Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens

Abstract

Background: Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedback about treatment response at the earliest stages of therapy to identify patients likely to benefit from changing treatment. Diffuse optical spectroscopic imaging (DOSI) has emerged as a promising functional imaging technique for NAC monitoring. DOSI uses non-ionizing near-infrared light to provide non-invasive measures of absolute concentrations of tissue chromophores such as oxyhemoglobin. In 2011, we reported a new DOSI prognostic marker, oxyhemoglobin flare: a transient increase in oxyhemoglobin capable of discriminating NAC responders within the first day of treatment. In this follow-up study, DOSI was used to confirm the presence of the flare as well as to investigate whether DOSI markers of NAC response are regimen dependent. Methods: This dual-center study examined 54 breast tumors receiving NAC measured with DOSI before therapy and the first week following chemotherapy administration. Patients were treated with either a standard of care maximum tolerated dose (MTD) regimen or an investigational metronomic (MET) regimen. Changes in tumor chromophores were tracked throughout the first week and compared to pathologic response and treatment regimen at specific days utilizing generalized estimating equations (GEE). Results: Within patients receiving MTD therapy, the oxyhemoglobin flare was confirmed as a prognostic DOSI marker for response appearing as soon as day 1 with post hoc GEE analysis demonstrating a difference of 48.77% between responders and non-responders (p < 0.0001). Flare was not observed in patients receiving MET therapy. Within all responding patients, the specific treatment was a significant predictor of day 1 changes in oxyhemoglobin, showing a difference of 39.45% (p = 0.0010) between patients receiving MTD and MET regimens. Conclusions: DOSI optical biomarkers are differentially sensitive to MTD and MET regimens at early timepoints suggesting the specific treatment regimen should be considered in future DOSI studies. Additionally, DOSI may help to identify regimen-specific responses in a more personalized manner, potentially providing critical feedback necessary to implement adaptive changes to the treatment strategy.

Early Assessment Window for Predicting Breast Cancer Neoadjuvant Therapy Using Biomarkers, Ultrasound, and Diffuse Optical Tomography

“…Diffuse optical tomography and diffuse optical spectroscopy exploit changes in tumor vascularity and metabolism and have demonstrated the potential for early prediction of breast cancer pathological response (18)(19)(20)(21)(22)(23)(24)(25)(26). Studies have shown accurate predictions in the neoadjuvant setting by utilizing pretreatment hemoglobin levels and changes in hemoglobin early in the course of treatment (19,(21)(22)(23)(24)(25)(26), or by monitoring changes of blood oxygen saturation sO2 at day 1 of dose dense treatment (18) or day 10 during early treatment (20). In the recent ACRIN 6691 trial evaluating 36 patients, the authors derived a tissue optical index (TOI), a product of deoxygenated Hb and water concentration over lipid, and reported that the mid-treatment TOI can predict pCR with AUC 0.6 to 0.83 (19).…”

“…Optical tomography and spectroscopy using near infrared (NIR) diffused light has been explored as a novel tool to predict and monitor tumor vasculature response to NAT (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The NIR technique utilizes intrinsic hemoglobin contrast, which is related to tumor angiogenesis.…”

“…The NIR technique utilizes intrinsic hemoglobin contrast, which is related to tumor angiogenesis. Recently studies have shown that pre-treatment total hemoglobin concentration (HbT) and changes in HbT measured at the early treatment cycles can predict treatment outcome (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Furthermore, the Diffuse Optical Tomography (DOT) can be easily integrated with ultrasound systems for dual-modality imaging assessment of breast cancer response to NAT.…”

Two-layer spatial frequency domain imaging of compression-induced hemodynamic changes in breast tissue

“…Near-infrared (NIR) optical imaging methods have shown potential for prediction of treatment outcome in women undergoing neoadjuvant chemotherapy (NAC) for breast cancer via longitudinal tracking of hemoglobin concentration within the breast. [1][2][3][4][5][6][7][8][9][10][11][12][13] Pathologic complete response (pCR) to NAC (assessed histologically after surgery) is associated with improved survival, 14,15 but the results of structural imaging modalities such as ultrasonography and x-ray mammography are poor predictors of patient outcome. 16,17 Predicating the response early in the course of therapy could potentially enable treatment alternatives.…”

A Novel Model Incorporating Tumor Stiffness, Blood Flow Characteristics, and Ki-67 Expression to Predict Responses After Neoadjuvant Chemotherapy in Breast Cancer

“…Angiogenesis (or neovascularization), as another important factor in the tumor microenvironment, is considered a rate-limiting step in BC progression, and carries prognostic significance (13). Several imaging modalities yielding different imaging-derived hemodynamic parameters have been proposed for the assessment of tumor vascularity and the response to treatment (14)(15)(16)(17)(18)(19)(20)(21). However, dynamic contrast-enhanced magnetic resonance imaging (MRI), and positron emission tomography with computed tomography (PET-CT) have practical constraints, including cost, the use of contrast agents, and exposure to ionizing radiation from PET; in addition, these techniques are not feasible or are contraindicated in some patients, which limits the frequency of monitoring during treatment (16,17,19).…”