Contrast-Enhanced Ultrasound for Breast Cancer

Recruiting at 2 trial locations

Overseen By Kibo Nam, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2 & 3

Sponsor: Kibo Nam

Must be taking: Neoadjuvant chemotherapy

Must not be taking: Endocrine therapy

Disqualifiers: Males, Metastatic disease, Unstable health, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Varies with NAC schedule

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial studies if contrast-enhanced ultrasounds using a contrast dye, perflutren lipid microspheres (Definity), can predict the response to chemotherapy by estimating the pressure in the cancer in patients with breast cancer that has spread to nearby tissues and lymph nodes (locally advanced). The efficacy of cancer therapy is affected by the pressure in the cancer. Definity is a contrast dye used to create better images during ultrasounds. The purpose of this trial is to determine if a special kind of ultrasound, called contrast-enhanced ultrasound, an experimental imaging test, can detect pressures in cancer to determine the response to neoadjuvant chemotherapy in patients with breast cancer.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Perflutren Lipid Microspheres, Definity, Definity RT for breast cancer?

The research does not provide direct evidence for the effectiveness of Perflutren Lipid Microspheres, Definity, or Definity RT in treating breast cancer, but it does highlight the use of similar contrast agents like perflubutane in enhancing ultrasound imaging to differentiate between benign and malignant breast lesions. ^{1 2 3 4 5}

Is contrast-enhanced ultrasound using Definity safe for humans?

Definity, a contrast agent used in ultrasound, has been associated with some serious heart and lung reactions, including a few deaths, but these are rare. Most studies show that severe adverse reactions are uncommon, and the use of Definity does not significantly increase the risk of severe events compared to not using it. ^{6 7 8 9 10}

How is contrast-enhanced ultrasound different from other breast cancer treatments?

Contrast-enhanced ultrasound (CEUS) for breast cancer is unique because it uses a special contrast agent, like perflubutane, to improve the imaging of breast tissue, helping to differentiate between benign and malignant lesions. Unlike traditional treatments, CEUS is primarily a diagnostic tool that enhances ultrasound images to assess tumor characteristics and predict responses to therapies, rather than directly treating the cancer itself. ^{1 2 4 11 12}

Research Team

Kibo Nam, PhD

Principal Investigator

Thomas Jefferson University

Eligibility Criteria

This trial is for adults over 21 with locally advanced breast cancer, scheduled for neoadjuvant chemotherapy, and willing to follow study procedures. It's not for those with other primary cancers, distal metastatic disease, pregnant or nursing women, or individuals with certain heart conditions, recent surgery, unstable cardiopulmonary issues, or allergies to Definity.

Inclusion Criteria

I am scheduled for chemotherapy before surgery.

I am a woman who can have children and my pregnancy test is negative.

Provide signed and dated informed consent form

Exclusion Criteria

I do not have serious heart rhythm problems.

I have severe lung problems like emphysema or blood clots in my lungs.

I do not have severe heart failure that limits my daily activities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Imaging

Participants undergo unenhanced baseline ultrasound imaging before NAC

1 week

1 visit (in-person)

Treatment

Participants receive neoadjuvant chemotherapy (NAC) and undergo contrast-enhanced ultrasound (CEUS) with perflutren lipid microspheres at multiple time points

Varies with NAC schedule

Multiple visits (in-person) for CEUS and NAC

Follow-up

Participants are monitored for safety and effectiveness after completion of NAC

4 weeks

Treatment Details

Interventions

• Perflutren Lipid Microspheres

Trial Overview The trial tests if contrast-enhanced ultrasounds using Definity can predict chemotherapy response by measuring pressure in the tumor. This phase II/III trial aims to improve imaging techniques during treatment of locally advanced breast cancer.

Participant Groups

Group I: Diagnostic (CEUS, Definity) Experimental Treatment 3 Interventions

Patients undergo CEUS and receive perflutren lipid microspheres IV over 10-15 minutes before NAC, after 10% of NAC, and after 30% of NAC. Patients also undergo unenhanced baseline ultrasound imaging before NAC, after 10% of NAC, after 30% of NAC, and after 100% of NAC

Who Is Running the Clinical Trial?

Kibo Nam

Lead Sponsor

Trials

1

Recruited

200+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Contrast-enhanced ultrasound (CEUS) using Sonazoid significantly improved the accuracy of diagnosing focal breast lesions compared to unenhanced ultrasound, with an accuracy rate of 87.2% versus 65.5%.

CEUS also demonstrated higher specificity than both unenhanced ultrasound and contrast-enhanced MRI, while maintaining a low incidence of mild adverse reactions (3.3%), indicating it is a safe and effective diagnostic tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of sonazoid (perflubutane) for contrast-enhanced ultrasound in the differentiation of focal breast lesions: phase 3 multicenter clinical trial. Miyamoto, Y., Ito, T., Takada, E., et al.[2016]

In a study of 100 patients with invasive breast cancer, perfusion parameters from contrast-enhanced ultrasonography were found to be significantly higher in estrogen receptor-negative tumors compared to positive ones, indicating a potential link between these parameters and tumor biology.

The study demonstrated that variations in peak intensity of Ki-67, a marker of cell proliferation, were strongly correlated with perfusion parameters, suggesting that these imaging techniques could effectively predict high-grade malignancy and inform treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Malignancy Grade of Breast Cancer Using Perflubutane-Enhanced Ultrasonography. Masumoto, N., Kadoya, T., Amioka, A., et al.[2017]

In a study involving 65 breast cancer patients, parametric imaging in contrast-enhanced ultrasound (CEUS) significantly improved the visibility of tumors compared to standard imaging methods, with the best average ranking for parametric images.

The maximal tumor diameter measured by CEUS showed a strong correlation with pathological findings, indicating that CEUS can be a reliable tool for assessing tumor size in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of parametric imaging on contrast-enhanced ultrasound of breast cancer. Noro, A., Nakamura, T., Hirai, T., et al.[2019]

Contrast-enhanced ultrasound (CEUS) demonstrated high sensitivity (88%) and specificity (82%) in distinguishing between benign and malignant breast lesions, based on a systematic review of 51 studies involving 4875 patients.

CEUS also effectively predicted the pathologic response to neoadjuvant chemotherapy in breast cancer patients, with a sensitivity of 89% and specificity of 83%, indicating its potential as a reliable imaging tool in breast cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Contrast-Enhanced Ultrasound in the Diagnosis and Pathologic Response Prediction in Breast Cancer: A Meta-analysis and Systematic Review. Zhou, SC., Le, J., Zhou, J., et al.[2021]

Molecular ultrasound using VEGFR2-targeted microbubbles (BR55) is effective for imaging very early breast carcinomas, particularly in small lesions (2 mm in diameter), where the binding of microbubbles is highest.

As tumors grow larger, the expression of VEGFR2 decreases, but the imaging technique remains reliable, indicating its potential for detecting and characterizing small breast lesions based on angiogenic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55). Bzyl, J., Palmowski, M., Rix, A., et al.[2022]

In a study involving 4,786 patients undergoing stress echocardiography, the use of perflutren-based contrast agents like Definity and Optison did not increase the risk of severe adverse events compared to patients who did not receive contrast.

The rates of serious complications, including death within 24 hours and cardiac arrest, were similar between those receiving contrast and those who did not, indicating that the use of these contrast agents is generally safe in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of ultrasound contrast agents in stress echocardiography. Gabriel, RS., Smyth, YM., Menon, V., et al.[2015]

In response to serious safety concerns, including 4 patient deaths and 190 serious reactions, the FDA issued a 'black box' warning for ultrasound contrast agents Definity and Optison, leading to a significant decline in their use in the US.

Recent safety data and discussions from the FDA Cardio-Renal panel indicate ongoing evaluation of these agents, with revised labeling aimed at improving safety protocols for contrast echocardiography.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound contrast agents: balancing safety versus efficacy. Main, ML., Goldman, JH., Grayburn, PA.[2022]

A 73-year-old patient experienced sudden death shortly after receiving a perflutren contrast agent during an echocardiogram, highlighting potential risks associated with its use in patients with severe heart conditions.

Despite the timing of the death, autopsy results did not establish a direct link between the perflutren agent and the fatal event, suggesting that this case may represent a pseudocomplication rather than a direct adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sudden death after intravenous administration of a perflutren contrast agent: a case of pseudocomplication? Mahjoub, H., Roméo, P., Leung, TK., et al.[2014]

In the first year of using the second-generation contrast agent Definity in echocardiography, 161 patients showed a significant improvement in endocardial definition scores (p=0.0001), enhancing the clarity of heart imaging.

The use of contrast echocardiography led to the detection of clinically significant conditions that were missed in standard 2D imaging, with a very low adverse event rate of only 0.6%, indicating its safety and efficacy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast echocardiography in Australian clinical practice. Hamilton-Craig, C., Boga, T., West, C., et al.[2022]

In a study involving 1,060 patients, Definity (perflutren lipid microsphere) was found to be well tolerated, with no deaths or serious adverse events reported during or within 30 minutes after administration.

The overall adverse event rate was 10.8%, with a low drug-related adverse event rate of 3.5%, indicating that most adverse events were mild or moderate, making Definity a safe option for patients with suboptimal echocardiograms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CaRES (Contrast Echocardiography Registry for Safety Surveillance): a prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice. Weiss, RJ., Ahmad, M., Villanueva, F., et al.[2022]

Haemodynamic contrast-enhanced ultrasound assessment demonstrated a high diagnostic sensitivity of 97% and specificity of 80% in distinguishing between benign and malignant breast lesions, based on a study of 50 patients.

Key metrics such as area under the curve (AUC) and peak enhancement (PE) were significant indicators of malignancy, suggesting that this ultrasound technique can effectively aid in breast cancer diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A contrast-enhanced ultrasound study of benign and malignant breast tissue. Barnard, S., Leen, E., Cooke, T., et al.[2016]

Contrast-enhanced ultrasonography is particularly effective for detecting and characterizing liver lesions, showcasing its utility in clinical settings.

Recent advancements in high-frequency transducers have expanded the application of ultrasound contrast agents to functional studies of organ and tumor perfusion, providing valuable insights into treatment responses in both animal and clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ultrasound contrast media--principles and clinical applications]. Delorme, S., Krix, M., Albrecht, T.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Efficacy of sonazoid (perflubutane) for contrast-enhanced ultrasound in the differentiation of focal breast lesions: phase 3 multicenter clinical trial. [2016]

2. England pubmed.ncbi.nlm.nih.gov

Evaluation of Malignancy Grade of Breast Cancer Using Perflubutane-Enhanced Ultrasonography. [2017]

3. Japan pubmed.ncbi.nlm.nih.gov

Impact of parametric imaging on contrast-enhanced ultrasound of breast cancer. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

The Role of Contrast-Enhanced Ultrasound in the Diagnosis and Pathologic Response Prediction in Breast Cancer: A Meta-analysis and Systematic Review. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55). [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Safety of ultrasound contrast agents in stress echocardiography. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Ultrasound contrast agents: balancing safety versus efficacy. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Sudden death after intravenous administration of a perflutren contrast agent: a case of pseudocomplication? [2014]

9. Australia pubmed.ncbi.nlm.nih.gov

Contrast echocardiography in Australian clinical practice. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

CaRES (Contrast Echocardiography Registry for Safety Surveillance): a prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice. [2022]

11. South Africa pubmed.ncbi.nlm.nih.gov

A contrast-enhanced ultrasound study of benign and malignant breast tissue. [2016]

12. Germany pubmed.ncbi.nlm.nih.gov

[Ultrasound contrast media--principles and clinical applications]. [2022]