Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Nutritional and Metabolic Diseases

Breast Neoplasms

Calcinosis

Metabolic Diseases

Calcium Metabolism Disorders

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.

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.

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).

Contrast enhanced mammography guided biopsy (diagnostic procedure)

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).

Mammography guided biopsy (diagnostic procedure)

Pierpaolo Pattacini, MD

Valentina Iotti, MD

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:

* 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).

Pathology results will be blindly reviewed by external pathologists.

Women with positive mammography for calcifications without mass, requiring biopsy

Biopsy of Calcifications Under Contrast Enhancement Guide (BoCCE)

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.

Completely anonimized IPD with main patients' characteristics, numerical test results (no images) and outcomes.

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).

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)

Proportion of diagnosis upgraded from DCIS G1/G2 in pre-operative biopsy to DCIS G3 in surgical specimen in the two arms.

Sensitivity of biopsy in the diagnosis of microinvasive/invasive tumors (pathology on surgical specimen as reference)

Waiting time between biopsy and surgery compared in the two arms, measured only in women needing surgery.

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.

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.

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.

General Electric

Azienda Unità Sanitaria Locale Reggio Emilia

Carcinoma

Carcinoma, Ductal

Carcinoma in Situ

Breast Carcinoma In Situ

Carcinoma, Intraductal, Noninfiltrating

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Patients with mammographically newly detected ductal in situ carcinoma who undergo surgery at CHC Rijeka in 2024, 2025, and 2026 (consecutively), who agree to have a CEM performed prior to surgery as part of the diagnostic work-up in addition to standard mammography, and who agree to participate in the examination. Group number: 50 patients.

Patients diagnosed with ductal in situ carcinoma who underwent surgery at CHC Rijeka in the period from 2019 to 2024 and whose clinical data are available in the prospectively managed clinical registry for breast diseases at CHC Rijeka and in the Hospital Information System (IBIS). Group number: 50 patients.

The CEM performance protocol involves the intravenous administration of non-ionic, low-osmolarity iodinated contrast medium using an automatic syringe that delivers the required bolus of contrast medium at a dose of 1.5 ml/kg body weight at a rate of 3 ml/s without compressing the breast. After a two-minute pause, necessary to allow the breast parenchyma to absorb (stain) the contrast agent, the patient is positioned for the mammogram and the breast is compressed. First the symptomatic and then the non-symptomatic breast is imaged in two or a total of four standard projections: craniocaudal (CC) and oblique mediolateral (MLO) projections of the breast. The delayed CC and MLO projections of the symptomatic breast are taken within eight minutes of the start of the examination. The delayed mammograms are used to assess the dynamics of the contrast uptake of the lesion and are compared to the same parameters of the breast MRI. The time required to perform the CEM is 8-10 minutes.

Contrast Enhanced Mammography

Petra Valkovic Zujic, PhD

Ana Car Peterko

Nina Bartolovic

Manuela Avirovic, PhD

Mateo Madunic

Emina Grgurevic Dujmic

Sabina Lenac Juranic

Jana Katunar

Doris Segota Ritosa

Slaven Jurkovic

The study hypothesis is that the rate of inadequate surgical margins after conservative breast surgery for DICS and the rate of reoperation (re-excision or/and mastectomy) is lower in the group of patients who underwent standard preoperative mammography and CEM to assess the extent of DICS, compared to the group of patients for whom the preoperative assessment of the extent of in situ breast cancer was not performed using one of the imaging techniques with contrast medium such as contrast mammography or magnetic resonance imaging.

Ductal carcinoma in situ (DCIS) is the earliest form of malignant lesion in the breast, which in most cases is diagnosed by mammography screening, usually in the form of asymptomatic calcifications. The question of whether DCIS is a true malignancy of the breast, which pathological criteria are used for diagnosing and classifying DCIS, but also the questions of the nature of the disease and its overtreatment are controversial. Surgery is still the primary treatment of DCIS, and the status of the surgical margins is of paramount importance. Compared to invasive ductal carcinoma, the re-excision rate in DCIS is relatively high (30-40%), probably because the change is not palpable. Segmental distribution, with areas affected by the disease that are not calcified and therefore not detected, and stricter guidelines for appropriate surgical margins may also contribute to the re-excision rate. Because the diagnosis of DCIS is closely associated with mammographic detection of pathologic calcifications, it was assumed that magnetic resonance (MR) imaging would provide little or no value for their detection and visualization. However, a study conducted by Kuhl et al. showed that breast MRI has a significantly higher sensitivity than mammography in detecting DCIS. In addition, subsequent studies have shown that MRI is more accurate than mammography in assessing the distribution of DCIS. In recent years, mammography with an iodine contrast agent, known as contrast mammography (CEM), has been introduced, which, like MRI, is based on the evaluation of tumor angiogenesis. It is important to emphasize that the sensitivity of CEM in detecting malignant lesions corresponds to the sensitivity of MR. CEM has several advantages over breast MRI, the most important of which are the availability and the shorter imaging time, as well as the shorter time required to analyze the mammogram and read the findings. Numerous studies show that patients tolerate CEM better than MRI.

The study hypothesis is that the rate of inadequate surgical margins after conservative breast surgery for DICS and the rate of reoperation (re-excision or/and mastectomy) is lower in the group of patients who underwent standard preoperative mammography and CEM to assess the extent of DICS, compared to the group of patients for whom the preoperative assessment of the extent of in situ breast cancer was not performed using one of the imaging techniques with contrast medium, such as contrast mammography or magnetic resonance imaging. The interventional cohort involves 50 consecutive patients with newly diagnosed DCIS who will undergo surgery at CHC Rijeka in 2024, 2025, and 2026 and who agree to have a CEM performed before surgery as part of the diagnostic work-up in addition to standard mammography and who agree to participate in the trial. Patients diagnosed with ductal in situ carcinoma who underwent surgery at CHC Rijeka in the period from 2019 to 2024 and whose clinical data are available in the prospectively managed clinical register for breast diseases at CHC Rijeka and the Integrated Hospital Informatics System (IBIS), are included in the second (control) cohort.

Two clinical radiology specialists with experience in breast radiology will evaluate the morphologic and functional features of standard MMG and CEM by consensus, and assess the extent of disease using the BI-RADS lexicon for imaging with contrast mammography. Demographic and imaging data (morphological and functional characteristics on CME such as background parenchymal enhancement, presence/absence of a lesion, location of the lesion in breast quadrant, type of lesion, size of the lesion in mm and BI-RADS category are analyzed for each lesion) will be recorded. Only one lesion per breast is considered, and if multiple lesions are visible, the overall diameter of the suspicious area will be considered. The above parameters are compared with the grade of the DCIS tumor, i. e. the morphological and functional characteristics of G1 and G2 lesions compared to G3 lesions.

The Added Value of Contrast Enhanced Mammography to Standard Mammography in Assessing the Extent of DCIS

The Added Value of Contrast Enhanced Mammography (CEM) to Standard Mammography in Assessing the Extent of Ductal Carcinoma in Situ (DCIS)

Number of patients in whom the estimated size of DCIS (longest diameter in mm) is larger on CEM than on MMG and in whom the actual size in PH report is greater than the size on estimated on MMG

Number of patients in whom the estimated size of DCIS (longest diameter in mm) on CEM is larger than on MMG, but the size in the PH report correlates better with the size estimated on MMG

Number of patients with no difference in the radiological assessment of the size of DCIS (longest diameter in mm), and in whom the size in the PH report correlates with the size on MMG

Number of patients with no difference in the radiological assessment of the size of DCIS (longest diameter in mm is similar on CEM and MMG), but in whom the size in the PH report is greater than the size on MMG and CEM

True positive rate = Number of true positive / (Number of true positive + Number of false negative)

True negative rate = Number of true negative / (Number of true negative + Number of false positive)

False positive rate = Number of false positive / (Number of false positive + Number of true negative)

False negative rate= Number of false negative / (Number of false negative + Number of true positive)

Accuracy = (Number of true positive + Number of true negative) / (Number of true positive+ Number of false positive + Number of true negative + Number of false negative)

Percentage of patients with inadequate surgical margins (\<2mm)

Percentage of repeated surgical procedures in breast

Percentage of breast resection volume based on CEM findings according to the formula (4 x (radius of the lesion + 1 cm)3 ) : (radius of the breast 2 x projection of the breast)

Percentage of breast resection volume based on MMG findings according to the formula (4 x (radius of the lesion + 1 cm)3 ) : (radius of the breast 2 x projection of the breast)

Number of days between the date of the first clinical examination at CHC Rijeka (surgeon or radiologist) and the date of surgery

Size of the lesion determined in millimetres.

Background parenchymal enhancement (symmetric or asymmetric) is categorized as minimal, mild, moderate and marked.

Non-mass enhancement (NME) classified as: focal, linear, segmental, regional, multiple regions or diffuse.

Lesion conspicuity (relative to background) is the degree of enhancement compared to background, described as low, moderate or high

Mass lesions are defined by shape and margin: descriptors for mass shape and margin include oval, round, or irregular shape, with circumscribed or not circumscribed (irregular, spiculated) margin.

Internal pattern can be homogeneous, heterogeneous, or rim enhancement.

All costs related to diagnostic workup and related to surgical treatment will be evaluated for each patient (costs of the procedure, hospital days, readmission rate after the first treatment).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Biopsy of Calcifications Under Contrast Enhancement Guide (BoCCE)	NCT04862429	Breast Cancer Calcification	Contrast enhanc... Mammography gui...	18 Years -	Azienda Unità Sanitaria Locale Reggio Emilia
The Added Value of Contrast Enhanced Mammography to Standard Mammography in Assessing the Extent of DCIS	NCT06217458	DCIS Breast Carcinom... Calcification	Contrast Enhanc...	18 Years - 99 Years	Clinical Hospital Center Rijeka
Biopsy of Calcifications Under Contrast Enhancement Guide (BoCCE)	NCT04862429	Breast Cancer Calcification	Contrast enhanc... Mammography gui...	18 Years -	Azienda Unità Sanitaria Locale Reggio Emilia
The Added Value of Contrast Enhanced Mammography to Standard Mammography in Assessing the Extent of DCIS	NCT06217458	DCIS Breast Carcinom... Calcification	Contrast Enhanc...	18 Years - 99 Years	Clinical Hospital Center Rijeka
Biopsy of Calcifications Under Contrast Enhancement Guide (BoCCE)	NCT04862429	Breast Cancer Calcification	Contrast enhanc... Mammography gui...	18 Years -	Azienda Unità Sanitaria Locale Reggio Emilia

Spots Global Cancer Trial Database for calcification