Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Abstract

Approximately 8-20% of breast cancer patients receiving neoadjuvant chemotherapy fail to achieve a measurable response and endure toxic side effects without benefit. Most clinical and imaging measures of response are obtained several weeks after the start of therapy. Here, we report that functional hemodynamic and metabolic information acquired using a noninvasive optical imaging method on the first day after neoadjuvant chemotherapy treatment can discriminate nonresponding from responding patients. Diffuse optical spectroscopic imaging was used to measure absolute concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipid in tumor and normal breast tissue of 24 tumors in 23 patients with untreated primary breast cancer. Measurements were made before chemotherapy, on day 1 after the first infusion, and frequently during the first week of therapy. Various multidrug, multicycle regimens were used to treat patients. Diffuse optical spectroscopic imaging measurements were compared with final postsurgical pathologic response. A statistically significant increase, or flare, in oxyhemoglobin was observed in partial responding (n = 11) and pathologic complete responding tumors (n = 8) on day 1, whereas nonresponders (n = 5) showed no flare and a subsequent decrease in oxyhemoglobin on day 1. Oxyhemoglobin flare on day 1 was adequate to discriminate nonresponding tumors from responding tumors. Very early measures of chemotherapy response are clinically convenient and offer the potential to alter treatment strategies, resulting in improved patient outcomes.

Fig. 1.

Percent change in ctO₂Hb during the first 7 d of chemotherapy in responding and nonresponding tumors. The number of tumors measured at each day is indicated. The maximum separation between these groups occurred on day 1. Error bars represent SE.

Fig. 2.

Percent change in ctO₂Hb, ctHHb, water, and lipids on day 1 compared with baseline. Based on longitudinal GEE models, statistically significant differences, noted with asterisks, were found for NR vs. PR (nominal P value = 3.6 × 10⁻¹⁶, multiple comparisons corrected P value = 5.0 × 10⁻¹⁵) and NR vs. pCR (nominal P value = 1.6 × 10⁻¹³, corrected P value = 2.2 × 10⁻¹²), which were adjusted for differences in tissue type and treatment. Error bars represent SE.

Fig. 3.

Absolute values of tumor ctO₂Hb at baseline and day 1 for the different response groups. Baseline and day 1 values in the NR group were 27.2 μM (±6.8 SD) and 20.9 μM (±4.3 SD), respectively, and this represents an average change of −22.5%. Baseline and day 1 values in the PR group were 22.0 μM (±5.9 SD) and 31.5 μM (±12.8 SD), respectively, with an average change of 44.5%. Baseline and day 1 values in the pCR group were 24.1 μM (±10.4 SD) and 33.1 μM (±13.0 SD), respectively, with an average change of 41.4%.

Fig. 4.

ctO₂Hb maps from three different subjects at baseline and day 1 after the start of neoadjuvant chemotherapy. Each map shows a 6 × 6-cm measurement area that includes the tumor and a surrounding normal margin. (Scale bar: 1 cm.) The circles represent the location and approximate anatomic size of the tumors determined by ultrasound. (Top) An example of a 17-mm tumor that did not respond to chemotherapy. Mean tumor ctO₂Hb dropped 21.6% at day 1, and spatial extent decreased by 54.3%. (Middle) An example of a partial response. Tumor was 20 mm before chemotherapy. Mean tumor ctO₂Hb increased 53.1% at day 1, and spatial extent increased by 142.1%. (Bottom) An example of a pathologic complete response. Tumor was 30 mm before chemotherapy. Mean tumor ctO₂Hb increased 5.6% at day 1, and spatial extent increased by 4.5%.

Fig. 5.

Percent change in ctO₂Hb magnitude (concentration), spatial extent, and magnitude × spatial extent for NR, PR, and pCR tumors. In all three cases, perfect separation was achieved between nonresponding and responding tumors.