Predicting Responses to Neoadjuvant Chemotherapy in Breast Cancer: ACRIN 6691 Trial of Diffuse Optical Spectroscopic Imaging

Abstract

The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)-derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from -82% to 321%, with a median of -36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39-0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63-1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933-44. ©2016 AACR.

Conflict of interest statement

of Potential Conflicts of Interest: A. Cerussi and B.J. Tromberg report patents, which are owned by the University of California, that are related to the technology and analysis methods described in this study. The University of California has licensed diffuse optical spectroscopic imaging technology and analysis methods to LG, Inc. This research was completed without LG, Inc. participation, knowledge, or financial support and data were acquired and processed from patients by coauthors unaffiliated with this entity. The Institutional Review Board and Conflict of Interest Office of the University of California, Irvine, have reviewed both patent and corporate disclosures and did not find any concerns. No potential conflicts of interest were disclosed by the other authors.

©2016 American Association for Cancer Research.

Figures

Figure 1

Example of DOSI measurement grids and the corresponding TOI images (Subject 6691-21).

Figure 2

Enrollment to analysis flowchart

Figure 3

DOSI Images throughout NAC for a pCR (6691-08) and a non-pCR (6691-13) subject. Scale bar illustrates Tissue Optical Index (TOI) values. B) Percent change in TOITN, HHbTN, H2OTN, LipidTN from baseline for both subjects. Error bars represent the SD of multiple measurement locations defined by the ROI for each subject (25 and 28 locations for 6691-08 and 6691-13, respectively).

Figure 4

Boxplot of percent change from baseline to mid-therapy in TOITN (%TOITN) by final pathologic status, dichotomized as pCR vs. non-pCR. A) in the overall evaluable dataset; B) in the subset of evaluable cases with baseline tumor oxygenation lower than the median value; C) in the subset of evaluable cases with baseline tumor oxygenation greater than the median value.

Figure 5

ROC curves for pathologic complete response using percent change from baseline to mid-therapy in TOITN (%TOITN) A) in the overall evaluable dataset, B) in the subset of evaluable cases with baseline tumor saturation lower than the median value, C) in the subset of evaluable cases with baseline tumor saturation greater than the median value. The reference standard is coded as follows: 0=pCR and 1=Non-pCR.