An interventional study of Contrast enhanced mammography guided biopsy (diagnostic procedure) and Mammography guided biopsy (diagnostic procedure) in Breast Cancer and Calcification, sponsored by Azienda USL Reggio Emilia - IRCCS. Completed at 1 site in Italy. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-05-07.
Sponsored by Azienda USL Reggio Emilia - IRCCS · Not applicable, Interventional, and Diagnostic
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.
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:
Within the CESM arm:
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).
14,825 studies on the registry are indexed under Breast Neoplasms; 3,319 are open to participants now.
This study's enrollment of 184 is above the median of 72 across 10,896 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →Azienda USL Reggio Emilia - IRCCS is the lead sponsor of 93 studies on the registry; 26 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients will be subjected to CESM; the two orthogonal mammographic projections, after intravenous administration of iodized contrast-enhancement (Omnipaque), will be performed. Surgical and medical treatments will be defined accordingly to the imaging and histological findings obtained with the experimental procedure.
Other: Contrast enhanced mammography guided biopsy (diagnostic procedure)
Patients will be subjected to stereotactic biopsy Mammotome as normal clinical practice. Surgical and medical treatments will be defined accordingly to the imaging and histological findings obtained with the standard procedure.
Other: Mammography guided biopsy (diagnostic procedure)
With visible contrast-enhancement, 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. 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).
Also known as: Contrast enhanced spectral mammography guided biopsy
For all lesions, 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. 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).
Also known as: stereotactic biopsy
Distance in mm between the biopsy site and the area of greatest malignancy/grade in the operating piece.
In patients sent to surgery, the main outcome will be determined on the operating piece by a single pathologist operating in blind, which will assess the type of lesion (B1-B5), invasiveness, grade, the extent of the lesion in mm, the percentage of invasive component, the distance in mm between the location of the biopsy and the area of greatest malignancy (DCIS G3 or invasive component). In patients not sent to surgery, the outcome will be determined by following the patients for a follow-up of at least 24 months, verifying if they have undergone surgery on that specific lesion during the follow-up (in particular if they have developed B5 lesions in situ or invasive in that location).
Time frame: 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.
Proportion of patients needing contrast imaging
Proportion of patients undergoing exam of pre-operative imaging with contrast will be compared between the two arms (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)
Time frame: 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.
Diagnosis upgrading
Proportion of diagnosis upgraded from DCIS G1/G2 in pre-operative biopsy to DCIS G3 in surgical specimen in the two arms.
Time frame: 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.
Biopsy sensitivity
Sensitivity of biopsy in the diagnosis of microinvasive/invasive tumors (pathology on surgical specimen as reference)
Time frame: 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.
Waiting time between biopsy and surgery
Waiting time between biopsy and surgery compared in the two arms, measured only in women needing surgery.
Time frame: The outcome measure is the time from biopsy to first surgical intervention, usually this time is in the range of 3 to 6 weeks.
Accuracy for lesion size
Lesion size (in terms of maximum diameter) from imaging (mammography or CESM). The outcome will be compared in the same lesion (paired analysis) only for women in experimental arm. Pathological measure on surgical specimen will be the reference standard.
Time frame: 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.
Accuracy for multifocality
Presence of multifocality (dichotomous variable) from imaging (mammography or CESM). The outcome will be compared in the same lesion (paired analysis) only for women in experimental arm. Pathological judgement on surgical specimen will be the reference standard.
Time frame: 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.
Association between enhancement and grade
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. The association will be measured on the same lesions (paired analysis) including only women in the experimental arm.
Time frame: 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.
Plan to share: Yes — Completely anonimized IPD with main patients' characteristics, numerical test results (no images) and outcomes.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: Seven years since publication of the result about main outcome.
Access criteria: A request to Area Vasta Emilia Nord Ethic Committee should be submitted.
This study is completed, as verified in May 2026. You cannot join it, but the record below documents what was studied.
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