Enrico Cassano

Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women.

PURPOSE Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

Ultrasound-guided vacuum-assisted core breast biopsy: experience with 406 cases

PurposeThe aim of this study was to determine the indications, accuracy and complications of vacuum-assisted breast biopsy (VABB) performed using ultrasonographic (US) guidance for non-palpable lesions.Materials and methodsThis was a prospective study in which results from consecutive US-guided VABB performed between January 1999 and April 2003 were subsequently compared to those from excisional biopsy or to long-term follow-up imaging.ResultsFour hundred and six lesions were submitted to VABB procedures. Out of those, 78.9% were benign, 18.8% were malignant, 1.7% was lobular neoplasia, and 0.4% was atypical duct hyperplasia. Underestimation occurred in 2.6% of the cases and false negative results in 0.6%. Sensitivity to VABB was 97%, specificity went up to 100%, negative predictive value was 99%, positive predictive value was 100%, and accuracy was 99%. Complications occurred in 9% of the patients.ConclusionUS-guided VABB is an accurate and safe procedure. The main indication is the non-palpable suspicious breast lesions (category 4). This new technique could be a good alternative for percutaneous and surgery biopsy.

Noninvasive assessment of breast cancer risk using time-resolved diffuse optical spectroscopy.

Breast density is a recognized strong and independent risk factor for breast cancer. We propose the use of time-resolved transmittance spectroscopy to estimate breast tissue density and potentially provide even more direct information on breast cancer risk. Time-resolved optical mammography at seven wavelengths (635 to 1060 nm) is performed on 49 subjects. Average information on breast tissue of each subject is obtained on oxy- and deoxyhemoglobin, water, lipids, and collagen content, as well as scattering amplitude and power. All parameters, except for blood volume and oxygenation, correlate with mammographic breast density, even if not to the same extent. A synthetic optical index proves to be quite effective in separating different breast density categories. Finally, the estimate of collagen content as a more direct means for the assessment of breast cancer risk is discussed.

Magnetic resonance mammography in the evaluation of recurrence at the prior lumpectomy site after conservative surgery and radiotherapy

IntroductionThe aim was to assess the value of magnetic resonance mammography (MRM) in the detection of recurrent breast cancer on the prior lumpectomy site in patients with previous conservative surgery and radiotherapy.MethodsBetween April 1999 and July 2003, 93 consecutive patients with breast cancer treated with conservative surgery and radiotherapy underwent MRM, when a malignant lesion on the site of lumpectomy was suspected by ultrasound and/or mammography. MRM scans were evaluated by morphological and dynamic characteristics. MRM diagnosis was compared with histology or with a 36-month imaging follow-up. Enhancing areas independent of the prior lumpectomy site, incidentally detected during the MRM, were also evaluated.ResultsMRM findings were compared with histology in 29 patients and with a 36-month follow-up in 64 patients. MRM showed 90% sensitivity, 91.6% specificity, 56.3% positive predictive value and 98.7% negative predictive value for detection of recurrence on the surgical scar. MRM detected 13 lesions remote from the scar. The overall sensitivity, specificity, positive predictive value and negative predictive value of MRM for detection of breast malignancy were 93.8%, 90%, 62.5% and 98.8%, respectively.ConclusionMRM is a sensitive method to differentiate recurrence from post-treatment changes at the prior lumpectomy site after conservative surgery and radiation therapy. The high negative predictive value of this technique can avoid unnecessary biopsies or surgical treatments.

Positive predictive value for malignancy on surgical excision of breast lesions of uncertain malignant potential (B3) diagnosed by stereotactic vacuum-assisted needle core biopsy (VANCB): A large multi-institutional study in Italy

Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.

Stereotactic Vacuum-Assisted Breast Biopsy Is Not a Therapeutic Procedure Even When All Mammographically Found Calcifications Are Removed: Analysis of 4,086 Procedures

OBJECTIVE The purpose of our study was to assess whether in case of total removal of microcalcifications there is still residual tumor on the surgical specimen and, secondarily, to assess whether complete rather than partial excision of the imaging target with microcalcifications may result in increased diagnostic accuracy. MATERIALS AND METHODS We retrospectively reviewed 4,086 stereotactic vacuum-assisted breast biopsy (VABB) procedures for microcalcifications and histologic findings to determine the frequency of malignancy, histologic underestimation, and complete removal of cancer. RESULTS No residual microcalcifications on postbiopsy mammograms were seen in 1,594 of 4,047 (39.4%) procedures successfully completed: 351 of 1,594 lesions were malignant, 1,109 benign and 134 atypical. After partial removal of microcalcifications at VABB, the postsurgical specimen had infiltrating carcinoma in 130 of 566 cases (23%), whereas in case of total removal of microcalcifications, the underestimation occurred in 13 of 234 (5.5%) cases. The atypical ductal hyperplasia underestimation rate was 6.6% when the mammography target was completely removed and 38.7% when the target was only sampled. The percentage of lobular carcinoma in situ underestimation was the same for the two groups with partial and total removal of microcalcifications (21.2%). Among 1,016 VABB procedures with pathologic result of malignancy, 882 (86.6%) had residual cancer at surgery. In the group with complete removal of microcalcifications at VABB, residual cancer was found in 70% of cases. CONCLUSION VABB may not be considered a therapeutic procedure, even in the case of complete removal of microcalcifications. However, a complete removal of microcalcifications may result in low rates of underestimation of malignancy and may consequently increase the diagnostic accuracy of the diagnostic procedure.

Estimate of tissue composition in malignant and benign breast lesions by time-domain optical mammography.

The optical characterization of malignant and benign breast lesions is presented. Time-resolved transmittance measurements were performed in the 630-1060 nm range by means of a 7-wavelength optical mammograph, providing both imaging and spectroscopy information. A total of 62 lesions were analyzed, including 33 malignant and 29 benign lesions. The characterization of breast lesions was performed applying a perturbation model based on the high-order calculation of the pathlength of photons inside the lesion, which led to the assessment of oxy- and deoxy-hemoglobin, lipids, water and collagen concentrations. Significant variations between tumor and healthy tissue were observed in terms of both absorption properties and constituents concentration. In particular, benign lesions and tumors show a statistically significant discrimination in terms of absorption at several wavelengths and also in terms of oxy-hemoglobin and collagen content.

Optical Identification of Subjects at High Risk for Developing Breast Cancer

Abstract. A time-domain multiwavelength (635 to 1060 nm) optical mammography was performed on 147 subjects with recent x-ray mammograms available, and average breast tissue composition (water, lipid, collagen, oxy- and deoxyhemoglobin) and scattering parameters (amplitude a and slope b) were estimated. Correlation was observed between optically derived parameters and mammographic density [Breast Imaging and Reporting Data System (BI-RADS) categories], which is a strong risk factor for breast cancer. A regression logistic model was obtained to best identify high-risk (BI-RADS 4) subjects, based on collagen content and scattering parameters. The model presents a total misclassification error of 12.3%, sensitivity of 69%, specificity of 94%, and simple kappa of 0.84, which compares favorably even with intraradiologist assignments of BI-RADS categories.

Sensitivity of imaging for multifocal-multicentric breast carcinoma.

BackgroundThis retrospective study aims to determine: 1) the sensitivity of preoperative mammography (Mx) and ultrasound (US), and re-reviewed Mx to detect multifocal multicentric breast carcinoma (MMBC), defined by pathology on surgical specimens, and 2) to analyze the characteristics of both detected and undetected foci on Mx and US.MethodsThree experienced breast radiologists re-reviewed, independently, digital mammography of 97 women with MMBC pathologically diagnosed on surgical specimens. The radiologists were informed of all neoplastic foci, and blinded to the original mammograms and US reports. With regards to Mx, they considered the breast density, number of foci, the Mx characteristics of the lesions and their BI-RADS classification. For US, they considered size of the lesions, BI-RADS classification and US pattern and lesion characteristics. According to the histological size, the lesions were classified as: index cancer, 2nd lesion, 3rd lesion, and 4th lesion. Any pathologically identified malignant foci not previously described in the original imaging reports, were defined as undetected or missed lesions. Sensitivity was calculated for Mx, US and re-reviewed Mx for detecting the presence of the index cancer as well as additional satellite lesions.ResultsPathological examination revealed 13 multifocal and 84 multicentric cancers with a total of 303 malignant foci (282 invasive and 21 non invasive). Original Mx and US reports had an overall sensitivity of 45.5% and 52.9%, respectively. Mx detected 83/97 index cancers with a sensitivity of 85.6%. The number of lesions undetected by original Mx was 165/303. The Mx pattern of breasts with undetected lesions were: fatty in 3 (1.8%); scattered fibroglandular density in 40 (24.3%), heterogeneously dense in 91 (55.1%) and dense in 31 (18.8%) cases. In breasts with an almost entirely fatty pattern, Mx sensitivity was 100%, while in fibroglandular or dense pattern it was reduced to 45.5%. Re-reviewed Mx detected only 3 additional lesions. The sensitivity of Mx was affected by the presence of dense breast tissue which obscured lesions or by an incorrect interpretation of suspicious findings.US detected 73/80 index cancers (sensitivity of 91.2%), US missed 117 malignant foci with a mean tumor diameter of 6.5 mm; the sensitivity was 52.9%Undetected lesions by US were those smallest in size and present in fatty breast or in the presence of microcalcifications without a visible mass.US sensitivity was affected by the presence of fatty tissue or by the extent of calcification.ConclusionMx missed MMBC malignant foci more often in dense or fibroglandular breasts. US missed small lesions in mainly fatty breasts or when there were only microcalcifications. The combined sensitivity of both techniques to assess MMBC was 58%. We suggest larger studies on multimodality imaging.

A two-by-two factorial trial comparing oral with transdermal estrogen therapy and fenretinide with placebo on breast cancer biomarkers

Purpose: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increase breast cancer risk, whereas the effect of transdermal estradiol (E2) and MPA is less known. Fenretinide may decrease second breast malignancies in premenopausal women but not in postmenopausal women, suggesting a hormone-sensitizing effect. We compared the 6 and 12-month changes in insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), IGF-I:IGFBP-3 ratio, sex-hormone binding-globulin, and computerized mammographic percent density during oral CEE or transdermal E2 with sequential MPA and fenretinide or placebo. Experimental Design: A total of 226 recent postmenopausal healthy women were randomly assigned in a two-by-two factorial design to either oral CEE 0.625 mg/day (n = 111) or transdermal E2, 50 μg/day (n = 115) and to fenretinide 100 mg/twice a day (n = 112) or placebo (n = 114) for 12 months. Treatment effects were investigated by the Kruskall-Wallis test and analysis of covariance. P values were two-sided. Results: After 12 months, oral CEE decreased IGF-I by 26% [95% confidence interval (CI), 22–30%] and increased sex-hormone binding-globulin by 96% (95% CI, 79–112%) relative to baseline, whereas no change occurred with transdermal E2 (P < 0.001 between groups). Fenretinide decreased IGFBP-3 relative to placebo (P = 0.04). Percentage of breast density showed an absolute increase of 3.5% (95% CI, 2.5–4.6%) during hormone therapy without differences between groups (P = 0.39). Conclusions: Oral CEE has more favorable changes than transdermal E2 on circulating breast cancer risk biomarkers but gives similar effects on mammographic density. Fenretinide exerted little modulation on most biomarkers. The clinical implications of these findings require additional studies.