Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using immunohistopathology and hemoglobin parameters

Abstract

BackgroundBreast cancer pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) varies with tumor subtype. The purpose of this study was to identify an early treatment window for predicting pCR based on tumor subtype, pretreatment total hemoglobin (tHb) level, and early changes in tHb following NAC.MethodsTwenty-two patients (mean age 56 years, range 34–74 years) were assessed using a near-infrared imager coupled with an Ultrasound system prior to treatment, 7 days after the first treatment, at the end of each of the first three cycles, and before their definitive surgery. Pathologic responses were dichotomized by the Miller-Payne system. Tumor vascularity was assessed from tHb; vascularity changes during NAC were assessed from a percentage tHb normalized to the pretreatment level (%tHb). After training the logistic prediction models using the previous study data, we assessed the early treatment window for predicting pathological response according to their tumor subtype (human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), triple-negative (TN)) based on tHb, and %tHb measured at different cycles and evaluated by the area under the receiver operating characteristic (ROC) curve (AUC).ResultsIn the new study cohort, maximum pretreatment tHb and %tHb changes after cycles 1, 2, and 3 were significantly higher in responder Miller-Payne 4–5 tumors (n = 13) than non-or partial responder Miller-Payne 1–3 tumors (n = 9). However, no significance was found at day 7. The AUC of the predictive power of pretreatment tHb in the cohort was 0.75, which was similar to the performance of the HER2 subtype as a single predictor (AUC of 0.78). A greater predictive power of pretreatment tHb was found within each subtype, with AUCs of 0.88, 0.69, and 0.72, in the HER2, ER, and TN subtypes, respectively. Using pretreatment tHb and cycle 1 %tHb, AUC reached 0.96, 0.91, and 0.90 in HER2, ER, and TN subtypes, respectively, and 0.95 regardless of subtype. Additional cycle 2 %tHb measurements moderately improved prediction for the HER2 subtype but did not improve prediction for the ER and TN subtypes.ConclusionsBy combining tumor subtypes with tHb, we predicted the pCR of breast cancer to NAC before treatment. Prediction accuracy can be significantly improved by incorporating cycle 1 and 2 %tHb for the HER2 subtype and cycle 1 %tHb for the ER and TN subtypes.Trial registrationClinicalTrials.gov, NCT02092636. Registered in March 2014.

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).…”

“…In Appendix A, we developed treatment prediction models using combined data from 38 patients reported in this study and 22 patients acquired in an earlier study with similar DOT system parameters, patient and treatment characteristics (19). Table 1 summarizes patient and tumor characteristics, NAT regimens and MP grading.…”

“…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.…”

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

“…DOSI measures absolute concentrations of oxyhemoglobin, deoxyhemoglobin, lipid, and water. These parameters have been shown by multiple research groups to be valuable prognostic markers at various points throughout NAC [6,9,16,21,27,45,46,48,49,50,53]. For example, a recent landmark multicenter study (ACRIN 6691) showed that changes in tumor deoxyhemoglobin, water, and lipid at midpoint of NAC correlated strongly to pCR [48].…”