactic effect of letrozole is not likely to be dependent on antiproliferative effects on normal breast. Studies in healthy patients will need to recognize the potential for enhanced bone resorption.