TNBC-DX genomic test in early-stage triple-negative breast cancer treated with neoadjuvant taxane-based therapy.

BACKGROUND: Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC. METHODS: Information from 1,259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) were used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in 3 studies: i) WSG-ADAPT-TN, ii) MMJ-CAR-2014-01, and iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes (pCR, distant disease-free survival [DDFS] or event-free survival [EFS], and overall survival [OS]) in the validation cohorts. RESULTS: TNBC-DX test was created incorporating 10-gene core immune gene module, 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the 2 independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen (odds ratio per 10-units increment=1.34, 95% CI 1.20-1.52, p<0.001). pCR rates for the TNBC-DX pCR-high, -medium, and -low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high vs pCR-low=3.48 [95% CI 1.72-7.15], p<0.001). Additionally, the TNBC-DX risk score was significantly associated with DDFS (hazard ratio [HR] high-risk vs low-risk=0.24, 95% CI 0.15-0.41, p<0.001) and OS (HR=0.19, 95% CI 0.11-0.35, p<0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS. CONCLUSIONS: TNBC-DX predicts pCR to neoadjuvant taxane-carboplatin in stage I-III TNBC and helps to forecast the patient´s long-term survival in the absence of neoadjuvant anthracycline/cyclophosphamide, and independent of pembrolizumab use.

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.

Co-expression of transcription factor AP-2beta (TFAP2B) and GATA3 in human mammary epithelial cells with intense, apicobasal immunoreactivity for CK8/18.

AP-2ß is a new mammary epithelial differentiation marker and its expression is preferentially retained and enhanced in lobular carcinoma in situ and invasive lobular breast cancer. In normal breast epithelium AP-2ß is expressed in a scattered subpopulation of luminal cells. So far, these cells have not been further characterized. Co-expression of AP-2ß protein and luminal epithelium markers (GATA3, CK8/18), hormone receptors [estrogen receptor (ER), androgen receptor (AR)] and candidate stem cells markers (CK5/14, CD44) were assessed by double-immunofluorescence staining in normal mammary gland epithelium. The subpopulation of AP-2ß-positive mammary epithelial cells showed an almost complete, superimposable co-expression with GATA3 and a peculiar intense, ring-like appearing immunoreactivity for CK8/18. Confocal immunofluorescence microscopy revealed an apicobasal staining for CK8/18 in AP-2ß-positive cells, which was not seen in in AP-2ß-negative cells. Furthermore, AP-2ß-positive displayed a partial co-expression with ER and AR, but lacked expression of candidate stem cell markers CK5/14 and CD44. In summary, AP-2ß is a new luminal mammary epithelial differentiation marker, which is expressed in the GATA3-positive subpopulation of luminal epithelial cells. These AP-2ß-positive/GATA3-positive cells also show a peculiar CK8/18-expression which may indicate a previously unknown functionally specialized mammary epithelial cell population.

[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.

[Donor liver histology : Joint recommendations of the DGP, DTG and DSO]. / Histologische Diagnostik bei Spenderlebern : Gemeinsame Empfehlungen von DGP, DTG und DSO.

BACKGROUND: The indications, implementation and reporting of liver biopsies for deceased organ donation are not mandatory or regulated. Reliable data on outcome quality and prognostic relevance are therefore not available. Defined standards are thus required to enable meaningful studies and to ensure high data quality of a national transplantation registry. OBJECTIVE: Presentation of a synopsis of available studies and literature-based recommendations. RESULTS AND CONCLUSION: Against the background of an organ shortage and a growing number of older donors, pretransplantation liver histology is of significant relevance to guide clinical decision making. With the joint recommendations of the German Transplantation Society (DTG), the German Society of Pathology (DGP) and the German Organ Transplantation Foundation (DSO) standardized procedures are defined for the first time.

[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.

[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.

[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.

[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.

[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.

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.

[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.

Primary Therapy of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: Opinions of German Specialists to the 14th St. Gallen International Breast Cancer Conference 2015 (Vienna 2015).

For the first time, this year's St. Gallen International Consensus Conference on the treatment of patients with primary breast cancer, which takes place every two years, was held not in St. Gallen (Switzerland) but - for logistical reasons - in Vienna (Austria) under its usual name. The 2015 St. Gallen International Consensus Conference was the 14th of its kind. As the international panel of the St. Gallen conference consists of experts from different countries, the consensus mirrors an international cross-section of opinions. From a German perspective, it was considered useful to translate the results of the votes of the St. Gallen conference into practical suggestions, particularly in light of the recently updated treatment guideline of the Gynecologic Oncology Group (AGO-Mamma 2015) in Germany. A German group consisting of 14 breast cancer experts, three of whom are members of the international St. Gallen panel, has therefore provided comments on the results of this year's votes at the 2015 St. Gallen Consensus Conference and their impact on clinical care in Germany. The 14th St. Gallen conference once again focused on surgery of the breast and the axilla, radio-oncologic and systemic treatment options for primary breast cancer depending on tumor biology, and the clinical use of multigene assays. The conference also considered targeted therapies for older and for younger patients, including the diagnosis/treatment of breast cancer during and after pregnancy and the preservation of fertility.

Role of immunohistochemistry and fluorescence in-situ hybridization (FISH) in the diagnosis of spindle and round cell tumors of the kidney.

UNLABELLED: Spindle cell/mesenchymal tumors of the kidney are rare. The diagnosis is supported mainly by the application of ancillary techniques such as immunohistochemistry (IH) and in-situ hybridization (FISH). An accurate diagnosis is essential because early management by complete resection and adjuvant chemotherapy improves the prognosis dramatically. Synovial sarcoma and primitive neuroectodermal tumor/Ewing sarcoma are infrequent malignancies which usually present in soft tissues but rarely in the kidney. The challenge for the pathologists is to histologically differentiate between different types of sarcomas such as PNET/Ewing's sarcoma, sarcomatous dedifferentiated renal cell carcinoma, metastasis, non-Hodgkin's lymphoma, nephroblastoma and angiomyolipoma. METHODS: We report from our experience six exemplary rare cases that presented in the kidney as spindle/round cell tumors. RESULTS: We have arrived at the accurate diagnosis after performing a large panel of IH and FISH. CONCLUSION: In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH) to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy.

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.

Overview and evaluation of the value of fine needle aspiration cytology in determining the histogenesis of liver nodules: 14 years of experience at Hannover Medical School.

Fine needle aspiration (FNA) is a sensitive and specific method (95%), often helpful in characterizing suspected liver lesions. It is appropriate to distinguish between primary and secondary liver neoplasia. Moreover, in most cases, the use of cell block preparations of small specimens allows immunocytochemical evaluation to determine the nature of the primary tumour. In a retrospective study at Hannover Medical School (MHH) from 1998 to 2012 (14 years), 4,136 sonographically guided FNAs were performed. The patients provided consent and the study protocol was approved by the local ethics committee. There were 39.6% malignant and 57.5% benign lesions in the liver, while 2.8% of the cases were undetermined. FNA was non-representative in 1.1% of the cases. The diagnostic utility of highly differentiated hepatocellular carcinoma (HCC; G1) remains difficult; cell bridges with cell atypia are pathognomonic for diagnosis. Ancillary techniques and immunocytochemical investigations will increase the sensitivity and specificity, particularly by using the cell block technique.