Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study

Background: Automated breast ultrasonography (ABUS) has the potential to be an important adjunct to mammography in women with dense breasts. Purpose: To compare reader performance and inter-observer variation of ABUS alone and in combination with mammography. Material and Methods: This retrospective study had ethical committee approval. All women gave written informed consent. One hundred and fourteen breasts in 90 women examined by digital mammography and ABUS were interpreted by five radiologists using BI-RADS categories. The 114 breasts included 38 cancers and 76 normal or benign findings. In the first reading session ABUS only was interpreted, and in the second ABUS plus digital mammography. Image interpretations were done without knowledge of clinical or imaging results. A consensus panel analyzed false negative and false positive interpretations. Reading time was recorded for one radiologist. AUC was used for performance measurement, and kappa statistic for inter-observer variability. Results: Mean size for cancers was 16.2 mm; area under the curve (AUC) values for ABUS alone and for combined reading were, respectively: reader A, 0.592–0.744; reader B, 0.740–0.947; reader, C 0.759–0.823; reader D, 0.670–0.688; reader E, 0.904–0.923; and all readers combined 0.730–0.823. The higher AUC for combined reading was statistically significant (P < 0.05) for reader B and for all readers. There was a considerable inter-observer variability. Observer agreement revealed following kappa values for ABUS alone and combined reading, respectively: reader A, 0.22–0.30; reader B, 0.33–0.44; reader C, 0.32–0.39; reader D, 0.07–0.14; and reader E, 0.34–0.43. Shadowing from dense parenchyma was the most common cause of false positive ABUS interpretations. Mean interpretation time for a bilateral normal ABUS examination was 9 min. Conclusion: Observer agreement was higher and all radiologists improved diagnostic performance using combined ABUS and mammography interpretation. Combined reading should be standard if ABUS is implemented in screening of women with dense breasts

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

<p>Abstract</p> <p>Background</p> <p>The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.</p> <p>Methods</p> <p>Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.</p> <p>Results</p> <p>Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.</p> <p>Conclusions</p> <p>Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.</p

RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women

Breast cancer risk is reduced by number of pregnancies and breastfeeding duration, however studies of breast changes during or after pregnancy are rare. Breast volume changes – although not linked to breast cancer risk – might be an interesting phenotype in this context for correlative studies, as changes of breast volume vary between pregnant women. Serum receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG) were measured prospectively before gestational week 12, and three-dimensional breast volume assessments were performed. A linear regression model including breast volume at the start of pregnancy, RANKL, OPG, and other factors was used to predict breast volume at term. The mean breast volume was 413 mL at gestational week 12, increasing by a mean of 99 mL up to gestational week 40. In addition to body mass index and breast volume at the beginning of pregnancy, RANKL and OPG appeared to influence breast volume with a mean increase by 32 mL (P = 0.04) and a mean reduction by 27 mL (P = 0.04), respectively. Linking the RANKL/RANK/OPG pathway with breast volume changes supports further studies aiming at analysing breast changes during pregnancy with regard to breast cancer risk

7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium

Background: Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies. Methods: The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. Results: For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p=0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p=0.001). The OR was greater at younger ages (p trend=0.01). Conclusion: This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10− 8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10− 4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10− 9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10− 69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction

Interpretation of automated breast ultrasound (ABUS) with and without knowledge of mammography: a reader performance study

Background: Automated breast ultrasonography (ABUS) has the potential to be an important adjunct to mammography in women with dense breasts. Purpose: To compare reader performance and inter-observer variation of ABUS alone and in combination with mammography. Material and Methods: This retrospective study had ethical committee approval. All women gave written informed consent. One hundred and fourteen breasts in 90 women examined by digital mammography and ABUS were interpreted by five radiologists using BI-RADS categories. The 114 breasts included 38 cancers and 76 normal or benign findings. In the first reading session ABUS only was interpreted, and in the second ABUS plus digital mammography. Image interpretations were done without knowledge of clinical or imaging results. A consensus panel analyzed false negative and false positive interpretations. Reading time was recorded for one radiologist. AUC was used for performance measurement, and kappa statistic for inter-observer variability. Results: Mean size for cancers was 16.2 mm; area under the curve (AUC) values for ABUS alone and for combined reading were, respectively: reader A, 0.592–0.744; reader B, 0.740–0.947; reader, C 0.759–0.823; reader D, 0.670–0.688; reader E, 0.904–0.923; and all readers combined 0.730–0.823. The higher AUC for combined reading was statistically significant (P < 0.05) for reader B and for all readers. There was a considerable inter-observer variability. Observer agreement revealed following kappa values for ABUS alone and combined reading, respectively: reader A, 0.22–0.30; reader B, 0.33–0.44; reader C, 0.32–0.39; reader D, 0.07–0.14; and reader E, 0.34–0.43. Shadowing from dense parenchyma was the most common cause of false positive ABUS interpretations. Mean interpretation time for a bilateral normal ABUS examination was 9 min. Conclusion: Observer agreement was higher and all radiologists improved diagnostic performance using combined ABUS and mammography interpretation. Combined reading should be standard if ABUS is implemented in screening of women with dense breasts

X-Ray Induced Formation of γ-H2AX Foci after Full-Field Digital Mammography and Digital Breast-Tomosynthesis

Purpose: To determine in-vivo formation of x-ray induced c-H2AX foci in systemic blood lymphocytes of patients undergoing full-field digital mammography (FFDM) and to estimate foci after FFDM and digital breast-tomosynthesis (DBT) using a biological phantom model. Materials and Methods: The study complies with the Declaration of Helsinki and was performed following approval by the ethic committee of the University of Erlangen-Nuremberg. Written informed consent was obtained from every patient. For in-vivo tests, systemic blood lymphocytes were obtained from 20 patients before and after FFDM. In order to compare invivo post-exposure with pre-exposure foci levels, the Wilcoxon matched pairs test was used. For in-vitro experiments, isolated blood lymphocytes from healthy volunteers were irradiated at skin and glandular level of a porcine breast using FFDM and DBT. Cells were stained against the phosphorylated histone variant c-H2AX, and foci representing distinct DNA damages were quantified. Results: Median in-vivo foci level/cell was 0.086 (range 0.067–0.116) before and 0.094 (0.076–0.126) after FFDM (p = 0.0004). In the in-vitro model, the median x-ray induced foci level/cell after FFDM was 0.120 (range 0.086–0.140) at skin level and 0.035 (range 0.030–0.050) at glandular level. After DBT, the median x-ray induced foci level/cell was 0.061 (range 0.040– 0.081) at skin level and 0.015 (range 0.006–0.020) at glandular level. Conclusion: In patients, mammography induces a slight but significant increase of c-H2AX foci in systemic blood lymphocytes. The introduced biological phantom model is suitable for the estimation of x-ray induced DNA damages in breast tissue in different breast imaging techniques

Validation of γ-H2AX foci quantification.

<p>(a) illustrates the dose effect curve. Samples were irradiated with doses ranging from 5 to 50 mGy and were incubated for 5 minutes (n = 3). (b) shows a time plot of foci in lymphocytes pre-treated with 1 nM Calyculin A after irradiation with 50 mGy (n = 3). Means and standard deviations are presented. P<0.05 was considered statistically significant.</p

In-vivo γ-H2AX foci/cell representing DNA damages in systemic blood lymphocytes of patients (n = 20) before (left) and after (right) two view full field digital mammography (FFDM) of both breasts.

<p>Dots show individual values of each patient, the middle horizontal line represents the median, and the error bars indicate the interquartile ranges. A p value is shown, p<0.05 was considered statistically significant.</p