Near-infrared optical imaging targeting the intrinsic contrast of tissue hemoglobin has emerged as a promising approach for visualization of vascularity in cancer research. We evaluated the usefulness of diffuse optical spectroscopy using time-resolved spectroscopic (TRS) measurements for functional imaging of primary breast cancer.

Purpose: Diffuse optical spectroscopic imaging (DOSI) is used as an indicator of tumor blood volume quantified by tissue hemoglobin concentrations. We aimed to determine whether early changes in tumor total hemoglobin (tHb) concentration can predict a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in patients with operable breast cancer, and we compared the predictive value of pCR between DOSI and 2-deoxy-2-¹⁸F-fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography (CT). Methods: Of the 100 patients enrolled, 84 patients were prospectively evaluated for primary objective analysis. Sixty four of the patients underwent both sequential DOSI scans at baseline after their first and second chemotherapy courses and FDG-PET/CT at baseline and after their second chemotherapy course. The mean tHb (tHbmean) concentration and maximum standardized uptake values (SUV_max) of the lesion were measured using DOSI and FDG-PET/CT, respectively, and the percentage change in tHbmean (∆tHbmean) and change in SUV_max (∆SUV_max) were calculated. We compared the diagnostic performances of DOSI and FDG-PET/CT for predicting pCR via the analysis of the receiver operating characteristic curves. Results: pCR was achieved in 16 patients, and NAC caused a significant reduction of ∆tHbmean in pCR compared with non-pCR after the two chemotherapy courses. Using the tentative ∆tHbmean cutoff values after the first and second courses, the ability to predict pCR was as follows: sensitivity 81.2%, specificity 47.0% and sensitivity 93.7%, specificity 47.7%, respectively. Comparison of the diagnostic performances of DOSI and FDG-PET/CT revealed areas under the curve (AUCs) of 0.69 and 0.75 of ∆tHbmean after the first and second courses, respectively, which were lower than those of ∆SUV_max (0.90). Conclusion: DOSI predicted pCR in patients with breast cancer with moderate accuracy. The diagnostic performance of DOSI was inferior to that of the early metabolic response as monitored by FDG-PET/CT.

Optical imaging techniques for measuring tissue hemoglobin concentration have been recently accepted as a way to assess tumor vascularity and oxygenation. We investigated the correlation between early optical response to single-agent bevacizumab and treatment outcome. Seven patients with advanced or metastatic breast cancer were treated with single-agent bevacizumab followed by addition of weekly paclitaxel. Optical imaging of patient's breasts was performed to measure tumor total hemoglobin concentration (tHb) and oxygen saturation (stO₂) at baseline and on days 1, 3, 6, 8, and 13 after the first infusion of bevacizumab. To assess early metabolic response, 2-deoxy-2-(¹⁸F)-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), ¹⁸F-fluoromisonidazole (FMISO)-PET/CT, and magnetic resonance imaging were performed at baseline and after two cycles of the regimen. Seven patients were grouped as responders (n = 4) and nonresponders (n = 3) on the basis of metabolic response measured by FDG-PET/CT. The responders showed remarkable tumor shrinkage and low accumulations of FMISO tracer relative to those of the nonresponders at the completion of two cycles of chemotherapy. Tumors of both groups showed remarkable attenuation of mean tHb as early as day 1 after therapy initiation. The nonresponders had lower baseline stO₂ levels compared with adjacent breast tissue stO₂ levels along with a pattern of steadily low stO₂ levels during the observation window. On the other hand, the responders appeared to sustain high stO₂ levels with temporal fluctuation. Low tumor stO₂ level after single-agent bevacizumab treatment was characteristic of the nonresponders. Tumor stO₂ level could be a predictor of an additional benefit of bevacizumab over that provided by paclitaxel.

Background This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer. Methods Patients with HER2-positive, stage I–III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m2, day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease. Results Fifty patients were enrolled in this study. Median age was 58 (range 32–75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%). Conclusion Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy. Clinical registration number: http://www.umin.org.auUMIN000013513.

This study reports data from three clinical studies using the time-resolved diffuse optical spectroscopy (TRS) system among breast cancer patients. The parameters of oxy-hemoglobin (O₂Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb), and oxygen saturation (SO₂) were evaluated using TRS, and its efficacy was tested in three trials. In trial 1, we recruited 118 patients with primary breast cancer to estimate the tumor detection rate. The cumulative detection rate was 62.7%, while that in T stage 0 was 31.3% and in T stage 1 was 44.7%. These were lower than those of T stage 2 (78.9%) and T stage 3 (100%). Next, we used TRS to monitor tumor hemodynamic response to neoadjuvant chemotherapy (n = 100) and found that pathological complete response (pCR) tumors had significantly lower tumor tHb than non-pCR tumors; a similar result was observed in estrogen receptor (ER)-negative tumors, but not in ER-positive tumors. The third trial monitored hemodynamic response to antiangiogenic therapy, bevacizumab (n = 28), and we demonstrated that sequential optical measurement of tumor SO₂ might be useful for detecting acute hypoxia 1–3 days after bevacizumab initiation. Next, response monitoring of neoadjuvant endocrine therapy (n = 30) suggested that changes in tumor tHb during treatment can predict and distinguish between responsive and non-responsive tumors early in letrozole therapy. In conclusion, our results show that hemodynamic monitoring of tumors by TRS could pair the unique features of tumor physiology to drug therapy and contribute to patient-tailored medicine. We recently established a platform for performing TRS in patients with breast cancer.

We had previously reported a close association between pathological response and the maximum tumor standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose positron emission tomography prior to chemotherapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that glucose hypermetabolism by luminal B tumors may result in chemotherapy responsiveness. Using a single-gene expression assay, TargetPrint® (Agendia) and a 70-gene expression classifier, MammaPrint® (Agendia), we divided 20 patients with ER-positive primary breast cancer into luminal A and luminal B subtypes and compared the tumor SUVmax value between the two groups. A significantly higher SUVmax was measured for luminal B tumors (n=10; mean±SD, 7.6±5.6) than for luminal A tumors (n=10; mean±SD, 2.6±1.2; p=0.01). Glucose hypermetabolism could help predict intrinsic subtyping and chemotherapy responsiveness as a supplement to ER, progesterone receptor, HER2, and Ki-67 histochemical scores.