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Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.

Purpose In clinically node-positive (cN+) breast cancer patients, evidence supporting response-guided treatment after neoadjuvant systemic therapy (NST) instead of axillary lymph node dissection (ALND) is increasing, but follow-up results are lacking. We assessed three-year axillary recurrence-free interval (aRFI) in cN+ patients with response-adjusted axillary treatment according to the ‘Marking Axillary lymph nodes with Radioactive Iodine seeds’ (MARI)-protocol. Methods We retrospectively assessed all stage II–III cytologically proven cN+ breast cancer patients who underwent the MARI-protocol between July 2014 and November 2018. Pre-NST axillary staging with FDG-PET/CT (less- or more than four suspicious axillary nodes; cALN Results Of 272 women included, the MARI-node was tumor-negative in 56 (32%) of 174 cALN p = 0.059). Conclusions De-escalation of axillary treatment according to the MARI-protocol prevented ALND in 80% of cN+ patients with an excellent three-year aRFI of 98%.

Background Neoadjuvant systemic treatment (NST) leads to pathologic complete response (pCR) in 10–89% of breast cancer patients depending on subtype. The added value of surgery is uncertain in patients who reach pCR; however, current imaging and biopsy techniques aiming to predict pCR are not accurate enough. This study aims to quantify the residual disease remaining after NST in patients with a favorable response on MRI and residual disease missed with biopsies. Methods In the MICRA trial, patients with a favorable response to NST on MRI underwent ultrasound-guided post-NST 14G biopsies followed by surgery. We analyzed pathology reports of the biopsies and the surgical specimens. Primary outcome was the extent of residual invasive disease among molecular subtypes, and secondary outcome was the extent of missed residual invasive disease. Results We included 167 patients. Surgical specimen showed residual invasive disease in 69 (41%) patients. The median size of residual invasive disease was 18 mm (interquartile range [IQR] 12–30) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) patients, 8 mm (IQR 3–15) in HR+/HER2-positive (HER2+) patients, 4 mm (IQR 2–9) in HR-negative (HR−)/HER2+ patients, and 5 mm (IQR 2–11) in triple-negative (TN) patients. Residual invasive disease was missed in all subtypes varying from 4 to 7 mm. Conclusion Although the extent of residual invasive disease is small in TN and HER2+ subtypes, substantial residual invasive disease is left behind in all subtypes with 14G biopsies. This may hamper local control and limits adjuvant systemic treatment options. Therefore, surgical excision remains obligatory until accuracy of imaging and biopsy techniques improve.

Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor.Experimental Design: Patients with ER+/HER2− breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), where upon the average of the top-10% late enhancement was calculated. This contralateral parenchymal enhancement (CPE) was analyzed with respect to routine prognostic models and molecular assays (Nottingham Prognostic Index, Dutch clinical chemotherapy-selection guidelines, 70-gene signature, and 21-gene recurrence score). CPE was split in tertiles and tested for overall and distant disease-free survival. CPE was adjusted for patient and tumor characteristics, as well as systemic therapy, using inverse probability weighting (IPW). Subanalyses were performed in patients at high risk according to prognostic models and molecular assays.Results: Four-hundred-and-fifteen patients were included, constituting the same group in which the association between CPE and survival was discovered. Median follow-up was 85 months, 34/415(8%) patients succumbed. After IPW-adjustment for patient and tumor characteristics, patients with high CPE had significantly better overall survival than those with low CPE in groups at high risk according to the Nottingham Prognostic Index [HR (95% CI): 0.08 (0.00–0.40), P < 0.001]; Dutch clinical guidelines [HR (95% CI): 0.22 (0.00–0.81), P = 0.021]; and 21-gene recurrence score [HR (95% CI): 0.14 (0.00–0.84), P = 0.030]. One group showed a trend [70-gene signature: HR (95% CI): 0.25 (0.00–1.02), P = 0.054].Conclusions: In patients at high risk based on the tumor, subgroups at relatively low risk were identified using pretreatment enhancement of the stroma on breast DCE-MRI. Clin Cancer Res; 23(21); 6505–15. ©2017 AACR.

Competing risk analysis; Cox proportional hazards models are shown for overall survival, breast�cancer related death, and non�breast cancer related death. For each model, pooled hazard ratios (HR) and 95% confidence intervals (CI) are shown. Contralateral parenchymal enhancement was inverse probability weighting� adjusted for age, tumor diameter on MRI, histological grade, axillary load, and systemic treatment. Pooled P�values are shown for a trend�test between all three groups, intermediate CPE versus low CPE, and high CPE versus low CPE.

Background Despite increasingly effective curative breast-conserving treatment (BCT) regimens for primary breast cancer, patients remain at risk for an ipsilateral breast tumor recurrence (IBTR). With increasing interest for repeat BCT in selected patients with IBTR, a reliable assessment of the size of IBTR is important for surgical planning. Aim The primary aim of this study is to establish the performance in size estimation of XMG, US, and breast MRI in patients with IBTR. The secondary aim is to compare the detection of multifocality and contralateral lesions between XMG and MRI. Patients and methods The sizes of IBTR on mammography (XMG), ultrasound (US), and magnetic resonance imaging (MRI) in 159 patients were compared to the sizes at final histopathology. The accuracy of the size estimates was addressed using Pearson’s coefficient and Bland–Altman plots. Secondary outcomes were the detection of multifocality and contralateral lesions between XMG and MRI. Results Both XMG and US significantly underestimated the tumor size by 3.5 and 4.8 mm, respectively, while MRI provided accurate tumor size estimation with a mean underestimation of 1.1 mm. The sensitivity for the detection of multifocality was significantly higher for MRI compared to XMG (25.5% vs. 5.5%). A contralateral malignancy was found in 4.4% of patients, and in 1.9%, it was detected by MRI only. Conclusion The addition of breast MRI to XMG and US in the preoperative workup of IBTR allows for more accurate size estimation. MRI provides a higher sensitivity for the detection of multifocality compared to XMG.

Background: Differences in imaging parameters influence computer-extracted parenchymal enhancement measures from breast MRI. Purpose: To investigate the effect of differences in dynamic contrast-enhanced MRI acquisition parameter settings on quantitative parenchymal enhancement of the breast, and to evaluate harmonization of contrast-enhancement values with respect to flip angle and repetition time. Study Type: Retrospective. Phantom/Populations: We modeled parenchymal enhancement using simulations, a phantom, and two cohorts (N = 398 and N = 302) from independent cancer centers. Sequence Field/Strength: 1.5T dynamic contrast-enhanced T1-weighted spoiled gradient echo MRI. Vendors: Philips, Siemens, General Electric Medical Systems. Assessment: We assessed harmonization of parenchymal enhancement in simulations and phantom by varying the MR parameters that influence the amount of T1-weighting: flip angle (8°–25°) and repetition time (4–12 msec). We calculated the median and interquartile range (IQR) of the enhancement values before and after harmonization. In vivo, we assessed overlap of quantitative parenchymal enhancement in the cohorts before and after harmonization using kernel density estimations. Cohort 1 was scanned with flip angle 20° and repetition time 8 msec; cohort 2 with flip angle 10° and repetition time 6 msec. Statistical Tests: Paired Wilcoxon signed-rank-test of bootstrapped kernel density estimations. Results: Before harmonization, simulated enhancement values had a median (IQR) of 0.46 (0.34–0.49). After harmonization, the IQR was reduced: median (IQR): 0.44 (0.44–0.45). In the phantom, the IQR also decreased, median (IQR): 0.96 (0.59–1.22) before harmonization, 0.96 (0.91–1.02) after harmonization. Harmonization yielded significantly (P < 0.001) better overlap in parenchymal enhancement between the cohorts: median (IQR) was 0.46 (0.37–0.58) for cohort 1 vs. 0.37 (0.30–0.44) for cohort 2 before harmonization (57% overlap); and 0.35 (0.28–0.43) vs.0.37 (0.30–0.44) after harmonization (85% overlap). Data Conclusion: The proposed practical harmonization method enables an accurate comparison between patients scanned with differences in imaging parameters. Level of Evidence: 3. Technical Efficacy Stage: 4.

Objectives To investigate whether contralateral parenchymal enhancement (CPE) on MRI during neoadjuvant endocrine therapy (NET) is associated with the preoperative endocrine prognostic index (PEPI) of ER+/HER2− breast cancer. Methods This retrospective observational cohort study included 40 unilateral ER+/HER2− breast cancer patients treated with NET. Patients received NET for 6 to 9 months with MRI response monitoring after 3 and/or 6 months. PEPI was used as endpoint. PEPI is based on surgery-derived pathology (pT- and pN-stage, Ki67, and ER-status) and stratifies patients in three groups with distinct prognoses. Mixed effects and ROC analysis were performed to investigate whether CPE was associated with PEPI and to assess discriminatory ability. Results The median patient age was 61 (interquartile interval: 52, 69). Twelve patients had PEPI-1 (good prognosis), 15 PEPI-2 (intermediate), and 13 PEPI-3 (poor). High pretreatment CPE was associated with PEPI-3: pretreatment CPE was 39.4% higher on average (95% CI = 1.3, 91.9%; p = .047) compared with PEPI-1. CPE decreased after 3 months in PEPI-2 and PEPI-3. The average reduction was 24.4% (95% CI = 2.6, 41.3%; p = .032) in PEPI-2 and 29.2% (95% CI = 7.8, 45.6%; p = .011) in PEPI-3 compared with baseline. Change in CPE was predictive of PEPI-1 vs PEPI-2+3 (AUC = 0.77; 95% CI = 0.57, 0.96). Conclusions CPE during NET is associated with PEPI-group in ER+/HER2− breast cancer: a high pretreatment CPE and a decrease in CPE during NET were associated with a poor prognosis after NET on the basis of PEPI. Key Points • Change in contralateral breast parenchymal enhancement on MRI during neoadjuvant endocrine therapy distinguished between patients with a good and intermediate/poor prognosis at final pathology. • Patients with a poor prognosis at final pathology showed higher baseline parenchymal enhancement on average compared to patients with a good prognosis. • Patients with an intermediate/poor prognosis at final pathology showed a higher average reduction in parenchymal enhancement after 3 months of neoadjuvant endocrine therapy.

Purpose We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment. Methods and Materials RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT. Results Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated. Conclusions Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT.

Background: To analyze the feasibility and accuracy of micro–computed tomography (micro-CT) for surgical margin assessment in breast excision specimen. Materials and methods: Two data sets of 30 micro-CT scans were retrospectively evaluated for positive resection margins by four observers in two phases, using pathology as a gold standard. Results of phase 1 were evaluated to define micro-CT evaluation guidelines for phase 2. Interobserver agreement was also assessed (kappa). In addition, a prospective study was conducted in which 40 micro-CT scans were directly acquired, reconstructed, and evaluated for positive resection margins by one observer. A suspect positive resection margin on micro-CT was annotated onto the specimen with ink, enabling local validation by pathology. Main outcome measures were accuracy, sensitivity, specificity, and positive predictive value (PPV). Results: Average accuracy, sensitivity, specificity, and PPV for the four observers were 63%, 38%, 70%, and 22%, respectively, in phase 1 and 72%, 40%, 78%, and 26%, respectively, in phase 2. The interobserver agreement was fair [kappa (range), 0.31 (0.12-0.80) in phase 1 and 0.23 (0-0.43) in phase 2]. In the prospective study 70% of the surgical resection margins were correctly evaluated. Ten specimens were annotated for positive resection margins, which correlated with three positive and three close (

Purpose This study aimed to find indicators for early response to radiation therapy in breast cancer. These would be of help in tailoring treatment for individual patients. Methods and Materials We analyzed 66 patients with low-risk breast cancer (≥60 years; cT1-2pN0) treated within the Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial. Patients received radiation therapy (RT; 10 x 4 Gray or 5 x 6 Gray), followed by a wide local excision after 6 weeks. Patients underwent magnetic resonance imaging (MRI) and 18F-fluorodexoyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before RT and 5 weeks after RT, before surgery. We assessed the response to PAPBI using a histopathologic assessment and correlated this with responses on MRI and FDG PET/CT. We calculated the positive predictive values (PPVs) of MRI and PET/CT as the number of true positives (complete response on MRI/normalized at visual evaluation on PET/CT and pathologic complete response) divided by the number of patients with a complete response on MRI/normalized at visual evaluation on PET/CT. Similarly, the negative predictive values (NPVs) of MRI and PET/CT were calculated. Results The pathologic response was (nearly) complete in 15 (23%) of the 66 patients and partially complete in 28 (42%). The remaining 23 patients (35%) were nonresponders. The PPV of MRI (Response evaluation criteria in solid tumors [RECIST]) was 87.5% and the NPV was 85%. The PPV and NPV of PET/CT were 25% and 92%, respectively. Conclusions The most accurate method to predict a response and residual disease after preoperative RT in low-risk breast cancer was MRI, using RECIST.

Objective: To investigate whether BIRADS MRI characteristics before or during neoadjuvant endocrine therapy (NET) are associated with the preoperative endocrine prognostic index (PEPI) in ER+/HER2- breast cancer patients. Methods: This retrospective observational cohort study included 35 ER+/HER2- patients with 38 tumors (3 bilateral cases) treated with NET. The pre- and midtreatment (after 3 months) MRIs were evaluated by two breast radiologists for BIRADS imaging characteristics, shrinkage pattern, and radiologic response. PEPI was used as end point. PEPI is based on the post-treatment surgical specimen’s pT- and pN-stage, Ki67, and ER-status. Tumors were assigned PEPI-1 (good prognosis) or PEPI-2/3 (poor prognosis). We investigated whether pre- and midtreatment BIRADS characteristics were associated with PEPI. Results: Median patient age was 65 years (interquartile interval [IQI]: 53, 70). 17 tumors (44.7%) were associated with good prognosis (PEPI-1), and 21 tumors (55.3%) with poor prognosis (PEPI-2/3). A larger reduction in tumor size after 3 months of NET was significantly associated with PEPI; 10 mm (IQI: 5, 13.5) in PEPI-1 tumors vs 4.5 mm (IQI: 3, 7; p = .045) in PEPI-2/3 tumors. Other BIRADS characteristics, shrinkage pattern or radiologic response were not associated with PEPI. Conclusion: Only a larger reduction in tumor size on MRI after 3 months of NET was associated with PEPI-1 (good prognosis) in ER+/HER2- breast cancer patients. Advances in knowledge: MRI characteristics previously reported to be associated with prognosis during neoadjuvant chemotherapy are not necessarily associated with prognosis during NET in ER+/HER2- breast cancer patients.

BackgroundThe added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI.MethodsWe performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1–4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR).ResultsBetween April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45–61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27–49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72–55.89;p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95–21.73;p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87–1.00;p = 0.051).ConclusionThe MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.

Purpose To assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. Methods Preoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). Results CPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate = .11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P = .143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P = .017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P = .020) for OS and 1.10 (95% CI = 1.02, 1.18; P = .012) for IDFS. Conclusion CPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data., Highlights • Contralateral parenchymal enhancement on MRI was associated with tumor proteasome gene expression in ER+/HER2-breast cancer. • A high contralateral parenchymal enhancement was associated with a low proteasome gene expression in the breast cancer. • Low proteasome tumor gene expression was associated with improved survival in an independent patient cohort.

To purpose of this paper was to assess the feasibility of volumetric breast density estimations on MRI without segmentations accompanied with an explainability step. A total of 615 patients with breast cancer were included for volumetric breast density estimation. A 3-dimensional regression convolutional neural network (CNN) was used to estimate the volumetric breast density. Patients were split in training (N = 400), validation (N = 50), and hold-out test set (N = 165). Hyperparameters were optimized using Neural Network Intelligence and augmentations consisted of translations and rotations. The estimated densities were evaluated to the ground truth using Spearman’s correlation and Bland–Altman plots. The output of the CNN was visually analyzed using SHapley Additive exPlanations (SHAP). Spearman’s correlation between estimated and ground truth density was ρ = 0.81 (N = 165, P

Importance For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM; and BRCA2, OMIM) or TP53 (OMIM) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce.Objective To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant.Design, Setting, and Participants In this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. A Dutch screening setting was modeled. Most data were obtained from the randomized Familial MRI Screening (FaMRIsc) trial, which included Dutch women aged 30 to 55 years. A health care payer perspective was applied.Interventions Several screening protocols with varying ages and intervals including those of the randomized FaMRIsc trial, consisting of the mammography (Mx) protocol (annual mammography and clinical breast examination) and the MRI protocol (annual MRI and clinical breast examination plus biennial mammography).MAIN OUTCOMES AND MEASURES Costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated and discounted by 3%. A threshold of (sic)22 000 (US $24 795.87) per QALY was applied.RESULTS This economic evaluation modeling study estimated that, on a lifetime horizon per 1000 women with the Mx protocol of the FaMRIsc trial, 346 breast cancers would be detected, and 49 women were estimated to die from breast cancer, resulting in 22 885 QALYs and total costs of (sic)7 084 767 (US $7 985 134.61). The MRI protocol resulted in 79 additional QALYs and additional (sic)2 657 266 (US $2 994 964.65). Magnetic resonance imaging performed only every 18 months between the ages of 35 and 60 years followed by the national screening program was considered optimal, with an ICER of (sic)21 380 (US $24 097.08) compared with the previous nondominated strategy in the ranking, when applying the National Institute for Health and Care Excellence threshold. Annual screening alternating MRI and mammography between the ages of 35 and 60 years, followed by the national screening program, gave similar outcomes. Higher thresholds would favor annual MRI screening. The ICER was most sensitive to the unit cost of MRI and the utility value for ductal carcinoma in situ and localized breast cancer.CONCLUSIONS AND RELEVANCE This study suggests that MRI screening every 18 months between the ages of 35 and 60 years for women with a family history of breast cancer is cost-effective within the National Institute for Health and Care Excellence threshold for all densities. Higher thresholds would favor annual MRI screening. These outcomes support a change of current screening guidelines for this specific risk group and support MRI screening.

Background Differences in imaging parameters influence computer‐extracted parenchymal enhancement measures from breast MRI. Purpose To investigate the effect of differences in dynamic contrast‐enhanced MRI acquisition parameter settings on quantitative parenchymal enhancement of the breast, and to evaluate harmonization of contrast‐enhancement values with respect to flip angle and repetition time. Study Type Retrospective. Phantom/Populations We modeled parenchymal enhancement using simulations, a phantom, and two cohorts (N = 398 and N = 302) from independent cancer centers. Sequence Field/Strength 1.5T dynamic contrast‐enhanced T1‐weighted spoiled gradient echo MRI. Vendors: Philips, Siemens, General Electric Medical Systems. Assessment We assessed harmonization of parenchymal enhancement in simulations and phantom by varying the MR parameters that influence the amount of T1‐weighting: flip angle (8°–25°) and repetition time (4–12 msec). We calculated the median and interquartile range (IQR) of the enhancement values before and after harmonization. In vivo, we assessed overlap of quantitative parenchymal enhancement in the cohorts before and after harmonization using kernel density estimations. Cohort 1 was scanned with flip angle 20° and repetition time 8 msec; cohort 2 with flip angle 10° and repetition time 6 msec. Statistical Tests Paired Wilcoxon signed‐rank‐test of bootstrapped kernel density estimations. Results Before harmonization, simulated enhancement values had a median (IQR) of 0.46 (0.34–0.49). After harmonization, the IQR was reduced: median (IQR): 0.44 (0.44–0.45). In the phantom, the IQR also decreased, median (IQR): 0.96 (0.59–1.22) before harmonization, 0.96 (0.91–1.02) after harmonization. Harmonization yielded significantly (P

Purpose Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer. Methods In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery. Results GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77–3.72), p

This study aims to evaluate if navigator-echo respiratory-triggered magnetic resonance acquisition can acquire supine high-quality breast magnetic resonance imaging (MRI). Supine respiratory-triggered magnetic resonance imaging (Trig-MRI) was compared to supine non-Trig-MRI to evaluate breathing-induced motion artifacts (group 1), and to conventional prone non-Trig-MRI (group 2, 16-channel breast coil), all at 3T. A 32-channel thorax coil was placed on top of a cover to prevent breast deformation. Ten volunteers were scanned in each group, including one patient. The acquisition time was recorded. Image quality was compared by visual examination and by calculation of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and image sharpness (IS). Scan time increased from 56.5 seconds (non-Trig-MRI) to an average of 306 seconds with supine Trig-MRI (range: 120-540 seconds). In group 1, the median values (interquartile range) of SNR, CNR, and IS improved from 11.5 (6.0), 7.3 (3.1), and 0.23 (0.2) cm on supine non-Trig-MRI to 38.1 (29.1), 32.8 (29.7), and 0.12 (0) cm (all P

Objectives Accurate tumour localisation is essential for breast-conserving surgery of non-palpable tumours. Current localisation technologies are associated with disadvantages such as logistical challenges and migration issues (wire guided localisation) or legislative complexities and high administrative burden (radioactive localisation). We present MAgnetic MArker LOCalisation (MaMaLoc), a novel technology that aims to overcome these disadvantages using a magnetic marker and a magnetic detection probe. This feasibility study reports on the first experience with this new technology for breast cancer localisation. Materials and methods Fifteen patients with unifocal, non-palpable breast cancer were recruited. They received concurrent placement of the magnetic marker in addition to a radioactive iodine seed, which is standard of care in our clinic. In a subset of five patients, migration of the magnetic marker was studied. During surgery, a magnetic probe and gammaprobe were alternately used to localise the markers and guide surgery. The primary outcome parameter was successful transcutaneous identification of the magnetic marker. Additionally, data on radiologist and surgeon satisfaction were collected. Results Magnetic marker placement was successful in all cases. Radiologists could easily adapt to the technology in the clinical workflow. Migration of the magnetic marker was negligible. The primary endpoint of the study was met with an identification rate of 100%. Both radiologists and surgeons reflected that the technology was intuitive to use and that it was comparable to radioactive iodine seed localisation. Conclusion Magnetic marker localisation for non-palpable breast cancer is feasible and safe, and may be a viable non-radioactive alternative to current localisation technologies.

Purpose To assess the 3D geometric sampling accuracy of a new PET-guided system for breast cancer biopsy (BCB) from areas within the tumour with high 18 F-FDG uptake. Materials and methods In the context of the European Union project MammoCare, a prototype semi-robotic stereotactic prototype BCB-device was incorporated into a dedicated high resolution PET-detector for breast imaging. The system consists of 2 stacked rings, each containing 12 plane detectors, forming a dodecagon with a 186 mm aperture for 3D reconstruction (1 mm 3 voxel). A vacuum-assisted biopsy needle attached to a robot-controlled arm was used. To test the accuracy of needle placement, the needle tip was labelled with 18 F-FDG and positioned at 78 target coordinates distributed over a 35 mm × 24 mm × 28 mm volume within the PET-detector field-of-view. At each position images were acquired from which the needle positioning accuracy was calculated. Additionally, phantom-based biopsy proofs, as well as MammoCare images of 5 breast cancer patients, were evaluated for the 3D automated locating of 18 F-FDG uptake areas within the tumour. Results Needle positioning tests revealed an average accuracy of 0.5 mm (range 0–1 mm), 0.6 mm (range 0–2 mm), and 0.4 mm (range 0–2 mm) for the x / y / z -axes, respectively. Furthermore, the MammoCare system was able to visualize and locate small ( 18 F-FDG uptake within the tumour suitable for PET-guided biopsy after being located by the 3D automated application. Conclusions Accuracy testing demonstrated high-precision of this semi-automatic 3D PET-guided system for breast cancer core needle biopsy. Its clinical feasibility evaluation in breast cancer patients scheduled for neo-adjuvant chemotherapy will follow.

Purpose To assess the 3D geometric sampling accuracy of a new PET-guided system for breast cancer biopsy (BCB) from areas within the tumour with high 18F-FDG uptake.

Background and Objectives: Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). In patients with an excellent response, imaging alone is not reliable enough to differentiate between patients with residual disease, who should be surgically treated or patients with pCR where surgery could be considered overtreatment. Several trials currently investigate the accuracy of minimal invasive biopsies to assess presence of pCR of the breast. We initiated the MICRA trial (Minimal Invasive Complete Response Assessment NTR6120) combining MRI and minimal invasive biopsies of the breast. Methods: Breast cancer patients treated with NST resulting in a radiologic complete (rCR) or partial response (rPR, > 30 % decrease and < 2 cm residual diameter) on MRI are eligible. Post-NST, eight ultrasound-guided 14G core biopsies of the pre-NST marked tumor area are obtained. Pathology results of biopsies and surgical specimens are compared. The primary endpoint is the false-negative rate (FNR) of the biopsy procedure i.e. the proportion of patients with non-pCR in the surgical specimen but with pCR in the biopsies. Here we report results of the interim analysis. Results: 219 patients were enrolled in the trial. Biopsies were successfully obtained and analyzed in 167 patients. Main age was 49 yrs (range 24-74). Tumor subtype was 26% hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-), 14% HR-/HER2+, 36% triple negative and 24% HR+HER2+. 135 patients had a rCR and 32 patients a rPR on MRI. There were 89 patients (53%) with pCR in the surgical specimen, all correctly identified by post-NST biopsies (false-positive rate 0%). Post-NST biopsies however missed residual disease in 29/78 patients (FNR 37%). FNR was higher in patients with rCR (FNR 45%; 26/55 patients with residual disease missed on biopsies) than in patients with rPR (FNR 13 %; 3/23 patients with residual disease missed with biopsies). The conditional power estimating the probability of the FNR being ≤ 8% at final analysis was < 1%. MICRA patients total n=167Specimen negSpecimen posBiopsy neg8929118FNR= 29/7837%Biopsy pos049498978167 Conclusions: Ultrasound-guided core biopsies of the breast in patients with excellent response on MRI after NST are not accurate enough to safely select patients with pCR for omission of surgery. Citation Format: Marie-Jeanne T.F.D. Vrancken Peeters, A van Loevezijn, M EM van der Noordaa, F H van Duijnhoven, C E Loo, E van Werkhoven, K K van de Vijver, T Wiersma, H AO Winter-Warnars, G S Sonke, C. Blanken, B. Zonnevels. Towards omitting breast surgery in patients with a pathologic complete response after neoadjuvant systemic treatment: interim analysis of the MICRA trial (Minimally Invasive Complete Response Assessment) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-06.

Purpose BRCA2 mutation carriers are offered annual breast screening with MRI and mammography. The aim of this study was to investigate the supplemental value of mammographic screening over MRI screening alone. Methods In this multicenter study, proven BRCA2 mutation carriers, who developed breast cancer during screening using both digital mammography and state-of-art breast MRI, were identified. Clinical data were reviewed to classify cases in screen-detected and interval cancers. Imaging was reviewed to assess the diagnostic value of mammography and MRI, using the Breast Imaging and Data System (BI-RADS) classification allocated at the time of diagnosis. Results From January 2003 till March 2019, 62 invasive breast cancers and 23 ductal carcinomas in situ were diagnosed in 83 BRCA2 mutation carriers under surveillance. Overall screening sensitivity was 95.2% (81/85). Four interval cancers occurred (4.7% (4/85)). MRI detected 73 of 85 breast cancers (sensitivity 85.8%) and 42 mammography (sensitivity 49.9%) (p Eight mammography-only lesions occurred. In 1 of 17 women younger than 40 years, a 6-mm grade 3 DCIS, retrospectively visible on MRI, was detected with mammography only in a 38-year-old woman. The other 7 mammography-only breast cancers were diagnosed in women aged 50 years and older, increasing sensitivity in this subgroup from 79.5% (35/44) to 95.5% (42/44) (p ≤ 0.001). Conclusions In BRCA2 mutation carriers younger than 40 years, the benefit of mammographic screening over MRI was very small. In carriers of 50 years and older, mammographic screening contributed significantly. Hence, we propose to postpone mammographic screening in BRCA2 mutation carriers to at least age 40.

Breast density, which is the ratio between fibroglandular tissue (FGT) and total breast volume, can be assessed qualitatively by radiologists and quantitatively by computer algorithms. These algorithms often rely on segmentation of breast and FGT volume. In this study, we propose a method to directly assess breast density on MRI, and provide interpretations of these assessments. We assessed breast density in 506 patients with breast cancer using a regression convolutional neural network (CNN). The input for the CNN were slices of breast MRI of 128 x 128 voxels, and the output was a continuous density value between 0 (fatty breast) and 1 (dense breast). We used 350 patients to train the CNN, 75 for validation, and 81 for independent testing. We investigated why the CNN came to its predicted density using Deep SHapley Additive exPlanations (SHAP). The density predicted by the CNN on the testing set was significantly correlated with the ground truth densities (N = 81 patients, Spearman's rho = 0.86, P < 0.001). When inspecting what the CNN based its predictions on, we found that voxels in FGT commonly had positive SHAP-values, voxels in fatty tissue commonly had negative SHAP-values, and voxels in non-breast tissue commonly had SHAP-values near zero. This means that the prediction of density is based on the structures we expect it to be based on, namely FGT and fatty tissue. To conclude, we presented an interpretable deep learning regression method for breast density estimation on MRI with promising results., This paper has been published as: Van der Velden, B.H.M., Ragusi, M.A.A., Janse, M.H.A., Loo, C.E., Gilhuijs, K.G.A. "Interpretable deep learning regression for breast density estimation on MRI." Medical Imaging 2020: Computer-Aided Diagnosis. Vol. 11314. International Society for Optics and Photonics, 2020

Background Better understanding of the molecular biology associated with MRI phenotypes may aid in the diagnosis and treatment of breast cancer. Purpose To discover the associations between MRI phenotypes of breast cancer and their underlying molecular biology derived from gene expression data. Materials and Methods This is a secondary analysis of the Multimodality Analysis and Radiologic Guidance in Breast-Conserving Therapy, or MARGINS, study. MARGINS included patients eligible for breast-conserving therapy between November 2000 and December 2008 for preoperative breast MRI. Tumor RNA was collected for sequencing from surgical specimen. Twenty-one computer-generated MRI features of tumors were condensed into seven MRI factors related to tumor size, shape, initial enhancement, late enhancement, smoothness of enhancement, sharpness, and sharpness variation. These factors were associated with gene expression levels from RNA sequencing by using gene set enrichment analysis. Statistical significance of these associations was evaluated by using a sample permutation test and the false discovery rate. Results Gene expression and MRI data were obtained for 295 patients (mean age, 56 years ± 10.3 [standard deviation]). Larger and more irregular tumors showed increased expression of cell cycle and DNA damage checkpoint genes (false discovery rate0.25; normalized enrichment statistic [NES], 2.15). Enhancement and sharpness of the tumor margin were associated with expression of ribosomal proteins (false discovery rate0.25; NES, 1.95). Smoothness of enhancement, tumor size, and tumor shape were associated with expression of genes involved in the extracellular matrix (false discovery rate0.25; NES, 2.25). Conclusion Breast cancer MRI phenotypes were related to their underlying molecular biology revealed by using RNA sequencing. The association between enhancements and sharpness of the tumor margin with the ribosome suggests that these MRI features may be imaging biomarkers for drugs targeting the ribosome. © RSNA, 2020

Purpose To retrospectively explore the relation between parenchymal enhancement of the healthy contralateral breast on dynamic contrast-enhanced magnetic resonance imaging (MRI) and genomic tests for estrogen receptor (ER)-pathway activity in patients with ER-positive/HER2-negative cancer. Methods A subset of 227 consecutively included patients with unilateral invasive ER-positive/HER2-negative breast cancer underwent dynamic contrast-enhanced MRI prior to breast-conserving therapy between 2000 and 2008. Perfusion of the parenchyma in the healthy breast was assessed using a previously reported measure of contralateral parenchymal enhancement (CPE), consisting of the mean of the top-10% late enhancement. ER-pathway activity was assessed from the surgical resection specimen by the previously reported sensitivity to endocrine therapy (SET)-index and ER-factor. The SET-index is a genetic test to estimate survival benefit from endocrine therapy, consisting of genes related to the ESR1 gene. The ER-factor examines other factors as well including protein expression. The relation between CPE and ER-pathway activity was modeled using linear regression. Results Patients had a median age of 59 years. CPE was not significantly associated with the SET-index (R-squared = 0.005) nor the ER-factor (R-squared = 0.0002). The only variable significantly different between low and high CPE was age at diagnosis (P Conclusions Contralateral parenchymal enhancement on dynamic contrast-enhanced MRI was not associated with tumor-derived estrogen receptor pathway activity.

Purpose In this multicenter phase 2 feasibility study, we investigated the impact of preoperative accelerated partial breast irradiation (PAPBI) on local control, breast fibrosis, and cosmetic outcome. Methods and Materials Women aged >60 years with an invasive, unifocal (mammography and magnetic resonance imaging), nonlobular adenocarcinoma of the breast were treated with PAPBI. Six weeks after radiation therapy, a wide local excision was performed. Radiation therapy consisted of 10 × 4 Gy (2010-2013) or 5 × 6 Gy (after 2013) to the tumor (gross target volume) with a 25 mm margin (20 mm from gross target volume to clinical target volume, 5 mm planning target volume). Results One hundred thirty-three patients treated between 2010 and 2016 were analyzed with a median follow-up of 5.0 years (0.9-8.8 years). Seventy-eight (59%) patients were treated with 10 × 4 Gy in 2 weeks and 55 (41%) patients with 5 × 6 Gy in 1 week. Eighteen postoperative complications (14%) occurred in 15 patients (11%). The proportion of patients with no to mild fibrosis in the treated part of the breast at 2 years and later time points was around 90%. Cosmesis improved over time in several patients: excellent to good cosmetic score as rated by the physician was 68% at 6 months and 92% at 5 years. Seventy-seven percent (6 months) to 82% (5 years) of patients were “satisfied” or “very satisfied” with their cosmetic outcome. Three recurrences were detected in the biopsy track and 1 recurrence in the ipsilateral breast. Conclusions PAPBI is a feasible method with a low postoperative complication rate, limited fibrosis, and good to excellent cosmetic outcome. The local recurrence rate was 3% at 5 years; however, no local recurrences were observed since removal of the needle biopsy track.

Background: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. Methods: In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30–55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. Findings: Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5–14] vs 17 mm [13–22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). Interpretation: MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. Funding: Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

We present a radiomics model to discriminate between patients at low risk and those at high risk of treatment failure at long-term follow-up based on eigentumors: principal components computed from volumes encompassing tumors in washin and washout images of pre-treatment dynamic contrast-enhanced (DCE-) MR images. Eigentumors were computed from the images of 563 patients from the MARGINS study. Subsequently, a least absolute shrinkage selection operator (LASSO) selected candidates from the components that contained 90% of the variance of the data. The model for prediction of survival after treatment (median follow-up time 86 months) was based on logistic regression. Receiver operating characteristic (ROC) analysis was applied and area-under-the-curve (AUC) values were computed as measures of training and cross-validated performances. The discriminating potential of the model was confirmed using Kaplan-Meier survival curves and log-rank tests. From the 322 principal components that explained 90% of the variance of the data, the LASSO selected 28 components. The ROC curves of the model yielded AUC values of 0.88, 0.77 and 0.73, for the training, leave-one-out cross-validated and bootstrapped performances, respectively. The bootstrapped Kaplan-Meier survival curves confirmed significant separation for all tumors (P < 0.0001). Survival analysis on immunohistochemical subgroups shows significant separation for the estrogen-receptor (ER) subtype tumors (P < 0.0001) and the triple-negative (TN) subtype tumors (P=0.0039), but not for tumors of the HER2 subtype (P=0.41). The results of this retrospective study show the potential of early-stage pre-treatment eigentumors for use in prediction of treatment failure of breast cancer.&#13.

Objectives: Breast cancer screening using magnetic resonance imaging (MRI) has limited accessibility due to high costs of breast MRI. Ultrafast dynamic contrast-enhanced breast MRI can be acquired within 2 minutes. We aimed to assess whether screening performance of breast radiologist using an ultrafast breast MRI-only screening protocol is as good as performance using a full multiparametric diagnostic MRI protocol (FDP).Materials and Methods: The institutional review board approved this study, and waived the need for informed consent. Between January 2012 and June 2014, 1791 consecutive breast cancer screening examinations from 954 women with a lifetime risk of more than 20% were prospectively collected. All women were scanned using a 3 T protocol interleaving ultrafast breast MRI acquisitions in a full multiparametric diagnostic MRI protocol consisting of standard dynamic contrast-enhanced sequences, diffusion-weighted imaging, and T2-weighted imaging. Subsequently, a case set was created including all biopsied screen-detected lesions in this period (31 malignant and 54 benign) and 116 randomly selected normal cases with more than 2 years of follow-up. Prior examinations were included when available. Seven dedicated breast radiologists read all 201 examinations and 153 available priors once using the FDP and once using ultrafast breast MRI only in 2 counterbalanced and crossed-over reading sessions.Results: For reading the FDP versus ultrafast breast MRI alone, sensitivity was 0.86 (95% confidence interval [CI], 0.81-0.90) versus 0.84 (95% CI, 0.78-0.88) (P = 0.50), specificity was 0.76 (95% CI, 0.74-0.79) versus 0.82 (95% CI, 0.79-0.84) (P = 0.002), positive predictive value was 0.40 (95% CI, 0.36-0.45) versus 0.45 (95% CI, 0.41-0.50) (P = 0.14), and area under the receiver operating characteristics curve was 0.89 (95% CI, 0.82-0.96) versus 0.89 (95% CI, 0.82-0.96) (P = 0.83). Ultrafast breast MRI reading was 22.8% faster than reading FDP (P Conclusions: Breast MRI screening using only an ultrafast breast MRI protocol is noninferior to screening with an FDP and may result in significantly higher screening specificity and shorter reading time.

Purpose Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). The MICRA trial (NTR6120) aims at identifying pCR with post-NST biopsies. Here, we report the study design and feasibility. Methods The MICRA-trial is a multi-center prospective cohort study. Patients with a pre-NST placed marker and radiologic complete (rCR) or partial response on MRI after NST are eligible for inclusion. Ultrasound guided biopsy of the original tumor area is performed. Pathology results of the biopsies and surgery specimens are compared. The primary endpoint is false-negative rate of biopsies in identifying pCR. Results During the first year of the trial 58 patients with rCR were included. One patient was a screening failure and excluded for analysis. Twenty-one percent had hormone receptor (HR)+/HER2- tumors, 21% HR+/HER2+ tumors, 18% HR-/HER2+ tumors and 40% TN tumors. Overall pCR was 68%. In seven patients biopsies could not be obtained: in 6 patients, the marker could not be identified on ultrasound in the OR and in 1 patient there were technical difficulties. A median of eight biopsies was obtained (range 4–9). The median of histopathological representative biopsies was 4 (range 1–8). Conclusion Ultrasound guided biopsy of the breast in patients with excellent response on MRI after NST is feasible. Accuracy results of the MICRA trial will be presented after inclusion of 525 patients to determine if ultrasound guided biopsy is an accurate alternative to surgical resection for assessment of pCR after NST.

Background Breast cancer screening, improved imaging and neoadjuvant systemic therapy (NST) have led to increased numbers of non-palpable tumours suitable for breast-conserving surgery (BCS). Accurate tumour localization is essential to achieve a complete resection in these patients. This study evaluated the role of radioactive seed localization (RSL) in improving breast- and axilla-conserving surgery in patients with breast cancer with or without NST. Methods Patients who underwent RSL between 2007 and 2014 were included. Learning curves were analysed by the rates of minimally involved (in situ/invasive tumour cells on a length of 0–4 mm on ink) and positive resection margins (over 4 mm on ink) after BCS, and the median resection volume over time. Results A total of 367 patients with in situ carcinomas and 199 with non-palpable invasive breast cancer underwent RSL before primary surgery. A further 697 patients had RSL before NST, of whom 206 also underwent RSL of a histologically verified axillary lymph node metastasis. BCS was performed in 93·2 and 87·9 per cent of patients undergoing primary surgery for in situ and invasive tumours respectively, and 57·5 per cent of those in the NST group. The rate of BCS with positive resection margins was low and stable over time in the three groups (9·1, 9·7 and 11·2 per cent respectively). The median resection volume decreased significantly with time in the invasive cancer and NST groups. Conclusion In the present study of more than 1200 patients and 7 years of experience, RSL was shown to facilitate breast- and axilla-conserving surgery in a diverse patient population. There was a significant reduction in resection volume while maintaining low positive resection margin rates after BCS.

Background The goal in treating patients with ductal carcinoma in situ (DCIS) is to prevent the development of invasive breast cancer (iBC). However, a substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing, low-grade DCIS. The conventional treatment of low-grade DCIS is similar to that of early-stage iBC, i.e. breast-conserving surgery (BCS) often followed by radiotherapy (RT), or mastectomy, and possibly hormonal therapy (HT). This implies that many women might be unnecessarily going through intensive treatment resulting in a decrease in quality of life and an increase in health care costs, without any survival benefit. Trial Design LORD is a randomized, international, multicenter, phase III non-inferiority trial. Patients will be randomized between active surveillance and standard treatment according to local policy. Active surveillance comprises monitoring by annual mammography and treatment if there is progression to iBC or higher grade DCIS. Standard treatment encompasses BCS only, BCS + RT, or mastectomy, possibly followed by HT, and follow-up by annual mammography. Eligibility criteria • Women ≥49 years • Referral to the hospital solely based on microcalcifications detected by population-based or opportunistic screening mammography • Unilateral, pure DCIS grade I based on multiple vacuum assisted biopsies • No prior history of iBC or DCIS Specific Aims Our aim is to investigate whether active surveillance of low-grade DCIS is as safe as the current standard treatment, and to study the effects on quality of life of these women by saving them from intensive treatment. The primary end-point is time to ipsilateral iBC (iiBC). Secondary end-points include rate of iBC at final pathology after standard treatment, radical intervention rate, and biopsy rate during follow-up. Tissue will be collected for genomic profiling and proteomics to detect iBC risk patterns in low-grade DCIS. Furthermore we aim to develop an online informational aid for clinicians and patients to facilitate the dissemination and understanding of information on low-grade DCIS and its treatment. Statistical Methods We apply a special type of non-inferiority design, where the alternative hypothesis corresponds to "minor inferiority". We assume that the iiBC-free rate in the standard arm at 5 years equals 97.6%. The hazard ratio under the null hypothesis is 3.4 and the hazard ratio under the alternative hypothesis is 2.1, corresponding to iiBC-free rates in the experimental arm of 92.0% and 95.0% respectively. With a one-sided log-rank test for non-inferiority with α=0.05 and β=0.2, 124 events are needed for which 1842 low-grade DCIS patients need to be randomized during an accrual period of 5.5 years, and the accrual period will be followed by a further follow-up period of 7.5 years. Present Accrual and Target accrual The LORD trial is endorsed by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organisation for Research and Treatment of Cancer (EORTC 1401). Participating sites will be identified mid-2014. Patient accrual is expected to start early 2015. Citation Format: Lotte E Elshof, Konstantinos Tryfonidis, Leen Slaets, A Elise van Leeuwen-Stok, Nicolas Dif, Victoria P Skinner, Claudette E Loo, Gonneke Warnars, Eveline Bleiker, Ruud M Pijnappel, Nina Bijker, Emiel JTh Rutgers, Jelle Wesseling. The LORD trial: A randomized, non-inferiority trial, between active surveillance versus standard treatment in patients with low risk ductal carcinoma in situ [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-6-01.

Background Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL. Methods We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen. Results Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6–21). Conclusion Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy.

There is growing interest in minimally invasive breast cancer therapy. Eligibility of patients is, however, dependent on several factors related to the tumor and treatment technology. The aim of this study is to assess the proportion of patients eligible for minimally invasive breast cancer therapy for different safety and treatment margins based on breast tumor location. Patients with invasive ductal cancer were selected from the MARGINS cohort. Semiautomatic segmentation of tumor, skin, and pectoral muscle was performed in Magnetic Resonance images. Shortest distances of tumors to critical organs (ie, skin and pectoral muscle) were calculated. Proportions of eligible patients were determined for different safety and treatment margins. Three-hundred-forty-eight patients with 351 tumors were included. If a 10 mm safety margin to skin and pectoral muscle is required without treatment margin, 72.3% of patients would be eligible for minimally invasive treatment. This proportion decreases to 45.9% for an additional treatment margin of 5 mm. Shortest distances between tumors and critical organs are larger in older patients and in patients with less aggressive tumor subtypes. If a 10 mm safety margin to skin and pectoral muscle is required, more than two-thirds of patients would be eligible for minimally invasive breast cancer therapy.

Multiobjective optimization approaches for deformable image registration (DIR) remove the need for manual adjustment of key parameters and provide a set of solutions that represent high-quality trade-offs between objectives of interest. Choosing a desired outcome a posteriori is potentially far more insightful as differences between solutions can be immediately visualized. The purpose of this work is to investigate whether such an approach allows clinical experts to intuitively select their preferred DIR outcome. To this end, we developed a simplex-based tool for solution navigation and asked 10 clinical experts to use it to choose their preferred DIR outcome from sets of trade-off solutions obtained for 10 breast magnetic resonance DIR cases of low (prone-prone DIR; [Formula: see text]) and high (prone-supine DIR; [Formula: see text]) difficulty, of patients and volunteers, respectively. The usability of the software is subsequently evaluated by the observers using the system usability scale. Further, the quality of the selected DIR outcomes is evaluated using the mean target registration error. Results show that the users are able to identify and select high-quality DIR outcomes, and attested to high learnability and usability of our software, supporting the validity of the presumed added value of taking a multiobjective perspective on DIR in clinical practice.

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (> 0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.