H-Scan Ultrasound Monitoring of Breast Cancer Response to Chemotherapy and Validation With Diffusion-Weighted Magnetic Resonance Imaging

Abstract

Objectives: H-scan ultrasound (US) imaging is a novel tissue characterization technique to detect apoptosis-induced changes in cancer cells after the initiation of effective drug treatment. The objective of the proposed research was to assess the sensitivity of 3-dimensional (3D) H-scan US technique for monitoring the response of breast cancer-bearing animals to neoadjuvant chemotherapy and correlate results to diffusion-weighted magnetic resonance imaging (DW-MRI) measurements of programmed cancer cell death.

Methods: Experimental studies used female mice (N = 18) implanted with human breast cancer cells. Animals underwent H-scan US and DW-MRI imaging on days 0, 1, 3, 7, and 10. After imaging at day 0, breast tumor-bearing nude mice were treated biweekly with an apoptosis-inducing drug. Texture analysis of H-scan US images explored spatial relationships between local US scattering. At day 10, H-scan measurements were compared with DW-MRI-derived apparent diffusion coefficient (ADC) values and histological findings.

Results: H-scan US imaging of low and high dose cisplatin-treated cancer-bearing animals revealed changes in image intensity suggesting a progressive decrease in aggregate US scatterer size that was not observed in control animals. Longitudinal trends discovered in H-scan US result matched with texture analysis and DW-MRI (P < .01). Further, analysis of the H-scan US image intensity and corresponding DW-MRI-derived ADC values revealed a strong linear correlation (R² = .93, P < .001). These changes were due to cancer cell apoptotic activity and consider as early detectable biomarker during treatment.

Conclusions: The 3D H-scan technique holds promise for assisting clinicians in monitoring the early response of breast cancer tumor to neoadjuvant chemotherapy and adding value to traditional diagnostic ultrasound examinations.

Keywords: H-scan; apoptosis; breast cancer; diffusion-weighted magnetic resonance imaging; tissue characterization; ultrasound.

Figure 1.

Following effective treatment with apoptosis-inducing chemotherapeutic drugs, cancer cell aggregates undergo morphological changes including nuclear condensation and then fragmentation at an early stage.

Figure 2.

Experimental timeline including animal preparation, drug treatment, and H-scan ultrasound (US) and diffusion-weighted magnetic resonance imaging (DW-MRI) schedules. At study conclusion, animals were euthanized and tumors excised for histological analysis.

Figure 3.

Schematic diagram highlighting the US data processing strategy for 3-dimensional (3D) H-scan US image reconstruction. Briefly, after attenuation correction, a pair of nth-order Gaussian-weighted Hermite polynomial filters (denoted GH₆ and GH₁₂) were applied to the US data for measuring the relative strength of the received signals. Thereafter, the isolated lower and higher frequency backscattered US signal content was assigned to bluer and redder hue channels to denote smaller and larger US scatterers, respectively.

Figure 4.

Representative 3D H-scan US images from breast cancer-bearing mice at baseline (day 0) and at day 1, 3, 7, and 10 after start of neoadjuvant chemotherapy with control drug, low dose cisplatin, or high dose cisplatin. A dot plot of mean H-scan US image intensities and textural analysis involving the image homogeneity parameter reveal changes within days of drug treatment initiation.

Figure 5.

Representative DW-MRI-derived apparent diffusion coefficient (ADC) maps from breast cancer-bearing mice at baseline (day 0) and at day 1, 3, 7, and 10 after start of neoadjuvant chemotherapy with control drug, low dose cisplatin, or high dose cisplatin. A summary of mean ADC values reveals changes within days of drug treatment initiation. A comparison of H-scan US and DW-MRI-based intratumoral measures reveals a linear trend.

Figure 6.

Representative histological images and mean group summary plots of tumor tissue after staining for cancer cell nuclear location (DAPI), proliferation (Ki67), apoptosis (AC3), and tissue morphology (H&E). *indicates P < .05 versus control.