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Introduction: Overexpression of vascular endothelial growth factor (VEGF) in breast cancer tumors has been associated with resistance to anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods: Patients were treated with a neoadjuvant regimen of letrozole, 2.5 mg/day (PO) and bevacizumab 15 mg/kg every 3 weeks (IV) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at three week intervals and tumor assessment (physical exam and tumor ultrasound) at six week intervals. Results: Twenty-five evaluable patients were treated. The regimen was well tolerated except for two patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The four patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. Two of the 17 responding patients were lost to follow-up; with a median follow-up of 50 months, no relapses have been seen in the 15 responsive patients, including 10 patients who received no adjuvant chemotherapy. Two patients with progressive disease at 9 and 16 weeks received neoadjuvant chemotherapy, surgery and radiation. One of these patients relapsed at 35 months and the other is NED at 44 months. Four patients had stable disease and all received adjuvant chemotherapy; one patient relapsed at 25 months, and the reminder are NED at 44-52 months. Overall, 2 out of 21 patients with adequate follow-up had disease reoccurrence (9.5%) at a median follow-up of 45 months. Conclusion: Combination neoadjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. Data suggest that patients having an objective response to neoadjuvant therapy had excellent 4 year disease-free survival (100%) while relapsed occurred in 2 out of 6 patients who failed to have an objective response despite additional neoadjuvant or adjuvant chemotherapy. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of letrozole ± bevacizumab in this patient population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-04.

Characterization of breast cancer cells by histology, flow cytometry, and steroid receptors was performed on 197 Stage I1 breast node positive cancer patients given adjuvant chemotherapy, plus tamoxifen for patients with positive hormone receptors. Histologic and steroid receptor assays were performed using standard techniques; flow cytometric analysis was performed from paraffin-embedded blocks obtained from the primary tumor. Quality control studies on reproducibility, tissue heterogeneity, and analysis procedures have been included. Of the 197 patients studied, aneuploidy was found in 102 (52%); the median %S value was 8% with a range of 0.4% to 38%. Our results demonstrated that number of positive nodes, receptor status, and grade were of prognostic value. Cell cycle kinetic data were not of independent prognostic value in this series. However, ploidy could differentiate in prognosis in the receptor-negative subgroup. Patients with receptor-negative tumors had a significantly better overall survival if the tumor was diploid in nature. Cell kinetics was not significantly prognostic for either receptor subgroup, although patients with higher %S tended to have better relapse-free and overall survival. This is in disagreement with other studies and may demonstrate that treatment has confounded our results and diminished the ability of flow cytometry data to help predict outcome. Cancer 66:1810-1816,1990. INCE ITS DEVELOPMENT, there has been great interest S in using flow cytometry to predict the clinical course of patients with breast cancer.'-3 Several groups have compared ploidy and cell kinetic measurements to other clinical parameters including age, menopausal status, receptor content, tumor size, histologic type and grade, and nodal status. There is general consensus that aneuploid

Purpose Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods Patients were treated with a neo-adjuvant regimen of letrozole, 2.5mg/day (P.O.) and bevacizumab 15mg/kg Q3 weeks (I.V.) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at 3 week intervals and tumor assessment (physical exam and tumor ultrasound) at 6 week intervals. PET scans were carried out prior to therapy and 6 weeks after initiation of therapy. Surgery was done 4 weeks after the last dose of bevacizumab. Results Twenty five evaluable patients were treated. The regimen was well tolerated except for 2 patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The 4 patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. 8/25 patients (32%) attained stage 0 or 1 status. PET scan response at 6 weeks correlated with clinical CR and breast pathologic CR at 24 weeks (p < 0.0036). Conclusion Combination neo-adjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1088.

625 Background: Preclinical studies suggest that up-regulation of tumor cell VEGF is a mechanism to subvert estrogen dependence in hormone responsive breast cancer resulting in reduced efficacy or acquired resistance; we hypothesized that the combination of bevacizumab (an anti-VEGF MoAb) and hormone therapy would be more effective than hormone therapy alone for the treatment of breast cancer. Methods: Postmenopausal, ER and/or PR positive and Her-2-neu negative, operable (T2–4a-c/N 0–2/M0) breast cancer patients were enrolled. Patients received letrozole (2.5 mg po daily) and bevacizumab (15 mg/kg IV q 3 wks). Patients were evaluated every 6 wks; patients with CR/PR/SD in the first evaluation continued; after an additional 6 weeks of therapy patients with PD or SD were taken off-study and those patients with PR/CR completed 24 weeks of therapy. Definitive surgery was performed no sooner than 4 wks after the last dose of bevacizumab. Patients continued letrozole while waiting for surgery. 26 patients were...

Characterization of breast cancer cells by histology, flow cytometry, and steroid receptors was performed on 197 Stage II breast node positive cancer patients given adjuvant chemotherapy, plus tamoxifen for patients with positive hormone receptors. Histologic and steroid receptor assays were performed using standard techniques; flow cytometric analysis was performed from paraffin-embedded blocks obtained from the primary tumor. Quality control studies on reproducibility, tissue heterogeneity, and analysis procedures have been included. Of the 197 patients studied, aneuploidy was found in 102 (52%); the median %S value was 8% with a range of 0.4% to 38%. Our results demonstrated that number of positive nodes, receptor status, and grade were of prognostic value. Cell cycle kinetic data were not of independent prognostic value in this series. However, ploidy could differentiate in prognosis in the receptor-negative subgroup. Patients with receptor-negative tumors had a significantly better overall survival if the tumor was diploid in nature. Cell kinetics was not significantly prognostic for either receptor subgroup, although patients with higher %S tended to have better relapse-free and overall survival. This is in disagreement with other studies and may demonstrate that treatment has confounded our results and diminished the ability of flow cytometry data to help predict outcome.

11020 Background: Our preclinical studies suggest that up-regulation of tumor cell VEGF is a mechanism to subvert estrogen dependence in hormone responsive breast cancer resulting in reduced efficacy or acquired resistance; we hypothesized that the combination of Bevacizumab (an anti-VEGF MoAb) and hormonal therapy would be more effective than hormonal therapy alone for breast cancer. Methods: Post-menopausal patients with ER and/or PR positive and Her-2-neu negative operable (T2–4a-c/N 0–2/M0) breast cancer were enrolled. Patients received letrozole (2.5 mg po daily) and Bevacizumab (15 mg/kg IV q 3 wks). Patients were reevaluated every 6 wks for a total of 24 wks; patients with CR/PR/SD in the first evaluation continued in the trial; after an additional 6 weeks of therapy patients with PD or SD were taken off-study and only patients with PR/CR completed 24 weeks of therapy. Definitive surgery was performed at the discretion of the surgeon no sooner than 4 wks after the last dose of bevacizumab. Patients continued letrozole while waiting for surgery. Up to December 2006, 27 patients have been enrolled with 13 patients too early to evaluate. Results: The 14 patients off-study had a median age of 63 years (range; 56 to 79) and an ECOG score of 0 for all patients. None of the patients received therapy for breast cancer before enrollment in the trial. 11 patients were stage II and 3 patients stage III. No treatment-related severe adverse events were seen. Treatment related toxicities were: grade 3 hypertension (n=1), grade 2 hypertension (n=7), grade 2 fatigue (n=2), grade 2 joint pain (n=3), grade 2 hot flashes (n=2), grade 1 proteinuria (n=1); 2 patients were taken off-study because of uncontrolled hypertension occurring on initial infusion of bevacizumab (not evaluable for efficacy). Of the 12 patients evaluable for response, 2 patients had pCR, 8 PR and 2 PD (at 9 weeks and 16 weeks). There have been no problems with wound healing or bleeding related to surgery or progressive disease while awaiting surgery. Conclusions: Combination letrozole and bevacizumab has substantial clinical efficacy and is well tolerated. The combination therapy will be evaluated in a randomized Breast Cancer Research Consortium Trial. [Table: see text]

The purpose of this technical report is to determine the reproducibility of flow cytometry data for ploidy and cell cycle kinetics using paraffin-embedded blocks of breast cancer tissue. One block from each of 39 tumors was studied in this report with each block having multiple sections analyzed independently. All of these sections gave ploidy analyses, while only 34 gave cell kinetic values. The standard deviation for the DNA index value in the multiple analysis study was less than 0.1 in all but three cases. The cell kinetic values gave larger variability, and the actual values were dependent on the method of analysis. Comparison of the variability for each method of analysis could not predict which procedure was superior. These results would indicate that ploidy is a reproducible value, while cell kinetic parameters should only be used as an indicator of proliferative activity that has been normalized to the mean or median of a large set of observations processed and analyzed by the same procedure.