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Objective: This 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). Methods: Patients 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. Results: Of 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. Conclusion: The 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.

Abstract 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

Abstract 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.

Abstract This review aims to identify factors causing heterogeneity in breast DWI–MRI and their impact on its value for identifying breast cancer patients with pathological complete response (pCR) on neoadjuvant systemic therapy (NST). A search was performed on PubMed until April 2020 for studies analyzing DWI for identifying breast cancer patients with pCR on NST. Technical and clinical study aspects were extracted and assessed for variability. Twenty studies representing 1455 patients/lesions were included. The studies differed with respect to study population, treatment type, DWI acquisition technique, post-processing (e.g., mono-exponential/intravoxel incoherent motion/stretched exponential modeling), and timing of follow-up studies. For the acquisition and generation of ADC-maps, various b-value combinations were used. Approaches for drawing regions of interest on longitudinal MRIs were highly variable. Biological variability due to various molecular subtypes was usually not taken into account. Moreover, definitions of pCR varied. The individual areas under the curve for the studies range from 0.50 to 0.92. However, overlapping ranges of mean/median ADC-values at pre- and/or during and/or post-NST were found for the pCR and non-pCR groups between studies. The technical, clinical, and epidemiological heterogeneity may be causal for the observed variability in the ability of DWI to predict pCR accurately. This makes implementation of DWI for pCR prediction and evaluation based on one absolute ADC threshold for all breast cancer types undesirable. Multidisciplinary consensus and appropriate clinical study design, taking biological and therapeutic variation into account, is required for obtaining standardized, reliable, and reproducible DWI measurements for pCR/non-pCR identification.

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.

Abstract Background Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) for real-time in vivo tissue characterization. Methods Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements. Results With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen. Conclusions It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery. Trail registration NIH US National Library of Medicine–clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365

To explore guidelines on the use of MRI and PET/CT monitoring primary tumor response to neoadjuvant chemotherapy (NAC), taking breast cancer subtype into account.In this prospective cohort study, 188 women were included with stages II and III breast cancer. MRI and 18F-FDG-PET/CT were acquired before and during NAC. Baseline pathology was assessed from tumor biopsy. Tumors were stratified into HER2-positive, ER-positive/HER2-negative (ER-positive), and ER-negative/PR-negative/HER2-negative (triple-negative) subtypes, and treated according to subtype. Primary endpoint was pathological complete response (pCRmic) defined as no or only small numbers of scattered invasive tumor cells. We evaluated imaging scenarios using MRI only, PET/CT only, and combinations.pCRmic was found in 35/46 (76.1%) of HER2-positive, 11/87 (12.6%) of ER-positive, and 31/55 (56.4%) of triple-negative tumors. For HER2-positive tumors, MRI yielded the strongest predictor (AUC: 0.735; sensitivity 36.2%), outperforming PET/CT (AUC: 0.543; p = 0.04), and with comparable results to combined imaging (AUC: 0.708; p = 0.213). In ER-positive tumors, the combination of MRI and PET/CT was slightly superior (AUC: 0.818; sensitivity 55.8%) over MRI alone (AUC: 0.742; p = 0.117) and PET/CT alone (AUC: 0.791). However, even though relatively large numbers of ER-positive tumor patients were included, no significant differences were yet found. For triple-negative tumors, MRI (AUC: 0.855; sensitivity 45.4%), PET/CT (AUC: 0.844; p = 0.220) and combined imaging (AUC: 0.868; p = 0.213) yielded comparable results.For HER2-positive tumors, MRI shows significant advantage over PET/CT. For triple-negative tumors, comparable results were seen for MRI, PET/CT and combined imaging. For ER-positive tumors, combining MRI with PET/CT may result in optimal response monitoring, although not yet significantly.