Clip Marker Placement in Primary Lesions of Breast Cancer Patients Receiving Neoadjuvant Therapy (Ultra3Detect)

Prospective, Multicenter Registry Study Evaluating the Feasibility of Ultrasound-guided Clipping of Suspicious Intramammary Lesions in Primary Breast Cancer Patients Receiving Neoadjuvant Therapy (Ultra3Detect)

Neoadjuvant systemic therapy (NST) is increasingly recommended for patients with early breast cancer, and the rate of patients with pathological complete remission (pCR) is increasing due to the use of modern chemotherapy regimens and targeted therapies, especially in patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer and triple negative breast cancer (TNBC). It is therefore important to mark a lesion (with e.g. clip) before the start of NST in order to safely identify and localize a clip and (former) tumor bed after completion of NST. Reliable sonographic detection of the clip would be preferred to mammography-guided detection and marking. In addition to avoiding radiation exposure by mammography and reducing time, personnel and financial expenditure, ultrasound-guided wire marking of the clip is less painful for the patient than stereotactic wire marking.

The present prospective registry study aims to evaluate how often the intramammary Tumark® Vision clip can be detected by ultrasound after completion of NST in patients with TNBC and HER2+ breast cancer and thus, in the case of pCR, how often the elaborate clipping with mammographic (stereotactic) guidance can be avoided.

Study Overview

• Status: Recruiting
• Conditions: Primary Breast Cancer
• Intervention / Treatment: Device: Tumark® Vision clip

Detailed Description

Breast cancer patients whose carcinomas have an aggressive tumor biology which implies the need for chemotherapy are increasingly being treated with NST. As a standard procedure, clip placement of the suspicious lesion is performed after ultrasound-guided core biopsy or mammography-guided vacuum biopsy. Clipping is necessary to enable the clear identification of the sonographically suspicious area of the breast and safe surgical removal of the remaining tumor tissue (if any) during a later surgery, even following a good response under NST. The placement of a marker (clip) is particularly important for the precise localization of the original tumor bed in patients with pCR.

There are a number of commercially available markers (clips) which are indicated for intramammary marking of a lesion and which differ in terms of shape and material. Difficulties may arise in placing the clip in the tumor or the tumor center. In addition, the clip can dislocate from the initial location and/or the clip might not be visualized during response monitoring. Evaluations of the ultrasound-visible clip made of nitinol investigated in this study showed very good results regarding marker dislocation and visibility within 7 days after inital placement.The clip, which immediately unfolds into a 3-dimensional spherical structure after insertion into the tissue, could be detected by both sonography and mammography in all 50 cases after the intervention; however, long-term data data at follow-up controls during and after NST are not available so far.

According to current German guidelines, imaging-assisted wire marking is recommended without restriction before breast conserving surgery for non-palpable lesions. The clip is considered the target lesion for wire marking, which can be done under sonographic or stereotactic control. If the clip is reliably visible on ultrasound (even in patients with pCR), the stereotactic control of wire marking can be omitted. Therefore, the ability to visualize a clip in breast ultrasonography is of great importance.

The present multicenter study aims to evaluate the sonographic detection rate of the intramammary Tumark® Vision clips after NST in clinical routine and the proportion of cases in which the clip cannot be detected, and thus the rate of mammography-guided wire markings.

• Study Type: Observational
• Enrollment (Anticipated): 400

Contacts and Locations

• Study Contact: Name: Sherko Kümmel, MD, PhD; Phone Number: 33001 +49 201174; Email: S.Kuemmel@kem-med.com
• Study Contact Backup: Name: Breast Cancer Trials group (several people), MD or PhD; Phone Number: 33001 +49201174; Email: breastcancer-trials@kem-med.com

Study Locations

• Germany
  • Essen, Germany, 45136
    • Recruiting
    • Interdisciplinary Breast Unit, Kliniken Essen-Mitte
    • Contact: Sherko Kuemmel, MD, PhD; Phone Number: 020117433001; Email: S.Kuemmel@kem-med.com
    • Contact: Mattea Reinisch, MD; Phone Number: +4920117433001; Email: M.Reinisch@kem-med.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Female patients with sonographically suspicious unilateral or bilateral intramammary foci, scheduled for sonography-guided core biopsy and marking of the lesion with the Tumark® Vision Clip.

Description

Inclusion Criteria:

• female patient aged ≥ 18 years
• written informed consent
• patient's consent to NST
• suspicious unilateral or bilateral intramammary foci that can be safely identified by ultrasound
• no evidence of distant metastasis (complete staging does not have to be present at inclusion)
• indication for breast conserving therapy
• no prior clip placement in the confirmed intramammary carcinoma
• patient is able to undergo NST treatment (even if the indication based on tumor biology is not yet available)
• high compliance and high number of planned relevant surgical interventions in participating study center
• patient can understand the scope of this prospective registry study

Exclusion Criteria:

• allergy to titanium and/or nickel
• pregnancy
• ipsilateral relapse (when NST: no exclusion criterion)
• prior extensive breast surgery (starting from quadrant resection)
• inflammatory breast cancer
• extramammary breast cancer
• multicentric or multifocal breast cancer
• patient is not operable
• patient is already undergoing adjuvant/neoadjuvant therapy
• inability to understand the purpose of the clinical trial or to comply with study procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
US-guided core biopsy and clip placement; Female patients with sonographically suspicious, intramammary foci, scheduled for ultrasound-guided core biopsy and marking of the lesion with the Tumark® Vision Clip	Device: Tumark® Vision clip; Suspicious intramammary lesion is marked with clip

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sonographic detection rate of clip at the time of surgery after completion of NST	Intraoperative detection rate of the clip in patients with HER2+ breast cancer or TNBC after at least 12 weeks of NST treatment	At the time of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of ultrasound-guided clip placements per patient	a) Number of lesions marked with a clip per patient and b) Number of clips per lesion	Immediately after placement of clip
Rate of successful clip placements in the tumor center	Not successful: clip placement technically not possible or clip was placed outside the tumor (indication of the distance from the tumor center in mm)	Immediately after placement of clip
Visibility of the device (Tumark® Vision) cannula	Visibility (very good, good, sufficient or bad) of the cannula during US-guided clip placement	During placement of clip
Complications associated with the application of the clip	e.g. hematoma, infection, dislocation, pain (in patients with or without NST)	Up to 6 months after placement of clip
Sonographic detection rate of clips in patients receiving NST	Detection rate at different time points in all patients receiving NST	Immediately after placement of clip as well as after 4-8, 9-12, 13-26 weeks of NST treatment and preoperatively
Sonographic detection rate of clips in TNBC and HER2+ patients receiving NST	Detection rate at different time points in TNBC or HER2+ breast cancer receiving NST	Immediately after clip placement as well as after 4-8, 9-12, 13-26 weeks of NST treatment and preoperatively
Sonographic detection rate of clips in all patients receiving NST and with pCR	Definition of pCR according to residual cancer burden (RCB) score	Immediately after clip placement as well as after 4-8, 9-12,13-26 weeks of NST treatment and preoperatively
Sonographic detection rate of clips in patients not receiving NST	Subgroup of study population not receiving NST	Immediately after clip placement and preoperatively
Intraoperative detection rate of the clip in specimen radiographs	Detection of clip in surgical specimen from the breast subjected to radiography	At the time of surgery
Intraoperative detection rate of the clip on specimen utrasound images	Detection of clip in surgical specimen from the breast subjected to ultrasonography	At the time of surgery
Proportion of patients requiring preoperative, mammography-guided wire marking	If ultrasound-guided wire marking is not feasible, mammography-guided wire marking is performed	Preoperatively
Proportion of patients with mammographic verification after sonographic wire-marking	If ultrasound-guided wire marking is inconclusive	Preoperatively
Proportion of patients with artifacts caused by clips	On ultrasound and/or mammography images	Up to 6 months after placement of clip
Number of patients with complete pathological remission	ypT0/is, ypN0 status after histological evaluation (according to Residual Cancer Burden [RCB] score) of Symmans (2007)	Up to 10 weeks after surgery

Collaborators and Investigators

• Sponsor: Kliniken Essen-Mitte
• Investigators: Principal Investigator: Sherko Kuemmel, MD, PhD, Interdisciplinary Breast Unit, Kliniken Essen-Mitte, Germany; Study Chair: Mattea Reinisch, MD, Interdisciplinary Breast Unit, Kliniken Essen-Mitte, Germany; Study Chair: Jörg Heil, MD, PhD, Department of Gynecology, Breast Center, Heidelberg University, Germany

Publications and helpful links

General Publications

• Ruland AM, Hagemann F, Reinisch M, Holtschmidt J, Kummel A, Dittmer-Grabowski C, Stoblen F, Rotthaus H, Dreesmann V, Blohmer JU, Kummel S. Using a New Marker Clip System in Breast Cancer: Tumark Vision(R) Clip - Feasibility Testing in Everyday Clinical Practice. Breast Care (Basel). 2018 Apr;13(2):116-120. doi: 10.1159/000486388. Epub 2018 Mar 9.
• Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Beckmann MW, Afenjar K, Fresco R, Helms HJ, Xu J, Lin YG, Sparano J, Slamon D. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):115-126. doi: 10.1016/S1470-2045(17)30716-7. Epub 2017 Nov 23.
• von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012 May 20;30(15):1796-804. doi: 10.1200/JCO.2011.38.8595. Epub 2012 Apr 16.
• Shah AD, Mehta AK, Talati N, Brem R, Margolies LR. Breast tissue markers: Why? What's out there? How do I choose? Clin Imaging. 2018 Nov-Dec;52:123-136. doi: 10.1016/j.clinimag.2018.07.003. Epub 2018 Jul 6.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2020
• Primary Completion (Anticipated): June 30, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: July 7, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): August 18, 2021
• Last Update Submitted That Met QC Criteria: August 17, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: breast cancer; ultrasound; neoadjuvant therapy; clip
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: V2_16-04-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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