Assessment of <i>HER2</i> gene status in breast carcinomas with polysomy of chromosome 17

Vranić, Semir; Teruya, Bryan; Repertinger, Susan; Ulmer, Pamela; Hagenkord, Jill; Gatalica, Zoran

doi:10.1002/cncr.25580

Cited by 74 publications

(46 citation statements)

References 30 publications

(40 reference statements)

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“…63 Single-nucleotide polymorphism karyotyping has also shown that true polysomy 17 is uncommon. 25 Collectively, these studies show that elevated CEP17 copy number is not a useful surrogate for polysomy 17 and that most cases previously assigned 'polysomic' status actually represent focal pericentromeric gains.…”

Section: Polysomy 17 and Response To Anti-her2 Therapymentioning

confidence: 95%

“…However, other studies have associated elevated CEP17 count ('polysomy'), particularly high CEP17 counts (CEP17 Z4), with IHC 3 þ staining. 25,47,52 In one series, 17 of 150 (9.8%) polysomic, HER2-nonamplified tumors showed positive (3 þ ) immunohistochemistry staining compared with 6 of 247 (1.5%) eusomic, HER2-nonamplified cases. 52 Others have found no evidence that elevated CEP17 count ('polysomy') contributes to HER2 overexpression.…”

Section: Polysomy 17 and Her2 Overexpressionmentioning

confidence: 99%

“…Nonetheless, these are important issues, as elevated CEP17 count ('polysomy') is frequently reported in breast cancer 23 and is a major reason for discordant ISH status, depending on whether mean HER2 copy number or HER2:CEP17 ratio is used. 24,25 Some have argued that correction for chromosome 17 copy number is essential for accurately defining HER status, 19,24 but others have questioned this view. 26,27 Currently, there is no consensus on whether or how elevated CEP17 count ('polysomy') should be integrated into HER2 test interpretation.…”

Section: Polysomy 17mentioning

confidence: 99%

“…The biological impact of such changes in genome organization may be rather heterogeneous, in line with contradictory reports of the correlation between apparent chromosome 17 polysomy and HER2 overexpression. [24][25][26] As a result, it may be important to obtain additional information on the HER2 locus and its expression profile at the mRNA and protein levels, going beyond the limited information that is provided by FISH using only two probes.…”

Section: Polysomy 17 and Her2 Overexpressionmentioning

confidence: 99%

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HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Hanna

Rüschoff²,

Bilous³

et al. 2014

Modern Pathology

249

201

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Trastuzumab-containing therapy is a standard of care for patients with HER2 þ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity.

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Section: Polysomy 17 and Response To Anti-her2 Therapymentioning

confidence: 95%

Section: Polysomy 17 and Her2 Overexpressionmentioning

confidence: 99%

Section: Polysomy 17mentioning

confidence: 99%

Section: Polysomy 17 and Her2 Overexpressionmentioning

confidence: 99%

See 2 more Smart Citations

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Hanna

Rüschoff²,

Bilous³

et al. 2014

Modern Pathology

249

201

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“…Finally, even the objectivity of FISH has been questioned. Abnormalities of chromosome 17 are frequent in breast cancer, and the measurement of ERBB2 gene status depends on the criteria used, a ratio of the ERBB2 copy number to the chromosome 17 centromere enumerating probe number (i.e., the HER2/CEP17 ratio) Ն2.0, a ratio Ն2.2, or a mean ERBB2 copy number Ն6.0; however, some tumors that show ERBB2 gene amplification according to an ERBB2 gene copy number Ͼ6 do not exhibit amplification according to the ERBB2/ CEP17 ratio (6 ). The rationale for assessing amplification status as a ratio to the centromeric region was to compensate for potential polysomy; however, detailed chromosomal analysis by comparative genomic hybridization and single-nucleotide polymorphism arrays have demonstrated that chromosome 17 polysomy is a rare event in breast cancer (7,8 ).…”

mentioning

confidence: 99%

Counterpoint: Both Immunohistochemistry and Fluorescence In Situ Hybridization Play Important Roles for HER2 Evaluation

Bloom

Côté

2011

Clinical Chemistry

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Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric cancers that overexpress human growth factor receptor 2 (HER2) 3 . Since its approval, controversy has existed over whether immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) is the best method for assessing HER2 status. Proponents of IHC point out that trastuzumab targets the HER2 protein molecule, which is assessed directly by IHC, and that the original "clinical trial assay" [and the basis of US Food and Drug Administration (FDA) clearance for the drug] was IHC. Proponents of FISH argue that IHC is more prone to technical issues (fixation, subjective interpretation, lack of proper controls on the actual procedure) and that evaluation by FISH is more objective. Although it is clear that most cases of invasive breast cancer show a direct correlation between amplification of the ERBB2 gene [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian); also known as HER2] and overexpression of HER2 protein, IHC and FISH are complementary tests and examine different aspects of the biology of HER2-driven cancer.The accuracy of HER2 testing has generated substantial interest, especially given the poor concordance of HER2 testing results in clinical trials (1, 2 ). For example, 2 of the adjuvant clinical trials for HER2-positive breast cancer [NCCTG (North Central Cancer Treatment Group) N9831 and NSABP (National Surgical Adjuvant Breast and Bowel Project) B31] enrolled patients on the basis of a positive HER2 test result from a local laboratory, but retesting by the central laboratory revealed a negative result by both IHC and FISH in approximately 20% of the patients. These patients were still enrolled in the adjuvant trials and surprisingly demonstrated hazard ratios similar to those of patients tested as positive by IHC and FISH in the central laboratory. These findings imply that any positive test result may be predictive of benefit from trastuzumab therapy in the adjuvant setting.Contrary to widespread belief, discordance in FISH interpretations may be as common as for IHC. A recent report from the NCCTG N9831 trial (3 ) described a study in which 3 expert pathologists performed independent reads of 381 IHC samples and 373 FISH samples and obtained the same discordance rates (8%) for both IHC and FISH, even after technical standardization. These results highlight the inherent limitations of both techniques. The similar discordances between FISH and IHC are not surprising, because FISH is also subject to such preanalytical variables as cold ischemia time, type of fixative, and length of fixation, as well as analytical variables. Samples fixed in Prefer, HistoChoice, UNIFIX, and GTF, as well as delay in fixation, were associated with absent or technically compromised FISH staining (4, 5 ). Furthermore, FISH analysis is only as good as the cells that are analyzed, and identifying the invasive tumor cells can be challenging, given the presence...

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Impact of an alternative chromosome 17 probe and the 2013 American Society of Clinical Oncology and College of American Pathologists guidelines on fluorescence in situ hybridization for the determination of HER2 gene amplification in breast cancer

Donaldson

Shetty

Wang

et al. 2017

Cancer

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Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

Cited by 74 publications

References 30 publications

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Counterpoint: Both Immunohistochemistry and Fluorescence In Situ Hybridization Play Important Roles for HER2 Evaluation

Impact of an alternative chromosome 17 probe and the 2013 American Society of Clinical Oncology and College of American Pathologists guidelines on fluorescence in situ hybridization for the determination of HER2 gene amplification in breast cancer

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