Clinical trial NCT04862429: Biopsy of Calcifications Under Contrast Enhancement Guide (BoCCE)
Official title: Studio BoCCE: Ruolo Della Biopsia Sotto Guida CEM (Mammografia Con Mezzo di Contrasto) Nella Caratterizzazione Delle Calcificazioni Dubbie o Sospette (BIRADS R3, R4, R5) Non Associate a Masse.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Breast Cancer
Calcification
Keywords: biopsy
contrast enhanced mammography
calcification
Lead sponsor: Azienda USL Reggio Emilia - IRCCS
Sponsor class: OTHER_GOV
Collaborators: name: General Electric
First posted: 2021-04-28
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Test and treat randomized trial.
Primary purpose: DIAGNOSTIC

Brief summary: Calcification clusters are 30-40% of recalls in mammographic screening, but have a low positive predictive value (\~15%) for ductal cancer in situ (DCIS) or invasive cancer. These calcifications often need histological assessment with stereotaxic guided biopsy (Mammotome). With extended calcifications, choosing the best area to biopsy may be challenging.

The main objective of this 1:1 randomized controlled clinical trial is to compare the accuracy of the CESM guide (study arm with biopsy under CESM guidance) with the traditional Mammotome (control arm with biopsy under stereotactic guidance) in conducting the biopsy in the area of greatest malignancy/grade of the lesion, using as gold-standard the histological exam of the operating piece. Women recalled with indication to perform stereotactic biopsy for clusters of suspicious calcifications on mammography (BIRADS R3 or R4 or R5) not mass-associated will be included. Anticipated sample size is 100 women per arm.

Detailed description: Rationale Suspicious calcifications requiring further assessment are about 30-40% of recalls in mammographic screening. Nevertheless these findings have low positive predictive value (\~15%) for ductal cancer in situ (DCIS) or invasive cancer. However, these calcifications are more frequently sent to biopsy than other doubt or suspect findings, due the difficulty in resolving the suspect with ultrasounds or with other imaging techniques.

For their histological check a biopsy with stereotaxic guidance (Mammotome) should be performed; when calcifications appear in several distinct clusters or over extended area, it is difficult to choose the best area to biopsy.

CESM is a technique that fuses mammographic images able to capture the morphology of calcifications (not visible at MRI) and the enanchement due to metabolic cellular and tissue vascular changes (not visible at usual X-ray imaging). Contrast-enhanced mammography (CESM) allows the description of both morphology and distribution of calcifications and contrast enhancement (CE). In the identification of pathological calcifications, CESM showed 91% sensitivity, 84% specificity, 77% VPP and 93% VPN, providing additional information for cancer diagnosis and dimensional definition of the pathological area.

This technique has the potential to allow a better sampling when biopsing calcifications than standard stereotactic biopsy.

Main objective: to compare the accuracy of CESM guide vs. stereotactic Mammotome guide in conducting biopsy in the area of major malignancy/grade of lesion.

Secondary objectives:

Between the two arms:

* To compare the proportion of patients undergoing pre-operative imaging with contrast media administration (it is expected to be almost 100% in intervention arm, but also in control arm some women will require additional pre-surgery assessment with MRI);
* To compare the proportion of upgrading from DCIS G1/G2 in pre-operative biopsy to DCIS G3 in surgical specimen;
* To compare the sensitivity of biopsy in the diagnosis of microinvasive/invasive tumors (pathology on surgical specimen as reference);
* Waiting time between biopsy and surgery;

Within the CESM arm:

* To compare mammography and CESM in terms of accuracy in the definition of lesion size and multifocality;
* To evaluate the association between the intensity of enhancement at CESM and the grade of malignancy of the lesion at histological examination on surgical specimen.

Population Women recalled with indication to perform stereotactic biopsy for clusters of suspicious calcifications on mammography (BIRADS R3 or R4 or R5) not mass-associated will be included. Anticipated sample size is 100 women per arm; this sample size will give a 75% power to detect.

Neoadjuvant therapy cannot be considered as an exclusion criteria, since the referral would occur after the enrollment and randomization. However, since it is extremely rare that not-mass associated lesions characterized by calcifications would require neoadjuvant therapy, the investigators do not anticipate to include patients who will be referred to therapy before surgery. If this unlikely event happens, women referred to neaodjuvant therapy will be included in the study without contributing to the analyses on the main objective and secondary objectives involving a comparison with post-operative pathological assessment.

Intervention Potentially eligible women will be informed about the study by the investigator radiologist during the visit in which mammography results are communicated. Women who express the willingness to participate will be asked to sign the informed consent and randomized to one arm with a 1:1 ratio.

Women in the experimental arm will undergo CESM. If in the images contrast-enhancement is visible, stereotactic biopsy will be performed under CESM guidance. After administration of an additional dose of iodized contrast-enhancement (Omnipaque), the insertion of the biopsy needle and the biopsy sampling will be targeted on the area of greatest enhancement in the context of calcifications. In the absence of contrast-enhancement, stereotactic biopsy Mammotome will be performed, using X-ray guidance. The insertion of the biopsy needle and biopsy will be targeted on the most suspicious calcification cluster or area.

Women in the control arm will undergo stereotactic biopsy (with Mammotome), using X-ray guidance. The insertion of the biopsy needle and biopsy will be targeted on the most suspicious calcification cluster or area.

In both arms, at the end of the procedure, a metal clip marker will be placed in the biopsy site; the placement will be verified with dual orthogonal mammography projection (as regular clinical practice).

According to the test and treat study design, surgical and medical treatments will be defined accordingly to the imaging and histological findings obtained in the arm of allocation.

Outcomes The main outcome is the accuracy of biopsy in collecting material from the most significant area.

Other outcomes will allow to measure downstream consequences of the biopsy. Surgical specimen will be used as the reference standard.

Analyses Main analyses will be conducted according to intention to treat strategy. The outcomes accuracy of biopsy, proportion of patients undergoing pre-operative imaging with contrast (CSM or MRI), proportion of upgraded lesions, biopsy sensitivity for microinvasive/invasive tumors, waiting time between biopsy and surgery will be compared between arms.

The outcomes accuracy in the definition of lesion size and multifocality, and enhancement predictivity for grade malignancy will be analysed within the experimental arm comparing CESM and mammography images in the same woman (paired analysis).

Eligibility criteria: Inclusion Criteria:

* Women with clinical mammography and screening recalls with mammographic confirmation of clusters of suspicious calcifications (BIRADS R3 or R4 or R5) not mass-associated will be included, with indication to perform stereotactic biopsy, evaluated at the Breast Care Facility of AUSL-IRCCS in Reggio Emilia.

Exclusion Criteria:

* Women with contraindication to the administration of iodized contrast medium will be excluded.

Primary outcomes:
measure: Distance in mm between the biopsy site and the area of greatest malignancy/grade in the operating piece.
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
Secondary outcomes:
measure: Proportion of patients needing contrast imaging
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
measure: Diagnosis upgrading
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
measure: Biopsy sensitivity
timeFrame: The reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. Women not needing surgery (negative at biopsy) will be followed up for 24 months in orther to assess the presence of cancers.
measure: Waiting time between biopsy and surgery
timeFrame: The outcome measure is the time from biopsy to first surgical intervention, usually this time is in the range of 3 to 6 weeks.
measure: Accuracy for lesion size
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
measure: Accuracy for multifocality
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
measure: Association between enhancement and grade
timeFrame: Cross-sectional: the reference standard will be collected during surgery, usually 3 to 6 weeks after biopsy. In any case, it cannot be collected more than 6 months after biopsy.
Other outcomes:
Locations:
city: Reggio Emilia
country: Italy
facility: Azienda USL - IRCCS di Reggio Emilia
state: RE
Study officials:
affiliation: AUSL-IRCCS Reggio Emilia
name: Pierpaolo Pattacini, MD
role: PRINCIPAL_INVESTIGATOR
References:
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