Predicting Responses to Neoadjuvant Chemotherapy in Breast Cancer: ACRIN 6691 Trial of Diffuse Optical Spectroscopic Imaging

Abstract

The prospective multi-center 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 and delivered to 6 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 4 times during NAC treatment: baseline, one-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 receiver-operating characteristic curve methodology, %TOITN AUC was 0.60 (95% CI 0.39 to 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 to 1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction.

Imaging Considerations and Interprofessional Opportunities in the Care of Breast Cancer Patients in the Neoadjuvant Setting

“…36 A recent multi-center trial showed that diffuse optical spectroscopic imaging of tumor metabolism in combination with baseline functional properties of oxygenation, as measured through tumor oxygen saturation levels, shows promise for clinical outcome prediction in breast cancer NAT. 37 Specifically, in the most recent published study, 34 patients were evaluated and the responders (about 30% attained pCR) demonstrated a greater decrease in the tissue optical index than non-pCR at the half way point of therapy. Other parameters investigated in single-center studies evaluating response to NAT in breast cancers were concentrations of deoxy-hemoglobin, oxy-hemoglobin, water, and lipids, which have shown sensitivity to microvasculature, cellular metabolism, angiogenesis, edema, hypoxia, and necrosis.…”

“…36,81–83 Combining the tumor oxygen saturation with the function properties of tissue optical index, demonstrated an area under the ROC of 0.83. 37 …”

Longitudinal optical monitoring of blood flow in breast tumors during neoadjuvant chemotherapy

“…These reconstructed quantities have been shown to discriminate between malignant and healthy tissue in the breast (Srinivasan et al 2005, Spinelli et al 2005, Cerussi et al 2006, Choe et al 2009, Wang et al 2010, Fang et al 2011, Mastanduno et al 2014). Importantly, several studies have employed DOSI techniques to investigate functional changes in malignant tissue over the course of NAC and have correlated these changes with the patients’ responses to treatment (Choe et al 2005, Tromberg et al 2005, Zhou et al 2007, Cerussi et al 2007, Zhu et al 2008, Jiang et al 2009, Soliman et al 2010, Cerussi et al 2011, Roblyer et al 2011, Falou et al 2012, Ueda et al 2012, Choe and Durduran 2012, Busch et al 2013a, Tromberg et al 2016, Sajjadi et al 2017). The present paper is focused on another diffuse optical technique, diffuse correlation spectroscopy (DCS), which utilizes the temporal fluctuations of detected light intensity to probe microvasculature blood flow in deep tissue (Durduran et al 2010).…”

Optical Mammography in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

“…Studies aiming to predict therapeutic response early in the treatment have shown significant differences between responders and non-responders one day [14] or one week [12, 27, 32, 33] after the start of therapy. Other studies report the response during the course of treatment, typically using 3–8 measurement time points, to determine if and when different therapeutic response levels can be distinguished during NAC [13, 15, 16, 20, 21, 26, 28, 34–37]. The primary focus of these studies has been on the chromophore concentrations measured at the tumor location over time, but some work has also focused on exploring the correlation between baseline, pre-treatment optical measurements and the level of response to NAC [16, 21, 38, 39].…”

“…When monitoring patients throughout the duration of therapy, hemoglobin parameters seemed to best differentiate response groups. In particular, as can be seen in Table 1, a consistent response to NAC is a decrease in the concentration of hemoglobin (often separated into the two components of oxy- and deoxy-hemoglobin) at the tumor location [12, 13, 15–17, 20, 21, 26, 28, 30–34, 36, 37, 41]. …”