Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023.

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

[Second opinions and reference pathology in breast cancer]. / Zweitmeinungs- und Referenzpathologie beim Mammakarzinom.

Second opinion in pathology recruits expert knowledge for the diagnosis in difficult cases and has a tradition in Germany with generation of a network between primarily diagnostic and academic institutes of pathology, active in research. The term reference pathology does mean a label for a class of institutes for pathology but rather specifies a function within prospective clinical trials with defined endpoints and a central pathology, which will derive expert knowledge from this function. On either way generated collection of samples and expertise will enable diagnostic support in difficult cases. Furthermore, research based on this tissue material might lead to the establishment of novel biomarkers and methods, which when transferred to decentral application will enhance diagnostic validity of pathological tissue analysis as a whole. Thus, for all institutes participating in the network, pathology as a diagnostic discipline and patients, second opinion and reference pathology provide considerable benefit with regard to quality of histopathological diagnoses.

[Second opinions and reference pathology]. / Zweitmeinungs- und Referenzpathologie.

Second opinions in pathology require expert knowledge for diagnosis in difficult cases and in Germany have a tradition that has grown into a network between primarily diagnostic care institutions and university-associated institutes of pathology that are active in research. The term reference pathology is not a designation for a class of institutes for pathology but rather indicates a function within prospective clinical trials with defined endpoints and a central pathology, which derives expert knowledge from this function. The thus generated collection of samples and expertise enable diagnostic support in difficult cases. Furthermore, research based on this tissue material might lead to the establishment of novel biomarkers and methods, which when transferred back for local application will enhance the overall diagnostic validity of pathological tissue analysis. Thus, for all institutes participating in the network second opinion and reference pathology provide considerable benefit.

The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.

BACKGROUND: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9-20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. METHODS: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients' hospitalization time. FINDINGS: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. INTERPRETATION: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. FUNDING: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

AGO Recommendations for the Surgical Therapy of Breast Cancer: Update 2022.

The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to "++". Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins ("no tumor on ink"), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1 - 3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options.

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2022.

Introduction: The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Task Force on Diagnosis and Treatment of Breast Cancer as an interdisciplinary team consists of specialists from gynecological oncology, pathology, diagnostic radiology, medical oncology, and radiation oncology with a special focus on breast cancer. Methods: The updated evidence-based treatment recommendation 2022 for early breast cancer (EBC) and metastatic breast cancer of the AGO Task Force has been released. Results and Conclusion: This paper captures the update of EBC.

[Drug-induced bone marrow changes]. / Medikamentös induzierte Knochenmarkveränderungen.

Cytomorphological and histomorphological analysis of bone marrow cells in cases with abnormal production of blood cells must always take the unwanted side effects of drugs into account. Drugs can affect single lineages or the complete bone marrow. Besides quantitative phenomena consisting of hypoplasia or hyperplasia, maturation of blood cells may be disturbed. Disturbances encompass left shifts, which may be extreme, or imitate states of vitamin deficiency and atypia occurring in myelodysplastic syndromes (MDS). In addition, all bone marrow lineages may be affected, simulating aplastic anemia. The spectrum of causative drugs is very broad, and the induced changes are generally not specific enough to identify the underlying drug culprit, which requires knowledge of the patient's drug history. Cytotoxic drugs applied in oncology can induce MDS with an average latency of 2-6 years, or even shorter in the case of drugs interfering with DNA repair.

Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2- Early Breast Cancer.

PURPOSE: To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. MATERIALS AND METHODS: Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental (v control) arm; secondary end points included distant DFS, overall survival, and translational research. RESULTS: Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority (P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% (P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). CONCLUSION: WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

Clinically latent and autopsy-verified inflammatory disorders and malignant tumours in transplant patients.

AIMS: The number of clinical autopsies decreases while the rate of missed relevant diagnoses is known to be 2%-20%. In this study, we focused on postmortem examinations of patients after transplantation of solid organs. METHODS: A total of 122 cases were assessed for this study. Transplant organs included liver (LiTx; n=42/122, 34%), heart (n=8/122, 7%), lungs (n=32/122, 26%), kidney (KTx; n=38/122, 31%) and KTx+LiTx (n=2/122, 2%). RESULTS: The most frequent autopsy-verified causes of death were cardiac or respiratory failure (together n=85/122, 70%). The frequency of malignant tumours that were identified at autopsy was 5% (n=6/122). In 3% (n=4/122) of cases, Goldman class I discrepancies between clinical diagnosis and autopsy findings were identified. CONCLUSIONS: The rate of missed relevant diagnoses might be relatively low, but these cases nevertheless refute the contention that modern diagnostic techniques negate the need for autopsies in patients who died after transplantation.

[Relevant mutations in predictive breast cancer pathology]. / Prädiktive Mutationsdiagnostik bei Mammakarzinomen.

Whereas predictive immunohistochemistry has represented a core element of breast cancer classification for decades, predictive molecular pathology, with the exception of in situ hybridization for assessment of HER2 amplification, has only recently gained importance because novel drugs have been approved for treatment of metastatic disease. For the use of PARP inhibitors, proof of BRCA1 or BRCA2 mutation is mandatory. When mutation of the catalytic subunit α of the phosphatidylinositol­4.5­bisphosphate 3­kinase gene (PIK3CA) is present, which can be encountered in up to 40% of luminal breast cancers, the option for treatment with the specific inhibitor alpelisib arises. The HER2 -encoded growth factor receptor contributes to neoplastic transformation not only by amplification and overexpression but also by activating the mutation of the kinase domain, which is responsive to tyrosine kinase inhibitors of the tucatinib/neratinib type. Up to 30% of metastatic and endocrine treated luminal breast cancers acquire an activating mutation of the estrogen receptor gene ESR1, resulting in an autocrine and ligand-independent growth stimulation resistant to aromatase inhibitors. Larotrectinib-sensitive mutation of tropomyosinreceptor kinase is present in up to 50% of secretory breast cancers, whereas the other histologic subtypes display an incidence of below 1%. In conclusion, predictive molecular pathology has gained importance in metastatic breast cancer.

Transcription factor AP-2beta in development, differentiation and tumorigenesis.

To date, the AP-2 family of transcription factors comprises five members. Transcription factor AP-2beta (TFAP2B)/AP-2ß was first described in 1995. Several studies indicate a critical role of AP-2ß in the development of tissues and organs of ectodermal, neuroectodermal and also mesodermal origin. Germline mutation of TFAP2B is known to cause the Char syndrome, an autosomal dominant disorder characterized by facial dysmorphism, patent ductus arteriosus and anatomical abnormalities of the fifth digit. Furthermore, single-nucleotide polymorphisms in TFAP2B were linked to obesity and specific personality traits. In neoplasias, AP-2ß was first described in alveolar rhabdomyosarcoma. Immunohistochemical staining of AP-2ß is a recommended ancillary test for the histopathological diagnosis of this uncommon childhood malignancy. In neuroblastoma, AP-2ß supports noradrenergic differentiation. Recently, the function of AP-2ß in breast cancer (BC) has gained interest. AP-2ß is associated with the lobular BC subtype. Moreover, AP-2ß controls BC cell proliferation and has a prognostic impact in patients with BC. This review provides a comprehensive overview of the current knowledge about AP-2ß and its function in organ development, differentiation and tumorigenesis.

Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group.

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.

A multicenter prospective, randomized, placebo-controlled phase II/III trial for preemptive acute graft-versus-host disease therapy.

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.

Bicentric Retrospective Analysis of en Bloc Resection and Muscularis Mucosae Detection Rate in Non-Muscle Invasive Bladder Tumors: A Real-World Scenario.

INTRODUCTION: For risk stratification of non-muscle invasive bladder cancer (NMIBC), the depth of stromal invasion can be further classified, where the lamina muscularis mucosae (MM) serves as a reference structure. While the overall identifiability of MM in standard transurethral specimens is low, en bloc resection may help in identification and overall orientation. The aims of this study were to report the detection rate of MM in en bloc resected bladder tumors (ERBT) and to provide real-world information on tissue stability and preservation of en bloc architecture during recovery and processing for histopathologic evaluation. METHODS: Thirty-four ERBT specimens were histologically re-evaluated with regard to MM detectability and structure as well as the presence of en bloc architecture and further histologic features. Associations with tumor size and energy source and within histologic parameters were assessed by standard Pearson's chi-squared analyses and Cramér's V effect size testing (V). RESULTS: The first parameter assessed was MM detection rate. In 19 out of 34 samples (56%) MM was detectable: scattered in 9 cases (26%), interrupted in 8 cases (24%) and continuous in 2 cases (6%). The second parameter assessed was preservation of en bloc architecture. In 11 out of 34 samples (32%), en bloc architecture could not be confirmed, and these samples served as a reference group for the detection of MM. Preservation of en bloc architecture was associated with an increased MM detection rate (MM in en bloc preserved 16/23, 70% vs. non-preserved 3/11, 27%; p = 0.020; V = 0.398) and with tumor size (p = 0.005; V = 0.595). Medium-sized tumors (1.1-2 cm) were best preserved. The choice of energy source did not show relevant association with en bloc architecture (p = n.s.). CONCLUSIONS: In line with recent publications, ERBT increases the MM detection rate considerably. However, a third of the ERBT specimens lost en bloc architecture during sample recovery and processing. Tumor size is a relevant factor, with optimal architecture preservation between 1 and 2 cm. Optimizing resection techniques, recovery, transport, and diagnostic processing of ERBT samples is warranted to verify the diagnostic value of MM-based substaging.

The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer.

BACKGROUND: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC). METHODS: The prospective WSG-ADAPT HR+/HER2- trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical-pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0-11 or RS 12-25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy. RESULTS: The ADAPT HR+/HER2- trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0-11, 58.3% RS 12-25, and 18.7% RS 26-100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26-100 versus others, RS 0-11 versus others) were significant (both p < 0.001); Ki-67 quotients were higher for RS 26-100 (p = 0.02, Mann-Whitney). In premenopausal women (n = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women (n = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry (p = 0.002) or real-time polymerase chain reaction (p < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (RS = 0.7, n = 181). CONCLUSIONS: This phase of the WSG-ADAPT HR+/HER2- trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%. CLINICALTRIALSGOV IDENTIFIER: NCT01779206.

[Quality assurance in diagnostic in situ hybridization-experience of QuIP]. / Qualitätssicherung in der diagnostischen In-situ-Hybridisierung ­ Erfahrungen der QuIP.

The Quality Assurance Initiative Pathology (QuIP) gives pathologists the opportunity to check the methodological processes of immunohistological and molecular diagnostics in a result-oriented manner and obtain a certificate reflecting the quality. For in situ hybridization (ISH), 5 round robin tests were organized in 2019, two recurrent (HER2-ISH gastric carcinomas and HER2-ISH breast carcinomas) and three prototypical (ROS1-NSCLC, ALK1-NSCLC, NTRK). The different round robin tests, which were provided by QuIP, are based on the development in diagnostics and the importance of the therapeutic relevance of the molecules which are tested. The results of the round robin tests in 2019 showed a sensitivity of at least 94.4%, a specificity of at least 96.6%, and a success rate of 85-99%. This reflected the high standard of quality of the round robin test and the participating institutes.