The P.I.N.K. Study Approach for Supporting Personalized Risk Assessment and Early Diagnosis of Breast Cancer.

Breast cancer is a clear example of excellent survival when it is detected and properly treated in the early stage. Currently, screening of this cancer relies on mammography, which may be integrated by new imaging techniques for more exhaustive evaluation. The Personalized, Integrated, Network, Knowledge (P.I.N.K.) study is a longitudinal multicentric study involving several diagnostic centres across Italy, co-ordinated by the Italian National Research Council and co-funded by the Umberto Veronesi Foundation. Aim of the study is to evaluate the increased diagnostic accuracy in detecting cancers obtained with different combinations of imaging technologies, and find the most effective diagnostic pathway matching the characteristics of an individual patient. The study foresees the enrolment of 50,000 women over the age of 40 years presenting for breast examination and providing informed consent to data handling. So far, the 15 participating centres across Italy have recruited a total of 22,848 patients. Based on the analyses of the first 175 histopathological-proven breast cancers, mammographic sensitivity was estimated to be 61.7% (n = 108 cancers), whereas diagnostic accuracy increased by 35.5% (n = 44 cancers) when mammography was integrated with other imaging modalities (ultrasound and/or digital breast tomosynthesis). Increase was mainly determined by ultrasound alone. Given the ongoing data collection and recruitment, the number of cancers detected is too low to allow any further in-depth analysis to explore links to patient characteristics. Past studies show that the uniform approach of population screening guidelines should be revised in favour of more personalised regimens, where known standards are integrated by imaging techniques most suitable for the individual's characteristics. With the ultimate goal of identifying early breast cancer detection strategies, our preliminary results suggest that integrated diagnostic approach could lead to a paradigm shift from an age-based regimen toward more specific and effective risk-based personalised screening regimens, in order to reduce mortality from breast cancer.

Combination of one-view digital breast tomosynthesis with one-view digital mammography versus standard two-view digital mammography: per lesion analysis.

OBJECTIVE: To evaluate the clinical value of combining one-view mammography (cranio-caudal, CC) with the complementary view tomosynthesis (mediolateral-oblique, MLO) in comparison to standard two-view mammography (MX) in terms of both lesion detection and characterization. METHODS: A free-response receiver operating characteristic (FROC) experiment was conducted independently by six breast radiologists, obtaining data from 463 breasts of 250 patients. Differences in mean lesion detection fraction (LDF) and mean lesion characterization fraction (LCF) were analysed by analysis of variance (ANOVA) to compare clinical performance of the combination of techniques to standard two-view digital mammography. RESULTS: The 463 cases (breasts) reviewed included 258 with one to three lesions each, and 205 with no lesions. The 258 cases with lesions included 77 cancers in 68 breasts and 271 benign lesions to give a total of 348 proven lesions. The combination, DBT(MLO)+MX(CC), was superior to MX (CC+MLO) in both lesion detection (LDF) and lesion characterization (LCF) overall and for benign lesions. DBT(MLO)+MX(CC) was non-inferior to two-view MX for malignant lesions. CONCLUSIONS: This study shows that readers' capabilities in detecting and characterizing breast lesions are improved by combining single-view digital breast tomosynthesis and single-view mammography compared to two-view digital mammography. KEY POINTS: • Digital breast tomosynthesis is becoming adopted as an adjunct to mammography (MX) • DBT (MLO) +MX (CC) is superior to MX (CC+MLO) in lesion detection (overall and benign lesions) • DBT (MLO) +MX (CC) is non-inferior to MX (CC+MLO) in cancer detection • DBT (MLO) +MX (CC) is superior to MX (CC+MLO) in lesion characterization (overall and benign lesions) • DBT (MLO) +MX (CC) is non-inferior to MX (CC+MLO) in characterization of malignant lesions.

Performance comparison of single-view digital breast tomosynthesis plus single-view digital mammography with two-view digital mammography.

OBJECTIVE: To determine the performance of combined single-view mediolateral oblique (MLO) digital breast tomosynthesis (DBT) plus single-view cranio-caudal (CC) mammography (MX) compared with that of standard two-view digital mammography. METHODS: A multi-reader multi-case (MRMC) receiver-operating characteristic (ROC) study was conducted, involving six breast radiologists. Two hundred fifty patients underwent bilateral MX and DBT imaging. MX and DBT images with the adjunct of the CC-MX view from 469 breasts were evaluated and rated independently by six readers. Differences in mean areas under the ROC curves (AUCs), mean sensitivity and mean specificity were analysed by analysis of variance (ANOVA) to assess clinical performance. RESULTS: The combined technique was found to be non-inferior to standard two-view mammography (MX((CC+MLO))) in mean AUC (difference: +0.021;95 % LCL = -0.011), but was not statistically significant for superiority (P = 0.197). The combined technique had equivalent sensitivity to standard mammography (76.2 % vs. 72.8 %, P = 0.269) and equivalent specificity (84.9 % vs. 83.0 %, P = 0.130). Specificity for benign lesions was significantly higher with the combination of techniques versus mammography (45.6 % vs. 36.8 %, P = 0.002). CONCLUSION: In this enriched study population, the combination of single-view MLO tomosynthesis plus single-view CC mammography was non-inferior to that of standard two-view digital mammography in terms of ROC curve area, sensitivity and specificity.

Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study): final results.

OBJECTIVES: : To prospectively compare clinical breast examination, mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (MRI) in a multicenter surveillance of high-risk women. MATERIALS AND METHODS: : We enrolled asymptomatic women aged ≥ 25: BRCA mutation carriers; first-degree relatives of BRCA mutation carriers, and women with strong family history of breast/ovarian cancer, including those with previous personal breast cancer. RESULTS: : A total of 18 centers enrolled 501 women and performed 1592 rounds (3.2 rounds/woman). Forty-nine screen-detected and 3 interval cancers were diagnosed: 44 invasive, 8 ductal carcinoma in situ; only 4 pT2 stage; 32 G3 grade. Of 39 patients explored for nodal status, 28 (72%) were negative. Incidence per year-woman resulted 3.3% overall, 2.1% <50, and 5.4% ≥ 50 years (P < 0.001), 4.3% in women with previous personal breast cancer and 2.5% in those without (P = 0.045). MRI was more sensitive (91%) than clinical breast examination (18%), mammography (50%), ultrasonography (52%), or mammography plus ultrasonography (63%) (P < 0.001). Specificity ranged 96% to 99%, positive predictive value 53% to 71%, positive likelihood ratio 24 to 52 (P not significant). MRI showed significantly better negative predictive value (99.6) and negative likelihood ratio (0.09) than those of the other modalities. At receiver operating characteristic analysis, the area under the curve of MRI (0.97) was significantly higher than that of mammography (0.83) or ultrasonography (0.82) and not significantly increased when MRI was combined with mammography and/or ultrasonography. Of 52 cancers, 16 (31%) were diagnosed only by MRI, 8 of 21 (38%) in women <50, and 8 of 31 (26%) in women ≥ 50 years of age. CONCLUSION: : MRI largely outperformed mammography, ultrasonography, and their combination for screening high-risk women below and over 50.

Digital breast tomosynthesis versus digital mammography: a clinical performance study.

OBJECTIVE: To compare the clinical performance of digital breast tomosynthesis (DBT) with that of full-field digital mammography (FFDM) in a diagnostic population. METHODS: The study enrolled 200 consenting women who had at least one breast lesion discovered by mammography and/or ultrasound classified as doubtful or suspicious or probably malignant. They underwent tomosynthesis in one view [mediolateral oblique (MLO)] of both breasts at a dose comparable to that of standard screen-film mammography in two views [craniocaudal (CC) and MLO]. Images were rated by six breast radiologists using the BIRADS score. Ratings were compared with the truth established according to the standard of care and a multiple-reader multiple-case (MRMC) receiver-operating characteristic (ROC) analysis was performed. Clinical performance of DBT compared with that of FFDM was evaluated in terms of the difference between areas under ROC curves (AUCs) for BIRADS scores. RESULTS: Overall clinical performance with DBT and FFDM for malignant versus all other cases was not significantly different (AUCs 0.851 vs 0.836, p = 0.645). The lower limit of the 95% CI or the difference between DBT and FFDM AUCs was -4.9%. CONCLUSION: Clinical performance of tomosynthesis in one view at the same total dose as standard screen-film mammography is not inferior to digital mammography in two views.

Correlation between magnetic resonance imaging and histopathological tumor response after neoadjuvant chemotherapy in breast cancer.

AIM: To evaluate the accuracy of magnetic resonance imaging in assessing tumor response following neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: Twenty-six patients entered a phase II study of neoadjuvant chemotherapy, undergoing bilateral breast magnetic resonance imaging before therapy and before surgery. Tumor response was classified using RECIST criteria, using tumor size at magnetic resonance imaging. The latter was then compared to residue found at histopathological examination. RESULTS: Magnetic resonance imaging showed 6 (23%) complete responses, 17 (65%) partial responses, 3 (11.5%) disease stabilizations and no disease progressions. Twenty-three tumors (88.5%) were considered responsive and 3 (11.5%) unresponsive. Pathological tumor response was: 6 complete responses (23%), 17 partial responses (65%), 2 stable disease (8%), 1 progression (4%). When results of the preoperative magnetic resonance imaging were compared to pathological tumor response, magnetic resonance imaging overestimated tumor size in 12 cases (46%) and underestimated it in 9 (35%). However, preoperative magnetic resonance imaging failed to detect invasive tumor in 2 false-negative cases (8%), 1 of which was multifocal. Mastectomy was performed in 12 cases: 1 case of disease progression even though the neoplasm appeared smaller at magnetic resonance imaging, 3 cases with stable disease, and 4 cases with T3 or T4 disease. The 9th patient was T2N2 with initial retroareolar disease and negative magnetic resonance imaging after chemotherapy. The 10th patient, affected by lobular cancer, was in partial remission but was T3N1. The 11th patient was 57 years old but was not interested in conservative surgery. The 12th patient requested bilateral prophylactic mastectomy due to her positive family history of breast cancer. CONCLUSIONS: Magnetic resonance imaging of the breast allowed conservative surgery in 54% of the patients. This low value is primarily due to overestimation of tumor size, with a negative predictive value of 67% in our population. However, surgeons were able to choose conservative surgery with relative safety in cases of small residual disease.

Serum proteomic analysis identifies a highly sensitive and specific discriminatory pattern in stage 1 breast cancer.

BACKGROUND: Mass spectrometry (MS)-based profiling was used to determine whether ion fingerprints could distinguish women with stage 1 breast cancer from women without breast cancer. METHODS: The initial study population consisted of 310 subjects: 155 women with yearly negative breast examination and negative mammography findings for at least 4 years, and 155 women undergoing surgery for pathology-proven stage 1 invasive ductal carcinoma. High-resolution SELDI-TOF (surface-enhanced laser desorption ionization-time of flight) analysis was performed on serum obtained from blood samples collected before mammography in controls, and before surgery in patients with breast cancer. Samples were divided into a training (109 controls and 109 cancers) and blinded (46 controls and 46 cancers) testing set; each group had similar age demographics. In addition, an independent study set of 46 serum samples was analyzed 14 months after the initial study to validate the robustness of the classifier. RESULTS: A discriminatory profile consisting of seven ion peaks found in the training set, when applied to the blinded test set, achieved a sensitivity and specificity of 95.6% and 86.5%, respectively. This same seven-peak profile achieved a 96.5% sensitivity and 85.7% specificity, with correct identification of all of 17 T1a tumors when applied to the validation study set. CONCLUSIONS: Mass spectrometry profiling of human serum generated a robust classifier composed of seven low-molecular-weight ions that yielded a highly sensitive and specific diagnostic procedure for the discrimination of women with stage 1 breast cancer compared with women without breast cancer in this research study set.

Grid removal and impact on population dose in full-field digital mammography.

The study purpose was to determine the impact of anti-scatter grid removal on patient dose, in full field digital mammography. Dose saving, phantom based, was evaluated with the constraint that images acquired with and without grid would provide the same contrast-to-noise ratio (CNR). The digital equipment employed a flat panel detector with cesium iodide for x-ray to light conversion, 100 microm pixel size; the x-ray source was a dual-track tube with selectable filtration. Poly(methyl-emathocrylate) (PMMA) layers in the range 20-70 mm were used to simulate the absorption of different breast thickness, while two Al foils, 0.1 and 0.2 mm thick were used to provide a certain CNR. Images with grid were acquired with the same beam quality as selected in full automatic exposure mode and the mAs levels as close as possible, and the CNR measured for each thickness between 20 and 70 mm. Phantom images without grid were acquired in manual exposure mode, by selecting the same anode/filter combination and kVp as the image with grid at the same thickness, but varying mAs from 10 to 200. For each thickness, an image without aluminum was acquired for each mAs value, in order to obtain a flat image to be used to subtract the scatter nonuniformity from the phantom images. After scatter subtraction, the CNR was measured on images without grid. The mAs value that should be set to acquire a phantom image without grid so that it has the same CNR as the corresponding grid image was calculated. Therefore, mAs reduction percentage was determined versus phantom thickness. Results showed that dose saving was lower than 30% for PMMA equivalent breast thinner than 40 mm, decreased below 10% for intermediate thickness (45-50 mm), but there was no dose gain for thickness beyond 60 mm. By applying the mAs reduction factors to a clinical population derived from a data base of 4622 breasts, dose benefit was quantified in terms of population dose. On the average, the overall dose reduction was about 8%. It was considered small, not sufficient to justify a clinical implementation, and the anti-scatter grid was maintained.

Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study): interim results.

PURPOSE: To prospectively compare clinical breast examination (CBE), mammography, ultrasonography (US), and contrast material-enhanced magnetic resonance (MR) imaging for screening women at genetic-familial high risk for breast cancer and report interim results, with pathologic findings as standard. MATERIALS AND METHODS: Institutional review board of each center approved the research; informed written consent was obtained. CBE, mammography, US, and MR imaging were performed for yearly screening of BRCA1 or BRCA2 mutation carriers, first-degree relatives of BRCA1 or BRCA2 mutation carriers, or women enrolled because of a strong family history of breast or ovarian cancer (three or more events in first- or second-degree relatives in either maternal or paternal line; these included breast cancer in women younger than 60 years, ovarian cancer at any age, and male breast cancer at any age). RESULTS: Two hundred seventy-eight women (mean age, 46 years +/- 12 [standard deviation]) were enrolled. Breast cancer was found in 11 of 278 women at first round and seven of 99 at second round (14 invasive, four intraductal; eight were

Dose comparison between screen/film and full-field digital mammography.

The study purpose was the comparison between doses delivered by a full-field digital mammography system and a screen/film mammography unit, both using the same type of X-ray tube. Exposure parameters and breast thickness were collected for 300 screen/film (GE Senographe DMR) and 296 digital mammograms (GE Senographe 2000D). The entrance surface air kerma (ESAK) was calculated from anode/filter combination, kV(p) and mAs values and breast thickness, by simulating spectra through a program based on a catalogue of experimental X-ray spectra. The average glandular dose (AGD) was also computed. Results showed an overall reduction of average glandular dose by 27% of digital over screen/film mammography. The dose saving was about 15% for thin and thick breasts, while it was between 30% and 40% for intermediate thicknesses. Full-field digital mammography dose reduction is allowed by wider dynamic range and higher efficiency of digital detector, which can be exposed at higher energy spectra than screen/film mammography, and by the separation between acquisition and displaying processes.

Are phantoms useful for predicting the potential of dose reduction in full-field digital mammography?

A phantom study was performed in full-field digital mammography to investigate the opportunity and the magnitude of a possible dose reduction that would leave the image quality above the accepted thresholds associated with some classical phantoms. This preliminary work is intended to lay the groundwork for a future clinical study on the impact of dose reduction on clinical results. Three different mammography phantoms (ACR RMI 156, CIRS 11A and CDMAM 3.4) were imaged by a full-field digital mammography unit (GE Senographe 2000D) at different dose levels. Images were rated by three observers with softcopy reading and scoring methods specific to each phantom. Different types of data analysis were applied to the ACR (American College of Radiology) and the other two phantoms, respectively. With reference to the minimum acceptance score in screen/film accreditation programmes, the ACR phantom showed that about 45% dose reduction could be applied, while keeping the phantom scores above that threshold. A relative comparison was done for CIRS and CDMAM, for which no threshold is defined. CIRS scoring remained close to the reference level down to 40% dose reduction, the inter- and intra-observer variability being the main source of uncertainty. Contrast-detail curves provided by CDMAM overlapped down to 50% dose reduction, at least for object contrast values ranging between 30% and 3%. This multi-phantom study shows the potential of further reducing the dose in full-field digital mammography beyond the current values. A common dose reduction factor around 50% seems acceptable for all phantoms. However, caution is required before extrapolating the results for clinical use, given the limitations of these widely used phantoms, mainly related to their limited dynamic range and uniform background.

Digital mammography: quality and dose control.

PURPOSE: For almost 3 years, Radiologists and Physicists from Padova and Ferrara Universities have collaborated together, with the aim of collecting and comparing experimental data useful to define the most significant parameters for quality controls in digital mammography. Successively, radiologists and physicists working in other sites where a digital mammography unit was installed joined the work-group. MATERIALS AND METHODS: In this study we report the results obtained from measurements of linearity, uniformity, short- and long-term reproducibility, AEC stability performed on 5 digital equipment by using a simple test object. X-ray beam quality and tube yield were preliminarily checked in such a way that possible uncertainties of digital system responses could be separated from those due to differences among X-ray tubes. RESULTS: Results showed that the equipment considered, comparable in terms of both beam quality (HVL) and tube yield, always displayed linear response and reproducibility errors lower than 5%. Uniformity was very good and the grey level compensation as a function of exposure parameters remained within 5%. Differences in choice of parameters by exposure control system (AOP) were emphasised, especially for crossing between track/filter combinations (from Mo/Mo to Mo/Rh and from Mo/Rh to Rh/Rh); those differences were attributed to the +/-2 mm tolerance of breast thickness measurement (mechanically obtained) greater than the AOP tolerance (+/-1 mm). DISCUSSION AND CONCLUSIONS: Obtained results can be useful, as comparison and reference values, for users employing a digital mammography unit of the same kind reported in this paper. Moreover, the same results could be used as "orientation" also by other users having different digital mammography technologies, whose operation should be nevertheless specifically studied and understood in order to find the most useful parameters for quality controls. The acquired experience clearly showed us that years of investigations will be necessary in order to be able to write reliable protocols. This should induce people to contemplate the necessity of not improvising "theoretical" protocols, that are unreliable and dangerous for their negative clinical implications.

State of the art of current modalities for the diagnosis of breast lesions.

With the availability of numerous diagnostic techniques comes the possible risk of the unjustified use of such techniques and a lack of rational clinical application. Clearly, errors of this nature would affect the diagnostic accuracy and therefore reduce the possibilities for treatment. It is not uncommon for women and also for general practitioners to be misinformed about which is the most suitable technique or rather, which is the best combination of the various techniques. For this reason, inappropriate tests are often requested or, conversely, there is failure to request tests which would in fact make a useful contribution to safeguarding the patient's health. This work has the following aims: (a) to set out precisely the real diagnostic contribution of each method, both radiological and otherwise, and suggest methods of application and indications consistent with the state of the art, and (b) to suggest the most effective and rational combinations of the various techniques and organisation of diagnostic activities.

Patient dose in full-field digital mammography: an Italian survey.

The aim of this study was to compare performance and patient dose of full-field digital mammography units for clinical use. Measurements of linearity and automatic exposure control stability were performed on four units installed in as many Italian sites. The tube output was also obtained by the same ionization chamber, permitting to evaluate ratios mGy/mAs for each available spectrum. The entrance air-kerma was calculated over a sample of 800 cranio-caudal mammograms and the average glandular dose obtained, assuming two mean glandular compositions of 50 and 30%, respectively. Digital systems showed very good linearity and comparable responses. The stability of the automatic exposure control was better than 5% for all systems. Regarding doses, the two mammography units that work mainly in contrast mode deliver, respectively, 17 and 28% more dose compared with those working in standard mode. For the latter mode, the mean average glandular dose was in the range 1.25-1.37 mGy and 1.37-1.49 mGy for the 50 and 30% glandular composition, respectively. Results of this study were compared with those of other surveys, showing that full-field digital mammography allows a significant clinical dose reduction compared with screen/film mammography.