Predicting response to breast cancer neoadjuvant chemotherapy using diffuse optical spectroscopy

Abstract

Diffuse optical spectroscopy (DOS) and imaging are emerging diagnostic techniques that quantitatively measure the concentration of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctO(2)Hb), water (ctH(2)O), and lipid in cm-thick tissues. In early-stage clinical studies, diffuse optical imaging and DOS have been used to characterize breast tumor biochemical composition and monitor therapeutic response in stage II/III neoadjuvant chemotherapy patients. We investigated whether DOS measurements obtained before and 1 week into a 3-month adriamycin/cytoxan neoadjuvant chemotherapy regimen can predict final, postsurgical pathological response. Baseline DOS measurements of 11 patients before therapy revealed significant increases in tumor ctHHb, ctO(2)Hb, ctH(2)O, and spectral scattering slope, and decreases in bulk lipids, relative to normal breast tissue. Tumor concentrations of ctHHb, ctO(2)Hb, and ctH(2)O dropped 27 +/- 15%, 33 +/- 7%, and 11 +/- 15%, respectively, within 1 week (6.5 +/- 1.4 days) of the first treatment for pathology-confirmed responders (n = 6), whereas nonresponders (n = 5) and normal side controls showed no significant changes in these parameters. The best single predictor of therapeutic response 1 week posttreatment was ctHHb (83% sensitivity, 100% specificity), while discrimination analysis based on combined ctHHb and ctH(2)O changes classified responders vs. nonresponders with 100% sensitivity and specificity. In addition, the pretreatment tumor-to-normal ctO(2)Hb ratio was significantly higher in responders (2.82 +/- 0.44) vs. nonresponders (1.82 +/- 0.49). These results highlight DOS sensitivity to tumor cellular metabolism and biochemical composition and demonstrate its potential for predicting and monitoring an individual's response to treatment.

Fig. 1.

Typical DOS measurement geometry, defining the optical linescan taken over a known tumor location. Complete NIR absorption and scattering spectra were measured at each location.

Fig. 2.

NIR absorption (Left) and reduced scattering (Right) spectra obtained noninvasively from a 30-mm diameter tumor in the breast of a neoadjuvant chemotherapy subject. (Left) The heightened absorption results from a combination of increased hemoglobin and water relative to normal breast tissue. (Right) The sharp spectral decrease in scattering for tumor tissue is likely due to increases in both cellular density and fibrous tissue in tumor tissue relative to normal breast tissue. Tumor spectra were obtained from the +10-mm position, whereas the normal spectra were taken from the corresponding contralateral position on the normal side. Error bars are the variation from two independent linescans (plotted every 50 nm for clarity).

Fig. 3.

Linescan results of ctH₂O (Upper) and ctHHb (Lower) from the same patient as in Fig. 2. NIR spectra at each linescan location are used to calculate NIR absorber concentrations at each spatial location. Error bars are the variations between two independent linescans.

Fig. 4.

Plots of changes in tumor ctHHb, ctO₂Hb, ctH₂O, and stO₂ for individual patients, stratified by final pathological response. The plotted value is the average of the DOS parameter within the FWHM. The baseline and ∼1 week points correspond to the measurements taken within 1 week before and within 1 week after the start of therapy, respectively. Responder changes are distinctive from nonresponders. Error bars for the individual measurements are not presented for clarity (5–10%).