<i>HER2</i>genetic heterogeneity in breast carcinoma

Öhlschlegel, Christian; Zahel, Katharina; Kradolfer, Doris; Hell, M.; Jochum, Wolfram

doi:10.1136/jclinpath-2011-200265

Cited by 94 publications

(52 citation statements)

References 21 publications

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“…Of note, HER2 heterogeneity was also frequently observed in cases with mean CEP17 copy numbers .3 (approximately 37%), as reported previously [13]. In diagnostic terms, this association may lead exponentially to troublesome interpretation of ISH results.…”

Section: Discussionsupporting

confidence: 72%

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

et al. 2014

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Section: Discussionsupporting

confidence: 72%

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

et al. 2014

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“…However, these same authors found that HER2 genetic heterogeneity according to the ASCO/CAP definition is most often present in breast carcinomas with an equivocal (2 þ ) HER2 score. 26 This correlates with our observation that patients who received an equivocal (2 þ ) HER2 score also tended to have the highest heterogeneity as well.…”

Section: Discussionsupporting

confidence: 87%

Evaluating tumor heterogeneity in immunohistochemistry-stained breast cancer tissue

Potts¹,

Krueger²,

Landis³

et al. 2012

Laboratory Investigation

110

101

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Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in evaluating patient therapeutic response and in identifying underlying issues in histopathology laboratory quality control. A heterogeneity scoring approach (HetMap) was designed to visualize a individual patient's immunohistochemistry heterogeneity in the context of a patient population. HER2 semiquantitative analysis was combined with ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). This approach was evaluated on HER2 immunohistochemistry-stained breast cancer samples using 200 specimens across two different laboratories with three pathologists per laboratory, each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines, H-score, and a new continuous HER2 score (HER2 cont ). Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cases where pathologists had disagreement over reads in the area of clinical importance ( þ 1 and þ 2) had statistically significantly higher levels of tumor-level heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region, while tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions. HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be used to identify tumors with differing degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues. Tumor heterogeneity plays a significant role in disconcordant reads between pathologists.

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“…Likewise, if 60 cells are examined and 3 or more cells have a ratio higher than 2.2, HER2 GH is present." Using this definition leads to substantially higher rates of HER2 heterogeneity by FISH ranging from 14% to 26% in breast cancers (47,48). However, use of the same definition in gastric cardia, GEJ, and esophagus adenocarcinomas demonstrated only 20 of 675 (2.9%) have HER2 genetic heterogeneity (42).…”

Section: Her2 Genomic Heterogeneitymentioning

confidence: 99%

HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib

Press

Ellis

Gagnon

et al. 2017

Molecular Cancer Therapeutics

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HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/ LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2.In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low.

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HER2genetic heterogeneity in breast carcinoma

Cited by 94 publications

References 21 publications

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

Evaluating tumor heterogeneity in immunohistochemistry-stained breast cancer tissue

HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib

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