[B3 lesions of the breast: histological, clinical, and epidemiological aspects : Update]. / B3-Läsionen der Mamma: Histologische, klinische und epidemiologische Aspekte : Update.

B3 lesions of the breast are a heterogeneous group of lesions with uncertain malignant potential encompassing a broad spectrum of histologically distinct alterations that often pose challenging decisions if diagnosed on the preoperative core or vacuum biopsies. B3 lesions are mostly detected due to mammographic calcifications or mass lesions and, in most cases, encompass a spectrum of atypical lesions such as atypical ductal hyperplasia, classic lobular neoplasia, flat epithelial atypia, papillomas, fibroepithelial tumors, and rarely other lesions such as mucocele-like lesions, atypical apocrine lesions, and rare stromal proliferations. The use of immunohistochemical stains (estrogen receptors, basal cytokeratin, myoepithelial markers, and stromal marker panel) is useful in the differentiation of these lesions and allowing proper classification. Regarding clinical management of B3 lesions, the radiological-pathological correlation of the given entity plays the most important key element for the proper next diagnostic and therapeutic step.

[Clinically relevant molecular pathological diagnostics in breast cancer]. / Klinisch relevante molekularpathologische Diagnostik beim Mammakarzinom.

In breast cancer, the current guideline for pathological workup includes recommendations for advanced molecular analysis of certain predictive molecular markers in addition to basic immunohistochemical diagnostics. These markers are determined depending on tumor stage, including sequencing techniques and immunohistochemical methods. This comprises the systematic investigation of molecular alterations such as PIK3CA or BRCA1,2 mutations, NTRK fusions, or microsatellite instability as a basis for targeted therapy. Further alterations, for example in the PI3K pathway, ESR1 alterations, or ERBB2 mutations, may also be relevant for individual therapy decisions especially in the context of resistant or relapsed disease. Thus, particularly in advanced stages, a more comprehensive molecular characterization of the tumor may reveal genetic alterations that act as tumor drivers and provide targets for personalized therapies. Due to the large number of potential molecular targets, NGS panel diagnostics are a suitable approach in this conjunction with immunohistochemical characterization and the individual clinical situation. Molecular based therapeutical strategies outside of entity-specific approvals should be discussed in an interdisciplinary team within the framework of a molecular tumor board.

[Immunohistology in breast diagnostics : Strategies for efficient diagnostics]. / Immunhistologie in der Mammadiagnostik : Strategien für effiziente Diagnostik.

Immunohistological examinations are useful for the histopathological diagnosis of breast carcinoma in various clinical situations. This review article aims to summarize the different immunohistological options. A distinction is made between diagnostic, prognostic, and predictive markers. Especially when a therapeutic decision results from the immunohistological expression pattern, a quantitative, quality-controlled, and validated diagnostic approach is essential.This is relevant, for example, for the classical markers ER, PR, and HER2, but also for Ki-67 and additional markers such as PD-L1. This article provides a practice-oriented summary of the most important immunohistochemical markers in routine breast cancer diagnosis and for the distinction of malignant findings from benign alterations or precursor lesions.

New treatment options for metastatic HER2-low breast cancer : Consequences for histopathological diagnosis.

The overexpression of HER2 in breast cancer is a classic example for molecular targeted therapy, and it has been shown that classical anti-HER2 therapeutics were only effective in patients with HER2 overexpressing tumors. Therefore, in recent decades, pathologists have been focused on the reliable identification of HER2 overexpressing tumors. Based on the results of recent clinical trials in metastatic breast cancer with antibody-drug conjugates (ADCs), this diagnostic strategy for evaluation of HER2 is currently changing. It has been shown that the ADC trastuzumab-deruxtecan is effective not only against tumors with classical HER2 overexpression, but also against HER2-low tumors. These clinical trial results lead to a paradigm shift in the treatment of patients whose tumours were previously classified as HER2 negative. In addition to the identification of HER2 (score 3+) overexpressing tumors, it is necessary to identify HER2-low expressing tumors (defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with negative in situ hybridization).Due to the therapeutic consequences, it is important to quickly adapt the diagnostic workup and reporting to the new requirements. In addition, the new therapeutic options for anti-HER2 therapy lead to new challenges for standardization as well as to new scientific questions for the characterization of tumors with low HER2 expression.

[New treatment options for metastatic HER2-low breast cancer : Consequences for histopathological diagnosis]. / Neue Therapiemöglichkeiten beim metastasierten HER2-low-Mammakarzinom : Konsequenzen für die histopathologische Diagnostik.

The overexpression of HER2 in breast cancer is a classic example for molecular targeted therapy, and it has been shown that classical anti-HER2 therapeutics were only effective in patients with HER2 overexpressing tumors. Therefore, in recent decades, pathologists have been focused on the reliable identification of HER2 overexpressing tumors. Based on the results of recent clinical trials in metastatic breast cancer with antibody-drug conjugates (ADCs), this diagnostic strategy for evaluation of HER2 is currently changing. It has been shown that the ADC trastuzumab-deruxtecan is effective not only against tumors with classical HER2 overexpression, but also against HER2-low tumors. These clinical trial results lead to a paradigm shift in the treatment of patients whose tumours were previously classified as HER2 negative. In addition to the identification of HER2 (score 3+) overexpressing tumors, it is necessary to identify HER2-low expressing tumors (defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with negative in situ hybridization).Due to the therapeutic consequences, it is important to quickly adapt the diagnostic workup and reporting to the new requirements. In addition, the new therapeutic options for anti-HER2 therapy lead to new challenges for standardization as well as to new scientific questions for the characterization of tumors with low HER2 expression.

[Updated WHO classification of tumors of the breast]. / Aktualisierte WHO-Klassifikation der Tumoren der Mamma.

In the fifth edition of the World Health Organization (WHO) classification of tumors of the breast, the histological features of the lesions continue to form the basis of the classification; however, molecular pathology nowadays provides approaches for improved diagnostics and prediction of prognosis and treatment response, which have been incorporated into the update of the classification. The most important changes are presented, which include changes in the histological classification of invasive carcinomas, the subtyping of lobular carcinoma in situ (LCIS) and the dignity criteria of phyllodes tumors.

Preoperative breast magnetic resonance imaging in patients with ductal carcinoma in situ: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC).

OBJECTIVE: To evaluate the impact of preoperative MRI in the management of Ductal carcinoma in situ (DCIS). METHODS: We searched the PubMed, EMBASE and Cochrane Library databases to identify randomised clinical trials (RCTs) or cohort studies assessing the impact of preoperative breast MRI in surgical outcomes, treatment change or loco-regional recurrence. We provided pooled estimates for odds ratios (OR), relative risks (RR) and proportions and assessed the certainty of the evidence using the GRADE approach. RESULTS: We included 3 RCTs and 23 observational cohorts, corresponding to 20,415 patients. For initial breast-conserving surgery (BCS), the RCTs showed that MRI may result in little to no difference (RR 0.95, 95% CI 0.90 to 1.00) (low certainty); observational studies showed that MRI may have no difference in the odds of re-operation after BCS (OR 0.96; 95% CI 0.36 to 2.61) (low certainty); and uncertain evidence from RCTs suggests little to no difference with respect to total mastectomy rate (RR 0.91; 95% CI 0.65 to 1.27) (very low certainty). We also found that MRI may change the initial treatment plans in 17% (95% CI 12 to 24%) of cases, but with little to no effect on locoregional recurrence (aHR = 1.18; 95% CI 0.79 to 1.76) (very low certainty). CONCLUSION: We found evidence of low to very low certainty which may suggest there is no improvement of surgical outcomes with pre-operative MRI assessment of women with DCIS lesions. There is a need for large rigorously conducted RCTs to evaluate the role of preoperative MRI in this population. KEY POINTS: • Evidence of low to very low certainty may suggest there is no improvement in surgical outcomes with pre-operative MRI. • There is a need for large rigorously conducted RCTs evaluating the role of preoperative MRI to improve treatment planning for DCIS.

[Updated WHO classification of tumors of the breast: the most important changes]. / Aktualisierte WHO-Klassifikation der Tumoren der Mamma: Die wichtigsten Änderungen.

The development of the WHO classification of tumors of the breast is driven by new knowledge from research whose translation into daily practice is considered clinically relevant. The fifth edition represents an update of the fourth edition and essentially follows the previously known systematics. The histologic features of the lesions continue to form the basis of the classification in the update. This also applies to the definition of invasive tumor types. However, several new molecular classifications as well as additional prognostic and predictive factors are presented and discussed, which improve prognosis estimation and therapy decisions. This paper aims to present the main changes in the current WHO classification. These include the revised definition of mixed invasive carcinomas, the introduction of new special invasive entities (tall cell carcinoma with reversed polarity, mucinous cystadenocarcinoma), the deletion of special invasive types and their classification as variants of invasive carcinoma, NST (no special type, including medullary, lipid-rich, glycogen-rich, among others), the typing of primary neuroendocrine neoplasms of the breast by analogy with other organ systems, changes in the dignity criteria of phyllodes tumors, and the revised subtyping of lobular carcinoma in situ (LCIS). In addition to improvements in the fifth edition of the classification, flaws are also highlighted. A section is devoted to new molecular parameters.

Digital breast tomosynthesis compared to diagnostic mammographic projections (including magnification) among women recalled at screening mammography: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC).

BACKGROUND: Diagnostic mammography projections (DxMM) have been traditionally used in the assessment of women recalled after a suspicious screening mammogram. Digital breast tomosynthesis (DBT) reduces the tissue overlap effect, thus improving image assessment. Some studies have suggested DBT might replace DxMM with at least equivalent performance. OBJECTIVE: To evaluate the replacement of DxMM with DBT in women recalled at screening. METHODS: We searched PubMed, EMBASE, and the Cochrane Library databases to identify diagnostic paired cohort studies or RCTs comparing DBT vs DxMM, published in English that: reported accuracy outcomes, recruited women recalled for assessment at mammography screening, and included a reference standard. Subgroup analysis was performed over lesion characteristics. We provided pooled accuracy estimates and differences between tests using a quadrivariate model. We assessed the certainty of the evidence using the GRADE approach. RESULTS: We included ten studies that reported specificity and sensitivity. One study included 7060 women while the remaining included between 52 and 738 women. DBT compared with DxMM showed a pooled difference for the sensitivity of 2% (95% CI 1%-3%) and a pooled difference for the specificity of 6% (95%CI 2%-11%). Restricting the analysis to the six studies that included women with microcalcification lesions gave similar results. In the context of a prevalence of 21% of breast cancer (BC) in recalled women, DBT probably detects 4 (95% CI 2-6) more BC cases and has 47 (95%CI 16-87) fewer false-positive results per 1000 assessments. The certainty of the evidence was moderate due to risk of bias. CONCLUSION: The evidence in the assessment of screen-recalled findings with DBT is sparse and of moderate certainty. DBT probably has higher sensitivity and specificity than DxMM. Women, health care providers and policymakers might value as relevant the reduction of false-positive results and related fewer invasive diagnostic procedures with DBT, without missing BC cases.

Recommendations from the European Commission Initiative on Breast Cancer for multigene testing to guide the use of adjuvant chemotherapy in patients with early breast cancer, hormone receptor positive, HER-2 negative.

BACKGROUND: Predicting the risk of recurrence and response to chemotherapy in women with early breast cancer is crucial to optimise adjuvant treatment. Despite the common practice of using multigene tests to predict recurrence, existing recommendations are inconsistent. Our aim was to formulate healthcare recommendations for the question "Should multigene tests be used in women who have early invasive breast cancer, hormone receptor-positive, HER2-negative, to guide the use of adjuvant chemotherapy?" METHODS: The European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG), a multidisciplinary guideline panel including experts and three patients, developed recommendations informed by systematic reviews of the evidence. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision frameworks were used. Four multigene tests were evaluated: the 21-gene recurrence score (21-RS), the 70-gene signature (70-GS), the PAM50 risk of recurrence score (PAM50-RORS), and the 12-gene molecular score (12-MS). RESULTS: Five studies (2 marker-based design RCTs, two treatment interaction design RCTs and 1 pooled individual data analysis from observational studies) were included; no eligible studies on PAM50-RORS or 12-MS were identified and the GDG did not formulate recommendations for these tests. CONCLUSIONS: The ECIBC GDG suggests the use of the 21-RS for lymph node-negative women (conditional recommendation, very low certainty of evidence), recognising that benefits are probably larger in women at high risk of recurrence based on clinical characteristics. The ECIBC GDG suggests the use of the 70-GS for women at high clinical risk (conditional recommendation, low certainty of evidence), and recommends not using 70-GS in women at low clinical risk (strong recommendation, low certainty of evidence).

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS: Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS: Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 (<1%: 15 cases; 1-5%: seven cases; >5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (≥1 versus <1%) were scored by trained readers from seven sites using online virtual microscopy. The adjusted mean of PD-L1-IC-positivity for SP263 (7.8%) was significantly higher than those for the other three assays (3.7-4.9%). Differences in adjusted means were statistically significant between SP263 and the other three assays (P < 0.0001) but not between the three remaining assays when excluding SP263 (P = 0.0961-0.6522). Intra-class correlation coefficients revealed moderate-to-strong inter-reader agreement for each assay (0.460-0.805) and poor-to-strong inter-assay agreement for each reader (0.298-0.678) on PD-L1-IC-positivity. CONCLUSIONS: In this first multicentre study of different PD-L1 assays in TNBC, we show that PD-L1-IC-positivity for SP142, 22C3 and 28-8 was reproducible and analytically concordant, indicating that these three assays may be analytically interchangeable. The relevance of the higher PD-L1-IC-positivity for SP263 should be further investigated.

Residual Axillary Burden After Neoadjuvant Chemotherapy (NACT) in Early Breast Cancer in Patients with a priori Clinically Occult Nodal Metastases - a transSENTINA Analysis.

Background Among patients with breast cancer undergoing neoadjuvant chemotherapy (NACT), the association between pathological complete remission (pCR) in the breast and clinical/pathological parameters is well established, whereas the association between these parameters and residual axillary involvement after NACT remains unclear. Methods Patients with clinically occult nodal metastases (i.e. negative by clinical assessment but positive by SLNB prior to NACT, i.e. Arm B of the SENTINA trial) were included in the presented analysis. All patients received a second sentinel lymph node biopsy (SLNB) and axillary dissection after NACT. Univariate and multivariate analyses were carried out to evaluate the association between clinical/pathological parameters and axillary involvement after NACT. Results Arm B of the SENTINA study contained 360 patients, 318 of which were evaluable for this analysis. After NACT, 71/318 (22.3%) patients had involved SLNs or non-SLNs after NACT. Overall, 71/318 (22.3%) patients achieved a pCR in the breast. Associations of extranodal spread, lack of multifocality and pCR in the breast with residual axillary burden were statistically significant. In a descriptive analysis including all patients with clinically negative axilla before NACT in the SENTINA trial 1.2% of triple negative (TN) patients and 0.5% of HER/2 positive patients had residual axillary disease in case of a breast pCR. Conclusions Patients in the SENTINA trial with clinically negative axilla and involved SLNs still carried a significant risk of nodal metastases after NACT. However, the risk of residual axillary burden was particularly low in TN and HER/2 positive tumors in case of a breast pCR.

Correction: Residual Axillary Burden After Neoadjuvant Chemotherapy (NACT) in Early Breast Cancer in Patients with a priori Clinically Occult Nodal Metastases - a transSENTINA Analysis.

[This corrects the article DOI: 10.1055/a-1298-3453.].

Monitoring and evaluation of breast cancer screening programmes: selecting candidate performance indicators.

BACKGROUND: In the scope of the European Commission Initiative on Breast Cancer (ECIBC) the Monitoring and Evaluation (M&E) subgroup was tasked to identify breast cancer screening programme (BCSP) performance indicators, including their acceptable and desirable levels, which are associated with breast cancer (BC) mortality. This paper documents the methodology used for the indicator selection. METHODS: The indicators were identified through a multi-stage process. First, a scoping review was conducted to identify existing performance indicators. Second, building on existing frameworks for making well-informed health care choices, a specific conceptual framework was developed to guide the indicator selection. Third, two group exercises including a rating and ranking survey were conducted for indicator selection using pre-determined criteria, such as: relevance, measurability, accurateness, ethics and understandability. The selected indicators were mapped onto a BC screening pathway developed by the M&E subgroup to illustrate the steps of BC screening common to all EU countries. RESULTS: A total of 96 indicators were identified from an initial list of 1325 indicators. After removing redundant and irrelevant indicators and adding those missing, 39 candidate indicators underwent the rating and ranking exercise. Based on the results, the M&E subgroup selected 13 indicators: screening coverage, participation rate, recall rate, breast cancer detection rate, invasive breast cancer detection rate, cancers > 20 mm, cancers ≤10 mm, lymph node status, interval cancer rate, episode sensitivity, time interval between screening and first treatment, benign open surgical biopsy rate, and mastectomy rate. CONCLUSION: This systematic approach led to the identification of 13 BCSP candidate performance indicators to be further evaluated for their association with BC mortality.

[Are men and women with breast cancer treated equally in Germany?] / Werden Männer und Frauen mit Brustkrebs in Deutschland gleichbehandelt?

INTRODUCTION: Within the statutory health insurance system of the Federal Republic of Germany, a system of quality assurance has been implemented and operationalised through the measurement of quality indicators. For breast surgery, these quality indicators are mainly based on recommendations of the German clinical guideline for screening, diagnosis, therapy and follow-up of breast cancer. The 2018 update of this guideline includes a new chapter on breast cancer in men. The aim of this analysis is to examine whether male and female patients with breast cancer are treated equally where appropriate and recommended by the clinical guideline, as measured by the quality indicators. METHOD: Data of ten quality assurance indicators were analysed, for each indicator separately, stratified by sex and pooled over a 5-year period to gain statistical power. This dataset constitutes the largest data pool of men with surgical interventions for breast neoplasm in Germany. Indicator results were then compared between male and female cases. Additional subgroup analyses were carried out for two quality indicators with substantial outcome difference between male and female cases in order to detect possible differences in the treatment of breast cancer between different medical departments. RESULTS: The database of the ten quality assurance indicators comprised 551,221 patients (546,324 females and 4,897 males) between 2014 and 2018. Pooled data of nine quality indicators (QIs) showed statistically significant outcome differences between male and female cases. In spite of pooling, the male sample size of four QIs was too small to allow for statistically reliable comparisons between male and female patients. Outcome differences in the remaining five QIs may, on the one hand, be explained by anatomical differences and different extent of the surgery, and on the other hand they confirm international data for lower HER2-positivity rates in male breast cancer patients. However, two process indicators, aiming at pretherapeutic biopsy and sentinel lymph node biopsy in invasive breast cancer recommended by the clinical guideline, show substantial differences of more than 6 percentage points between the sexes: although recommended by the clinical guideline, both procedures are carried out less often in male cases. Further analysis regarding the medical departments that recorded the treatment revealed that risk for non-adherence to guideline recommendation was high if treatment took place in non-gynaecological departments. Compared to gynaecological departments, procedures such as pretherapeutic biopsy and sentinel lymph node biopsy were carried out less frequently if cases were documented to be handled by surgery or plastic surgery departments. DISCUSSION AND CONCLUSION: Analysis of breast surgery quality indicators reveals a lower level of adherence to guideline recommendations for men with breast cancer compared to women in some aspects of the guideline, as measured by statutory quality indicators in breast surgery. Male breast cancer might be a rare disease, but nevertheless, awareness-rising is needed in diagnostics, treatment and interdisciplinarity in order to avoid inequality between the sexes.

Development and use of health outcome descriptors: a guideline development case study.

BACKGROUND: During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed 'health outcome descriptors' for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers. METHODS: We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys. RESULTS: Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. CONCLUSIONS: Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.

Statistical modelling of HER2-positivity in breast cancer: Final analyses from two large, multicentre, non-interventional studies in Germany.

BACKGROUND: The German NIU HER2 model was developed based on five variables found to have statistically significant influences on HER2-positivity, to allow exploration of deviations between model-predicted and actual HER2-positivity rates as a measure of testing quality. The prospective, non-interventional EPI HER2 BC study (NCT02666261) compared NIU and EPI data, aiming to validate the NIU model. METHODS: HER2 status and patient-/tumour-related information were collected from eligible patients with invasive breast cancer. The influence of variables on HER2-positivity was compared between studies and the NIU model validated using EPI data with cut-off and variable coefficients from the NIU study. The influences of additional variables, centre effects and laboratory-specific parameters were also explored. RESULTS: The study included 14,729 EPI and 15,281 NIU samples; HER2-positivity rates were comparable (13.5% versus 14.2%). The five covariates from NIU were shown to significantly affect HER2-positivity using EPI data. The Youden Index for the NIU model refitted to EPI data (0.3632) and the NIU model for prediction of HER2-positivity in EPI (0.3552) was close to that for the NIU model fitted to NIU data (0.3888), validating the NIU model. Replacing hormone receptor status with progesterone and oestrogen receptor expression, and adding method of sample extraction as a variable improved the model's predictive strength (ROC AUC 0.7402; Youden Index 0.3935). CONCLUSIONS: Reliable, high-quality HER2-testing methods are essential for selection of patients with HER2-positive breast cancer for HER2-tageted treatment. Integration of our model into a locally used software or website may improve its viability for use in clinical practice.