ABSTRACT
Pan-Trk immunohistochemistry has been described as a screening test for the detection of NTRK fusions in a broad spectrum of tumor types. However, pan-Trk testing in the clinical setting may be limited by many factors, including analytical parameters such as clones, platforms, and protocols used. This study aimed to harmonize pan-Trk testing using various clones and immunohistochemical (IHC) platforms and to evaluate the level of analytical variability across pathology laboratories. We developed several IHC pan-Trk assays using clones EPR17341 (Abcam) and A7H6R (Cell Signaling Technology) on Ventana/Roche, Agilent, and Leica platforms. To compare them, we sent unstained sections of a tissue microarray containing 9 cases with NTRK3 fusions to participating laboratories, to perform staining on Ventana/Roche (10 centers), Agilent (4 centers), and Leica (3 centers) platforms. A ready-to-use pan-Trk IVD assay (Ventana/Roche) was also performed in 3 centers. All slides were centrally and blindly reviewed for the percentage of stained tumor cells. Laboratory-developed tests with clone EPR17341 were able to detect pan-Trk protein expression in all cases, whereas lower rates of positivity were observed with clone A7H6R. Moderate to strong variability of the positive cases rate was observed with both antibodies in each IHC platforms type and each of the positivity cut points evaluated (≥1%, ≥10%, and ≥50% of stained tumor cells). The rate of false-negative cases was lower when pan-Trk staining was assessed with the lowest positivity threshold (≥1%). In conclusion, most evaluated pan-Trk IHC laboratory-developed tests were able to detect NTRK3-fusion proteins; however, a significant analytical variability was observed between antibodies, platforms, and centers.
Subject(s)
Biomarkers, Tumor , Receptor, trkA , Humans , Immunohistochemistry , Biomarkers, Tumor/genetics , Oncogene Proteins, Fusion/metabolismABSTRACT
The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.
Subject(s)
Breast Neoplasms , Biomarkers, Tumor , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Receptor, ErbB-2/geneticsABSTRACT
In 2017, we implemented CTNNA1 germline analysis in probands suspected of having hereditary diffuse gastric cancer. Here, we report the results from a retrospective series of 41 cases, including the identification of a new family with a CTNNA1 mutation and the first prophylactic total gastrectomy in an asymptomatic carrier after a normal upper endoscopy. Diffuse gastric cancer foci with loss of catenin alpha-1 expression were seen in the resected tissue, suggesting that CTNNA1 and CDH1 germline mutations behave in a similar manner. Life-changing prophylactic total gastrectomy should therefore also be considered in CTNNA1 mutation carriers.
Subject(s)
Asymptomatic Diseases/therapy , Carcinoma, Signet Ring Cell/genetics , Germ-Line Mutation , Stomach Neoplasms/genetics , alpha Catenin/genetics , Adult , Carcinoma, Signet Ring Cell/metabolism , Carcinoma, Signet Ring Cell/pathology , Carcinoma, Signet Ring Cell/surgery , Female , Follow-Up Studies , Gastrectomy , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Pedigree , Prognosis , Retrospective Studies , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , alpha Catenin/metabolismABSTRACT
In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Biomarkers, Tumor/genetics , Cell Differentiation , Gene Fusion , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Sarcoma, Small Cell/genetics , Soft Tissue Neoplasms/genetics , Transcription Factors/genetics , Adult , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Cell Movement , Cell Proliferation , Female , Genetic Predisposition to Disease , HEK293 Cells , Humans , Male , Molecular Diagnostic Techniques , Neoplasm Invasiveness , Phenotype , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Sarcoma, Small Cell/metabolism , Sarcoma, Small Cell/pathology , Sarcoma, Small Cell/therapy , Soft Tissue Neoplasms/metabolism , Soft Tissue Neoplasms/pathology , Soft Tissue Neoplasms/therapy , Transcription Factors/metabolismABSTRACT
Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).
Subject(s)
Breast Neoplasms/pathology , Breast/pathology , Lymph Nodes/pathology , Neoadjuvant Therapy , Specimen Handling/standards , Biomarkers, Tumor , Biopsy/methods , Biopsy/standards , Breast Neoplasms/chemistry , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Chemotherapy, Adjuvant/standards , Drug Screening Assays, Antitumor , Female , France , Humans , Lymph Nodes/drug effects , Lymph Nodes/surgery , Medical Records/standards , Microscopy , Neoplasm, Residual/pathology , Prognosis , Sentinel Lymph Node Biopsy/methods , Specimen Handling/methods , Treatment Outcome , Tumor Burden/drug effectsABSTRACT
PURPOSE: Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. METHOD: This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient's outcome (relapse-free survival, RFS, and overall survival, OS). RESULT: Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS. CONCLUSION: The personalization of the patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.
Subject(s)
Breast Neoplasms/blood , Breast Neoplasms/mortality , Plasminogen Activator Inhibitor 1/blood , Urokinase-Type Plasminogen Activator/blood , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Clinical Decision-Making , Female , Humans , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Recurrence , Survival Analysis , Treatment OutcomeSubject(s)
Biomarkers, Tumor , Breast Neoplasms , Breast , Breast Neoplasms/diagnosis , Female , Humans , Staining and LabelingABSTRACT
Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Immunohistochemistry/methods , In Situ Hybridization/methods , Receptor, ErbB-2/analysis , Receptors, Steroid/analysis , Breast Neoplasms/pathology , Female , Fixatives , France , Histological Techniques , Humans , Prognosis , Quality Control , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Specimen Handling/methodsABSTRACT
International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Receptor, ErbB-2/analysis , Breast Neoplasms/drug therapy , False Negative Reactions , Female , France , Humans , Immunohistochemistry/methods , In Situ Hybridization , In Situ Hybridization, Fluorescence , Neoplasm Metastasis/pathology , Neoplasm Recurrence, Local , PrognosisSubject(s)
Biopsy, Large-Core Needle , Breast Neoplasms/pathology , Phyllodes Tumor/pathology , Breast Neoplasms/diagnosis , Breast Neoplasms/diagnostic imaging , Carcinoma/diagnosis , Carcinoma/pathology , Diagnosis, Differential , Epithelial Cells/ultrastructure , Female , Fibroadenoma/diagnosis , Humans , Magnetic Resonance Imaging , Middle Aged , Phyllodes Tumor/diagnosis , Phyllodes Tumor/diagnostic imagingABSTRACT
We report a case of solitary fibrous tumour (SFT) involving the posterior fossa in a fetus of 25 weeks' gestation. SFT is a rare mesenchymal neoplasm, arising in various locations including the meninges. After disclosure of severe ventriculomegaly and posterior fossa mass measuring 45 mm in diameter, termination of pregnancy was performed in accordance with French legislation. Our neuropathological study revealed a tumour covered by meninges, with severe compression of the cerebellum and the brain stem. Microscopically, the tumour was highly cellular, made of packed small fusiform cells with branching vasculature and consistent expression of CD34. No extraneurological lesion was noted. Except cysts and vascular malformations, posterior fossa tumours have been exceptionally reported in fetuses. SFT was distinguished from hemangiopericytoma. In spite of the fact these tumours share many similarities, some criteria such as the staining pattern for CD34 instead indicated a SFT. Histology was distinctive of hemangioblastoma and primitive neuroectodermal tumour. The prognosis of solitary fibrous tumour, which is usually a benign tumour, was there worsened by the precocity of the onset and the local invasion causing disruption of the cerebellum, compression of the brain stem and severe ventriculomegaly.
Subject(s)
Brain Neoplasms/pathology , Fetus/pathology , Solitary Fibrous Tumors/pathology , 12E7 Antigen , Antigens, CD/metabolism , Antigens, CD34/metabolism , Brain Neoplasms/metabolism , Cell Adhesion Molecules/metabolism , Female , Humans , Magnetic Resonance Imaging , Male , Pregnancy , Proto-Oncogene Proteins c-bcl-2/metabolism , Solitary Fibrous Tumors/metabolismABSTRACT
PEComa group is a heterogeneous group of rare mesenchymal tumors supposed to derive from perivascular cells and characterized by a coexpression of myogenic and melanocytic markers. We describe an 11-year-old female patient presenting a 2 cm ulcerated rectal polyp, exteriorized by anus, which was totally resected. Morphologically, this tumour was composed of cells arranged in nests or large cords separated by fibrous stroma, with abundant clear cytoplasms and with round regular small nuclei without atypia. There was no necrotic area and mitotic activity was very low. Immunohistochemically, the tumours cells stained for HMB45. Only 17 cases have been reported in literature and this case is the 18th. Here, we present a literature review focusing on both malignancy criteria and differential diagnosis.
Subject(s)
Perivascular Epithelioid Cell Neoplasms/pathology , Rectal Neoplasms/pathology , Child , Female , Humans , Polyps/pathologyABSTRACT
HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5-98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis.
ABSTRACT
Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
ABSTRACT
BACKGROUND: Inflammatory blood markers, such as neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), have been reported as putative prognostic factors for survival and predictive factors for pathological complete response and toxicity in cancers, however with conflicting results. METHODS: We retrospectively analyzed data of 280 patients with early breast cancer receiving neo-adjuvant chemotherapy between 2005 and 2013 in our center. Neutrophil count, lymphocyte count and platelet count before treatment were collected as well as data on pathological complete response, toxicity, recurrence and survival. RESULTS: In multivariate analysis, high PLR was an independent prognostic factor for relapse-free survival (hazard ratio [HR] = 1.91; 95%CI = 1.15-3.16; p = 0.012) and for shorter overall survival (HR = 1.83; 95%CI = 1.03-3.24; p = 0.039). NLR was an independent predictive factor for febrile neutropenia (HR = 0.28; 95%CI = 0.13-0.58; p = 0.001). In triple negative breast cancer molecular subtype, low white blood cell count (<6.75 G/L) was predictive for a higher pathological complete response rate (odds ratio [OR] = 0.29; 95%CI = 0.14-0.61; p < 0.01). CONCLUSION: In the present study, PLR was found as an independent prognostic factor for survival, while NLR was an independent predictive factor for febrile neutropenia.
ABSTRACT
Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.
Subject(s)
Antineoplastic Agents , Liposarcoma , Antineoplastic Agents/therapeutic use , Humans , Liposarcoma/drug therapy , Liposarcoma/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Serine/therapeutic use , Tumor Suppressor Protein p53/geneticsABSTRACT
The decision to administer adjuvant chemotherapy in treatment of early invasive breast cancer (EBC) is often complex, particularly for hormone receptor-positive (HR+) diseases, and current guidelines often classify these patients in an intermediate-risk group. Several biomarkers are currently available in this indication, in order to obtain additional and more accurate prognostic information compared to classic clinicopathological characteristics and guide the indication of adjuvant chemotherapy, optimizing the efficacy/toxicity ratio. We conducted a systematic review to evaluate the clinical validity and clinical utility of five biomarkers (uPA/PAI-1, OncotypeDX®, MammaPrint®, PAM50, and EndoPredict®) in HR+/HER2- EBC, whatever the nodal status. A total of 89 studies met the inclusion criteria. Even though data currently available confirm the clinical validity of these biomarkers, there is a lack of data regarding clinical utility for most of them. Prospective studies in well-defined populations are needed to integrate these biomarkers in a decision strategy.
ABSTRACT
Diagnostics of high-risk breast lesions have increased these last years with the augmentation of breast percutaneous biopsies. They are lesions that confer an enlarged risk of breast cancer, either because of an increased probability of finding cancer after open surgery, a possible evolution toward in situ or invasive cancer, or because of an increased probability of developing breast cancer over the long term. Much progress has been made these last years in their histological diagnostic, classification and pathogenesis. Nevertheless, no consensus exists to date on the management of these "high-risk" lesions. In particular, surgical indications and follow-up modalities remain controversial for each histological type. In this review, the principal factors that could impact surgical decision and long-term follow-up are discussed with areas of controversy highlighted.
Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/surgery , Breast/pathology , Precancerous Conditions/pathology , Age Factors , Biopsy , Calcinosis/diagnostic imaging , Carcinoma in Situ/pathology , Carcinoma in Situ/surgery , Carcinoma, Lobular/pathology , Carcinoma, Lobular/surgery , Cicatrix/etiology , Cicatrix/pathology , Epithelial Cells/pathology , Female , Humans , Hyperplasia/diagnostic imaging , Hyperplasia/pathology , Metaplasia/pathology , Papilloma, Intraductal/pathology , Papilloma, Intraductal/surgery , Population Surveillance , Precancerous Conditions/surgery , Radiation Injuries/etiology , Radiation Injuries/pathology , Radiation Injuries/surgery , Radiography , RiskABSTRACT
The management of pT1a-bN0M0 breast cancer remains an area of controversy. Data from 714 patients classified as having pT1a-bN0M0 breast cancer and treated, from 1999 to 2004 in the Languedoc-Roussillon France, were analyzed. The human epidermal growth factor receptor 2 (HER2) status analyses were centralized. The objective of this study was to describe the prognosis of pT1a-bN0M0 breast cancer according to HER2 distribution and hormonal status. The median follow-up was 6.4 years. Ten-year overall survival was 94%. HER2 overexpression was observed in 6.1% of the patients. The 10-year prognosis of patients with HER2-positive tumors was worse than that of those with HER2-negative (disease-free survival 73% vs. 89%, P < 0.0001). Tumor size (T1a/T1b) was not a relevant prognostic factor. The co-expression of HER2 with hormonal receptors (HR) was associated with high recurrence at 10 years. In both univariate and multivariate analyses, the most relevant prognostic factor for this population was HER2 amplification. In multivariate analysis, patients with HER2-positive tumors had higher risk of mortality (HR, 3.89; 95% CI, 1.58-9.56). In pT1a-bN0M0 breast cancers, HER2 amplification or overexpression is a risk factor for recurrence. In HER2-positive breast cancers, HR expression is associated with a poor prognosis despite the hormone therapy. For this population, a personalized management may be required.