scholarly journals Double-Equivocal HER2 Invasive Breast Carcinomas: Institutional Experience and Review of Literature

2018 ◽  
Vol 142 (12) ◽  
pp. 1511-1516 ◽  
Author(s):  
Brannan B. Griffin ◽  
Jennifer L. Pincus ◽  
Kalliopi P. Siziopikou ◽  
Luis Z. Blanco
Keyword(s):  
Chromosome 17 ◽  
Her2 Status ◽  
Breast Carcinomas ◽  
Her2 Positive ◽  
Close Proximity ◽  
Reference Probe ◽  
Institutional Experience ◽  
Reflex Testing ◽  
Invasive Breast Carcinomas ◽  
American Society

Context.— HER2 status is a prognostic factor and therapeutic target in invasive breast carcinomas. Reflex testing using an alternate method is recommended on equivocal cases via immunohistochemistry or fluorescence in situ hybridization (FISH). Therapeutic dilemmas arise when both tests are equivocal. The standard chromosome 17 centromere reference probe (CEP17) is in close proximity to the HER2 locus and may be coamplified, leading to equivocal results. Alternate chromosome 17 reference probes may aid in establishing the true HER2 status. Objective.— To describe our institutional experience using D17S122 probe for reflex FISH testing on double-equivocal invasive breast carcinomas and review the literature on alternate reference probes. Data Sources.— Twenty-two patients with double-equivocal invasive breast carcinomas, defined as HER2 immunohistochemistry score 2+ and FISH equivocal per the 2013 guidelines, were reviewed. Reflex FISH was performed with alternate probe D17S122 and the HER2 status classified for 11 cases by using a revised HER2:D17S122 ratio. Seven of 11 cases (63.6%) were ultimately classified as HER2 positive, while 4 cases (36.4%) remained equivocal. The 7 positive cases showed a HER2:D17S122 greater than 2.0. Conclusions.— Alternate probe D17S122 reclassified more than half of our cases as HER2 positive. Alternate probes may establish true HER2 status and direct proper management, as evidenced by our experience and the literature. Additional investigation is needed to determine which alternate probe(s) is(are) best for reflex testing. Finally, the American Society of Clinical Oncology/College of American Pathologists guidelines may need to be updated to reflect more specific recommendations for the utilization of appropriate probes in double-equivocal HER2 cases.

HER2 genetic heterogeneity in breast carcinoma

2011 ◽  
Vol 64 (12) ◽  
pp. 1112-1116 ◽  
Author(s):  
Christian Öhlschlegel ◽  
Katharina Zahel ◽  
Doris Kradolfer ◽  
Margreth Hell ◽  
Wolfram Jochum
Keyword(s):  
Breast Carcinoma ◽  
Genetic Heterogeneity ◽  
Gene Clusters ◽  
Clinicopathological Characteristics ◽  
Receptor Expression ◽  
Chromosome 17 ◽  
Clinicopathological Parameters ◽  
Breast Carcinomas ◽  
Invasive Breast Carcinomas ◽  
American Society

AimsTo determine the frequency of HER2 genetic heterogeneity according to the recent American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) definition (2009) in invasive breast carcinoma, and to identify clinicopathological features that characterise breast carcinomas with HER2 genetic heterogeneity.Methods530 invasive breast carcinomas were retrospectively analysed for HER2 genetic heterogeneity, and investigated for a potential association of HER2 genetic heterogeneity with other HER2 FISH findings, clinicopathological parameters, oestrogen/progesterone receptor expression and DNA cytometric parameters in breast carcinomas with an equivocal (2+) HER2 immunohistochemical score.ResultsThe overall frequency of HER2 genetic heterogeneity was 14.7% in a cohort of 218 consecutive breast carcinomas. HER2 genetic heterogeneity was most frequent in invasive breast carcinomas with an equivocal (2+) HER2 immunohistochemical score. Among the 151 carcinomas lacking HER2 amplification, 16.1% showed HER2 genetic heterogeneity. In an extended cohort of 345 carcinomas with a (2+) HER2 score, the frequency of HER2 genetic heterogeneity was 41%, and was associated with the absence of HER2 gene clusters, chromosome 17 polysomy, histological tumour grade, DNA ploidy category and 5c exceeding rate.ConclusionHER2 genetic heterogeneity according to the ASCO/CAP definition is frequent in breast carcinoma, and is most often present in carcinomas with an equivocal (2+) HER2 score. Many carcinomas with HER2 genetic heterogeneity have a negative HER2 amplification status, although they contain a significant number of tumour cells with HER2 gene amplification. Single cell scoring of the HER2/17 centromeric probe (CEP17) ratio is necessary to identify carcinomas with HER2 genetic heterogeneity, because they lack specific clinicopathological characteristics.

A Retrospective Population-Based Comparison of HER2 Immunohistochemistry and Fluorescence In Situ Hybridization in Breast Carcinomas: Impact of 2007 American Society of Clinical Oncology/ College of American Pathologists Criteria

2013 ◽  
Vol 138 (2) ◽  
pp. 213-219 ◽  
Author(s):  
Kurt A. Schalper ◽  
Sudha Kumar ◽  
Pei Hui ◽  
David L. Rimm ◽  
Peter Gershkovich
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Clinical Oncology ◽  
Scoring Systems ◽  
Population Based ◽  
Breast Carcinomas ◽  
Her2 Testing ◽  
Invasive Breast Carcinomas ◽  
American Society

Context.—In 2007 the American Society of Clinical Oncology/College of American Pathologists made new recommendations for HER2 testing and redefined HER2 positivity. Objective.—To analyze results from simultaneous HER2 testing with immunohistochemistry and fluorescence in situ hybridization (FISH) in 2590 invasive breast carcinomas between 2002 and 2010, using 2 scoring systems. Design.—Cases from between 2002 and 2006 were scored by using original US Food and Drug Administration criteria (N = 1138) and those from between 2007 and 2010 were evaluated according to American Society of Clinical Oncology/College of American Pathologists criteria (N = 1452). Concordance between testing methods and clinicopathologic associations were determined. Results.—Overall concordance between immunohistochemistry/FISH in the 9-year period was 96.2% (κ = 0.82), and positive concordance was lower. After 2007, the proportion of HER2/neu-positive and HER2/neu-negative cases was not significantly changed when using immunohistochemistry (10.5% versus 8.9%, P = .22 and 69.4% versus 63%, P = .13, respectively), but the number of equivocal cases was higher (19.9% versus 28%, P < .001). While the proportion of negative cases by FISH remained unchanged after 2007 (86.5% versus 88.2%, P = .76), the number of positive cases was lower (13.4% versus 9.2%, P < .001). In addition, 38 cases (2.6%) were FISH equivocal, 16 of which were also equivocal by immunohistochemistry. Overall, immunohistochemistry/FISH concordance was 95.9% between 2002 and 2006 (κ = 0.82) and 96.4% after 2007 (κ = 0.82). However, an approximately 13% lower positive assay concordance was noted in the last period. Conclusions.—Application of American Society of Clinical Oncology/College of American Pathologists recommendations is associated with comparable overall immunohistochemistry/FISH concordance, reduced positive concordance, and increased equivocal results.

scholarly journals Outcome of HER2 Testing by FISH applying ASCO/CAP 2007 and 2013 guideline in IHC equivocal group of breast cancer: Experience at tertiary cancer care centre

2017 ◽  
Vol 06 (02) ◽  
pp. 045-046
Author(s):  
Manoj Kumar Panigrahi ◽  
Dushyant Kumar ◽  
Anurag Mehta ◽  
Kandarpa Kumar Saikia
Keyword(s):  
Breast Cancer ◽  
Final Analysis ◽  
Chromosome 17 ◽  
Research Centre ◽  
Her2 Status ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Polysomy 17 ◽  
Cancer Experience ◽  
The Impact

Abstract Background and Objectives: HER2 testing guideline of ASCO/CAP for interpretation and reporting has recently been revised. The study is aimed to measure the impact of 2013 CAP guideline on equivocal HER2 test outcome (immunohistochemistry [IHC] 2+) when tested by fluorescent in situ hybridization (FISH). The study also aims at finding the frequency of polysomy and monosomy of chromosome 17. Materials and Methods: Specimens were collected in Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India. IHC was performed in every case, and FISH was performed in IHC2+ cases. Results: In final analysis includes 557 subjects on the basis of CAP guideline 2007 and CAP guideline 2013. One hundred ninety-two subjects (34.4%) were HER2 amplified according to CAP scoring 2007, and 246 subjects (44%) according to 2013 CAP scoring. Conclusions: FISH results were evaluated (IHC2 + interpreted according to CAP 2007 guideline) with both 2007 and 2013 ASCO/CAP scoring criteria, we identified significantly more HER2 positive cases as compared to cases evaluated using the 2007 criteria (P < 0.05). We also found that in breast carcinoma, HER2 status in the presence of polysomy 17 may vary with the scoring criteria used. Evaluation of FISH result using 2013 ASCO/CAP criteria means that more patients with breast cancer may be appropriate for targeted treatment with trastuzumab, potentially improving their outcome.

scholarly journals Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor–Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint

2017 ◽  
Vol 3 (4) ◽  
pp. 314-322 ◽  
Author(s):  
Ettienne J. Myburgh ◽  
Lizanne Langenhoven ◽  
Kathleen A. Grant ◽  
Lize van der Merwe ◽  
Maritha J. Kotze
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Molecular Subtype ◽  
Chromosome 17 ◽  
Her2 Status ◽  
Luminal A ◽  
Her2 Positive ◽  
Molecular Subtyping ◽  
Predictive Values ◽  
Her2 Positivity

Purpose Human epidermal growth factor receptor 2 (HER2) positivity is an important prognostic and predictive indicator in breast cancer. HER2 status is determined by immunohistochemistry and fluorescent in situ hybridization (FISH), which are potentially inaccurate techniques as a result of several technical factors, polysomy of chromosome 17, and amplification or overexpression of CEP17 (centromeric probe for chromosome 17) and/or HER2. In South Africa, HER2-positive tumors are excluded from a MammaPrint (MP; Agendia BV, Amsterdam, Netherlands) pretest algorithm. Clinical HER2 status has been reported to correlate poorly with molecular subtype. The aim of this study was to investigate the correlation of clinical HER2 status with BluePrint (BP) molecular subtyping. Methods Clinico-pathologic and genomic information was extracted from a prospectively collected central MP database containing records of 256 estrogen receptor–positive and/or progesterone receptor–positive tumors. Twenty-one tumors considered HER2 positive on immunohistochemistry or FISH were identified for this study. Results The median age of patients was 56 years (range, 34 to 77 years), with a median tumor size of 16 mm (3 to 27 mm). Four (19%) tumors were confirmed HER2-enriched subtype, six (29%) were luminal A, and 11 (52%) were luminal B. The positive predictive values of HER2/CEP17 ratio ≥ 2 and HER2 copy number ≥ 6 were only 29% and 40%, respectively. The differences in means for HER2/CEP17 ratio were significant between BP HER2-enriched versus luminal ( P = .0249; 95% CI, 0.12 to 1.21) and MP high-risk versus low-risk tumors ( P = .0002; 95% CI, 0.40 to 1.06). Conclusion Of the 21 tumors considered clinically HER2 positive, only four were HER2-enriched subtype with BP, indicating an overestimation of HER2 positivity. FISH testing has a poor positive predictive value.

scholarly journals Clinical relevance and concordance of HER2 status in local and central testing—an analysis of 1581 HER2-positive breast carcinomas over 12 years

2017 ◽  
Vol 31 (4) ◽  
pp. 607-615 ◽  
Author(s):  
Berit M Pfitzner ◽  
Bianca Lederer ◽  
Judith Lindner ◽  
Christine Solbach ◽  
Knut Engels ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Her2 Status ◽  
Breast Carcinomas ◽  
Her2 Positive

scholarly journals Single HER2-positive tumor cells are detected in initially HER2-negative breast carcinomas using the DEPArray™–HER2-FISH workflow

Breast Cancer ◽  
2022 ◽  
Author(s):  
Lisa Grüntkemeier ◽  
Aditi Khurana ◽  
Farideh Zamaniyan Bischoff ◽  
Oliver Hoffmann ◽  
Rainer Kimmig ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Validation Cohort ◽  
Single Cells ◽  
Chromosome 17 ◽  
Antigen Retrieval ◽  
Her2 Status ◽  
Fish Analysis ◽  
Cell Recovery ◽  
Her2 Positive ◽  
Ffpe Tumor

Abstract Background In breast cancer (BC), overexpression of HER2 on the primary tumor (PT) is determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to stratify samples as negative, equivocal and positive to identify patients (pts) for anti-HER2 therapy. CAP/ASCO guidelines recommend FISH for analyzing HER2/neu (ERBB2) gene amplification and for resolving equivocal HER2 IHC results. However, pre-analytical and analytical aspects are often confounded by sample related limitations and tumor heterogeneity and HER2 expression may differ between the PT and circulating tumor cells (CTCs), the precursors of metastasis. We used a validation cohort of BC patients to establish a new DEPArray™-PT-HER2-FISH workflow for further application in a development cohort, characterized as PT-HER2-negative but CTC-HER2/neu-positive, to identify patients with PT-HER2 amplified cells not detected by routine pathology. Methods 50 µm FFPE tumor curls from the validation cohort (n = 49) and the development cohort (n = 25) underwent cutting, deparaffinization and antigen retrieval followed by dissociation into a single-cell suspension. After staining for cytokeratin, vimentin, DAPI and separation via DEPArray™, single cells were processed for HER2-FISH analysis to assess the number of chromosome 17 and HER2 loci signals for comparison, either with available IHC or conventional tissue section FISH. CTC-HER2/neu status was determined using the AdnaTest BreastCancer (QIAGEN, Hilden, Germany). Results Applying CAP/ASCO guidelines for HER2 evaluation of single PT cells, the comparison of routine pathology and DEPArray™-HER2-FISH analysis resulted in a concordance rate of 81.6% (40/49 pts) in the validation cohort and 84% (21/25 pts) in the development cohort, respectively. In the latter one, 4/25 patients had single HER2-positive tumor cells with 2/25 BC patients proven to be HER2-positive, despite being HER2-negative in routine pathology. The two other patients showed an equivocal HER2 status in the DEPArray™-HER2-FISH workflow but a negative result in routine pathology. Whereas all four patients with discordant HER2 results had already died, 17/21 patients with concordant HER2 results are still alive. Conclusions The DEPArray™ system allows pure tumor cell recovery for subsequent HER2/neu FISH analysis and is highly concordant with conventional pathology. For PT-HER2-negative patients, harboring HER2/neu-positive CTCs, this approach might allow caregivers to more effectively offer anti-HER2 treatment.

Clinicopathologic Features of Unexpectedly HER2 Positive Breast Carcinomas: An Institutional Experience

2021 ◽  
pp. 153441
Author(s):  
Carissa LaBoy ◽  
Kalliopi P. Siziopikou ◽  
Lauren Rosen ◽  
Luis Z. Blanco ◽  
Jennifer L. Pincus
Keyword(s):  
Clinicopathologic Features ◽  
Breast Carcinomas ◽  
Her2 Positive ◽  
Institutional Experience

scholarly journals Utility of Alternate, Noncentromeric Chromosome 17 Reference Probe for Human Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization Testing in Breast Cancer Cases

2018 ◽  
Vol 142 (5) ◽  
pp. 626-633 ◽  
Author(s):  
Trupti Pai ◽  
Tanuja Shet ◽  
Asawari Patil ◽  
Omshree Shetty ◽  
Angad Singh ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
In Situ Hybridization ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Chromosome 17 ◽  
Her2 Status ◽  
Breast Cancers ◽  
Reference Probe ◽  
Epidermal Growth

Context PathVysion—a US Food and Drug Administration–approved dual-probe human epidermal growth factor receptor (HER2) fluorescence in situ hybridization (FISH) assay—provides the HER2:CEP17 ratio, a centromeric enumeration probe ratio for determining HER2 status in breast cancers. However, pericentromeric amplifications might then skew the HER2:CEP17 ratio, underestimating the HER2 status, which calls into question the use of CEP17 as the reference probe. Objective To analyze the utility of a noncentromeric chromosome 17 reference locus (D17S122) to assess HER2 gene status in cases showing “nonclassical” FISH patterns with the CEP17 probe. Design The HER2 status of breast cancers accessioned in the years 2015–2017, displaying “nonclassical” or “equivocal” results by the PathVysion (Abbott Molecular Inc, Des Plaines, Illinois) HER2 DNA Probe Kit were reflex tested using an alternate FISH probe (ZytoLight SPEC/D17S122, ZytoVision, Bremerhaven, Germany) and interpreted with American Society of Clinical Oncology/College of American Pathologists 2013 guidelines. Results Of 37 cases, 17 were FISH equivocal. With the alternate D17S122 probe, 13 (76.4%) were reclassified as amplified, 3 (17.6%) as nonamplified, and a single case retained an equivocal result. Of the 17 cases with a chromosome 17 polysomy pattern, disomy, polysomy, and monosomy patterns were seen with 14 cases, 2 cases, and 1 case, respectively. Within the 17 cases with polysomy pattern, 3 (17.6%) demonstrated an unusual colocalization pattern of HER2 and CEP17, which was not observed with the alternate probe. Conclusions The denominator-stable alternate probe is a useful adjunct in the diagnostic armamentarium to analyze HER2 status in cases with FISH equivocal and complex patterns.

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