Test-Retest Data for the Assessment of Breast MRI Radiomic Feature Repeatability.

BACKGROUND: Radiomic features extracted from breast MRI have potential for diagnostic, prognostic, and predictive purposes. However, before they can be used as biomarkers in clinical decision support systems, features need to be repeatable and reproducible. OBJECTIVE: Identify repeatable radiomics features within breast tissue on prospectively collected MRI exams through multiple test-retest measurements. STUDY TYPE: Prospective. POPULATION: 11 healthy female volunteers. FIELD STRENGTH/SEQUENCE: 1.5 T; MRI exams, comprising T2-weighted turbo spin-echo (T2W) sequence, native T1-weighted turbo gradient-echo (T1W) sequence, diffusion-weighted imaging (DWI) sequence using b-values 0/150/800, and corresponding derived ADC maps. ASSESSMENT: 18 MRI exams (three test-retest settings, repeated on 2 days) per healthy volunteer were examined on an identical scanner using a fixed clinical breast protocol. For each scan, 91 features were extracted from the 3D manually segmented right breast using Pyradiomics, before and after image preprocessing. Image preprocessing consisted of 1) bias field correction (BFC); 2) z-score normalization with and without BFC; 3) grayscale discretization using 32 and 64 bins with and without BFC; and 4) z-score normalization + grayscale discretization using 32 and 64 bins with and without BFC. STATISTICAL TESTS: Features' repeatability was assessed using concordance correlation coefficient(CCC) for each pair, i.e. each MRI was compared to each of the remaining 17 MRI with a cut-off value of CCC > 0.90. RESULTS: Images without preprocessing produced the highest number of repeatable features for both T1W sequence and ADC maps with 15 of 91 (16.5%) and 8 of 91 (8.8%) repeatable features, respectively. Preprocessed images produced between 4 of 91 (4.4%) and 14 of 91 (15.4%), and 6 of 91 (6.6%) and 7 of 91 (7.7%) repeatable features, respectively for T1W and ADC maps. Z-score normalization produced highest number of repeatable features, 26 of 91 (28.6%) in T2W sequences, in these images, no preprocessing produced 11 of 91 (12.1%) repeatable features. DATA CONCLUSION: Radiomic features extracted from T1W, T2W sequences and ADC maps from breast MRI exams showed a varying number of repeatable features, depending on the sequence. Effects of different preprocessing procedures on repeatability of features were different for each sequence. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Axillary lymph node response to neoadjuvant systemic therapy with dedicated axillary hybrid 18F-FDG PET/MRI in clinically node-positive breast cancer patients: a pilot study.

AIM: To investigate the diagnostic performance of dedicated axillary hybrid 18F-2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) in detecting axillary pathological complete response (pCR) following neoadjuvant systemic therapy (NST) in clinically node-positive breast cancer patients. MATERIALS AND METHODS: Ten prospectively included clinically node-positive breast cancer patients underwent dedicated axillary hybrid 18F-FDG PET/MRI after completing NST followed by axillary surgery. PET images were reviewed by a nuclear medicine physician and coronal T1-weighted and T2-weighted MRI images by a radiologist. All axillary lymph nodes visible on PET/MRI were matched with those removed during axillary surgery. Diagnostic performance parameters were calculated based on patient-by-patient and node-by-node validation with histopathology of the axillary surgical specimen as the reference standard. RESULTS: Six patients achieved axillary pCR at final histopathology. A total of 84 surgically harvested axillary lymph nodes were matched with axillary lymph nodes depicted on PET/MRI. Histopathological examination of the matched axillary lymph nodes resulted in 10 lymph nodes with residual axillary disease of which eight contained macrometastases and two micrometastases. The patient-by-patient analysis yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 25%, 100%, 100%, and 67%, respectively. The diagnostic performance parameters of the node-by-node analysis were 0%, 96%, 0%, and 88%, respectively. Excluding micrometastases from the node-by-node analysis increased the negative predictive value to 90%. CONCLUSION: This pilot study suggests that the negative predictive value and sensitivity of dedicated axillary 18F-FDG PET/MRI are insufficiently accurate to detect axillary pCR or exclude residual axillary disease following NST in clinically node-positive breast cancer patients.

The effect of breast MRI on disease-free and overall survival in breast cancer patients: a retrospective population-based study.

PURPOSE: To evaluate the effect of breast MRI on overall survival (OS) and disease-free survival (DFS) of patients with invasive breast cancer in the Netherlands. METHODS: We selected all women from the Netherlands Cancer Registry diagnosed with invasive breast cancer (a) between 2011 and 2013 for the OS-cohort and (b) in the first quarter of 2012 for the DFS-cohort. The study population was subdivided into an MRI and non-MRI group. In addition, subgroups were created according to breast cancer subtype: invasive carcinoma of no special type (NST) versus invasive lobular carcinoma (ILC). OS and DFS were compared between the MRI and non-MRI group using the Kaplan-Meier method and the log-rank test. Cox proportional hazard regression analysis was performed to estimate hazard ratios (HR) with a 95% confidence interval (CI). To account for missing data, multiple imputation was performed. RESULTS: Of the 31,756 patients included in the OS-cohort (70% non-MRI and 30% MRI), 27,752 (87%) were diagnosed with invasive carcinoma NST and 4004 (13%) with ILC. Of the 2464 patients included in the DFS-cohort (72% non-MRI and 28% MRI), 2161 (88%) were diagnosed with invasive carcinoma NST and 303 (12%) with ILC. The distribution of breast MRI use was significantly lower over different age categories, from 49.0% aged < 50 to 16.5% aged > 70. Multivariable Cox regression showed that breast MRI was not significantly associated with OS overall (HR 0.91, 95%-CI 0.74-1.11, p = 0.35), nor in the different histological subtypes. Multivariable Cox regression analysis showed that breast MRI was also not significantly associated with DFS (HR 1.16, 95%-CI 0.81-1.67), nor in the different histological subtypes. CONCLUSION: Use of breast MRI was not significantly associated with an improved OS or DFS in patients treated with primary surgery.

Risk of Positive Sentinel Lymph Node After Neoadjuvant Systemic Therapy in Clinically Node-Negative Breast Cancer: Implications for Postmastectomy Radiation Therapy and Immediate Breast Reconstruction.

BACKGROUND: Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer. METHODS: All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN. RESULTS: In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+ , and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2-11.5%, 0-6.3%, and 2.9-6.2%, respectively. cT1-3N0 ER+HER2- and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8-41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01-3.96), cT3 (OR 2.56; 95% CI 1.30-5.38), grade 3 (OR 0.44; 95% CI 0.21-0.91), and ER+HER2- subtype (OR 3.94; 95% CI 1.77-8.74) were correlated with positive SLN. CONCLUSIONS: In cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2- and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.

Population-based study of the effect of preoperative breast MRI on the surgical management of ductal carcinoma in situ.

BACKGROUND: Determinants of the use of breast MRI in patients with ductal carcinoma in situ (DCIS) in the Netherlands were studied, and whether using MRI influenced the rates of positive resection margins and mastectomies. METHODS: All women aged less than 75 years, and diagnosed with DCIS between 2011 and 2015, were identified from the Netherlands Cancer Registry. Multivariable logistic regression analyses were performed, adjusting for incidence year, age, hospital type, DCIS grade and multifocality. RESULTS: Breast MRI was performed in 2382 of 10 415 DCIS cases (22·9 per cent). In multivariable analysis, patients aged less than 50 years, those with high- or intermediate-grade DCIS and patients with multifocal disease were significantly more likely to have preoperative MRI. Patients undergoing MRI were more likely to have a mastectomy, either as first surgical treatment or following breast-conserving surgery (BCS) in the event of positive margins (odds ratio (OR) 2·11, 95 per cent c.i. 1·91 to 2·33). The risk of positive surgical margins after BCS was similar for those with versus without MRI. The secondary mastectomy rate after BCS was higher in patients who had MRI, especially in women aged less than 50 years (OR 1·94, 1·31 to 2·89). All findings were similar for low- and intermediate/high-grade DCIS. CONCLUSION: Adding MRI to conventional breast imaging did not improve surgical outcome in patients diagnosed with primary DCIS. The likelihood of undergoing a mastectomy was twice as high in the MRI group, and no reduction in the risk of margin involvement was observed after BCS.

ANTECEDENTES: Se estudiaron los determinantes del uso de la resonancia magnética (RM) de mama en pacientes con carcinoma ductal in situ (ductal carcinoma in situ, DCIS) en los Países Bajos y si el uso de la RM influía en las tasas de márgenes de resección positivos y de mastectomías. MÉTODOS: Todas las mujeres menores de 76 años de edad y diagnosticadas de DCIS fueron identificadas a partir del Registro de Cáncer de los Países Bajos de 2011-2015. Se realizaron análisis de regresión logística multivariable, ajustando por año de incidencia, edad, tipo de hospital, grado de DCIS y multifocalidad. RESULTADOS: Se realizó una RM de mama en 2.382 de 10.415 (23%) pacientes con DCIS. En el análisis multivariable, en las pacientes de edad < 50 años, con DCIS de grado alto o intermedio y enfermedad multifocal era estadísticamente significativo más probable que se sometieran a una RM preoperatoria. Las pacientes que se sometieron a RM tuvieron más probabilidades de que se efectuara una mastectomía, ya fuera como primer tratamiento quirúrgico o después de una cirugía conservadora de mama (breast conserving surgery, BCS) en el caso de presentar márgenes positivos (razón de oportunidades, odds ratio, OR = 2,1, i.c. del 95%: 1,9-2,3). El riesgo de obtener márgenes quirúrgicos positivos después de la BCS fue similar para aquellas pacientes con RM versus sin RM. Sin embargo, la tasa de mastectomía secundaria después de la BCS fue mayor en pacientes con RM, especialmente en mujeres menores de 50 años (OR = 1,9, i.c. del 95%: 1,3-2,9). CONCLUSIÓN: Agregar la RM a las imágenes radiológicas convencionales de mama no mejoró el resultado quirúrgico en pacientes diagnosticadas de DCIS primario. En el grupo de RM, la probabilidad de someterse a una mastectomía fue dos veces más alta, sin observarse una reducción en el riesgo de afectación del margen después de la BCS.

Evaluation of pressure-controlled mammography compression paddles with respect to force-controlled compression paddles in clinical practice.

OBJECTIVES: To reduce pain and discomfort associated with breast compression in mammography, a pressure-controlled compression paddle was recently introduced. The objective was to evaluate the pressure-controlled paddle by comparing it to the standard force-controlled paddle. METHODS: Differences of compressed breast thickness (CBT), compression force, compression pressure, and average glandular dose (AGD) between annual follow-up full-field digital mammography exams of 3188 patients were retrospectively examined. Two groups were compared: (1) force-force group (FF-group), both examinations were performed with the force-controlled paddle, and (2) force-pressure group (FP-group), only the follow-up examination was performed with the pressure-controlled paddle. In an additional group of patients, pain scores on a scale of 0 (no pain at all) to 10 (worst pain imaginable) were evaluated prospectively (n = 343) who were randomly assigned to either paddle. RESULTS: Median differences between follow-up exams in CBT, compression force, compression pressure, and AGD were for the FF- and FP-group respectively - 1.0 vs 0.0 mm (p < 0.001); 0.0 vs - 1.0 daN (p = 0.002); - 1.0 vs - 0.5 kPa (p = 0.005); and 0.05 vs - 0.02 mGy (p < 0.001). These differences were, although statistically significant, clinically non-relevant (defined as ΔCBT > ± 2 mm; Δforce > ± 2 daN; Δpressure > ± 1 kPa and ΔAGD > ± 0.1 mGy). The subanalysis dividing CBT into five categories revealed similar results. The median [interquartile range] pain scores were 6 [3, 7] and 5 [3, 7] for the force-controlled and pressure-controlled paddle, respectively, which was not significantly different (p = 0.113). CONCLUSIONS: We observed no clinically relevant differences in CBT, compression force, compression pressure, AGD, or pain score between the force- and pressure-controlled paddle. As such, we found no basis for preferring one paddle over the other. KEY POINTS: • The pressure-controlled paddle did not show any clinically relevant changes in breast compression parameters compared to the force-controlled paddle. • The pressure-controlled paddle did not lead to significant reduction in pain scores indicated by the patients compared to the force-controlled paddle. • A large variation in compression force and compression pressure was observed in mammography exams for the both the force- and pressure-controlled compression paddle.

Evaluation of single-view contrast-enhanced mammography as novel reading strategy: a non-inferiority feasibility study.

BACKGROUND: Guidelines recommend screening of high-risk women using breast magnetic resonance imaging (MRI). Contrast-enhanced mammography (CEM) has matured, providing excellent diagnostic accuracy. To lower total radiation dose, evaluation of single-view (1 V) CEM exams might be considered instead of double-view (2 V) readings as an alternative reading strategy in women who cannot undergo MRI. METHODS: This retrospective non-inferiority feasibility study evaluates whether the use of 1 V results in an acceptable sensitivity for detecting breast cancer (non-inferiority margin, - 10%). CEM images from May 2013 to December 2017 were included. 1 V readings were performed by consensus opinion of three radiologists, followed by 2 V readings being performed after 6 weeks. Cases were considered "malignant" if the final BI-RADS score was ≥ 4, enabling calculation of sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Histopathological results or follow-up served as a gold standard. RESULTS: A total of 368 cases were evaluated. Mean follow-up for benign or negative cases was 20.9 months. Sensitivity decreased by 9.6% from 92.9 to 83.3% when only 1 V was used for evaluation (p < 0.001). The lower limit of the 90% confidence interval around the difference in sensitivity between 1 V and 2 V readings was - 15% and lies below the predefined non-inferiority margin of - 10%. Hence, non-inferiority of 1 V to 2 V reading cannot be concluded. AUC for 1 V was significantly lower, 0.861 versus 0.899 for 2 V (p = 0.0174). CONCLUSION: Non-inferiority of 1 V evaluations as an alternative reading strategy to standard 2 V evaluations could not be concluded. 1 V evaluations had lower diagnostic performance compared with 2 V evaluations. KEY POINTS: • To lower radiation exposure used in contrast-enhanced mammography, we studied a hypothetical alternative strategy: single-view readings (1 V) versus (standard) double-view readings (2 V). • Based on our predefined margin of - 10%, non-inferiority of 1 V could not be concluded. • 1 V evaluation is not recommended as an alternative reading strategy to lower CEM-related radiation exposure.

Post-mortem computed tomography in forensic investigations of lethal gunshot incidents: is there an added value?

The aim of this study is to assess the added value of post-mortem computed tomography (PMCT) in fatal shooting incidents compared with autopsy findings. For this study, the analysis was restricted to the following four features: location of the entrance and exit wounds, internal injuries, location of projectiles or metal fragments and course of the trajectories. These features were selected because they provide essential information on the cause and manner of death. All data were retrospectively collected from medical forensic examinations of fatal shooting incidents in the Netherlands that occurred in 2010-2014. Twenty-one fatal shooting victims were included in this study, with a total of 100 trajectories. For all 100 trajectories, the forensic radiologist and pathologist came to a consensus on which examination had the highest diagnostic value for each of the four features. PMCT provides superior information on the presence of metal fragments, internal injuries and the course of trajectories. PMCT provides limited information on the discrimination of entrance and exit wounds. In conclusion, PMCT provides additional relevant information in over 60% of forensic medical examinations of deceased victims of shooting incidents. We therefore recommend adding PMCT as a standard examination in these cases.

Added value of dedicated axillary hybrid 18F-FDG PET/MRI for improved axillary nodal staging in clinically node-positive breast cancer patients: a feasibility study.

PURPOSE: To investigate the feasibility and potential added value of dedicated axillary 18F-FDG hybrid PET/MRI, compared to standard imaging modalities (i.e. ultrasound [US], MRI and PET/CT), for axillary nodal staging in clinically node-positive breast cancer. METHODS: Twelve patients with clinically node-positive breast cancer underwent axillary US and dedicated axillary hybrid 18F-FDG PET/MRI. Nine of the 12 patients also underwent whole-body PET/CT. Maximum standardized uptake values (SUVmax) were measured for the primary breast tumor and the most FDG-avid axillary lymph node. A positive axillary lymph node on dedicated axillary hybrid PET/MRI was defined as a moderate to very intense FDG-avid lymph node. The diagnostic performance of dedicated axillary hybrid PET/MRI was calculated by comparing quantitative and its qualitative measurements to results of axillary US, MRI and PET/CT. The number of suspicious axillary lymph nodes was subdivided as follows: N0 (0 nodes), N1 (1-3 nodes), N2 (4-9 nodes) and N3 (≥ 10 nodes). RESULTS: According to dedicated axillary hybrid PET/MRI findings, seven patients were diagnosed with N1, four with N2 and one with N3. With regard to mean SUVmax, there was no significant difference in the primary tumor (9.0 [±5.0] vs. 8.6 [±5.7], p = 0.678) or the most FDG-avid axillary lymph node (7.8 [±5.3] vs. 7.7 [±4.3], p = 0.767) between dedicated axillary PET/MRI and PET/CT. Compared to standard imaging modalities, dedicated axillary hybrid PET/MRI resulted in changes in nodal status as follows: 40% compared to US, 75% compared to T2-weighted MRI, 40% compared to contrast-enhanced MRI, and 22% compared to PET/CT. CONCLUSIONS: Adding dedicated axillary 18F-FDG hybrid PET/MRI to diagnostic work-up may improve the diagnostic performance of axillary nodal staging in clinically node-positive breast cancer patients.

Diagnostic performance of gadofosveset-enhanced axillary MRI for nodal (re)staging in breast cancer patients: results of a validation study.

AIM: To evaluate diagnostic performance of gadofosveset (GDF)-enhanced magnetic resonance imaging (MRI) in addition to T2-weighted (T2W) MRI for nodal (re)staging in newly diagnosed breast cancer patients. MATERIALS AND METHODS: Ninety patients underwent axillary T2W- and GDF-MRI. Two radiologists independently scored each lymph node; first on T2W-MRI, subsequently adjusting their score on GDF-MRI. Diagnostic performance parameters were calculated on node-by-node and patient-by-patient validation with histopathology as the reference standard. Furthermore, learning curve analysis for reading GDF-MRI was performed. RESULTS: In patient-by-patient validation, overall reader performances for T2W- and GDF-MRI were similar with area under the receiver operating characteristic curves (AUC) of 0.75 and 0.77 (p=0.731) for reader 1 and 0.79 and 0.72 (p=0.156) for reader 2. For node-by-node validation, AUC values of T2W- and GDF-MRI were 0.76 and 0.82 (p=0.018) and 0.77 and 0.77 (p=0.998) for reader 1 and 2. The AUC for reader 1 was 0.71 for first one-third of nodes evaluated, improving to 0.80 and 0.95 for the next and last one-third, respectively. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) improved from 38%, 89%, 56%, and 79% to 60%, 93%, 64%, and 92%. The AUC of reader 2 improved from 0.69 to 0.79. CONCLUSION: The present study confirmed that GDF-MRI, in addition to T2W-MRI, has potential as a non-invasive method for nodal (re)staging in breast cancer.

Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts.

AIM: To determine the willingness of women with extremely dense breasts to undergo breast cancer screening with magnetic resonance imaging (MRI) in a research setting, and to examine reasons for women to participate or not. MATERIALS AND METHODS: Between 2011 and 2015, 8,061 women (50-75 years) were invited for supplemental MRI as part of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial (ClinicalTrials.gov Identifier: NCT01315015), after a negative screening mammography in the national population-based mammography screening programme. Demographics of participants and non-participants were compared. All invitees were asked to report reasons for (non)participation. Ethical approval was obtained. Participants provided written informed consent. RESULTS: Of the 8,061 invitees, 66% answered that they were interested, and 59% eventually participated. Participants were on average 54-years old (interquartile range: 51-59 years), comparable to women with extremely dense breasts in the population-based screening programme (55 years). Women with higher socio-economic status (SES) were more often interested in participation than women with lower SES (68% versus 59%, p<0.001). The most frequently stated reasons for non-participation were "MRI-related inconveniences and/or self-reported contraindications to MRI" (27%) and "anxiety regarding the result of supplemental screening" (21%). "Expected personal health benefit" (68%) and "contribution to science" (43%) were the most frequent reasons for participation. CONCLUSION: Of women invited for MRI because of extremely dense breasts, 59% participated. Common reasons for non-participation were "MRI-related inconveniences" and "anxiety regarding the result of supplemental screening". In case of future implementation, availability of precise evidence on benefits and harms might reduce this anxiety.

Does the TNM classification of solitary internal mammary lymph node metastases in breast cancer still apply?

PURPOSE: TNM classification of solitary internal mammary lymph node metastases (IMLNMs) in breast cancer varies depending on their method of detection: sentinel lymph node biopsy (pN1b) or clinical examination including radiological and/or physical examination (pN2b). This study aimed to evaluate whether there is a difference in prognosis between both groups. METHODS: Data of all patients diagnosed with primary invasive epithelial breast cancer between 2005 and 2008 were obtained from the Netherlands Cancer Registry. Patients with IMLNMs were divided in groups according to their pN1b and pN2b status. The main outcome measures disease-free survival (DFS) after 5 years and overall survival (OS) after 8 years were analyzed using Kaplan-Meier survival analysis. Cox regression analysis was used to determine independent predictors for DFS and OS. RESULTS: A total of 73 patients with pN1b status and 28 patients with pN2b status were included. DFS rate was 74.1% in the pN1b group compared to 85.0% in the pN2b group (p = 0.211). Regarding OS, 20.5% (pN1b) and 25.0% (pN2b) of the patients deceased within 8 years of follow-up (p = 0.589). In multivariable cox regression analysis, nodal status was not statistically significant for DFS (HR 0.29 [95% CI 0.04-2.33], p = 0.244) or OS (HR 1.04 [95% CI 0.37-2.89], p = 0.947). CONCLUSIONS: Although the TNM classification considers pN1b and pN2b to be distinct prognostic entities, we did not observe any prognostic differences between these groups. Therefore, solitary IMLNMs may be regarded as a single category in the future and revision of TNM classification should be considered.

Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases.

PURPOSE: The aim of this study was to compare disease-free survival (DFS) and overall survival (OS) between clinically node-positive breast cancer patients, treated with neoadjuvant chemotherapy (NAC), with axillary pathologic complete response (ypN0), residual axillary isolated tumor cells or micrometastases (ypNitc/mi), and residual axillary macrometastases (ypN1-3). METHODS: All patients diagnosed with clinically node-positive primary invasive breast cancer treated with NAC and subsequent axillary lymph node dissection between 2005 and 2008 were retrospectively analyzed. Data were obtained from the Netherlands Cancer Registry. Patients were stratified by final pathological axillary status: ypN0, ypNitc/mi, or ypN1-3. The main outcome measures DFS and OS were analyzed using Kaplan-Meier survival analysis. Uni- and multivariable cox regression analyses were used to determine independent predictors for DFS and OS. RESULTS: A total of 1347 patients were included. Pathologic nodal status was ypN0 in 22.2%, ypNitc/mi in 3.8%, and ypN1-3 in 74.0% of patients. Overall, 5-year DFS was 57.8% and mean OS was 7.4 years. DFS and OS were comparable between ypN0 and ypNitc/mi (HR 1.38 (0.40-4.79, p = 0.613) and HR 0.92 (0.27-3.09, p = 0.889), respectively), but significantly different between ypN0 and ypN1-3 (HR 1.78 (1.06-3.00, p = 0.031) and HR 1.70 (1.07-2.71, p = 0.026), respectively). CONCLUSIONS: Clinically node-positive patients, treated with NAC, with axillary nodal status ypN0 or ypNitc/mi carry similar prognosis regarding DFS and OS. Axillary nodal status ypN1-3 is associated with a less favorable prognosis. Future studies should consider ypN0 and ypNitc/mi as one entity.

Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08).

BACKGROUND: Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. METHODS: The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. DISCUSSION: If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. TRIAL REGISTRATION: The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828.

Contrast-enhanced spectral mammography in recalls from the Dutch breast cancer screening program: validation of results in a large multireader, multicase study.

OBJECTIVES: Contrast-enhanced spectral mammography (CESM) is a promising problem-solving tool in women referred from a breast cancer screening program. We aimed to study the validity of preliminary results of CESM using a larger panel of radiologists with different levels of CESM experience. METHODS: All women referred from the Dutch breast cancer screening program were eligible for CESM. 199 consecutive cases were viewed by ten radiologists. Four had extensive CESM experience, three had no CESM experience but were experienced breast radiologists, and three were residents. All readers provided a BI-RADS score for the low-energy CESM images first, after which the score could be adjusted when viewing the entire CESM exam. BI-RADS 1-3 were considered benign and BI-RADS 4-5 malignant. With this cutoff, we calculated sensitivity, specificity and area under the ROC curve. RESULTS: CESM increased diagnostic accuracy in all readers. The performance for all readers using CESM was: sensitivity 96.9 % (+3.9 %), specificity 69.7 % (+33.8 %) and area under the ROC curve 0.833 (+0.188). CONCLUSION: CESM is superior to conventional mammography, with excellent problem-solving capabilities in women referred from the breast cancer screening program. Previous results were confirmed even in a larger panel of readers with varying CESM experience. KEY POINTS: • CESM is consistently superior to conventional mammography • CESM increases diagnostic accuracy regardless of a reader's experience • CESM is an excellent problem-solving tool in recalls from screening programs.

The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07).

BACKGROUND: Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013-07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy. DESIGN: This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up. DISCUSSION: We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival. TRIAL REGISTRATION: The BOOG 2013-07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .

Evaluation of low-energy contrast-enhanced spectral mammography images by comparing them to full-field digital mammography using EUREF image quality criteria.

OBJECTIVE: Contrast-enhanced spectral mammography (CESM) examination results in a low-energy (LE) and contrast-enhanced image. The LE appears similar to a full-field digital mammogram (FFDM). Our aim was to evaluate LE CESM image quality by comparing it to FFDM using criteria defined by the European Reference Organization for Quality Assured Breast Screening and Diagnostic Services (EUREF). METHODS: A total of 147 cases with both FFDM and LE images were independently scored by two experienced radiologists using these (20) EUREF criteria. Contrast detail measurements were performed using a dedicated phantom. Differences in image quality scores, average glandular dose, and contrast detail measurements between LE and FFDM were tested for statistical significance. RESULTS: No significant differences in image quality scores were observed between LE and FFDM images for 17 out of 20 criteria. LE scored significantly lower on one criterion regarding the sharpness of the pectoral muscle (p < 0.001), and significantly better on two criteria on the visualization of micro-calcifications (p = 0.02 and p = 0.034). Dose and contrast detail measurements did not reveal any physical explanation for these observed differences. CONCLUSIONS: Low-energy CESM images are non-inferior to FFDM images. From this perspective FFDM can be omitted in patients with an indication for CESM. KEY POINTS: • Low-energy CESM images are non-inferior to FFDM images. • Micro-calcifications are significantly more visible on LE CESM than on FFDM. • There is no physical explanation for this improved visibility of micro-calcifications. • There is no need for an extra FFDM when CESM is indicated.

The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients.

Several independent randomized controlled trials are initiated to investigate whether sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients with negative axillary ultrasound findings, who are treated with breast conserving therapy. A consequence of omitting sentinel lymph node biopsy is absence of pathological lymph node status information. We aimed to investigate the impact of omitting sentinel lymph node biopsy on adjuvant systemic treatment recommendations. Data from all consecutive patients with invasive breast cancer and negative axillary ultrasound findings treated with breast conserving therapy and sentinel lymph node biopsy between 2008 and 2012 were collected from a prospective database. Two methods, Adjuvant! Online and the Dutch breast cancer guideline 2012, were used to determine the adjuvant systemic treatment recommendations of every patient. At first, each patient was considered to be lymph node negative, and secondly the patients' true pathological lymph node status was used. A total of 303 patients were consecutively included. Pathological lymph node status was pN0 in 72.3 %, pN0(i+) in 12.9 %, pN1mi+ in 5.6 %, pN1 in 7.3 %, and pN2 in 2.0 % of the patients. The decision to recommend adjuvant systemic treatment changed due to the pathological lymph node status in 1.0 % of the patients (3/303) when using Adjuvant! Online and in 3.6 % (11/303) when using the 2012 Dutch breast cancer guideline. The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients with negative axillary ultrasound findings treated with breast conserving therapy is limited. The safety of omitting the sentinel lymph node biopsy should be confirmed by the initiated randomized controlled trials.

Quality assurance of radiation therapy after breast-conserving surgery among patients in the BOOG 2013-08 trial.

BACKGROUND AND PURPOSE: In the BOOG 2013-08 trial (NCT02271828), cT1-2N0 breast cancer patients were randomized between breast conserving surgery with or without sentinel lymph node biopsy (SLNB) followed by whole breast radiotherapy (WBRT). While awaiting primary endpoint results (axillary recurrence rate), this study aims to perform a quality assurance analysis on protocol adherence and (incidental) axillary radiation therapy (RT) dose. MATERIALS AND METHODS: Patients were enrolled between 2015 and 2022. Data on prescribed RT and (in 25% of included patients) planning target volumes (PTV) parameters were recorded for axillary levels I-IV and compared between treatment arms. Multivariable linear regression analysis was performed to determine prognostic variables for incidental axillary RT dose. RESULTS: 1,439/1,461 included patients (98.5%) were treated according to protocol and 87 patients (5.9%) received regional RT (SLNB 10.9%, no-SLNB 1.5 %). In 326 patients included in the subgroup analysis, the mean incidental PTV dose at axilla level I was 59.5% of the prescribed breast RT dose. In 5 patients (1.5%) the mean PTV dose at level I was ≥95% of the prescribed breast dose. No statistically or clinically significant differences regarding incidental axillary RT dose were found between treatment arms. Tumour bed boost (yes/no) was associated with a higher incidental mean dose in level I (R2 = 0.035, F(6, 263) = 1.532, p 0.168). CONCLUSION: The results indicate that RT-protocol adherence was high, and that incidental axillary RT dose was low in the BOOG 2013-08 trial. Potential differences between treatmentarms regarding the primary endpoint can thus not be attributed to different axillary radiation doses.

Pre-treatment differences and early response monitoring of neoadjuvant chemotherapy in breast cancer patients using magnetic resonance imaging: a systematic review.

OBJECTIVES: To assess whether magnetic resonance imaging (MRI) can identify pre-treatment differences or monitor early response in breast cancer patients receiving neoadjuvant chemotherapy. METHODS: PubMed, Cochrane library, Medline and Embase databases were searched for publications until January 1, 2012. After primary selection, studies were selected based on predefined inclusion/exclusion criteria. Two reviewers assessed study contents using an extraction form. RESULTS: In 15 studies, which were mainly underpowered and of heterogeneous study design, 31 different parameters were studied. Most frequently studied parameters were tumour diameter or volume, K(trans), K(ep), V(e), and apparent diffusion coefficient (ADC). Other parameters were analysed in only two or less studies. Tumour diameter, volume, and kinetic parameters did not show any pre-treatment differences between responders and non-responders. In two studies, pre-treatment differences in ADC were observed between study groups. At early response monitoring significant and non-significant changes for all parameters were observed for most of the imaging parameters. CONCLUSIONS: Evidence on distinguishing responders and non-responders to neoadjuvant chemotherapy using pre-treatment MRI, as well as using MRI for early response monitoring, is weak and based on underpowered study results and heterogeneous study design. Thus, the value of breast MRI for response evaluation has not yet been established. KEY POINTS: Few well-validated pre-treatment MR parameters exist that identify responders and non-responders. Eligible studies showed heterogeneous study designs which hampered pooling of data. Confounders and technical variations of MRI accuracy are not studied adequately. Value of MRI for response evaluation needs to be established further.