HER2gene status in primary breast cancers and matched distant metastases

Tapia, Coya; Savic, Spasenija; Wagner, Urs; Schönegg, René; Novotny, Hedvika; Grilli, Bruno; Herzog, Michelle; Barascud, Audrey; Zlobec, Inti; Cathomas, Gieri; Terracciano, Luigi; Feichter, Georg E.; Bubendorf, Lukas

doi:10.1186/bcr1676

Cited by 108 publications

(70 citation statements)

References 43 publications

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“…Comparative analyses of matched primary/metastatic colorectal tumors revealed >90% concordance of KRAS, BRAF, and PIK3CA mutations (15)(16)(17). In breast cancer, ERBB2 testing has been shown to be concordant between primary tumors and metastases in >90% of cases (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

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Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited effi cacy. A potential reason for the failure of such therapies is that genomic profi ling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, fi nding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed signifi cant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplifi cation profi les commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifi cations not detected in PT sampling. Lastly, we profi led paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profi ling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profi ling to enhance selection of therapy. SIGNIFICANCE:We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profi ling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1);[37][38][39][40][41][42][43][44][45][46][47][48]

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Section: Introductionmentioning

confidence: 99%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

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“…22,23 However, the pattern seen in breast cancer has not yet been fully confirmed in gastric carcinoma. 24 In the stomach, the frequency of immunohistochemistry 0/1 þ and fluorescence in situ hybridization (FISH)-positive gastric carcinoma is almost as high as that of immunohistochemistry 2 þ and FISH-positive samples (23% vs 27%), and ERBB2 expression, rather than ERBB2 amplification, is significantly correlated with longer overall survival.…”

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confidence: 99%

Heterogeneity of ERBB2 in gastric carcinomas: a study of tissue microarray and matched primary and metastatic carcinomas

Cho

Park

et al. 2013

Modern Pathology

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Trastuzumab in association with systemic cytotoxic chemotherapy is a therapeutic option for patients with advanced or metastatic ERBB2 þ gastric carcinoma. The status of the ERBB2 overexpression or gene amplification is an important predictive marker in gastric cancer. However, it is controversial whether the primary tumor is representative of distant metastases in terms of ERBB2 status. Quadruplicated tissue microarrays from formalin-fixed paraffin-embedded tissues from 498 advanced primary gastric carcinomas and 97 matched metastatic lymph nodes were investigated by immunohistochemistry with HercepTest and silver in situ hybridization. For further comparison, another set of 41 paired primary and distant metastatic gastric carcinomas were also tested. Intratumoral heterogeneity was defined as different results between tissue microarray cores. ERBB2-positivity was observed in 52 gastric carcinomas (10%) and was not associated with recurrence of disease or survival of patients. In ERBB2-positive primary gastric carcinomas, heterogeneous ERBB2 overexpression was observed in 21/63 (33%) gastric carcinomas and heterogeneous ERBB2 gene amplification in 14/62 (23%) cases. Repeated immunohistochemistry and silver in situ hybridization in representative paraffin tumor blocks confirmed focal ERBB2 overexpression and ERBB2 gene amplification and did not change the final results. Discrepancies in ERBB2 results between primary and paired metastatic lymph nodes were observed in 11% of cases by immunohistochemistry and 7% by silver in situ hybridization. Out of the 41 paired primary and distant metastases, 5 (12%) cases were ERBB2-positive, and discrepancy was observed in one case. Intratumoral heterogeneity and discrepant ERBB2 results in primary and metastatic tumor are not uncommon in gastric carcinoma. Results of silver in situ hybridization showed less frequent heterogeneity compared with immunohistochemistry. Wherever possible, ERBB2 immunohistochemistry testing should be performed in both primary and distant metastatic sites. The human protooncogene ERBB2 (commonly referred to as HER2) is a 185-kDa transmembrane tyrosine kinase receptor and a member of the epidermal growth factor receptor family. 1 Overexpression of ERBB2 has been found to promote tumorigenesis and is involved in the pathogenesis of several human cancers. Amplification of ERBB2 gene and overexpression of ERBB2 protein in gastric carcinoma were first described in 1986, and since then a number of studies have confirmed these findings. 2 There is growing evidence that ERBB2 is an important biomarker and key driver of tumorigenesis in gastric cancer, showing amplification or overexpression in 7-53% of tumors. 3-20 A recent

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“…Her2/neu overexpression is associated with a poor prognosis for breast, gastric, and ovarian cancer (4)(5)(6). On the basis of these characteristics, Her2/neu is an attractive therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

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HER2gene status in primary breast cancers and matched distant metastases

Cited by 108 publications

References 43 publications

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Heterogeneity of ERBB2 in gastric carcinomas: a study of tissue microarray and matched primary and metastatic carcinomas

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

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