HER2 heterogeneity | ScienceGate

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and clinically heterogeneous disease with a limited benefit from human epidermal growth factor receptor 2 (HER2)-targeted therapy. Recently, some studies have addressed the antitumoral effect of novel anti-HER2 drugs in HER2 low-expressing tumors. However, there have been few studies on the significance of low HER2 expression and genetic heterogeneity in PDAC. Using immunohistochemistry and dual-color silver-enhanced in situ hybridization based on the Trastuzumab for a gastric cancer scoring scheme, we evaluated HER2 protein expression, gene amplification, and genetic heterogeneity in three groups (HER2-neg, HER2-low, HER2-pos) of 55 patients. Among the 55 cases, 41.8% (23/55) showed HER2 expression of any intensity. HER2 amplification independent of HER2 expression was 25.5% (14/55). Patients in both these groups had a shorter overall survival than did patients in the HER2-neg group. HER2 genetic heterogeneity was identified in 37 (70.9%) of the 55 cases, mainly in HER2-neg and HER2-low groups. HER2 genetic heterogeneity significantly correlated with worse survival in the HER2-low and HER2-neg groups of PDAC. These findings support the hypothesis that low-level HER2 expression and heterogeneity have significant clinical implications in PDAC. HER2 heterogeneity might indicate the best strategies of combination therapies to prevent the development of subdominant clones with resistance potential.

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Prognostic implications of HER2 heterogeneity in gastric cancer

Oncotarget ◽

10.18632/oncotarget.24265 ◽

2018 ◽

Vol 9 (10) ◽

pp. 9262-9272 ◽

Cited By ~ 7

Author(s):

Shigenobu Motoshima ◽

Koji Yonemoto ◽

Hideki Kamei ◽

Michi Morita ◽

Rin Yamaguchi

Keyword(s):

Gastric Cancer ◽

Prognostic Implications ◽

Her2 Heterogeneity

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Intratumoral HER2 heterogeneity in early gastric carcinomas: potential bias in therapeutic management

Virchows Archiv ◽

10.1007/s00428-018-2502-2 ◽

2018 ◽

Vol 474 (3) ◽

pp. 401-402 ◽

Cited By ~ 2

Author(s):

Antonio Ieni ◽

Roberta Cardia ◽

Maria Lentini ◽

Giovanni Tuccari

Keyword(s):

Therapeutic Management ◽

Potential Bias ◽

Gastric Carcinomas ◽

Her2 Heterogeneity

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Abstract CS1-1: Origins and Clinical Implications of HER2 Heterogeneity

10.1158/1538-7445.sabcs19-cs1-1 ◽

2020 ◽

Author(s):

A Richardson

Keyword(s):

Clinical Implications ◽

Her2 Heterogeneity

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HER2 heterogeneity and resistance to anti-HER2 antibody-drug conjugates

Breast Cancer Research ◽

10.1186/s13058-020-1252-7 ◽

2020 ◽

Vol 22 (1) ◽

Cited By ~ 3

Author(s):

Alberto Ocaña ◽

Eitan Amir ◽

Atanasio Pandiella

Keyword(s):

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Her2 Heterogeneity ◽

Antibody Drug

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Significance of accurate HER2 testing as a new biomarker in advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.106 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 106-106

Author(s):

Tetsuya Kusumoto ◽

Hajime Ohtsu ◽

Hiroyuki Kawano ◽

Koji Ando ◽

Satoshi Ida ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Gastroesophageal Junction ◽

Tumor Biology ◽

Japanese Patients ◽

Her2 Expression ◽

Her2 Positive ◽

Her2 Testing ◽

Gastroesophageal Junction Cancer ◽

Her2 Heterogeneity

106 Background: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2)-positive advanced or recurrent gastric or gastroesophageal junction cancer, which demonstrated that trastuzumab plus chemotherapy improved overall survival in the overall population (hazard ratio 0.74). HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the standard criteria in Japanese patients with advanced gastric cancer (AGC) and to investigate the relationships between HER2 expression and therapeutic responses. Methods: A total of 199 tumor samples were assessed for HER2 expression both by immunohistochemistry (IHC) and HER2 amplification by fluorescence in situ hybridization (FISH). HER2-positive status was defined as IHC2+ and FISH-positive or IHC3+. Objective responses were evaluated in the patients with AGC who were treated with chemotherapy plus trastuzumab or chemotherapy alone based on the HER2 expression status. Results: HER2-positive tumors were identified in 12 patients (5.5%), less than 28.1% in the Japanese subgroup analyses of ToGA study. The positive rates varied with histological type; 14%, 5.3% and 0.95% in the well, moderately and poorly differentiated adenocarcinoma, respectively. Although high concordance between the results of IHC and FISH in all samples was found, IHC2+ samples retested here showed FISH-negative. Of all 10 patients with AGC, 3 patients with HER2-positive tumor were treated with capecitabine/cisplatin plus trastuzumab, and partial response was found in 2 cases; response rates were 67%. Conclusions: Specific consideration and scoring modification are required before embarking on HER2 testing in gastric cancer. Accurate and reliable HER2 testing and scoring will allow appropriate selection of patients eligible for treatment with trastuzumab.

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Mass spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: Comparison to IHC and FISH

10.1101/018747 ◽

2015 ◽

Author(s):

Daniel Catenacci ◽

Wei-Li Liao ◽

Lei Zhao ◽

Emma Whitcomb ◽

Les Henderson ◽

...

Keyword(s):

Cell Lines ◽

High Specificity ◽

Roc Curves ◽

Selected Reaction Monitoring ◽

Her2 Expression ◽

Multivariate Regression Model ◽

Her2 Positive ◽

Upper Level ◽

Her2 Heterogeneity

Abstract Background: Trastuzumab showed survival benefit for Her2-positive gastroesophageal cancers (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, both assays are low throughput with various limitations. Methods: We developed a selected reaction monitoring mass spectrometric (SRM-MS) assay and quantified levels (amol/ug) of Her2-SRM in cell lines (n=27) and GEC tissues (n=139). We compared Her2-SRM expression with IHC/FISH, seeking to determine optimal SRM expression cut-offs to identify HER2 amplification. Results: After demonstrating assay development, precision, and stability, Her2-SRM measurement was observed to be highly concordant with HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM-expression of Met, Egfr, Her3, and HER2-heterogeneity covariates, and their interactions (cell lines r2=0.9842; FFPE r2=0.7643). In GEC tissues, Her2-SRM was detected in 71.2% of cases, and 12.3% were identified as ‘HER2+’. ROC curves demonstrated HER2-SRM levels to have high specificity (100%) at an upper-level cut-off of >750 amol/µg and sensitivity (75%) at lower-level cut-off of <450 amol/ug. We observed an ‘equivocal-zone’ between 450-750 amol/ug, analogous to ‘IHC2+’, but less frequent (9-16% of cases versus 36-41%). Significance: Compared to IHC, SRM-MS provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer ‘equivocal’ cases. Along with the multiplex capability for other relevant oncoproteins, these results demonstrated a refined HER2 expression assay for clinical application.

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Adverse prognostic impact of heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma (EAC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4009 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4009-4009

Author(s):

Harry H. Yoon ◽

Qian Shi ◽

William R. Sukov ◽

Christopher A. Sattler ◽

Anne E. Wiktor ◽

...

Keyword(s):

Genetic Heterogeneity ◽

Multivariable Analysis ◽

Chromosome 17 ◽

Prognostic Impact ◽

Her2 Amplification ◽

Her2 Gene ◽

Digestive Cancer ◽

Cox Models ◽

Her2 Heterogeneity ◽

Risk Of Cancer

4009 Background: HER2 expression in upper digestive cancer is reported to be heterogeneous, which substantially affects interpretation of HER2 positivity in the clinic. Yet the frequency and prognostic impact of HER2 genetic heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: HER2 amplification (fluorescence in situ hybridization) and protein expression were examined in untreated surgical EAC specimens (N = 661) at Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as amplification (HER2/CEP17 ratio ≥ 2) in 5-50% of cancer cells; poly17 refers to ≥ 3 copies of chromosome 17. Most tumors were T3-4 (68%) or lymph node (LN)-positive (73%). Cox models were used to assess disease-specific (DSS) and overall survival (OS). Results: HER2 amplification was detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 heterogeneity. HER2 heterogeneous tumors had a significantly higher frequency of poly17 and high tumor grade. HER2 heterogeneity by amplification vs expression were correlated. Since heterogeneity was limited to HER2-amplified tumors, survival analysis was stratified by amplification status. In multivariable analysis, only HER2 heterogeneity and metastatic LN number were prognostic (Table). Conclusions: Among HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated with increased poly17 and independently predicts 2-fold higher risk of cancer-specific death. Among HER2-nonamplified cases, poly17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and evaluation of benefit from HER2 targeted therapy. [Table: see text]

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