ARFI, VisR and DDAI Ultrasound for Improving Discrimination of Malignant and Unresponsive Breast Cancer

Purpose: The purpose of this study is to evaluate in vivo the diagnostic relevance of ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy.

Participants: Forty women with breast lesions that have a BIRADS-4 or BIRADS-5 rating and forty women undergoing neoadjuvant chemotherapy (NAC) for malignant breast lesions will be recruited. Subjects will be recruited from the Breast Imaging Division of UNC Hospitals.

Procedures (methods): In this exploratory clinical study, the investigators will attempt to demonstrate that ARFI, VisR, and DDAI ultrasound reliably detect malignant breast masses (Aim #1) and distinguish masses that respond to chemotherapy from those that do not (Aim #2). The ARFI, VisR, and DDAI imaging location will be on the surface of the breast, above the suspicious or malignant mass. This unblinded, open-label, exploratory study will be conducted in 40 women with diagnosed BIRADS-4 or -5 masses in Aim #1 and in 40 women with malignant masses undergoing neoadjuvant chemotherapy (NAC) in Aim #2.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Device: Ultrasound

Detailed Description

The primary objective of breast cancer screening is to identify early stage cancer, or precancerous lesions, at a time before symptoms emerge and when treatment is likely to result in a cure. Screening is beneficial when it averts progression of disease to metastasis and/or death, but adverse effects to patients (and unnecessary medical expense) may result downstream from false positives and indiscrimination of masses that will not respond to treatment. The sensitivity of digital mammography, the current screening standard in the US, has been reported in the range of 0.40 to 0.85, with a positive predictive value of 0.31. Sensitivity is increased by augmenting mammography with MRI and B-Mode ultrasound, but false positive rates may also increase3. There exists a vital need for a screening technology that exhibits high sensitivity and specificity for cancer detection with early identification of unresponsive masses.

This urgent need could be met by exploiting new imaging biomarkers. Specifically, the mechanical properties of breast tissue have been used for cancer detection, with both elasticity and viscosity demonstrated for discriminating malignant from benign lesions. Further, tissue anisotropy has been shown to correlate with core biopsy result and tumor grade, with large cancers significantly more anisotropic than small cancers. Importantly, while both MRI and ultrasound can be used to measure these biomarkers, ultrasound's cost effectiveness and ease of implementation render it an efficient platform to pursue.

The long-term goal of this research program is to develop a new ultrasound-based breast-screening tool to augment mammography. As a critical first step toward achieving this goal, the primary objective of the proposed research is to evaluate in vivo the diagnostic relevance of ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy. These biomarkers will be measured using novel, noninvasive ultrasound technologies under development in Dr. Gallippi's laboratory: 1) Acoustic Radiation Force Impulse (ARFI) ultrasound for interrogating tissue stiffness, 2) Viscoelastic Response (VisR) ultrasound for assessing tissue elasticity and viscosity, and 3) Dynamic Displacement Anisotropy Imaging (DDAI) for measuring tissue anisotropy. These technologies have been demonstrated previously for delineating atherosclerosis, muscular dystrophy, and renal dysfunction.

A.1.2.State the research question(s) (i.e., specific study aims and/or hypotheses).

The investigators hypothesize that ultrasound-derived stiffness, elasticity, viscosity, and anisotropy will correlate with lesion malignancy and response to treatment. To test this hypothesis, they will pursue the following specific aims:

Aim #1: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and anisotropy to detect malignancy. ARFI, VisR, and DDAI imaging will be performed on suspicious breast lesions in 40 women with BIRADS-4a, 4b, 4c, or -5 ratings. The diagnostic accuracy of imaging metrics will analyzed, with malignancy confirmed by histology as the outcome.

Aim #2: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and anisotropy to predict a positive response to treatment. ARFI, VisR, and DDAI imaging will be performed serially - once every four weeks over the course of neoadjuvant chemotherapy (NAC) - on malignant breast lesions in 40 women. Changes in outcome metrics over time will be correlated to overall reduction in tumor size (diameter and area). The ability of ultrasound metrics to predict a positive response to treatment will be examined. A positive response to treatment will be determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

• Study Type: Observational
• Enrollment (Actual): 45

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Forty women with breast lesions that have a BIRADS-4 or BIRADS-5 rating and forty women undergoing neoadjuvant chemotherapy (NAC) for malignant breast lesions will be recruited.

Description

Inclusion Criteria:

-

Aim 1:

Inclusion Criteria:

• Patients are 30-90 years of age
• Patients have breast masses with BIRADS 4a, 4b, 4c, or 5 rating
• Lesion is sonographically visible with B-Mode ultrasound on diagnostic workup
• Informed consent obtained and signed

Aim 2:

Inclusion Criteria:

• Patients are 30-90 years
• Patients who are or will be undergoing neoadjuvant chemotherapy (NAC) for stage 2 or 3 malignant breast lesions
• Lesion is sonographically visible with B-Mode ultrasound on diagnostic workup
• Informed consent is obtained and signed

Exclusion Criteria: Subjects who meet any of the exclusion criteria will be excluded from study participation for both Aim 1 and Aim 2.

• Inability to provide informed consent
• Inability to communicate in English
• Inability to remain motionless for 15 minutes
• Suspicious or malignant breast mass deeper than 3 cm from skin surface
• Previous biopsy or surgery to the site of the suspicious or malignant mass
• Patients who are pregnant
• Patients who are lactating
• Patients with a history of masectomy
• Patients with breast implants

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Women scheduled for biopsy; 40 participants with diagnosed BIRADS-4a, 4b, 4c, or -5 masses will be recruited. The investigators aim to have approximately 10 in each of the BIRADS categories (4a, 4b, 4c, 5), resulting in 40 total subjects for Aim #1.	Device: Ultrasound; Breast ultrasound
Women scheduled for neoadjuvant chemo; 40 participants with malignant masses undergoing neoadjuvant chemotherapy (NAC) will be recruited.	Device: Ultrasound; Breast ultrasound

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of Peak Displacement (PD) for Detecting Malignancy	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate peak displacement (PD) and correlated with biopsy findings of malignant or benign. Peak Displacement (PD) - Maximum displacement of tissue in the breast lesion after an Acoustic Radiation Force Impulse (ARFI) excitation. Participants who have undergone breast ultrasonogram were categorized as BIRADS-4a, 4b, 4c, or -5 masses.	Baseline imaging
Weighted Correlation Between Peak Displacement (PD) to Predict Response to Neoadjuvant Chemotherapy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate peak displacement (PD) and correlated with biopsy findings of malignant or benign. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans. Peak Displacement (PD) - Maximum displacement of tissue in the breast lesion after an Acoustic Radiation Force Impulse (ARFI) excitation.	Up to 8 months
Weighted Correlation Between Displacement at a Given Time (TD) for ARFI to Predict Response to Neoadjuvant Chemotherapy	The ultrasound data was processed to calculate displacement at a given time (TD) for ARFI and statistically correlated to response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Acoustic Radiation Force Impulse (ARFI) - Ultrasound imaging technique in which a sacoustic pulse is transmitted into tissue, causing it to displace and recover in <1 ms. The tissue displacement was used to estimate stiffness and viscosity. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesion not shrinking by 25% or more over the course of chemotherapy. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans.	Up to 8 months
Weighted Correlation Between Relative Elasticity (RE) to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data will be processed to calculate relative elasticity (RE) and statistically correlated to response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Relative Elasticity (RE) - Qualitative estimate for tissue stiffness in the breast lesion based on VisR imaging. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesion not shrinking by 25% or more over the course of chemotherapy. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans.	Up to 8 months
Weighted Correlation Between Relative Viscosity (RV) to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data will be processed to calculate relative viscosity (RV) and statistically correlated to response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Relative Viscosity (RV) - Qualitative estimate for tissue viscosity in the breast lesion based on VisR imaging. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesions not shrinking by 25% or more over the course of chemotherapy. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans.	Up to 8 months
Weighted Correlation Between Tissue Mass (TM) for VisR to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data will be processed to calculate tissue mass (TM) for VisR and statistically correlated to the response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Tissue Mass (TM) - Qualitative estimate for tissue mass in the breast lesion based on VisR imaging. Viscoelastic Response (VisR) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into the tissue, causing it to displace and recover. The tissue recovery curve is then fit to a mass-spring-damper physics model to estimate stiffness and viscosity. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesions not shrinking by 25% or more over the course of chemotherapy. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans.	Up to 8 months
Comparison of ARFI PD Values at 90o Versus 0o Transducer Orientations for DDAI to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data will be processed to calculate the ratio of ARFI PD values at 90o versus 0 o transducer orientations for DDAI and statistically correlated to the response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Acoustic Radiation Force Impulse (ARFI) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into the tissue, causing it to displace and recover in less than a millisecond. The tissue displacement can be tracked and used to estimate stiffness and viscosity. Peak Displacement (PD) - Maximum displacement of tissue in the breast lesion after an ARFI excitation. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesions not shrinking by 25% or more. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks btwn.	Up to 8 months
Comparison of Ratio of ARFI PD Values at 90o Versus 0o Transducer Orientations for DDAI to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data was processed to calculate ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI and statistically correlated to response of treatment with neoadjuvant chemotherapy. Values were weighted based on the number of imaging visits during subjects' treatment. Participants were imaged at baseline and end of each chemo cycle. Patients were imaged 3-8 times w/ 3-4 weeks btwn scans. Viscoelastic Response (VisR) - Ultrasound technique in which an acoustic pulse is transmitted into the tissue, causing it to displace and recover. Tissue recovery is fit to a mass-spring-damper physics model to estimate stiffness and viscosity. Relative Elasticity (RE) - Qualitative estimate for tissue stiffness in the breast lesion based on VisR imaging. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesions not shrinking by 25% or more over the course of chemotherapy.	Up to 60 days
Weighted Correlation Between Ratio of RV Values at 90o Versus 0o Transducer Orientations for DDAI to Predict Response to Neoadjuvant Chemotherapy.	The ultrasound data will be processed to calculate ratio of RV values at 90o versus 0o transducer orientations for DDAI and statistically correlated to response of treatment with neoadjuvant chemotherapy. These values were weighted based on the number of imaging visits during subjects' treatment. Participants were imaged at baseline and end of each chemotherapy cycle. Patients were imaged 3-8 times w/ 3-4 weeks between scans. Relative Viscosity (RV) - Qualitative estimate for tissue viscosity in the breast lesion based on VisR imaging. Response to chemo - Defined as the lesion shrinking by 25% or more over the course of chemotherapy. Non-responders to chemo - Defined as lesion not shrinking by 25% or more over the course of chemotherapy.	Up to 8 months
Correlation of Displacement at a Given Time (TD) for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate displacement at a given time (TD) for ARFI and correlated with biopsy findings of malignant or benign. Acoustic Radiation Force Impulse (ARFI) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into tissue, causing it to displace and recover in less than a millisecond. The tissue displacement can be tracked and used to estimate stiffness and viscosity. Participants were imaged at baseline.	Baseline
Correlation of Relative Elasticity (RE) for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate relative elasticity (RE) and correlated with biopsy finding of malignant or benign. Relative Elasticity (RE) - Qualitative estimate for tissue stiffness in the breast lesion based on VisR imaging.	Baseline
Correlation of Relative Viscosity (RV) for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate relative viscosity (RV) and correlated with biopsy findings of malignant or benign. Relative Viscosity (RV) - Qualitative estimate for tissue viscosity in the breast lesion based on VisR imaging. Participants were imaged according to their neoadjuvant chemotherapy schedule, at baseline and end of each chemotherapy type	Baseline
Correlation of Tissue Mass (TM) for VisR for Detecting Malignancy	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate tissue mass (TM) for VisRand correlated with biopsy findings of malignant or benign. Participants were imaged according to their neoadjuvant chemotherapy schedule, at baseline and end of each chemotherapy type Viscoelastic Response (VisR) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into the tissue, causing it to displace and recover. The tissue recovery curve is then fit to a mass-spring-damper physics model to estimate stiffness and viscosity.	Baseline
Correlation of Ratio of ARFI PD Values at 90o Versus 0o Transducer Orientations for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate ratio of ARFI PD values at 90o versus 0o transducer orientations for DDAI and correlated with biopsy findings of malignant or benign. Participants were imaged according to their neoadjuvant chemotherapy schedule, at baseline and end of each chemotherapy type Acoustic Radiation Force Impulse (ARFI) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into the tissue, causing it to displace and recover in less than a millisecond. The tissue displacement can be tracked and used to estimate stiffness and viscosity. Peak Displacement (PD) - Maximum displacement of tissue in the breast lesion after an ARFI excitation.	Baseline
Correlation of Ratio of VisR RE Values at 90o Versus 0o Transducer Orientations for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate the ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI and correlated with biopsy findings of malignant or benign. Participants were imaged according to their neoadjuvant chemotherapy schedule, at baseline and end of each chemotherapy type Viscoelastic Response (VisR) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into the tissue, causing it to displace and recover. The tissue recovery curve is then fit to a mass-spring-damper physics model to estimate stiffness and viscosity. Relative Elasticity (RE) - Qualitative estimate for tissue stiffness in the breast lesion based on VisR imaging.	Baseline
Correlation of Ratio of VisR RV Values at 90o Versus 0o Transducer Orientations for Detecting Malignancy.	The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data were processed to calculate ratio of VisR RV values at 90o versus 0o transducer orientations for DDAI and correlated with biopsy findings of malignant or benign. Participants were imaged according to their neoadjuvant chemotherapy schedule, at baseline and end of each chemotherapy type Displacement at Time (TD) - Displacement of tissue in the breast lesion at time t=0.2 ms after an ARFI excitation. Viscoelastic Response (VisR) - Ultrasound imaging technique in which a strong acoustic pulse is transmitted into tissue, causing it to displace and recover. The tissue recovery curve is then fit to a mass-spring-damper physics model to estimate stiffness and viscosity. Relative Viscosity (RV) - Qualitative estimate for tissue viscosity in the breast lesion based on VisR imaging.	Baseline

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Investigators: Principal Investigator: Caterina Gallippi, PhD, University of North Carolina

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2018
• Primary Completion (Actual): July 15, 2021
• Study Completion (Actual): July 15, 2021

Study Registration Dates

• First Submitted: December 14, 2018
• First Submitted That Met QC Criteria: December 19, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 18, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Screening
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: LCCC1745

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: 9 to 36 months following publication
• IPD Sharing Access Criteria: The investigator who proposes to use the data has approval from an IRB, IEC, or REB, as applicable, and an executed data use/sharing agreement with UNC.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No