Can Radiologists Predict the Presence of Ductal Carcinoma In Situ and Invasive Breast Cancer?

OBJECTIVE: We hypothesize that radiologists' estimated percentage likelihood assessments for the presence of ductal carcinoma in situ (DCIS) and invasive cancer may predict histologic outcomes. MATERIALS AND METHODS: Two hundred fifty cases categorized as BI-RADS category 4 or 5 at four University of California Medical Centers were retrospectively reviewed by 10 academic radiologists with a range of 1-39 years in practice. Readers assigned BI-RADS category (1, 2, 3, 4a, 4b, 4c, or 5), estimated percentage likelihood of DCIS or invasive cancer (0-100%), and confidence rating (1 = low, 5 = high) after reviewing screening and diagnostic mammograms and ultrasound images. ROC curves were generated. RESULTS: Sixty-two percent (156/250) of lesions were benign and 38% (94/250) were malignant. There were 26 (10%) DCIS, 20 (8%) invasive cancers, and 48 (19%) cases of DCIS and invasive cancer. AUC values were 0.830-0.907 for invasive cancer and 0.731-0.837 for DCIS alone. Sensitivity of 82% (56/68), specificity of 84% (153/182), positive predictive value (PPV) of 66% (56/85), negative predictive value (NPV) of 93% (153/165), and accuracy of 84% ([56 + 153]/250) were calculated using an estimated percentage likelihood of 20% or higher as the prediction threshold for invasive cancer for the radiologist with the highest AUC (0.907; 95% CI, 0.864-0.951). Every 20% increase in the estimated percentage likelihood of invasive cancer increased the odds of invasive cancer by approximately two times (odds ratio, 2.4). For DCIS, using a threshold of 40% or higher, sensitivity of 81% (21/26), specificity of 79% (178/224), PPV of 31% (21/67), NPV of 97% (178/183), and accuracy of 80% ([21 + 178]/250) were calculated. Similarly, these values were calculated at thresholds of 2% or higher (BI-RADS category 4) and 95% or higher (BI-RADS category 5) to predict the presence of malignancy. CONCLUSION: Using likelihood estimates, radiologists may predict the presence of invasive cancer with fairly high accuracy. Radiologist-assigned estimated percentage likelihood can predict the presence of DCIS, albeit with lower accuracy than that for invasive cancer.

Inter-reader Variability in the Use of BI-RADS Descriptors for Suspicious Findings on Diagnostic Mammography: A Multi-institution Study of 10 Academic Radiologists.

RATIONALE AND OBJECTIVES: The study aimed to determine the inter-observer agreement among academic breast radiologists when using the Breast Imaging Reporting and Data System (BI-RADS) lesion descriptors for suspicious findings on diagnostic mammography. MATERIALS AND METHODS: Ten experienced academic breast radiologists across five medical centers independently reviewed 250 de-identified diagnostic mammographic cases that were previously assessed as BI-RADS 4 or 5 with subsequent pathologic diagnosis by percutaneous or surgical biopsy. Each radiologist assessed the presence of the following suspicious mammographic findings: mass, asymmetry (one view), focal asymmetry (two views), architectural distortion, and calcifications. For any identified calcifications, the radiologist also described the morphology and distribution. Inter-observer agreement was determined with Fleiss kappa statistic. Agreement was also calculated by years of experience. RESULTS: Of the 250 lesions, 156 (62%) were benign and 94 (38%) were malignant. Agreement among the 10 readers was strongest for recognizing the presence of calcifications (k = 0.82). There was substantial agreement among the readers for the identification of a mass (k = 0.67), whereas agreement was fair for the presence of a focal asymmetry (k = 0.21) or architectural distortion (k = 0.28). Agreement for asymmetries (one view) was slight (k = 0.09). Among the categories of calcification morphology and distribution, reader agreement was moderate (k = 0.51 and k = 0.60, respectively). Readers with more experience (10 or more years in clinical practice) did not demonstrate higher levels of agreement compared to those with less experience. CONCLUSIONS: Strength of agreement varies widely for different types of mammographic findings, even among dedicated academic breast radiologists. More subtle findings such as asymmetries and architectural distortion demonstrated the weakest agreement. Studies that seek to evaluate the predictive value of certain mammographic features for malignancy should take into consideration the inherent interpretive variability for these findings.

Mammographic quantitative image analysis and biologic image composition for breast lesion characterization and classification.

PURPOSE: To investigate whether biologic image composition of mammographic lesions can improve upon existing mammographic quantitative image analysis (QIA) in estimating the probability of malignancy. METHODS: The study population consisted of 45 breast lesions imaged with dual-energy mammography prior to breast biopsy with final diagnosis resulting in 10 invasive ductal carcinomas, 5 ductal carcinomain situ, 11 fibroadenomas, and 19 other benign diagnoses. Analysis was threefold: (1) The raw low-energy mammographic images were analyzed with an established in-house QIA method, "QIA alone," (2) the three-compartment breast (3CB) composition measure-derived from the dual-energy mammography-of water, lipid, and protein thickness were assessed, "3CB alone", and (3) information from QIA and 3CB was combined, "QIA + 3CB." Analysis was initiated from radiologist-indicated lesion centers and was otherwise fully automated. Steps of the QIA and 3CB methods were lesion segmentation, characterization, and subsequent classification for malignancy in leave-one-case-out cross-validation. Performance assessment included box plots, Bland-Altman plots, and Receiver Operating Characteristic (ROC) analysis. RESULTS: The area under the ROC curve (AUC) for distinguishing between benign and malignant lesions (invasive and DCIS) was 0.81 (standard error 0.07) for the "QIA alone" method, 0.72 (0.07) for "3CB alone" method, and 0.86 (0.04) for "QIA+3CB" combined. The difference in AUC was 0.043 between "QIA + 3CB" and "QIA alone" but failed to reach statistical significance (95% confidence interval [-0.17 to + 0.26]). CONCLUSIONS: In this pilot study analyzing the new 3CB imaging modality, knowledge of the composition of breast lesions and their periphery appeared additive in combination with existing mammographic QIA methods for the distinction between different benign and malignant lesion types.

Reducing false-positive biopsies: a pilot study to reduce benign biopsy rates for BI-RADS 4A/B assessments through testing risk stratification and new thresholds for intervention.

The aim of this study is to evaluate Breast Imaging Reporting and Data Systems (BI-RADS) 4A/B subcategory risk estimates for ductal carcinoma in situ (DCIS) and invasive cancer (IC), determining whether changing the proposed cutoffs to a higher biopsy threshold could safely increase cancer-to-biopsy yields while minimizing false-positive biopsies. A prospective clinical trial was performed to evaluate BI-RADS 4 lesions from women seen in clinic between January 2006 and March 2007. An experienced radiologist prospectively estimated a percent risk-estimate for DCIS and IC. Truth was determined by histopathology or 4-year follow-up negative for malignancy. Risk estimates were used to generate receiver-operating characteristic (ROC) curves. Biopsy rates, cancer-to-biopsy yields, and type of malignancies missed were then calculated across postulated risk thresholds. A total of 124 breast lesions were evaluated from 213 women. An experienced radiologist gave highly accurate risk estimates for IC, DCIS alone, or the combination with an area under ROC curve of 0.91 (95 % CI 0.84-0.99) (p < 0.001), 0.81 (95 % CI 0.69-0.93) (p = 0.011), and 0.89 (95 % CI 0.83-0.95) (p < 0.001), respectively. The cancer-to-biopsy yield was 30 %. Three hypothetical thresholds for intervention were analyzed: (1) DCIS or IC ≥ 10 %; (2) DCIS ≥ 50 % or IC ≥ 10 %; and (3) IC ≥ 10 %, which translated to 22, 48, and 56 % of biopsies avoided; cancer-to-biopsy yields of 36, 47, and 46 %; and associated chance of missing an IC of 0, 1, and 2 %, respectively. Expert radiologists estimate risk of IC and DCIS with a high degree of accuracy. Increasing the cut off point for recommending biopsy, substituting with a short-term follow-up protocol with biopsy if any change, may safely reduce the number of false-positive biopsies.

Beyond mammography: new frontiers in breast cancer screening.

Breast cancer screening remains a subject of intense and, at times, passionate debate. Mammography has long been the mainstay of breast cancer detection and is the only screening test proven to reduce mortality. Although it remains the gold standard of breast cancer screening, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. Mammography also has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dose, cost, and patient anxiety. In response to these challenges, new technologies for breast cancer screening have been developed, including low-dose mammography, contrast-enhanced mammography, tomosynthesis, automated whole breast ultrasound, molecular imaging, and magnetic resonance imaging. Here we examine some of the current controversies and promising new technologies that may improve detection of breast cancer both in the general population and in high-risk groups, such as women with dense breasts. We propose that optimal breast cancer screening will ultimately require a personalized approach based on metrics of cancer risk with selective application of specific screening technologies best suited to the individual's age, risk, and breast density.

Breast cancer screening: the questions answered.

Early detection of cancer has long been thought to be the first step towards eradicating the mortality associated with the disease. National screening programmes for breast cancer have been implemented in many countries. However, there is controversy regarding the efficacy and optimal methods of screening, which is regularly discussed in articles, at conferences and is apparent in conflicting guidelines. In this article, Nature Reviews Clinical Oncology asks four experts their opinions on some of the pressing questions associated with breast cancer screening.

Benefit of semiannual ipsilateral mammographic surveillance following breast conservation therapy.

PURPOSE: To compare cancer recurrence outcomes on the basis of compliant semiannual versus noncompliant annual ipsilateral mammographic surveillance following breast conservation therapy (BCT). MATERIALS AND METHODS: A HIPAA-compliant retrospective review was performed of post-BCT examinations from 1997 through 2008 by using a deidentified database. The Committee on Human Research did not require institutional review board approval for this study, which was considered quality assurance. Groups were classified according to compliance with institutional post-BCT protocol, which recommends semiannual mammographic examinations of the ipsilateral breast for 5 years. A compliant semiannual examination was defined as an examination with an interval of 0-9 months, although no examination had intervals less than 3 months. A noncompliant annual examination was defined as an examination with an interval of 9-18 months. Cancer recurrence outcomes were compared on the basis of the last examination interval leading to diagnosis. RESULTS: Initially, a total of 10 750 post-BCT examinations among 2329 asymptomatic patients were identified. Excluding initial mammographic follow-up, there were 8234 examinations. Of these, 7169 examinations were semiannual with 94 recurrences detected and 1065 examinations were annual with 15 recurrences detected. There were no differences in demographic risk factors or biopsy rates. Recurrences identified at semiannual intervals were significantly less advanced than those identified at annual intervals (stage I vs stage II, P = .04; stage 0 + stage I vs stage II, P = .03). Nonsignificant findings associated with semiannual versus annual intervals included smaller tumor size (mean, 11.7 vs 15.3 mm; P = .15) and node negativity (98% vs 91%, P = .28). CONCLUSION: Results suggest that a semiannual interval is preferable for ipsilateral mammographic surveillance, allowing detection of a significantly higher proportion of cancer recurrences at an earlier stage than noncompliant annual surveillance.

Clinical and imaging surveillance following breast cancer diagnosis.

Breast cancer is the most common malignancy affecting women worldwide. Women have a 1 in 8 lifetime risk of breast cancer. Breast conservation therapy (BCT) is the most common method of definitive treatment. Patients who previously have had to undergo mastectomy may be now eligible for BCT or a multitude of options for reconstruction, either immediate or delayed. Surveillance imaging after a breast cancer diagnosis is important because there is an increased risk of recurrence developing in patients, and early detection has been shown to improve survival. There is currently no consensus on a protocol for imaging the postoperative breast. In patients who have undergone mastectomy, detection of recurrence has mostly been via clinical symptoms and physical exam, often at a later stage. New imaging modalities, such as magnetic resonance imaging (MRI), ultrasound (US), and positron emission mammography (PEM) are changing the way we image the postsurgical breast. MRI, coupled with physical exam and mammography, approaches 100% sensitivity and high specificity for the identification of recurrent disease. We present a review of major academic institutions' imaging protocols and discuss the advantages of including MRI in traditional mammographic and clinical exams.

Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study.

BACKGROUND: False-positive mammography results are common. Biennial screening may decrease the cumulative probability of false-positive results across many years of repeated screening but could also delay cancer diagnosis. OBJECTIVE: To compare the cumulative probability of false-positive results and the stage distribution of incident breast cancer after 10 years of annual or biennial screening mammography. DESIGN: Prospective cohort study. SETTING: 7 mammography registries in the National Cancer Institute-funded Breast Cancer Surveillance Consortium. PARTICIPANTS: 169,456 women who underwent first screening mammography at age 40 to 59 years between 1994 and 2006 and 4492 women with incident invasive breast cancer diagnosed between 1996 and 2006. MEASUREMENTS: False-positive recalls and biopsy recommendations stage distribution of incident breast cancer. RESULTS: False-positive recall probability was 16.3% at first and 9.6% at subsequent mammography. Probability of false-positive biopsy recommendation was 2.5% at first and 1.0% at subsequent examinations. Availability of comparison mammograms halved the odds of a false-positive recall (adjusted odds ratio, 0.50 [95% CI, 0.45 to 0.56]). When screening began at age 40 years, the cumulative probability of a woman receiving at least 1 false-positive recall after 10 years was 61.3% (CI, 59.4% to 63.1%) with annual and 41.6% (CI, 40.6% to 42.5%) with biennial screening. Cumulative probability of false-positive biopsy recommendation was 7.0% (CI, 6.1% to 7.8%) with annual and 4.8% (CI, 4.4% to 5.2%) with biennial screening. Estimates were similar when screening began at age 50 years. A non-statistically significant increase in the proportion of late-stage cancers was observed with biennial compared with annual screening (absolute increases, 3.3 percentage points [CI, -1.1 to 7.8 percentage points] for women age 40 to 49 years and 2.3 percentage points [CI, -1.0 to 5.7 percentage points] for women age 50 to 59 years) among women with incident breast cancer. LIMITATIONS: Few women underwent screening over the entire 10-year period. Radiologist characteristics influence recall rates and were unavailable. Most mammograms were film rather than digital. Incident cancer was analyzed in a small sample of women who developed cancer. CONCLUSION: After 10 years of annual screening, more than half of women will receive at least 1 false-positive recall, and 7% to 9% will receive a false-positive biopsy recommendation. Biennial screening appears to reduce the cumulative probability of false-positive results after 10 years but may be associated with a small absolute increase in the probability of late-stage cancer diagnosis. PRIMARY FUNDING SOURCE: National Cancer Institute.

Full field digital mammography and breast density: comparison of calibrated and noncalibrated measurements.

RATIONALE AND OBJECTIVES: Mammographic breast density is an important and widely accepted risk factor for breast cancer. A statement about breast density in the mammographic report is becoming a requirement in many States. However, there is significant inter-observer variation between radiologists in their interpretation of breast density. A properly designed automated system could provide benefits in maintaining consistency and reproducibility. We have developed a new automated and calibrated measure of breast density using full field digital mammography (FFDM). This new measure assesses spatial variation within a mammogram and produced significant associations with breast cancer in a small study. The costs of this automation are delays from advanced image and data analyses before the study can be processed. We evaluated this new calibrated variation measure using a larger dataset than previously. We also explored the possibility of developing an automated measure from unprocessed (raw data) mammograms as an approximation for this calibrated breast density measure. MATERIALS AND METHODS: A case-control study comprised of 160 cases and 160 controls matched by age, screening history, and hormone replacement therapy was used to compare the calibrated variation measure of breast density with three variants of a noncalibrated measure of spatial variation. The operator-assisted percentage of breast density measure (PD) was used as a standard reference for comparison. Odds ratio (OR) quartile analysis was used to compare these measures. Linear regression analysis was applied to assess the calibration's impact on the raw pixel distribution. RESULTS: All breast density measures showed significant breast cancer associations. The calibrated spatial variation measure produced the strongest associations (OR: 1.0 [ref.], 4.6, 4.3, 7.4). The associations for PD were diminished in comparison (OR: 1.0 [ref.], 2.7, 2.9, 5.2). Two additional non-calibrated measures restricted in region size also showed significant associations (OR: 1.0 [ref.], 2.9, 4.4, 5.4), and (OR: 1.0 [ref.], 3.5, 3.1, 4.9). Regression analyses indicated the raw image mean is influenced by the calibration more so than its standard deviation. CONCLUSION: Breast density measures can be automated. The associated calibration produced risk information not retrievable from the raw data representation. Although the calibrated measure produced the stronger association, the non-calibrated measures may offer an alternative to PD and other operator based methods after further evaluation, because they can be implemented automatically with a simple processing algorithm.

Compositional breast imaging using a dual-energy mammography protocol.

PURPOSE: Mammography has a low sensitivity in dense breasts due to low contrast between malignant and normal tissue confounded by the predominant water density of the breast. Water is found in both adipose and fibroglandular tissue and constitutes most of the mass of a breast. However, significant protein mass is mainly found in the fibroglandular tissue where most cancers originate. If the protein compartment in a mammogram could be imaged without the influence of water, the sensitivity and specificity of the mammogram may be improved. This article describes a novel approach to dual-energy mammography, full-field digital compositional mammography (FFDCM), which can independently image the three compositional components of breast tissue: water, lipid, and protein. METHODS: Dual-energy attenuation and breast shape measures are used together to solve for the three compositional thicknesses. Dual-energy measurements were performed on breast-mimicking phantoms using a full-field digital mammography unit. The phantoms were made of materials shown to have similar x-ray attenuation properties of the compositional compartments. They were made of two main stacks of thicknesses around 2 and 4 cm. Twenty-six thickness and composition combinations were used to derive the compositional calibration using a least-squares fitting approach. RESULTS: Very high accuracy was achieved with a simple cubic fitting function with root mean square errors of 0.023, 0.011, and 0.012 cm for the water, lipid, and protein thicknesses, respectively. The repeatability (percent coefficient of variation) of these measures was tested using sequential images and was found to be 0.5%, 0.5%, and 3.3% for water, lipid, and protein, respectively. However, swapping the location of the two stacks of the phantom on the imaging plate introduced further errors showing the need for more complete system uniformity corrections. Finally, a preliminary breast image is presented of each of the compositional compartments separately. CONCLUSIONS: FFDCM has been derived and exhibited good compositional thickness accuracy on phantoms. Preliminary breast images demonstrated the feasibility of creating individual compositional diagnostic images in a clinical environment.

Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer.

The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.