PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node–positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE2). FAC (500, 50, and 500 mg/m2, respectively) was administered intravenously once every 4 weeks for four cycles. EE2 (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence–free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

#1154 Background Aromatase inhibitors (AIs) given to women with early breast cancer may adversely affect bone metabolism. We studied the effect of exemestane (E) on bone mineral density (BMD) and bone turnover and compared it to the effect of tamoxifen (T) treatment in a group of women participating in the Dutch and Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. In this trial, postmenopausal women with hormone sensitive early breast cancer (n=3168) were randomised between 5 years E or 2½-3 years T followed by 2½-2 years of E.
 Methods In this subprotocol, 87 women were followed for two years. Patients with bone diseases were excluded. Total hip and lumbar spine BMD were assessed at baseline and after 1 and 2 years. The bone resorption marker cross-linked telopeptide of type-I collagen (CTX) and the bone formation marker N-terminal propeptide of type I collagen (PINP) were measured in fasting serum at baseline and after 3, 6, 12 and 24 months.
 Results At baseline, there was no difference in total hip (E: 0.85g/cm2, T: 0.80g/cm2; p=0.642) and lumbar spine BMD (E: 0.99g/cm2, T: 1.02g/cm2; p=0.545) between both groups. After 2 years, there were no significant changes in total hip BMD (E: 0.02 g/cm2 95%CI -0.05;0.08, p=0.849; T: 0.03 g/cm2, 95%CI -0.02;0.09, p=0.466) and in spine BMD (E: -0.02 g/cm2 95%CI -0.11;0.06, p=0.834; T: 0.02 g/cm2 95%CI -0.05;0.10, p=0.747). At baseline, there was no difference in serum CTX (E: 0.34ng/mL, T: 0.29ng/mL; p=0.271) and P1NP (E: 57ng/L, T:58ng/L, p=0.973) between both groups. After 2 years of treatment, serum CTX increased, although not significantly in the E group (20%, 95%CI -6%;54%, p=0.223) while it decreased significantly in the T group (-40%, 95%CI -23%;-53%, p<0.001). At 24 months, the CTX was 0. 44ng/mL (E) and 0. 18ng/mL (T). Serum P1NP did not change in the E group (-2%, 95%CI -20%;19%, p=0.837) but decreased significantly in the T group (-48%, 95%CI -36%;-58%, p<0.001). At 24 months, the P1NP was 55ng/L (E) and 28ng (T).
 Conclusion Although there was a trend for an increase in bone resorption with E treatment, this was not significant and was not associated with a decrease in BMD. The magnitude of the reported negative effect of aromatase inhibitors on bone metabolism in studies using T as comparator treatment may be overestimated by the effect of T on bone turnover. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1154.

Background: First-line treatment of HER2−negative LR/MBC with paclitaxel (T) and bevacizumab (A) has demonstrated improved progression-free survival (PFS) and overall response rate (ORR) when compared with T alone (E2100). We determined whether addition of capecitabine (X) to AT is safe and would be better effective than AT in women with HER2−negative LR/MBC. Methods: Eligibility criteria were age ≥18 & ≤75 years, measurable or non-measurable HER2−negative LR/MBC, ECOG PS 0–1 and no prior chemotherapy for LR/MBC. Patients were randomized in 1:1 ratio to receive AT (4-week cycle of T 90 mg/m2 on days 1, 8, 15 and A 10 mg/kg on days 1, 15 for 6 cycles, followed by A 15 mg/kg on day 1 given 3-weekly for subsequent cycles) or ATX (3-week cycle of T 90 mg/m2 on days 1, 8, A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 for 8 cycles, followed by A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 given 3-weekly for subsequent cycles). Treatment was discontinued at disease progression, unmanageable toxicity or withdrawal of consent. The primary endpoint was PFS. Secondary endpoints were overall survival, ORR, duration of response and toxicity. Efficacy was evaluated according to RECIST 1.0 and toxicity was assessed according to NCI CTCAE 3.0. Results: From June 2007 till December 2010, 312 patients were recruited at 36 sites. The median age was 56 years (range 32–76). Among all patients, 52% had ECOG 0, 85% were hormone-receptor positive, 86% had measurable disease and 8% had bone-only metastases. These factors were well balanced between both arms. A total of 48% and 33% of patients, respectively, received prior hormonal therapy or radiotherapy for LR/MBC. At the data cut-off of 1st June 2011, the median follow-up duration was 23 months. 311 patients received at least one cycle of treatment and were evaluable for safety. The median number of treatment cycles in AT was 9 and in ATX was 11 (both 33 weeks). An ORR of ≥40% was reached in patients with measurable disease in both groups. The incidence of serious adverse events (SAEs) was 47% and 40% for AT and ATX, respectively, while that of treatment-related SAEs was 12% and 19%, respectively. Treatment-related deaths were 2% for AT and 2% for ATX. The overall rate of AEs grade 3 or 4 was similar in both arms as shown in Table 1, except for hand-foot syndrome grade 3 and neutropenia grade 3 in ATX. In addition, 6 patients with pulmonary embolism were reported in ATX. Conclusions: ATX was well tolerable, although more patients experienced hand-foot syndrome grade 3 and thromboembolic events than patients treated with AT. The efficacy data will be presented at the meeting. Support: This study was supported by Roche. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-07.