Abstract
HER2-amplified (HER2 + ) breast cancers are treated with the anti-HER2 monoclonal antibody trastuzumab. Although trastuzumab reduces production of the angiogenic factor VEGF in HER2 + tumors, the acute and sustained effects of trastuzumab on the tumor vasculature are not understood fully, particularly in trastuzumab-resistant tumors. We used mouse models of trastuzumab sensitive and trastuzumab-resistant HER2 + breast cancers to measure dynamic changes in tumor microvessel density and hemoglobin oxygenation (sO2) in vivo using quantitative hyperspectral imaging at 2, 5, 9, and 14 days after antibody treatment. Further analysis quantified the distribution of microvessels into low and high oxygenation groups, and monitored changes in these distributions with trastuzumab treatment. Gold standard immunohistochemistry was performed to validate complementary markers of tumor cell and vascular response to treatment. Trastuzumab treatment in both responsive and resistant tumors resulted in decreased sO2 5 days after initial treatment when compared to IgG-treated controls (p<0.05). Importantly, responsive tumors showed significantly higher vessel density and significantly lower sO2 than all other groups at 5 days post-treatment (p<0.05). Distribution analysis of vessel sO2 showed a significant (p<0.05) shift of highly oxygenated vessels towards lower oxygenation over the time-course in both trastuzumab-treated responsive and resistant tumors. This study suggests that longitudinal hyperspectral imaging of microvessel sO2 and density could distinguish trastuzumab-responsive from trastuzumab-resistant tumors, a finding that could be exploited in the post-neoadjuvant setting to guide post-surgical treatment decisions.
Highlights
In 2013, more than 200,000 new cases of breast cancer were diagnosed, with breast cancers accounting for more than 40,000 deaths in the United States [1]
Immunohistochemistry in BT474 tumors (Figs. 2(a) and 2(c)) showed that trastuzumab treatment reduced vascular endothelial growth factor (VEGF) expression compared to control IgG on days 2 and 5 post-treatment, in agreement with previous studies [11,12]. These previous studies showed increased CD31 + vessel density in trastuzumab treated BT474 tumors at 14 days post-treatment [12], consistent with our results showing increased CD31 + vessel density in trastuzumab-treated BT474 tumors at day 2, but we do not see any significance by day 14
VEGF expression was decreased in trastuzumab-treated BT474 tumors on day 2
Summary
In 2013, more than 200,000 new cases of breast cancer were diagnosed, with breast cancers accounting for more than 40,000 deaths in the United States [1]. The HER2 gene is amplified in approximately 20% of breast cancers. Trastuzumab, a humanized monoclonal antibody specific to HER2, improves survival in patients with HER2-amplified breast cancers [4,5]. Several mechanisms of action contribute to the clinical success of trastuzumab, one mechanism involves trastuzumab-mediated inhibition of HER2 signaling pathways that control tumor cell proliferation and survival. Because HER2 signaling induces expression of the angiogenic factor vascular endothelial growth factor (VEGF), HER2 inhibition dampens VEGF production, normalizing tumor vasculature [6]. Normalized vasculature improves drug, oxygen, and nutrient delivery in tumors [7], thereby improving tumor response to chemotherapy and radiation therapy [8]. HER2 inhibition has the dual effect of inhibiting tumor cell growth and normalizing tumor vasculature for improved treatment response. The effect of trastuzumab resistance on tumor vasculature remains poorly understood
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