Background Abbreviated MRI may reduce costs and time of supplemental breast cancer screening. The Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial provides an opportunity to study this protocol in a true screening population. Purpose To compare multireader diagnostic accuracy of various abbreviated screening breast MRI protocols with that of the full multiparametric protocol in the DENSE trial, focusing on identifying the minimal protocol necessary to maintain high diagnostic accuracy. Materials and Methods In this secondary analysis of a subset from the DENSE trial, seven radiologists performed incremental readings of first-round screening MRI scans in women with extremely dense breasts and findings negative for cancer at mammography. Different sequences were added in four incremental steps. The first step included both high-temporal low-spatial and low-temporal high-spatial dynamic T1-weighted series, up to 120 seconds after contrast agent injection. The final step added all full-protocol sequences. Each radiologist assessed the same MRI scans and provided Breast Imaging Reporting and Data System scores for all four incremental steps. Pooled sensitivity and specificity were calculated across all readers per step using a generalized estimating equation model, and pooled reading time per step was calculated using a linear mixed model. Results The first-round screening included 518 MRI scans from 518 women (median age, 53 years; IQR, 51-59 years), including 83 breast cancers: 68 invasive cancers (82%) and 15 ductal carcinomas in situ (18%). There was no evidence of a difference in sensitivity between abbreviated protocol (84.3%; 95% CI: 77.7, 89.2) and the full multiparametric MRI protocol (85.9%; 95% CI: 80.0, 90.3; P = .68). There was also no evidence of a difference in specificity between abbreviated protocol (73.9%; 95% CI: 70.7, 76.9) and full protocol (75.8%; 95% CI: 72.8, 78.5; P = .39). The abbreviated protocol had a pooled reading time (49.7 seconds; 95% CI: 48.5, 50.9) that was almost 50% shorter than the full protocol (96.4 seconds; 95% CI: 94.3, 98.5; P < .001) with 70%-80% shorter scanning time, depending on hospital and scanner vendor. Conclusion In women in the DENSE trial with extremely dense breasts and findings that were negative for cancer at mammography, abbreviated breast MRI for first-round screening had high diagnostic accuracy that was comparable to full multiparametric protocol, at much shorter reading and scanning times. ClinicalTrials.gov Identifier: NCT01315015 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Kataoka and Honda in this issue.

Purpose: Axillary lymph node staging techniques after primary systemic therapy (PST) show low false negative rates, stimulating the omission of axillary lymph node dissection (ALND). Breast cancer patients with extensive nodal disease are underreported in studies on response-guided axillary treatment. In this study, we present the oncologic outcome of breast cancer patients with >= 4 involved axillary lymph nodes treated according to the MARI-protocol. Methods: This prospective single arm registration study included breast cancer patients with extensive nodal disease defined as >= 4 involved axillary lymph nodes on FDG-PET/CT pre-PST between July 2014 and December 2021. After PST, the marked (MARI) lymph node was excised. Patients with a pathologic complete response (pCR) of the MARI node (ypN0) received locoregional radiation treatment (RT). In patients with residual disease of the MARI node (ypN+), ALND was performed followed by RT. Primary endpoint was axillary recurrence rate. Secondary endpoints were invasive disease-free survival (DFS) and overall survival (OS). Results: In total, 218 patients were registered of which 39 % of patients also had extra-axillary nodal disease. Median (IQR) age was 50 (42-57) years. After PST 47 % of patients (103/218) had ypN0, whereas 53 % of patients (115/218) had ypN+. After a median follow up of 44 (26-62) months, axillary recurrence rate was 2.9 % (n = 3) in the ypN0 group and 3.5 % (n = 4) in the ypN + group. Five-year invasive DFS and OS were respectively 89 % (95 % CI 83 %-96 %) and 95 % (95 % CI 91 %-99 %) in ypN0 patients. Conclusion: Omission of ALND after PST in breast cancer patients with extensive nodal involvement who achieve pCR of the MARI node is associated with excellent five-year oncologic outcome.

Importance:Most patients with clinically node-positive (cN+) breast cancer receive primary systemic treatment (PST) followed by axillary lymph node dissection (ALND) and/or locoregional radiation (RT). The necessity of axillary treatment in patients achieving nodal pathologic complete response (pCR) after PST remains uncertain. Objective:To assess oncologic outcomes of response-guided axillary treatment determined by marking the axillary lymph node with a radioactive iodine seed (MARI) in patients with cN+ breast cancer who experience pCR after PST. Design, Setting, and Participants:This cohort study was conducted at a single center including patients with breast cancer with 3 or fewer axillary lymph nodes on fluorodeoxyglucose positron emission tomography-computed tomography who were treated according to the MARI protocol from July 2014 to December 2021. Patients with intramammary or periclavicular lymph node involvement were excluded. Median (IQR) follow-up was 49 (32-70) months. Data were analyzed from March to June 2025. Exposure:After PST, the MARI-marked lymph node was excised. Patients with pCR of the MARI node (ypN0) received no further axillary treatment, whereas patients with residual disease (ypN+) received locoregional radiation therapy. Main Outcomes and Measures:The primary outcome measure was axillary recurrence rate. The secondary outcome measures were 5-year invasive disease-free survival (iDFS) and overall survival (OS). Results:In total, 350 patients (median [IQR] age, 49 [41-56] years) were included and analyzed; of these, 135 (39%) had ypN0 and received no further axillary treatment. The remaining 215 patients with ypN+ (61%) received RT. After a median (IQR) follow-up of 49 (32-70) months, axillary recurrence rate was 0.7% (n = 1; 95% CI, 0.04%-4.1%) in patients with ypN0 and 2.3% (n = 7; 95% CI, 1.0%-5.3%) in patients with ypN+. In patients with ypN0, the 5-year iDFS was 93% (95% CI, 88%-98%) and the OS was 98% (95% CI, 95%-100%); in patients with ypN+, iDFS was 87% (95% CI, 82%-93%) and OS, 93% (95% CI, 89%-97%). Conclusions and Relevance:This cohort study found that response-guided axillary treatment, using the MARI protocol, in patients with limited nodal disease who received PST was associated with a very low risk of axillary recurrence and should be considered to protect patients from axillary overtreatment.

514 Background: In breast cancer, the majority of clinically node positive (cN1) patients are treated with primary systemic treatment (PST), with increasing rates of axillary pathologic complete response (pCR). Evidence supporting tailoring axillary treatment according to the response is growing. However, it is still debatable whether ALND is beneficial in cN1 patients with residual nodal disease and if any further axillary treatment is necessary in patients achieving pCR. In this study, we present the four-year oncologic outcome of cN1 patients undergoing either axillary radiation treatment or no axillary treatment according to the ‘Marking Axillary lymph nodes with Radioactive Iodine seeds’ (MARI)-protocol. Methods: Between 2014 and 2021, we prospectively enrolled patients with node positive breast cancer and 1 - 3 involved axillary lymph nodes on FDG-PET/CT pre-PST, who were treated according to the MARI-protocol. Patients with residual disease of the MARI node (ypN1) received axillary radiotherapy (RT), while patients with a pCR of the MARI node (ypN0) received no further axillary treatment. The primary endpoint was the axillary recurrence rate. Secondary endpoints include invasive disease free survival (iDFS) and overall survival (OS), calculated using the Kaplan-Meier method. Results: Of the 367 included patients, more than half (54%, n= 198) had hormonal receptor positive (HR+)/Human Epidermal growth factor 2 negative (HER2-) breast cancer; 59 patients (16%) had HR+/HER2+; 39 patients (11%) had HR-/HER2+ and 71 patients (19%) had triple negative (TN) subtype. Median age was 49 (IQR 41 – 56) years. 231 (63%) patients who had ypN1 received RT and 136 patients (37%) who achieved ypN0 received no further axillary treatment. Median follow up was 49 (IQR 32 – 70) months. Axillary recurrence rate was 3.5% ( n= 8) in patients with ypN1 and 0.7% ( n= 1) in patients with ypN0. Most axillary recurrences ( n= 6) occurred simultaneously with distant metastases in the ypN1 group. In patients with ypN1, the iDFS was 86% and the OS 93%; in ypN0 patients, the iDFS was 93% and the OS 98%. Conclusions: Response-guided axillary treatment in patients with limited nodal disease according to the MARI protocol is associated with favorable oncologic outcome without performing ALND’s. De-escalation can therefore be considered safe. [Table: see text]

Supplemental MRI screening improves early breast cancer detection and reduces interval cancers in women with extremely dense breasts in a cost-effective way. Recently, the European Society of Breast Imaging recommended offering MRI screening to women with extremely dense breasts, but the debate on whether to implement it in breast cancer screening programs is ongoing. Insight into the participant experience and willingness to re-attend is important for this discussion. We calculated the re-attendance rates of the second and third MRI screening rounds of the DENSE trial. Moreover, we calculated age-adjusted odds ratios (ORs) to study the association between characteristics and re-attendance. Women who discontinued MRI screening were asked to provide one or more reasons for this. The re-attendance rates were 81.3

ObjectiveThis study aims to evaluate the response to and surgical benefits of neoadjuvant endocrine therapy (NET) in ER+/HER2-breast cancer patients who are clinically high risk, but genomic low risk according to the 70-gene signature (MammaPrint).MethodsPatients with ER+/HER2-invasive breast cancer with a clinical high risk according to MINDACT, who had a genomic low risk according to the 70-gene signature and were treated with NET between 2015 and 2023 in our center, were retrospectively analyzed. RECIST 1.1 criteria were used to assess radiological response using MRI or ultrasound. Surgical specimens were evaluated to assess pathological response. Two breast cancer surgeons independently scored the eligibility of breast conserving therapy (BCS) pre- and post- NET.ResultsOf 72 included patients, 23 were premenopausal (100% started with tamoxifen of which 4 also received OFS) and 49 were postmenopausal (98% started with an aromatase inhibitor). Overall, 8 (11%) showed radiological complete response. Only 1 (1.4%) patient had a pathological complete response (RCB-0) and 68 (94.4%) had a pathological partial response (RCB-1 or RCB-2). Among the 26 patients initially considered for mastectomy, 14 (53.8%) underwent successful BCS. In all 20 clinical node-positive patients, a marked axillary lymph node was removed to assess response. Four out of 20 (20%) patients had a pathological complete response of the axilla.ConclusionThe study showed that a subgroup of patients with a clinical high risk and a genomic low risk ER+/HER2-breast cancer benefits from NET resulting in BCS instead of a mastectomy. Additionally, NET may enable de-escalation in axillary treatment.

This study aims to identify which breast cancer patients benefit from the routine use of FDG-PET/CT in a large cohort of patients scheduled for neoadjuvant systemic therapy (NST). A total of 1337 breast cancer patients eligible for NST were identified from a retrospective database between 2011 and 2020 at a single tertiary care hospital. All patients underwent staging with FDG-PET/CT prior to NST. The incidence and extent of asymptomatic distant metastases in different patient subgroups were determined, as well as the impact on treatment. Logistic regression analysis was used to identify prognostic patient and tumor characteristics. FDG-PET/CT detected distant metastases in 109 patients (8

Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). We included 191 patients. After NAC, 107 (56

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

PURPOSE:Breast cancer (BC) patients undergoing FDG-PET/CT scans for neoadjuvant chemotherapy (NAC) may have additional non-BC related findings. The aim of this study is to describe the clinical implications of these findings. METHODS:We included BC patients who underwent an FDG-PET/CT scan in our institute between 2011-2020 prior to NAC. We focused on patients with an additional non-BC related finding (i.e. BC metastases were excluded) for which diagnostic work-up was performed. Information about the diagnostic work-up and the clinical consequences was retrospectively gathered. A revision of all FDG-PET/CT scans was conducted by an independent physician to assess the suspicion level of the additional findings. RESULTS:Of the 1337 patients who underwent FDG-PET/CT, 202 patients (15%) had an non-BC related additional finding for which diagnostic work-up was conducted, resulting in 318 examinations during the first year. The non-BC related findings were mostly detected in the endocrine region (26%), gastro-intestinal region (16%), or the lungs (15%). Seventeen patients (17/202: 8%, 17/1337: 1.3%) had a second primary malignancy. Only 8 patients (8/202: 4%, 8/1337: 0.6%) had a finding that was considered more prognosis-determining than their BC disease. When revising all FDG-PET/CT scans, 57 (202/57: 28%) of the patients had an additional finding categorized as low suspicious, suggesting no indication for diagnostic work-up. CONCLUSION:FDG-PET/CT scans used for dissemination imaging in BC patients detect a high number of non-BC related additional findings, often clinically irrelevant and causing a large amount of unnecessary work-up. However, in 8% of the patients undergoing diagnostic work-up for an additional finding, a second primary malignancy was detected, warranting diagnostic attention in selected patients.

Background Calcifications on mammography can be indicative of breast cancer, but the prognostic value of their appearance remains unclear. This systematic review and meta-analysis aimed to evaluate the association between mammographic calcification morphology descriptors (CMDs) and clinicopathological factors. Methods A comprehensive literature search in Medline via Ovid, Embase.com, and Web of Science was conducted for articles published between 2000 and January 2022 that assessed the relationship between CMDs and clinicopathological factors, excluding case reports and review articles. The risk of bias and overall quality of evidence were evaluated using the QUIPS tool and GRADE. A random-effects model was used to synthesize the extracted data. This systematic review is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Results Among the 4715 articles reviewed, 29 met the inclusion criteria, reporting on 17 different clinicopathological factors in relation to CMDs. Heterogeneity between studies was present and the overall risk of bias was high, primarily due to small, inadequately described study populations. Meta-analysis demonstrated significant associations between fine linear calcifications and high-grade DCIS [pooled odds ratio (pOR), 4.92; 95% confidence interval (CI), 2.64–9.17], (comedo)necrosis (pOR, 3.46; 95% CI, 1.29–9.30), (micro)invasion (pOR, 1.53; 95% CI, 1.03–2.27), and a negative association with estrogen receptor positivity (pOR, 0.33; 95% CI, 0.12–0.89). Conclusions CMDs detected on mammography have prognostic value, but there is a high level of bias and variability between current studies. In order for CMDs to achieve clinical utility, standardization in reporting of CMDs is necessary. Critical relevance statement Mammographic calcification morphology descriptors (CMDs) have prognostic value, but in order for CMDs to achieve clinical utility, standardization in reporting of CMDs is necessary. Systematic review registration CRD42022341599 Key points • Mammographic calcifications can be indicative of breast cancer. • The prognostic value of mammographic calcifications is still unclear. • Specific mammographic calcification morphologies are related to lesion aggressiveness. • Variability between studies necessitates standardization in calcification evaluation to achieve clinical utility. Graphical Abstract

Breast cancer patients undergoing PET/CT scans for neoadjuvant systemic therapy may have non-breast cancer (BC) related finding. The aim of this study is to describe the incidence, additional work-up and possible impact of these findings. We included BC patients who underwent a PET/CT scan in our institute between 2011-2019 prior to neoadjuvant systemic therapy. An additional finding was defined as a non-physiologic abnormal lesion only depicted by PET/CT. Patients with a BC-related or no additional finding were excluded. For the remaining patients with a non-BC related additional finding, we retrospectively gathered information on the additional work-up and the clinical consequences. Of the 1337 patients included, 561 had additional findings on PET-CT, of whom 258 had a non-BC related additional finding. Further work-up was conducted in 202 patients (78%), including 282 examinations during initial work-up. In these 202 patients the non-BC related findings were detected in the endocrine region (26%), gastro-intestinal region (16%), lungs (15%), bones (14%), distant lymph nodes (11%), urogenital region (11%), liver (10%) and other (5%). In the end, 17 (8%) of the 202 patients were diagnosed with malignant and 138 patients (68%) with benign lesions. Only 8 patients (4%) had an additional non-BC related finding that was considered a more prognosis-determining diagnosis than their breast cancer disease. Malignant and prognosis-determining non-BC related additional findings mostly occurred in the endocrine, gastro-intestinal and urogenital region. PET/CT scans used for dissemination imaging in breast cancer patients detect a high number of non-BC related additional findings, with the majority being clinically irrelevant and causing a relatively large amount of unnecessary additional work-up. Additional non-BC related findings in the endocrine, gastro-intestinal and urogenital region have a higher change of being malignant. Clinicians should be aware of potential non-BC related PET/CT findings and carefully consider the clinical implications.

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 (), 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.

Accurately determining the molecular subtypes of breast cancer is important for the prognosis of breast cancer patients and can guide treatment selection. In this study, we develop a deep learning-based model for predicting the molecular subtypes of breast cancer directly from the diagnostic mammography and ultrasound images. Multi-modal deep learning with intra- and inter-modality attention modules (MDL-IIA) is proposed to extract important relations between mammography and ultrasound for this task. MDL-IIA leads to the best diagnostic performance compared to other cohort models in predicting 4-category molecular subtypes with Matthews correlation coefficient (MCC) of 0.837 (95% confidence interval [CI]: 0.803, 0.870). The MDL-IIA model can also discriminate between Luminal and Non-Luminal disease with an area under the receiver operating characteristic curve of 0.929 (95% CI: 0.903, 0.951). These results significantly outperform clinicians’ predictions based on radiographic imaging. Beyond molecular-level test, based on gene-level ground truth, our method can bypass the inherent uncertainty from immunohistochemistry test. This work thus provides a noninvasive method to predict the molecular subtypes of breast cancer, potentially guiding treatment selection for breast cancer patients and providing decision support for clinicians.

Hazard ra􀆟o of intermediate contralateral parenchymal enhancement (CPE) (yellow) and high CPE (green) with respect to low CPE. CPE was calculated as the average of the late enhancement values above the threshold. CPE groups were subsequently obtained by spli􀆫ng CPE on ter􀆟les. The colored bands indicate 95% confidence intervals. The do􀆩ed line at 90% represents the original threshold.

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution ( p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III ( n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II ( n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069.

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.