Anais Leproux

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

Tissue hemoglobin oxygen saturation (i.e., oxygenation) is a functional imaging endpoint that can reveal variations in tissue hypoxia, which may be predictive of pathologic response in subjects undergoing neoadjuvant chemotherapy. In this study, we used diffuse optical spectroscopic imaging (DOSI) to measure concentrations of oxyhemoglobin (ctO(2)Hb), deoxy-hemoglobin (ctHHb), total Hb (ctTHb = ctO(2)Hb + ctHHb), and oxygen saturation (stO(2) = ctO(2)Hb/ctTHb) in tumor and contralateral normal tissue from 41 patients with locally advanced primary breast cancer. Measurements were acquired before 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 conducted to determine the ability of optical and clinical biomarkers to classify subjects into response groups. Twelve (28.6%) of 42 tumors achieved pathologic complete response (pCR) and 30 (71.4%) were non-pCR. Tumor measurements in pCR subjects had higher stO(2) levels (median 77.8%) than those in non-pCR individuals (median 72.3%, P = 0.01). There were no significant differences in baseline ctO(2)Hb, ctHHb, and ctTHb between response groups. An optimal tumor oxygenation threshold of stO(2) = 76.7% was determined for pCR versus non-pCR (sensitivity = 75.0%, specificity = 73.3%). Multivariate discriminant analysis combining estrogen receptor staining and stO(2) further improved the classification of pCR versus non-pCR (sensitivity = 100%, specificity = 85.7%). These results show that elevated baseline tumor stO(2) are correlated with a pCR. Noninvasive DOSI scans combined with histopathology subtyping may aid in stratification of individual patients with breast cancer before neoadjuvant chemotherapy.

Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy

IntroductionIn addition to being a risk factor for breast cancer, breast density has beenhypothesized to be a surrogate biomarker for predicting response toendocrine-based chemotherapies. The purpose of this study was to evaluate whethera noninvasive bedside scanner based on diffuse optical spectroscopic imaging(DOSI) provides quantitative metrics to measure and track changes in breast tissuecomposition and density. To access a broad range of densities in a limited patientpopulation, we performed optical measurements on the contralateral normal breastof patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSIparameters, including tissue hemoglobin, water, and lipid concentrations, wereobtained and correlated with magnetic resonance imaging (MRI)-measuredfibroglandular tissue density. We evaluated how DOSI could be used to assessbreast density while gaining new insight into the impact of chemotherapy on breasttissue.MethodsThis was a retrospective study of 28 volunteers undergoing NAC treatment forbreast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtainedfrom the contralateral normal breast before and during NAC. Longitudinal DOSImeasurements were used to calculate breast tissue concentrations of oxygenated anddeoxygenated hemoglobin, water, and lipid. These values were compared withMRI-measured fibroglandular density before and during therapy.ResultsWater (r = 0.843; P < 0.001), deoxyhemoglobin (r =0.785; P = 0.003), and lipid (r = -0.707; P = 0.010)concentration measured with DOSI correlated strongly with MRI-measured densitybefore therapy. Mean DOSI parameters differed significantly between pre- andpostmenopausal subjects at baseline (water, P < 0.001;deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NACtreatment measured at about 90 days, significant reductions were observed inoxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) andpostmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentrationfor premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline.Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), andwater increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6).Percentage change in water at the end of therapy compared with baseline correlatedstrongly with percentage change in MRI-measured density (r = 0.864; P = 0.012).ConclusionsDOSI functional measurements correlate with MRI fibroglandular density, bothbefore therapy and during NAC. Although from a limited patient dataset, theseresults suggest that DOSI may provide new functional indices of density based onhemoglobin and water that could be used at the bedside to assess response totherapy and evaluate disease risk.

Predicting responses to neoadjuvant chemotherapy in breast cancer: ACRIN 6691 trial of diffuse optical spectroscopic imaging

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.

Assessing tumor contrast in radiographically dense breast tissue using Diffuse Optical Spectroscopic Imaging (DOSI)

IntroductionRadiographic density adversely affects the performance of X-ray mammography and can be particularly problematic in younger and high-risk women. Because of this limitation, there is significant ongoing effort to develop alternative cancer screening and detection strategies for this population. This pilot study evaluates the potential of Diffuse Optical Spectroscopic Imaging (DOSI) to image known tumors in dense breast tissue.MethodsWe performed a retrospective analysis on 24 radiographically dense breast cancer subjects measured with DOSI over a four-year period (Breast Imaging Reporting and Data System - BI-RADS, category 3 and 4, average age = 39 ± 7.6, average maximum size 31 ± 17 mm). Two previously-described DOSI contrast functions, the tissue optical index (TOI) and the specific tumor component (STC), which are based upon the concentrations and spectral signatures of hemoglobin, water and lipids, respectively, were used to form 2D optical images of breast tumors.ResultsUsing TOI and STC, 21 out of 24 breast tumors were found to be statistically different from the surrounding highly vascularized dense tissue and to be distinguishable from the areolar region. For these patients, the tumor to normal contrast was 2.6 ± 1.2 (range 1.3 to 5.5) and 10.0 ± 7.5 (range 3.3 to 26.4) for TOI and STC, respectively. STC images were particularly useful in eliminating metabolic background from the retroareolar region which led to identification of two out of four retroareolar tumors.ConclusionsUsing both the abundance and the disposition of the tissue chromophores recovered from the DOSI measurements, we were able to observe tumor contrast relative to dense breast tissue. These preliminary results suggest that DOSI spectral characterization strategies may provide new information content that could help imaging breast tumors in radiographically dense tissue and in particular in the areolar complex.

Performance assessment of diffuse optical spectroscopic imaging instruments in a 2-year multicenter breast cancer trial

Abstract. We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received multiple DOSI scans prior to and during 3- to 6-month NAC. The impact of three sources of error on accuracy and precision, including different operators, instruments, and calibration standards, was evaluated using a broadband reflectance standard and two different solid tissue-simulating optical phantoms. Instruments showed <0.0010  mm−1 (10.3%) and 0.06  mm−1 (4.7%) deviation in broadband absorption and reduced scattering, respectively, over the 2-year duration of ACRIN-6691. These variations establish a useful performance criterion for assessing instrument stability. The proposed procedures and tests are not limited to DOSI; rather, they are intended to provide methods to characterize performance of any instrument used in translational optical imaging.

Mapping breast cancer blood flow index, composition, and metabolism in a human subject using combined diffuse optical spectroscopic imaging and diffuse correlation spectroscopy

Abstract. Diffuse optical spectroscopic imaging (DOSI) and diffuse correlation spectroscopy (DCS) are model-based near-infrared (NIR) methods that measure tissue optical properties (broadband absorption, μa, and reduced scattering, μs′) and blood flow (blood flow index, BFI), respectively. DOSI-derived μa values are used to determine composition by calculating the tissue concentration of oxy- and deoxyhemoglobin (HbO2, HbR), water, and lipid. We developed and evaluated a combined, coregistered DOSI/DCS handheld probe for mapping and imaging these parameters. We show that uncertainties of 0.3  mm−1 (37%) in μs′ and 0.003  mm−1 (33%) in μa lead to ∼53% and 9% errors in BFI, respectively. DOSI/DCS imaging of a solid tissue-simulating flow phantom and a breast cancer patient reveals well-defined spatial distributions of BFI and composition that clearly delineates both the flow channel and the tumor. BFI reconstructed with DOSI-corrected μa and μs′ values had a tumor/normal contrast of 2.7, 50% higher than the contrast using commonly assumed fixed optical properties. In conclusion, spatially coregistered imaging of DOSI and DCS enhances intrinsic tumor contrast and information content. This is particularly important for imaging diseased tissues where there are significant spatial variations in μa and μs′ as well as potential uncoupling between flow and metabolism.

Differential diagnosis of breast masses in South Korean premenopausal women using diffuse optical spectroscopic imaging

Abstract. Young patients with dense breasts have a relatively low-positive biopsy rate for breast cancer (∼1 in 7). South Korean women have higher breast density than Westerners. We investigated the benefit of using a functional and metabolic imaging technique, diffuse optical spectroscopic imaging (DOSI), to help the standard of care imaging tools to distinguish benign from malignant lesions in premenopausal Korean women. DOSI uses near-infrared light to measure breast tissue composition by quantifying tissue concentrations of water (ctH2O), bulk lipid (ctLipid), deoxygenated (ctHHb), and oxygenated (ctHbO2) hemoglobin. DOSI spectral signatures specific to abnormal tissue and absent in healthy tissue were also used to form a malignancy index. This study included 19 premenopausal subjects (average age 41±9), corresponding to 11 benign and 10 malignant lesions. Elevated lesion to normal ratio of ctH2O, ctHHb, ctHbO2, total hemoglobin (THb=ctHHb+ctHbO2), and tissue optical index (ctHHb×ctH2O/ctLipid) were observed in the malignant lesions compared to the benign lesions (p<0.02). THb and malignancy index were the two best single predictors of malignancy, with >90% sensitivity and specificity. Malignant lesions showed significantly higher metabolism and perfusion than benign lesions. DOSI spectral features showed high discriminatory power for distinguishing malignant and benign lesions in dense breasts of the Korean population.

Abstract OT3-2-07: Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study

Background: The goal of this multi-site prospective study is to validate a safe, painless imaging method to measure the change in breast density caused by hormonal chemotherapy treatments such as tamoxifen. Recent studies have demonstrated that hormonal therapies are more effective at reducing risk in women who exhibit >10% reduction in breast density compared to women who had little or no density change, suggesting that breast density is a predictor of tamoxifen effectiveness. Current methods to measure breast density include MRI and mammography, however frequent applications of these modalities are limited due to cost and x-ray exposure, respectively. Alternatively, we are testing an imaging method that uses safe near-infrared light to measure breast tissue physiology called diffuse optical spectroscopic imaging (DOSI). Trial Design and Eligibility: The primary aim of the study is to determine whether the percentage change in the DOSI measurement of water correlates with the change in the MRI measurement of breast density after 18 months of treatment in the contralateral normal breast of breast cancer patients receiving tamoxifen. Other DOSI-derived parameters such as lipid content and hemoglobin concentration will be examined in secondary aims. Two groups of women are being recruited for the study: Pre-menopausal subjects receiving tamoxifen (treatment group) and pre-menopausal subjects not receiving chemoprevention agents (control group). Participants are measured with DOSI and non-contrast MRI before, and 6, 12 and 18 months after beginning tamoxifen. Eligible subjects are pre- and peri-menopausal females older than 21 years of age who have not and do not intend to receive chemotherapy, radiation, or surgical cancer treatment to the imaged breast, and are not pregnant or nursing. Study sites include the University of California, Irvine and San Francisco campuses. Statistical Methods: At a 5% significance level, the pre-determined power of the study is sufficient to detect the difference between the treatment and control groups by measuring the percentage change of breast tissue water concentration with DOSI. The research hypothesis is that the mean difference from baseline for tissue water concentration from DOSI will be greater for the tamoxifen-treated group than the control group. For water concentration and for MRI breast density, a two-sided independent sample t-test will be used to test the null hypothesis that the mean difference from baseline is the same for the tamoxifen-treated and control groups. As a secondary analysis, a multivariate mixed effects model will be built using the observed DOSI parameter or MRI breast density measured from each patient as the outcome variable, and predictor variables to include treatment group and measurement time, in addition to relevant clinical and demographic variables. Accrual Update: Out of the target accrual of 36, 11 subjects (6 treatment and 5 control group) have been enrolled to date. Enrollment is open until 11/30/2015. Citation Format: Thomas D OSullivan, Anais Leproux, Alice M Police, Dorota Wisner, Christine McLaren, Wen-Pin Chen, Albert E Cerussi, Min-Ying Su, Bruce J Tromberg. Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-07.

Abstract S4-04: Predicting pre-surgical neoadjuvant chemotherapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Results from the ACRIN 6691 study

Background: DOSI is an experimental imaging technique that employs risk-free near-infrared light for quantitative measurements of breast tissue perfusion, metabolism, and composition without exogenous contrast. A multi-center ACRIN 6691 study was designed to evaluate whether changes from baseline to mid-therapy in a DOSI-derived Tissue Optical Index (TOI) could predict pathologic complete response (pCR) in breast cancer neoadjuvant chemotherapy (NAC). Methods: DOSI instruments were constructed at the University of California, Irvine and delivered to 6 participating sites. Bedside measurements were conducted by scanning a handheld probe over a region of interest (up to ∼10 x 10 cm2) on both breasts. Instruments were standardized and validated using a common set of tissue simulating phantoms and protocols. DOSI-derived near-infrared absorption and scattering spectra (650-1000 nm) were used to calculate the tissue concentration of oxy- and deoxyhemoglobin (ctO2Hb, ctHHb), water (ctH2O), %lipid and the tissue optical index (TOI=ctHHb x ctH2O/%lipid) in each probe location. Baseline to mid-therapy changes in the tumor to normal (T/N) TOI ratio were evaluated from DOSI images as the primary imaging endpoint for predicting clinical outcome (pCR). 60 female breast cancer patients (ages 28-69 years, mean 48.9±11), with locally advanced disease (tumors >2cm) were enrolled across the 6 institutions. DOSI measurements were performed at baseline, during the first week of therapy, at midpoint, and at the completion of NAC. Logistic regression was used to assess the association between pathologic complete response (pCR) and % change in T/N TOI from baseline to mid-therapy. In addition, area under the receiver operating characteristic curve (ROC AUC) and its corresponding 95% confidence interval were calculated. Results: Of the 34 participants (mean age 48.4 ± 10.7) with complete and evaluable data, 10 (29%) achieved pCR as determined by central pathology review. The % change in TOI ratio ranged from -82% to 321%, with a median of -36%. Using -40% as a threshold, we found that subjects in the group with a 40% or more decrease in T/N TOI were more likely to be pCR (p=0.0586, OR=4.667, 95% CI: 0.945 to 23.038). The % change in TOI ratio from baseline to mid-therapy has an AUC of 0.604 (95% CI: 0.394 to 0.814) to distinguish pCR from non-pCR. Conclusions: DOSI has been successfully implemented in a multi-center setting and changes in T/N TOI are a promising predictor of NAC clinical outcome (pCR). A larger study population is needed to fully assess the utility of TOI and other DOSI imaging endpoints for guiding therapies and predicting NAC response in individual subjects. ACRIN receives funding from the NCI through U01 CA079778 and U01 CA080098. Citation Format: Bruce J Tromberg, Zheng Zhang, Anais Leproux, Thomas D O9Sullivan, Albert E Cerussi, Philip Carpenter, Rita Mehta, Darren Roblyer, Wei Yang, Keith D Paulsen, Brian W Pogue, Shudong Jiang, Peter Kaufman, Arjun G Yodh, So-Hyun Chung, Mitchell Schnall, Brad Snyder, Nola Hylton, David A Boas, Stefan A Carp, Steven J Isakoff, David Mankoff. Predicting pre-surgical neoadjuvant chemotherapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Results from the ACRIN 6691 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S4-04.

P2-09-15: Functional Measurements of Tumor Response during Neoadjuvant Chemotherapy Infusion and Early during Treatment Using Diffuse Optical Spectroscopic Imaging.

Background: Non-invasive markers of neoadjuvant chemotherapy response early during treatment would provide physicians a valuable tool to make evidence-based changes to treatment strategies. In a retrospective study of 23 patients presented at SABCS 2011 we demonstrated that Diffuse Optical Spectroscopic Imaging (DOSI) can discriminate non-responding from responding subjects on the first day after the start therapy based on the presence or absence of an oxyhemoglobin flare. Here we present results of an ongoing prospective study designed to confirm the predictive nature and biological origins of oxyhemoglobin flare and to determine if similar functional changes occur at even earlier timepoints such as during infusion. Methods: DOSI was used to measure hemodynamic and metabolic information from tumors and surrounding normal tissue in patients prior to neoadjuvant chemotherapy, during chemotherapy infusion, and daily for the first week of treatment. DOSI uses temporally modulated near-infrared light to determine absolute tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water and lipid content and requires no exogenous contrast agent. Measurements are made using a simple handheld probe placed on the skin. Blood samples were also collected at baseline and daily for seven days after the first infusion and tested for a panel inflammatory cytokines. Patients received paclitaxel + carboplatin + bevacizumab. Overall response to therapy was determined by the decrease in anatomic tumor size. Results: To date three subjects have been measured, two of which have completed neoadjuvant chemotherapy and undergone surgery. One subject was a pathologic complete responder (pCR) and the other a non-responder (NR). In both the pCR subject and the subject still undergoing therapy there were significant functional changes measured in the tumor during infusion. A decrease in oxyhemoglobin and oxygen saturation occurred after paclitaxel infusion (saturation changes: −4.8% and −9.7% for each subject respectively), followed by an increase in these quantities after carboplatin infusion (saturation: 3.8% and 5.9% respectively). In the NR subject both oxyhemoglobin and oxygen saturation had only small fluctuations during infusion (saturation: 1.1%). Oxyhemoglobin flare was also observed 24 hours after infusion for each of the patients. Plasma levels of several inflammatory cytokines including G-CSF, MIP-1α, and C-reactive protein increased 24 hours after infusion for the first two subjects and subsequently decreased at 48 hours. Discussion: We have confirmed the presence of oxyhemoglobin flare on day one after infusion in this small prospective patient cohort. Increased plasma levels of inflammatory cytokines were correlated in time with the presence of oxyhemoglobin flare suggesting a possible link between optical measurements and inflammatory processes induced by chemotherapy. Additionally, we report for the first time significant changes in tumoral oxyhemoglobin and oxygen saturation during chemotherapy infusion. These changes may be of prognostic significance. DOSI allows functional measurements of tumor response at timepoints unachievable with current functional medical imaging modalities. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-15.