Predictive and prognostic value of total tumor load in sentinel lymph nodes in breast cancer patients after neoadjuvant treatment using one-step nucleic acid amplification: the NEOVATTL study

Objective To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). Methods This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. Results A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). Conclusions TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST (AU)

Predictive and prognostic value of total tumor load in sentinel lymph nodes in breast cancer patients after neoadjuvant treatment using one-step nucleic acid amplification: the NEOVATTL study.

OBJECTIVE: To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). METHODS: This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. RESULTS: A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). CONCLUSIONS: TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST.

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy (AU)

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The ever-evolving role of pathologists in the management of breast cancer with neoadjuvant treatment: recommendations based on the Spanish clinical experience

Purpose. To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice. Materials and methods. A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling. Results. Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly. Conclusions. Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain (AU)

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Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.

The ever-evolving role of pathologists in the management of breast cancer with neoadjuvant treatment: recommendations based on the Spanish clinical experience.

PURPOSE: To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice. MATERIALS AND METHODS: A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling. RESULTS: Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly. CONCLUSIONS: Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain.

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study.

PURPOSE: Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients. METHODS: We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee. RESULTS: A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2). CONCLUSIONS: The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience

Purpose. Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival. Methods/patients. All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed. Results. Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7). Conclusions. Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified (AU)

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Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival. METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7). CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

Loss of the tumor suppressor spinophilin (PPP1R9B) increases the cancer stem cell population in breast tumors.

The spinophilin (Spn, PPP1R9B) gene is located at 17q21.33, a region frequently associated with microsatellite instability and loss of heterozygosity, especially in breast tumors. Spn is a regulatory subunit of phosphatase1a (PP1), which targets the catalytic subunit to distinct subcellular locations. Spn downregulation reduces PPP1CA activity against the retinoblastoma protein, pRb, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in the tumorigenic properties of cells in certain contexts. Here, we explored the mechanism of how Spn downregulation contributes to the malignant phenotype and poor prognosis in breast tumors and found an increase in the stemness phenotype. Analysis of human breast tumors showed that Spn mRNA and protein are reduced or lost in 15% of carcinomas, correlating with a worse prognosis, a more aggressive tumor phenotype and triple-negative tumors, whereas luminal tumors showed high Spn levels. Downregulation of Spn by shRNA increased the stemness properties along with the expression of stem-related genes (Sox2, KLF4, Nanog and OCT4), whereas ectopic overexpression of Spn cDNA reduced these properties. Breast tumor stem cells appeared to have low levels of Spn mRNA, and Spn loss correlated with increased stem-like cell appearance in breast tumors as indicated by an increase in CD44+/CD24- cells. A reduction of the levels of PPP1CA mimicked the cancer stem-like cell phenotype of Spn downregulation, suggesting that the mechanism of Spn involves PP1a. These increased cancer stem cell-like properties with reduced Spn might account for the malignant phenotype observed in Spn-loss tumors and may contribute to a worse patient prognosis.

Ganglio centinela en cáncer de mama: ¿histológico o molecular? Estudio diagnóstico comparativo multicéntrico español. Grupo de Estudios Senológicos / Nodisponible

Introducción: La biopsia del ganglio centinela (GC) estáaceptada como el procedimiento estándar para la cirugía conservadorade la axila en el cáncer de mama, pero la gran variabilidadexistente en los protocolos de estudio anatomopatológicoshan impedido una correcta estandarizacióndiagnóstica.Objetivo: Comparar los resultados de un nuevo métodomolecular (“One-step-Nucleic-Acid-Amplification”, OSNA)con los resultados de los procedimientos habituales y evaluar sies posible la implementación del OSNA como procedimientode elección para el diagnóstico intraoperatorio.Material y métodos: Se estudió una serie de 181 GC procedentesde seis hospitales. De cada ganglio, se realizaron seccionesde 2 mm de espesor hasta agotar el ganglio. Se incluyerontodas las secciones de manera alternativa “a” y “c” paraestudio histológico, y “b” y “d” para OSNA.Resultados: Se obtuvo un nivel de concordancia entre elprocedimiento histológico y el molecular del 99,45%.Conclusiones: El estudio multicéntrico demuestra que elOSNA es un procedimiento altamente sensible, específico yreproducible y que permite la estandarización del diagnósticointraoperatorio del GC en cáncer de mama(AU)

Background: The biopsy of the sentinel node (SN) hasbeen established as the standard procedure for conservativeaxillary surgery but its adequate diagnostic standardization hasnot yet been achieved since the protocols for histopathologicstudy have been highly variable.Objective: Our goal is to compare the results of this newmethod with the results of conventional histological tests, toevaluate the feasibility of this procedure for the intra-operativestudy of SN in breast cancer surgery and to evaluate it as away to standardize the sentinel node procedure.Material and methods: The study included 181 cases. Parallel,2 mm-thick sections were performed to drain the lymphnode which were then processed alternately for histologicalanalysis (“a” and “c”) and the others (“b” and d”) following theOSNA procedure.Results: A concordance level of 99.45% was found betweenthe histological and the molecular procedure.Conclusions: Our multicentric OSNA assay for sentinelnode in breast cancer demonstrates that this is a highly sensitive,specific and reproducible technique that allows the standardizationof the diagnostic procedure, a needed and up tonow unresolved question(AU)

Goodpasture antigen-binding protein, the kinase that phosphorylates the goodpasture antigen, is an alternatively spliced variant implicated in autoimmune pathogenesis.

The non-collagenous C-terminal domain of the alpha(3) chain of collagen IV is the autoantigen in Goodpasture disease, an autoimmune disorder described only in humans. Specific N-terminal phosphorylation is a biological feature unique to the human domain when compared with other homologous domains lacking immunopathogenic potential. We have recently cloned from a HeLa-derived cDNA library a novel serine/threonine kinase (Goodpasture antigen-binding protein (GPBP)) that phosphorylates the N-terminal region of the human domain (Raya, A. Revert, F, Navarro, S. and Saus J. (1999) J. Biol. Chem. 274, 12642-12649). We show here that the pre-mRNA of GPBP is alternatively spliced in human tissues and that the most common transcript found encodes GPBPDelta26, a molecular isoform devoid of a 26-residue serine-rich motif. Recombinantly expressed GPBPDelta26 exhibits lower activity than GPBP, due at least in part to a reduced ability of GPBPDelta26 to interact and to form very active high molecular weight aggregates. In human tissues, GPBP shows a more limited expression than GPBPDelta26 but displays a remarkable preference for the small vessels and for histological structures targeted by natural autoimmune responses including alveolar and glomerular basement membranes, the two main targets in Goodpasture disease. GPBP expression is, in turn, up-regulated in the striated muscle of a Goodpasture patient and in other autoimmune conditions including cutaneous lupus erythematosus, pemphigoid, and lichen planus.