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1.
Oncotarget ; 7(34): 54526-54536, 2016 Aug 23.
Article in English | MEDLINE | ID: mdl-27203738

ABSTRACT

BACKGROUND & AIMS: Less than 10% of registered drug intervention trials for pancreatic ductal adenocarcinoma (PDAC) include a biomarker stratification strategy. The ability to identify distinct mutation subsets via endoscopic ultrasound fine needle aspiration (EUS FNA) molecular cytology could greatly aid clinical trial patient stratification and offer predictive markers. We identified chemotherapy treatment naïve ampullary adenocarcinoma and PDAC patients who underwent EUS FNA to assess multigene mutational frequency and diversity with a surgical resection concordance assessment, where available. METHODS: Following strict cytology smear screening criteria, targeted next generation sequencing (NGS) using a 160 cancer gene panel was performed. RESULTS: Complete sequencing was achieved in 29 patients, whereby 83 pathogenic alterations were identified in 21 genes. Cytology genotyping revealed that the majority of mutations were identified in KRAS (93%), TP53 (72%), SMAD4 (31%), and GNAS (10%). There was 100% concordance for the following pathogenic alterations: KRAS, TP53, SMAD4, KMT2D, NOTCH2, MSH2, RB1, SMARCA4, PPP2R1A, PIK3R1, SCL7A8, ATM, and FANCD2. Absolute multigene mutational concordance was 83%. Incremental cytology smear mutations in GRIN2A, GATA3 and KDM6A were identified despite re-examination of raw sequence reads in the corresponding resection specimens. CONCLUSIONS: EUS FNA cytology genotyping using a 160 cancer gene NGS panel revealed a broad spectrum of pathogenic alterations. The fidelity of cytology genotyping to that of paired surgical resection specimens suggests that EUS FNA represents a suitable surrogate and may complement the conventional stratification criteria in decision making for therapies and may guide future biomarker driven therapeutic development.


Subject(s)
Adenocarcinoma/pathology , Ampulla of Vater , Common Bile Duct Neoplasms/pathology , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , High-Throughput Nucleotide Sequencing/methods , Pancreatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/therapy , Aged , Aged, 80 and over , Common Bile Duct Neoplasms/genetics , Common Bile Duct Neoplasms/therapy , Female , Genes, p53 , Humans , Male , Middle Aged , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Proto-Oncogene Proteins p21(ras)/genetics , Smad4 Protein/genetics , Pancreatic Neoplasms
2.
Gastrointest Endosc ; 84(6): 950-958.e3, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27118626

ABSTRACT

BACKGROUND AND AIMS: In an era of precision medicine, customized genotyping of GI stromal tumors by screening for driver mutations will become the standard of care. The fidelity of genotype concordance between paired cytology smears and surgical pathology specimens is unknown. In patients with either primary or metastatic sporadic disease, we sought to determine the frequency of KIT and PDGFRA pathogenic alterations within such specimens, imatinib sensitivity, and the concordance of pathogenic alterations between paired specimens. METHODS: DNA obtained from cytology smears from 36 patients, 24 of whom had paired surgical pathology specimens, underwent targeted next-generation sequencing by using a custom panel to evaluate somatic mutations within KIT (exon 2, 9, 10, 11, 13, 14, 15, 17, 18) and PDGFRA (exon 12, 14, 15, 18) genes. Patients with KIT and PDGRFA wild-type genes completed the Qiagen Human Comprehensive Cancer GeneRead DNAseq Targeted Array V2. RESULTS: Genotyping revealed KIT and PDGFRA mutations in 68% and 15% of patients. The wild-type population did not harbor mutations in BRAF, RAS family, SDHB, SETD2, or NF1. Imatinib sensitivity based on the oncogenic kinase mutation prevalence was estimated to be 68%. Mutational concordance between paired cytology and surgical pathology specimens was 96%. CONCLUSIONS: Our data have demonstrated the ability to stratify either primary or metastatic gastrointestinal stromal tumors by mutational subtype using a targeted next-generation sequencing 2 gene mutation panel. We highlight the ability to use cytology specimens obtained via minimally invasive techniques as a surrogate to surgical specimens given the high mutational landscape concordance between paired specimens.


Subject(s)
DNA, Neoplasm/analysis , Gastrointestinal Neoplasms/genetics , Gastrointestinal Stromal Tumors/genetics , Genotyping Techniques , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant , Cytogenetic Analysis , Drug Resistance, Neoplasm/genetics , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/therapy , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/therapy , High-Throughput Nucleotide Sequencing , Histone-Lysine N-Methyltransferase/genetics , Humans , Imatinib Mesylate/therapeutic use , Neurofibromin 1/genetics , Precision Medicine , Proto-Oncogene Proteins B-raf/genetics , Radiology, Interventional , Succinate Dehydrogenase/genetics , Tomography, X-Ray Computed , ras Proteins/genetics
3.
Am J Clin Pathol ; 143(6): 879-88, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25972331

ABSTRACT

OBJECTIVES: In an era of precision medicine, our aim was to determine the frequency and theranostic potential of mutations identified in malignant lymph nodes (LNs) sampled by endoscopic ultrasound fine-needle aspiration (EUS FNA) of patients with rectal cancer by targeted next-generation sequencing (NGS). METHODS: The NGS Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA) and MiSeq (Illumina, San Diego, CA) sequencers were used to sequence and assess for 2,800 or more possible mutations in 50 established cancer-associated genes. RESULTS: Among 102 patients, 89% had 194 pathogenic alterations identified in 19 genes. The identification of KRAS, NRAS, or BRAF mutations suggests that 42% are likely nonresponders to anti-epidermal growth factor receptor therapy. Among KRAS, NRAS, or BRAF wild-type patients, alterations in eight genes linked to alternative therapies were identified in 44%. CONCLUSIONS: Our data demonstrate the successful ability to apply a single multiplex test to allow multigene mutation detection from malignant LN cytology specimen DNA collected by EUS FNA.


Subject(s)
DNA Mutational Analysis/methods , Lymphatic Metastasis/genetics , Precision Medicine/methods , Rectal Neoplasms/genetics , Aged , Antineoplastic Agents/therapeutic use , Biopsy, Fine-Needle , Disease-Free Survival , Female , High-Throughput Nucleotide Sequencing , Humans , Lymphatic Metastasis/pathology , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Proctoscopy , Prognosis , Proportional Hazards Models , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Treatment Outcome
4.
Gastrointest Endosc ; 82(3): 550-6.e1, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25887718

ABSTRACT

BACKGROUND: Targeted next-generation sequencing has the potential to stratify a tumor by molecular subtype and aid the development of a biomarker profile for prognostic risk stratification and theranostic potential. OBJECTIVE: To assess the frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens. DESIGN: Multigene molecular profiling of archived malignant EUS-FNA lymph node cytology specimens using the Ion Ampliseq Cancer Hotspot Panel v2, which targets at least 2855 possible mutations within 50 cancer-associated genes. SETTING: Single tertiary referral center. PATIENTS: Sporadic, treatment naive, locally advanced primary rectal cancer by EUS-FNA (n = 76) who subsequently completed neoadjuvant therapy with on-site oncologic surgery. MAIN OUTCOME MEASUREMENTS: The frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens by the mitogen-activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K) signaling pathways, by KRAS or NRAS wild-type lymph node status, by extramesenteric lymph node status, and by a complete pathologic response status. RESULTS: Eleven patients (14.5%) were 50-gene panel wild-type. Sixty-five patients had 139 pathogenic alterations (2 [1-3] per patient) in 13 of 50 evaluated genes. The following represent a spectrum of identified alterations: TP53 (n = 52; 68.4%), APC (n = 36; 47.4%), KRAS (n = 22; 28.9%), FBXW7 (n = 8; 10.5%), NRAS (n = 6; 7.9%), PIK3CA (n = 4; 5.3%), SMAD4 (n = 3; 3.9%), and BRAF (n = 3; 3.9%). Pathogenic alterations were identified in the MAPK and PI3K signaling pathways in 41% and 5% of patients, respectively. LIMITATIONS: Findings were limited to a 50 cancer-associated gene analysis. CONCLUSIONS: Molecular EUS lymph node assessments using cancer "hotspot" panels can identify pathogenic alteration frequency and distribution and have theranostic potential for individualized patient care.


Subject(s)
Lymph Nodes/metabolism , Mitogen-Activated Protein Kinases/genetics , Phosphatidylinositol 3-Kinases/genetics , Rectal Neoplasms/genetics , Adenomatous Polyposis Coli Protein/genetics , Adult , Aged , Cell Cycle Proteins/genetics , Class I Phosphatidylinositol 3-Kinases , Endoscopic Ultrasound-Guided Fine Needle Aspiration , F-Box Proteins/genetics , F-Box-WD Repeat-Containing Protein 7 , Female , GTP Phosphohydrolases/genetics , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Membrane Proteins/genetics , Middle Aged , Neoplasm Staging , Precision Medicine , Proto-Oncogene Proteins p21(ras)/genetics , Rectal Neoplasms/pathology , Signal Transduction/genetics , Smad4 Protein/genetics , Theranostic Nanomedicine , Tumor Suppressor Protein p53/genetics , Ubiquitin-Protein Ligases/genetics
5.
J Thorac Oncol ; 10(3): 531-4, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25695224

ABSTRACT

Somatic serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) is a tumor suppressor gene and ranks as the third most frequently mutated gene in lung adenocarcinoma. However, current molecular testing guidelines recommend evaluating for epidermal growth factor receptor mutations and ALK fusions to guide therapy in all patients with advanced stage adenocarcinoma, regardless of gender, race, or smoking history. Identifying alternative "driver" mutations and using actionable targeted pharmacotherapy is a key approach to providing effective individualized medical care. The analytical sensitivity and parallel multigene approach of targeted next-generation sequencing is an attractive methodology for use for cytology specimens. The presented lung adenocarcinoma study revealed that STK11 mutations alone and concomitant KRAS/STK11 mutations were identified in 18.2% and 4.5% of solitary adrenal metastases, respectively. Molecular profiling of epidermal growth factor receptor tyrosine kinase inhibitor resistant tumors may help to identify patients who would most benefit from alternative single or dual pathway inhibition potentially leading to a revision in current molecular testing guidelines.


Subject(s)
Adenocarcinoma/genetics , Adrenal Gland Neoplasms/genetics , Lung Neoplasms/genetics , Mutation/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , AMP-Activated Protein Kinase Kinases , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adrenal Gland Neoplasms/mortality , Adrenal Gland Neoplasms/secondary , Aged , Aged, 80 and over , Female , Follow-Up Studies , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival Rate
6.
Clin Gastroenterol Hepatol ; 13(1): 202-6, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24997326

ABSTRACT

Gastric gastrointestinal stromal tumors (GISTs) usually contain the mast/stem cell growth factor receptor Kit gene (KIT) or platelet-derived growth factor receptor A (PDGFRA) mutations that can be targeted by, or mediate resistance to, imatinib. Diagnostic material often is obtained by endoscopic ultrasound-guided fine-needle aspiration, which often is unsuitable for molecular analysis. We investigated whether targeted next-generation sequencing (NGS) can be used in multiplex genotype analysis of cytology samples collected by endoscopic ultrasound-guided fine-needle aspiration. We used the Ion AmpliSeq V2 Cancer Hotspot NGS Panel (Life Technologies, Carlsbad, CA) to identify mutations in more than 2800 exons from 50 cancer-associated genes in GIST samples from 20 patients. We identified KIT mutations in 58% of samples (91% in exon 11 and 9% in exon 17) and PDGFRA mutations in 26% (60% in exon 18 and 40% in exon 12); 16% of samples had no mutations in KIT or PDGFRA. No pathogenic alterations were found in PIK3CA, BRAF, KRAS, NRAS, or FGFR3. We predicted that 32% of patients would have primary resistance to imatinib, based on mutations in exon 17 of KIT, exon 18 of PDGFRA (D842V), or no mutation in either gene. Targeted NGS of cytology samples from GISTs is feasible and provides clinically relevant data about kinase genotypes that can help guide individualized therapy.


Subject(s)
Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Stromal Tumors/pathology , Genotyping Techniques , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Adult , Aged , Aged, 80 and over , Biopsy, Fine-Needle , Female , Genotype , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged
7.
Cancer Cytopathol ; 122(11): 822-32, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25045116

ABSTRACT

BACKGROUND: Multigene molecular testing to guide personalized therapy for oncology patients is of increasing clinical relevance. Molecular testing of fine-needle aspiration samples is underused, but when acquired with minimally invasive techniques could become the standard of care to obtain theranostic specimens. The aims of the current study were to identify key cytology specimen selection criteria suitable for next-generation sequencing (NGS) and to determine the prevalence and spectrum of pathogenic alterations in a cohort of patients with AJCC stage IV lung cancer. METHODS: A total of 70 adrenal gland cytology specimens with direct smears were screened to identify 56 patients with a single slide containing at least 300 total cells and 20% tumor nuclei. After DNA extraction, the NGS protocols were used to simultaneously detect mutations in >2800 exonic regions in 50 key cancer genes. RESULTS: A total of 28 specimens produced acceptable NGS results. Specimens with a combined critical cell mass (>5000 viable cells) and a DNA concentration >5 ng/µL resulted in a 95% chance of successful sequencing. A total of 37 pathogenic alterations were identified in 10 genes and in 25 patients (85%). A pathogenic alteration (≥1) linked to available or developing targeted therapies was revealed in 50% of cases. CONCLUSIONS: The data from the current study demonstrate that theranostic NGS can be applied to adrenal gland metastasis using routine cytologic smear specimens. The characteristics of such smears could be evaluated during onsite adequacy assessment by cytopathology professionals. This model greatly augments the opportunity for customized genotype-directed therapy from minimally invasive techniques.


Subject(s)
Adrenal Gland Neoplasms/secondary , Lung Neoplasms/pathology , Lung/pathology , Adrenal Gland Neoplasms/drug therapy , Adrenal Gland Neoplasms/genetics , Aged , Aged, 80 and over , Cytodiagnosis/methods , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Female , Genetic Predisposition to Disease/genetics , High-Throughput Nucleotide Sequencing , Humans , Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Middle Aged , Molecular Targeted Therapy/methods , Mutation , Papanicolaou Test
8.
Diagn Cytopathol ; 42(12): 1063-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24866385

ABSTRACT

Transthoracic fine needle aspiration (TFNA)/core needle biopsy (CNB) under computed tomography (CT) guidance has proved useful in the assessment of pulmonary nodules. We sought to determine the TFNA false-negative (FN) rate at our institution and identify potential causes of FN diagnoses. Medical records were reviewed from 1,043 consecutive patients who underwent CT-guided TFNA with or without CNB of lung nodules over a 5-year time period (2003-2007). Thirty-seven FN cases of "negative" TFNA/CNB with malignant outcome were identified with 36 cases available for review, of which 35 had a corresponding CNB. Cases were reviewed independently (blinded to original diagnosis) by three pathologists with 15 age- and sex-matched positive and negative controls. Diagnosis (i.e., nondiagnostic, negative or positive for malignancy, atypical or suspicious) and qualitative assessments were recorded. Consensus diagnosis was suspicious or positive in 10 (28%) of 36 TFNA cases and suspicious in 1 (3%) of 35 CNB cases, indicating potential interpretive errors. Of the 11 interpretive errors (including both suspicious and positive cases), 8 were adenocarcinomas, 1 squamous cell carcinoma, 1 metastatic renal cell carcinoma, and 1 lymphoma. The remaining 25 FN cases (69.4%) were considered sampling errors and consisted of 7 adenocarcinomas, 3 nonsmall cell carcinomas, 3 lymphomas, 2 squamous cell carcinomas, and 2 renal cell carcinomas. Interpretive and sampling error cases were more likely to abut the pleura, while histopathologically, they tended to be necrotic and air-dried. The overall FN rate in this patient cohort is 3.5% (1.1% interpretive and 2.4% sampling errors).


Subject(s)
Thyroid Neoplasms/pathology , Thyroid Nodule/pathology , Adult , Aged , Biopsy, Fine-Needle/methods , Biopsy, Large-Core Needle , False Negative Reactions , Female , Humans , Male , Middle Aged
9.
Am J Clin Pathol ; 137(2): 270-6, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22261453

ABSTRACT

Image analysis of the HER2 immunohistochemical (IHC) stain can help determine which breast cancer patients may benefit from HER2-targeted therapy. We studied the concordance of HER2 IHC and fluorescence in situ hybridization (FISH) as well as reproducibility of surgical pathologist (SP) and cytotechnologist (CT) interpretations using manual and image analysis methodologies on 154 IHC cases. Concordances with FISH were good for IHC negative (0, 1+) cases (range, 97%-100%) and positive (3+) cases (range, 87%-100%). Image analysis had fewer equivocal (2+) results (10.4%) than CT (14.9%) and SP (16.2%) manual methods, with higher concordances to FISH (31%, 26%, and 20% for image analysis, CT manual, and SP manual, respectively). CT manual (κ = 0.747) and image analysis (κ = 0.779) methods had better interobserver reproducibility than SP manual (κ = 0.697). CT image analysis had better intraobserver reproducibility (κ = 0.882) than CT (κ = 0.828) and SP (κ = 0.766) manual methods. HER2 IHC analysis performed by image analysis can produce accurate results with improved reproducibility.


Subject(s)
Breast Neoplasms/diagnosis , Image Processing, Computer-Assisted/methods , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , DNA, Neoplasm/analysis , Female , Humans , Image Processing, Computer-Assisted/standards , In Situ Hybridization, Fluorescence , Middle Aged , Observer Variation , Reproducibility of Results , Retrospective Studies , Trastuzumab , Young Adult
10.
Diagn Cytopathol ; 40(10): 876-81, 2012 Oct.
Article in English | MEDLINE | ID: mdl-21433003

ABSTRACT

To examine the performance of our large pulmonary transthoracic fine needle aspiration/core biopsy (FNA/CB) practice over time, we performed a retrospective analysis of data from 333 consecutive procedures performed in 1996-1998 and 568 consecutive procedures performed in 2003-2005. Fluoroscopic guidance was performed more frequently in the earlier cohort, while a larger majority of procedures in the later cohort were by computed tomography (CT-guidance). A follow-up histologic diagnosis of cancer or clinical evidence of disease was considered the gold-standard. FNA/CB procedures during the later time period were performed on smaller lesions overall (3.60 cm versus 2.97 cm; P = 0.003) and malignant lesions also tended to be smaller (3.87 cm versus 3.14 cm; P = 0.006). Minimal improvements in sensitivity (94% versus 91%), specificity (99% versus 95%), diagnostic accuracy (95% versus 92%), negative predictive value (NPV) (80% versus 74%), and positive predictive value (PPV) (100% versus 99%) were noted during 2003-2005 when compared with 1996-1998 in all lesions. Larger improvements in sensitivity (94% versus 73%), diagnostic accuracy (95% versus 79%), and NPV (79% versus 50%) were identified in very small lesions (<1 cm) in the later patient cohort in comparison to the earlier patient cohort, as well as a significant decrease in total procedure complications. CT-guided transthoracic FNA/CB continues to be a very effective tool in our practice assessing lung lesions and performance has improved considerably at our institution for very small lesions.


Subject(s)
Biopsy, Fine-Needle/statistics & numerical data , Biopsy, Large-Core Needle/statistics & numerical data , Lung Diseases/pathology , Lung/pathology , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , Female , Humans , Image-Guided Biopsy/statistics & numerical data , Lung Diseases/diagnosis , Male , Middle Aged , Sensitivity and Specificity
11.
Mod Pathol ; 24(2): 277-87, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21076460

ABSTRACT

Minichromosome maintenance protein 7 (MCM7) is involved in replicative licensing and synthesis of DNA. It was previously identified as an overexpressed gene in high-grade serous carcinomas compared with serous borderline tumors of the ovary in cDNA microarray studies. In this study, we sought to validate MCM7 expression in 342 ovarian tumors on tissue microarrays. MCM7 expression was quantified as the MCM7 labeling index, and it was independently generated by two methods: a score provided by manual review of each sample by a pathologist observer and by an automated cellular imaging system. Analyses of MCM7 scores indicated a high degree of concordance and distribution between the observer- and machine-generated MCM7 labeling indexes. MCM7 expression was significantly higher in high-grade serous carcinomas than in serous borderline tumors or other histological subtypes of ovarian cancer. For both observer- and machine-derived scores, univariate analyses indicated the significant association of a high MCM7 labeling index with better progression-free survival in high-grade serous carcinomas. These results suggest the clinical importance of MCM7 expression in high-grade serous carcinomas of the ovary and the need for further evaluation of MCM7 as a potential prognostic factor in ovarian cancer.


Subject(s)
Cell Cycle Proteins/metabolism , Cystadenocarcinoma, Serous/metabolism , DNA-Binding Proteins/metabolism , Nuclear Proteins/metabolism , Ovarian Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Cell Count/methods , Cystadenocarcinoma, Serous/pathology , Disease-Free Survival , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Minichromosome Maintenance Complex Component 7 , Neoplasm Staging , Ovarian Neoplasms/pathology , Prognosis , Tissue Array Analysis
12.
Am J Clin Pathol ; 132(1): 133-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19864244

ABSTRACT

The goal of this study was to assess the performance characteristics of the Automated Cellular Imaging System (ACIS III) for HER2 immunohistochemical analysis. The study was performed on 187 biopsy slides from patients who underwent HER2 testing between January and February 2008. Three scoring methods by the ACIS III were compared with the manual score and fluorescence in situ hybridization (FISH) results for HER2 amplification. The equal distribution score (EQD) method, in which 2 areas each of high-, moderate-, and low-intensity staining were measured, most closely matched the FISH HER2 amplification result. The numbers of immunohistochemically negative (0 or 1+)/FISH+ cases were equivalent for all methods. The EQD method had significantly fewer 2+ cases (n = 16) (P < .001) vs the manual method (n = 35) and yielded a higher positive predictive value (38%) for HER2 amplification compared with the manual method (20%). The EQD method may more accurately identify FISH-amplified HER2 cases with fewer 2+ cases that would be "reflexed" to FISH compared with the manual method.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Image Processing, Computer-Assisted/methods , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , DNA, Neoplasm/analysis , Female , Gene Amplification , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Reproducibility of Results , Retrospective Studies , Young Adult
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