Comparative Genomic and Protein Signatures and Intratumoral Treatment Responses in Patients with Metastatic Breast Cancer (MBC) Treated with Paclitaxel (PTX) and 2-Methoxyestradiol (2ME2)

e22049 Background: Tumors respond to both chemotherapy and radiation through a number of poorly understood survival mechanisms. These potential mechanisms include upregulation of anti-apoptotic and pro-angiogenic pathways, including those regulated by HIF-1α. Sequential MBC biopsies were used to examine 1) the effects of PTX on intratumoral HIF-1α mediated pathways; and 2) the ability of a HIF-1α inhibitor (2ME2) to modulate the tumor's HIF- 1α response to PTX. Methods: Key eligibility included pts with MBC, ECOG 0–2, unlimited prior therapies, and biopsiable tumors. Pts were treated on a 28-day schedule with weekly PTX (90 mg/m2 D1, D8, D15) and daily oral 2ME2 (1000, 1250,1500 or 2000 mg qid starting D8) and had 3 tumor biopsies: baseline (A); D8 post-PTX/pre-2ME2 (B); D22 post-PTX/post- 2ME2 (C). Serial biopsies were compared for genomic and single protein changes. Results: 20 pts (median age 52 yrs [31- 75]) were treated. 60% had ≥2 prior regimens for MBC, 35% had ≥3. No unexpected grade 3/4 toxicities were seen: neutropenia (n=6), anemia (2), hypophosphatemia (2), PE (1). The clinical benefit rate was 25% (4 PR, 1 SD). There were 13 pairs of tumor biopsies to compare points A/B and 10 to compare B/C. There were no consistent gene expression changes between A and B. Significant differences at C vs. B included changes in hypoxia-responsive genes (including CA9, HIF-2α) and upregulation of pro- angiogenic factors and hemoglobin transcripts. For the B/C comparison, 2 distinct groups emerged: the first (biopsy site liver) showed downregulation of gene expression programs driven by ER and the second (lymph node, breast) showed upregulation of endothelial cell- related genes. Conclusions: Combination therapy with PTX and 2ME2 is a well-tolerated and viable option for delaying disease progression for patients with heavily pretreated MBC. Significant gene expression changes before and after exposure to 2ME2 may reflect changes in tumor microcirculation consistent with the idea of vascular normalization. The potential significance of the differences in gene expression observed in the 2 distinct groups remains to be investigated. Supported by Komen Grant BCTR0504044 (MWD). [Table: see text]