Baseline Tumor Oxygen Saturation Correlates with a Pathologic Complete Response in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Abstract

Tissue hemoglobin oxygen saturation (i.e. oxygenation) is a functional imaging endpoint that can reveal variations in tissue hypoxia which may be predictive of pathological response in subjects undergoing Neoadjuvant Chemotherapy (NCT). In this study we used Diffuse Optical Spectroscopic Imaging (DOSI) to measure concentrations of oxyhemoglobin (ctO2Hb), deoxy-hemoglobin (ctHHb), total Hb (ctTHb = ctO2Hb + ctHHb) and oxygen saturation (stO2=ctO2Hb/ctTHb) in tumor and contralateral normal tissue from forty-one patients with locally advanced primary breast cancer. Measurements were acquired prior to the start of neoadjuvant chemotherapy. Optically derived parameters were analyzed separately and in combination with clinical biomarkers to evaluate correlations with pathologic response. Discriminant analysis was performed to determine the ability of optical and clinical biomarkers to classify subjects into response groups. Twelve (28.6%) of 42 tumors achieved pCR and 30 (71.4%) were non-pCR. Tumor measurements in pCR subjects had higher stO2 levels (median 77.8%) than those in non-pCR individuals (median 72.3%, p = 0.01). There were no significant differences in baseline ctO2Hb, ctHHb, and ctTHb between response groups. An optimal tumor oxygenation threshold of stO2 = 76.7% was determined for pCR vs. non-pCR (sensitivity = 75.0%, specificity = 73.3%). Multivariate discriminant analysis combining estrogen receptor (ER) staining and stO2 further improved the classification of pCR vs. non-pCR (sensitivity = 100% specificity = 85.7%). These results demonstrate that elevated baseline tumor stO2 are correlated with a pathologic complete response. Non-invasive DOSI scans combined with histopathology subtyping may aid in stratification of individual breast cancer patients prior to NCT.

Multiparametric Monitoring of Chemotherapy Treatment Response in Locally Advanced Breast Cancer Using Quantitative Ultrasound and Diffuse Optical Spectroscopy

“…Multivariate analysis of the combined parameters demonstrated an increase in the sensitivity and specificity for predicting NAC response. The results of this study from Ueda et al support the need for further exploration into combination analysis to improve the predictive performance of multiple imaging and clinical biomarkers [11].…”

“…At the same time, the total hemoglobin (HbT) in responders reduced to 32.8 ± 4.0% in comparison to non-responders that showed a decrease to only 80.7% ± 8.1% from the baseline value. A possible explanation in responders could be due to decreased vessel viability within the tumor [11,40]. Conversely, non-responding patients may have tumors with more aggressive tumor cells that prompt blood vessel growth to support metabolic demands.…”

“…Combination pairs were analyzed using a logistic regression model, and the AUC was estimated using a receiver-operating characteristic. A complete list of all pairwise combinations (AUC > 0.8) are presented in Supplementary Table 1. www.impactjournals.com/oncotarget immunohistochemistry [11]. Markers for cell proliferation (Ki67), and molecular features (estrogen and progesterone receptor) were combined with optical measurements such as [HbO 2 ], [Hb], or the tumor oxygen saturation (StO 2 ).…”

“…Research into imaging biomarkers have aimed to match the sensitivity and specificity of gold-standard approaches from immunohistochemistry and microscopy, while providing quantitative and "real-time" results non-invasively. Emerging technologies are demonstrating that imaging biomarkers can detect important tumor characteristics such as cell death, tumor vascularity, and metabolic activity that relate to tumor response [11]. Rousseau et al measured tumor metabolic activity using 18 F-FDG-PET by quantifying the passage and clearance of radioactively labeled metabolites in solid tumors.…”

Optical Mammography Using Diffuse Optical Spectroscopy for Monitoring Tumor Response to Neoadjuvant Chemotherapy in Women with Locally Advanced Breast Cancer

“…Therefore, novel, noninvasive imaging techniques are needed to improve early monitoring response of the tumor to NAC. In addition to DCE-MRI and PET modalities, optical imaging has received new interest as a noninvasive and nonionizing technique to assess tumor response (9)(10)(11)(12)(13)(14).…”