Low-dose, short-course sunitinib may normalize tumor vasculature and improve tumor blood flow to enhance chemotherapy efficacy in breast cancers.

Abstract

1064 Background: Small molecule VEGFR inhibitors (VEGFR-I) have failed to improve outcome with chemotherapy in most solid tumors. Continuous administration of a potent VEGFR-I may destroy vasculature and impede drug delivery; in contrast, low-dose, short-course VEGFR-I before chemotherapy may normalize tumor vasculature and enhance drug delivery. Methods: We conducted a phase Ib followed by phase II randomized study in patients with measurable primary breast tumors using low-dose sunitinib (Su) for 1 week prior to doxorubicin/cyclophosphamide (AC) and measured tumor blood flow with DCE-MRI and microvessel density and pericyte recoverage with CD31 and α-smooth muscle actin (SMA) staining on tumor biopsies, at baseline, after 1 week of Su, and 2 weeks after cycle 1 AC. Patients in phase Ib received 12.5-25mg Su prior to AC; in phase II, patients were randomized to AC+/-12.5mg Su. Results: 21 patients have been enrolled, including 3 patients on 25mg Su+AC, 11 on 12.5mg Su+AC, and 7 on AC alone. After 1 week of 25mg Su, 2/3 patients had reduced tumor blood flow on DCE-MRI indicating anti-angiogenic effects. After 1 week of 12.5mg Su, significant increase in tumor fractional plasma volume (Vp) occurred (+28%±28%, p=0.025) suggesting increased perfusion, followed by decrease 2 weeks after AC (-33%±26%,p=0.035) corresponding to mean tumor size change of -17±15%, while no significant Vp changes occurred with AC alone (p=0.823); CD31 expression reduced (20.7 vs 15.7, p=0.173) while SMA/CD31 double staining increased (2.45 vs 7.34, p=0.046) indicating lower microvessel density and normalization of residual vasculature, which was not seen with AC alone (CD31, p=0.434; CD31/SMA, p=0.605). The main toxicity of Su+AC and AC alone was febrile neutropenia (29% vs 43%). 14 patients had surgery with pathological complete response in 1/6 patients who received 12.5mg Su+AC. Conclusions: 25mg Su for 1 week can reduce tumor blood flow, suggesting that concomitant standard dose Su may compromise drug delivery. Low dose 12.5mg Su for 1 week is sufficient to normalize tumor vasculature and increase tumor fractional plasma volume, and may potentially improve drug delivery and treatment outcome.