Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial.

BACKGROUND: In high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC), nanoparticle albumin-bound (nab)-paclitaxel showed promising efficacy versus solvent-based (sb)-paclitaxel in neoadjuvant trials; however, optimal patient and therapy selection remains a topic of ongoing research. Here, we investigate the potential of Oncotype DX® recurrence score (RS) and endocrine therapy (ET) response (low post-endocrine Ki67) for therapy selection. PATIENTS AND METHODS: Within the WSG-ADAPT trial (NCT01779206), high-risk HR+/HER2- EBC patients were randomized to (neo)adjuvant 4× sb-paclitaxel 175 mg/m2 q2w or 8× nab-paclitaxel 125 mg/m2 q1w, followed by 4× epirubicin + cyclophosphamide (90 mg + 600 mg) q2w; inclusion criteria: (i) cN0-1, RS 12-25, and post-ET Ki67 >10%; (ii) cN0-1 with RS >25. Patients with cN2-3 or (G3, baseline Ki67 ≥40%, and tumor size >1 cm) were allowed to be included without RS and/or ET response testing. Associations of key factors with pathological complete response (pCR) (primary) and survival (secondary) endpoints were analyzed using statistical mediation and moderation models. RESULTS: Eight hundred and sixty-four patients received neoadjuvant nab-paclitaxel (n= 437) or sb-paclitaxel (n = 427); nab-paclitaxel was superior for pCR (20.8% versus 12.9%, P = 0.002). pCR was higher for RS >25 versus RS ≤25 (16.0% versus 8.4%, P = 0.021) and for ET non-response versus ET response (15.1% versus 6.0%, P = 0.027); no factors were predictive for the relative efficacy of nab-paclitaxel versus sb-paclitaxel. Patients with pCR had longer distant disease-free survival [dDFS; hazard ratio 0.42, 95% confidence interval (CI) 0.20-0.91, P = 0.024]. Despite favorable prognostic association of RS >25 versus RS ≤25 with pCR (odds ratio 3.11, 95% CI 1.71-5.63, P ≤ 0.001), higher RS was unfavorably associated with dDFS (hazard ratio 1.03, 95% CI 1.01-1.05, P = 0.010). CONCLUSIONS: In high-risk HR+/HER2- EBC, neoadjuvant nab-paclitaxel q1w appears superior to sb-paclitaxel q2w regarding pCR. Combining RS and ET response assessment appears to select patients with highest pCR rates. The disadvantage of higher RS for dDFS is reduced in patients with pCR. These are the first results from a large neoadjuvant randomized trial supporting the use of RS to help select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- EBC.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

[Bone marrow fibrosis in primary myelofibrosis in relation to myelodysplasia- and age-related mutations of hematopoietic cells]. / Knochenmarkfibrose bei primärer Myelofibrose in Abhängigkeit von myelodysplasie- und altersassoziierten Mutationen der Hämatopoese.

Besides histopathological findings, there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPNs). Age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indetermined potential (CHIP) are frequent findings in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for the development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (n = 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared to prefibrotic PMF samples without the development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations that are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (P = 0.0028). Determination of tumor mutational burden (TMB) in a subgroup of cases (n = 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when already manifest at first presentation.

[Neuroendocrine differentiation in breast cancer]. / Neuroendokrine Differenzierung beim Mammakarzinom.

To classify as breast cancer with neuroendocrine differentiation a growth pattern as encountered in well differentiated (G1, G2) neuroendocrine tumors (NET) of the gastrointestinal tract and the lung must be present in addition to the immunohistochemical expression of neuroendocrine markers (chromogranin, synaptophysin). The majority of breast cancers fulfilling these criteria show hormone receptor positivity and with regard to prognosis resemble luminal type of breast cancer from which they are not fundamentally different. Despite lacking clinical relevance the up-coming WHO classification of breast cancer will nevertheless introduce the new category of NET luminal type. Immunohistochemical detection of neuroendocrine marker alone cannot be considered as sufficient for classification because it can frequently be encountered in other types of breast cancer (e.g. mucinous, solid papillary). From low grade NET with good differentiation those with poor differentiation and most frequently small cell appearance have to be differentiated. Poorly differentiated NET can primarily originate in the breast, which may be indicated by intraductal growth and co-expression of GATA3 but in these cases metastasis of extra mammary cancers has to be considered and correlation with the clinical findings is required for correct classification.

[Ki67: biological intertumor variance versus variance of assay]. / Ki67-Tumorheterogenität vs. Assayheterogenität.

Since its first description at the Institute of Pathology in Kiel more than 34 years ago, the immunohistochemical proliferation marker Ki67 has been shown to be of prognostic significance in a huge number of retrospective and even some prospective trials on malignant tumours of various tissue derivation. Lack of standardization in the evaluation provides potential sources of variance in assessment. Tumour area to be assessed, minimum number of cells to be analyzed, tedious counting cell by cell or semiquantitative eyeballing, choice of immunohistochemical techniques represent nonstandardized issues that potentially lead to considerable assay heterogeneity. In addition, interpretation is not homogeneous, in particular with regard to thresholds between high and low proliferative activity. Due to these numerous potential methodological limitations, for a long time Ki67 was not generally accepted as a prognostic marker, in particular outside Germany and by nonpathologists. However, in recent years a shift has taken place. Despite the challenge that biological heterogeneity may be hidden by differences in assay performance, Ki67 now plays an important auxiliary role in grading of malignant neoplasms such as breast cancer, neuroendocrine tumours and malignant lymphomas. In this context it is applied in clinical diagnostics as well as in clinical trials for the purpose of stratification. Because of its widespread use, it is of utmost importance to raise awareness of the potential methodological limitations in order to use Ki67 in a meaningful way.

[Ectopia of mammary tissue]. / Ektopien des Mammagewebes.

Ectopic breast tissue may represent the complete breast (accessory breast), glandular tissue without areola or nipple (aberrant breast tissue), or exclusively the nipple (polythelia). Localization is along the embryonic milk ridge extending from the axilla to the vulva. Only rarely, is ectopic tissue found outside of the milk ridge. Most frequently affected are the axilla, the breast itself, and its close neighbourhood. Ectopic breast tissue may rarely give rise to tumours such as fibroadenoma or carcinoma.

[Clinical and pathological characteristics of intravascular lymphomas]. / Klinische und pathologische Charakteristika intravaskulärer Lymphome.

Intravascular B­cell lymphomas (IVL) are rare neoplasms that can manifest at any age (mean age ~62-63 years). About half of the cases are associated with Epstein-Barr virus. The most common sites of manifestation are the brain, skin, and bone marrow. The diagnosis is difficult due to unspecific clinical presentation and laboratory changes. FACS (fluorescence-activated cell sorting) and clonality analysis from peripheral blood and radiological findings are often not diagnostic. The most sensitive and most specific diagnostic method is the histopathological and immunohistochemical evaluation of a tissue biopsy. Because of the rarity of this disease, little is known about therapy and prognosis, whereby therapy is mainly similar to non-IVL lymphomas. The prognosis is poor; median survival after diagnosis is approximately one year.

[Possibilities and limitations of molecular pathology in dermatohistology]. / Möglichkeiten und Grenzen der Molekularpathologie in der Dermatohistologie.

Malignant tumours, infections caused by microorganisms or genodermatoses are diagnosed with additional help of molecular pathology methods. Polymerase chain reaction (PCR), sequencing and in situ hybridisations play an important role. It remains to be seen if methods such as "liquid biopsies" or "single cell genomics" can be developed as routine diagnostics. High technical efforts, high costs and no possibility for resistency testing is accompanied by fast verification, high sensitivity and high specificity. Overall, molecular pathology results have to be combined with the clinical picture, histology or immunohistochemistry and culturing results to achieve a correct diagnosis for the patient.

De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel.

BACKGROUND: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. PATIENTS AND METHODS: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients. RESULTS: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. CONCLUSION: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

[Analysis of therapy-relevant receptors in bone marrow carcinosis : Comparison of pathological and clinical parameters]. / Untersuchung von therapierelevanten Rezeptoren bei Knochenmarkkarzinosen : Ein Vergleich pathologischer und klinischer Parameter.

BACKGROUND: Bone marrow carcinosis is a sign of advanced tumor stage with nonspecific clinical and hematological symptoms. Diagnosis is based on bone marrow biopsy and histopathology, but biopsies are not part of the standard work-up in oncological diseases and data on the correlation between clinical presentation and pathological findings are sparse. MATERIAL AND METHODS: In a retrospective single-center study, data from 20 tumor patients with bone marrow carcinosis were analyzed. Bone marrow biopsies were re-evaluated regarding quantity of tumor cells, fibrosis/necrosis, and bone changes. Immunohistochemistry of potential therapy-relevant receptors and PD-L1 was performed. RESULTS: The median age in these 20 patients (13 women, 7 men) was 65 years. The most frequent diagnoses were breast (n = 8) and lung cancer (n = 5). Anemia (94% of patients), thrombocytopenia (72%), and elevated LDH (83%) were frequent findings. The degree of bone marrow infiltration was highly variable and accounted for between 1 and 95% of biopsy space. Significant bone remodeling was present in 14/20 biopsies. No correlation could be found between histological and radiological findings. Treated patients showed some clinical and biochemical improvement, but the overall survival was poor (median 4.5 months, range < 0.5 to 21.5 months). DISCUSSION: Anemia and thrombocytopenia are frequently associated with bone marrow carcinosis, but are nonspecific. The extent of tumor cell infiltration and osteolytic/osteoblastic changes did not correlate with radiological findings. Therapy-relevant target factors should be evaluated, but therapeutic options are often limited and the prognosis is bad.

[Necrotizing funisitis : Histopathological indicator of occult congenital syphilis]. / Nekrotisierende Funikulitis : Histopathologischer Indikator für eine okkulte konnatale Syphilis.

Congenital syphilis is a rare disease in central Europe. Placental changes may be non-specific but a typical finding is necrotizing funisitis of the umbilical cord. In a case report we describe how the histopathological incidental finding of B lymphocyte-rich, necrotizing funisitis led to the diagnosis of a previously unknown Treponema pallidum infection in parents and their newborn child. The pathological suspicion of congenital syphilis, although rare, has implications for the clinical management (serological evaluation of parents and child as well as the social environment, evaluation of viral coinfection and treatment decision) and is a notifiable disease.

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial.

INTRODUCTION: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). METHODS: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). RESULTS: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. CONCLUSION: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. TRIAL REGISTRATION: The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

[HER2 testing in gastric cancer - results of a German expert meeting]. / HER2-Testung beim Magenkarzinom - Ergebnisse eines deutschen Expertentreffens.

Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.

[Histological grading of breast cancer]. / Histologisches Grading beim Mammakarzinom.

From a historical perspective, histological grading was the earliest cell-based method for assessing tumor biology and the prognosis of breast cancer. This review article provides detailed and practical instructions for grading of breast cancer in routine diagnostics. Furthermore, the increasing relevance of precise histological grading in the era of molecular pathology is discussed.

[HER2 testing in gastric cancer : Results of a meeting of German experts]. / HER2-Testung beim Magenkarzinom : Ergebnisse eines deutschen Expertentreffens.

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.

Standardized processing of native tissue in breast pathology.

In breast surgery, replacement of intraoperative frozen section by core needle and vacuum biopsies hampers collections of unfixed breast specimens. We practice immediate intraoperative macroscopic analysis of resection margins and vacuum-cooling of breast specimens to enable native tissue asservation for assessment of biological markers and tissue banking of tumor tissue. In addition, slicing of native tissue before formalin fixation guarantees a standardized and uniform fixation. Starting in 2013, more than 350 breast specimens were processed as native specimens in the Institute of Pathology of Hannover Medical School. Breast specimens with an invasive carcinoma and request of an intraoperative resection margin assessment were processed with an immediate intraoperative pathological analysis. All other breast specimens without assessment of an intraoperative resection margin were vacuum-fixed processed. In all cases, native tissue for biomarker analyses and tumor banking could be preserved.

[Cytopathology in the diagnostics of hematological diseases]. / Zytopathologie in der Diagnostik hämatologischer Erkrankungen.

Whereas in many fields of surgical pathology examination of cytological smears and analysis of histological tissue sections provide alternative methods which are chosen according to the clinical requirements, in hematopathology both types of morphological investigation are routinely applied in parallel and simultaneously. This procedure improves the diagnostic precision and safety. Unlike other European countries in Germany both procedures are performed by different specialties. Cytology is the responsibility of hematologists whereas histology is carried out by pathologists, which interferes with an integrative diagnostic approach unless intense communication takes place. Ideally, in the diagnosis of hematological disorders histology of bone marrow trephines should be studied in conjunction with smears of peripheral blood and bone marrow. In many instances, further complementary investigations, such as flow cytometry, cytogenetics and increasingly molecular pathological studies are necessary to guarantee an adequate modern state of diagnostics in hematopathology.

[Diagnostic molecular pathology of lymphatic and myeloid neoplasms]. / Diagnostische Molekularpathologie bei lymphatischen und myeloischen Neoplasien.

Molecular pathology has been an integral part of the diagnostics of tumors of the hematopoietic system substantially longer than for solid neoplasms. In contrast to solid tumors, the primary objective of molecular pathology in hematopoietic neoplasms is not the prediction of drug efficacy but the diagnosis itself by excluding reactive proliferation and by using molecular features for tumor classification. In the case of malignant lymphomas, the most commonly applied molecular tests are those for gene rearrangements for immunoglobulin heavy chains and T-cell receptors. However, this article puts the focus on new and diagnostically relevant assays in hematopathology. Among these are mutations of MYD88 codon 265 in lymphoplasmacytic lymphomas, B-raf V600E in hairy cell leukemia and Stat3 exon 21 in indolent T-cell lymphomas. In myeloproliferative neoplasms, MPL W515, calreticulin exon 9 and the BCR-ABL and JAK2 V617F junctions are the most frequently analyzed differentiation series. In myelodysplastic and myeloproliferative neoplasms, SRSF2, SETBP1 and CSF3R mutations provide important differential diagnostic information. Genes mutated in myelodysplastic syndromes (MDS) are particularly diverse but their analysis significantly improves the differential diagnostics between reactive conditions and MDS. The most frequent changes in MDS include mutations of TET2 and various genes encoding splicing factors.