Intratumoral heterogeneity of HER-2 gene amplification and protein overexpression in breast cancer

Wu, Julie M.; Halushka, Marc K.; Argani, Pedram

doi:10.1016/j.humpath.2009.10.022

Cited by 41 publications

(27 citation statements)

References 13 publications

(12 reference statements)

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“…Striebel et al 22 supported this idea by showing that the HER2 status of 10 (59%) of 17 breast cancers with equivocal HER2 amplification on core biopsy changed in the resection specimens, and they stressed the heterogeneity of gene amplification and protein expression in breast cancers with low HER2 gene copy numbers. Recently, Wu et al 38 reported a case of intratumoral heterogeneity of HER2 gene amplification, which showed HER2 gene amplification on core biopsy but not in metastases. In that case, only focal HER2 amplification was found in the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

et al. 2012

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Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. We used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. We examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections, and determined the clincopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification/negative or amplification/equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18%) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in 5-50% of the tumor cells, was found in 11 cases (11%), all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low grade or equivocal HER2 amplification and equivocal (2 þ ) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification, and this effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. In conclusion, intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression. Modern Pathology (2012) 25, 938-948;

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Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

et al. 2012

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“…[31][32][33][34][35] Moreover, aneuploidy of Chr17 and alterations of Cep17 represent indicators of genetic instability, which contributes to the progression of breast cancer through accumulation of genomic aberrations; discovery of recurrent DNA alterations 32 and of the genes that are deregulated by these aberrations will help to understand the mechanisms of breast cancer biology and lead to improvements in its diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 99%

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

Petroni

Addati²,

Mattioli³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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N Context.-Chromosome 17 polysomy has been identified in 5% to 50% of invasive breast cancers; even though a relationship with human epidermal growth factor receptor 2 (HER2/neu) status has been reported, other studies have shown that coincident centromere 17 (Cep17) amplification may be the cause of an overestimation of chromosome 17 polysomy in fluorescence in situ hybridization (FISH) testing.Objective.-To evaluate polysomy/amplification of Cep17 in invasive breast cancer with relation to proliferative activity (Ki-67), estrogen receptor, progesterone receptor, and HER2/neu status, in an attempt to identify a subgroup of patients with a worse prognosis.Design.-A total of 647 cases of invasive ductal breast cancer were collected and subjected to FISH analysis for HER2/neu gene and centromere 17 alteration, HercepTest for HER2/neu protein expression, and routine immunohistochemistry for Ki-67 and hormone receptor status.Results.-Copy number gain of Cep17 was observed in 27.3% of cases. Within this group, HER2/neu gene amplification was detected in 14.1% of cases, whereas HER2/neu expression was scored 3+ in 20.1% of cases; about half of the HER2/neu overexpressing cases (9.8%) did not show amplification by FISH. Moreover, 69% of polysomic cases showed high Ki-67 index.Conclusions.- (1) Centromere 17-altered cases are frequently HER2/neu overexpressing but not amplified, resulting in HercepTest/FISH disagreement; (2) HER2/neu amplification is seen at a higher incidence in cases without Cep17 copy number alterations, which are therefore not necessarily due to chromosome 17 disorder; (3) proliferation index is significantly higher in aneusomic tumors. These data suggest that the presence of Cep17 alterations could identify a subset of breast cancers with more aggressive biological and clinical behavior, which may show nonresponsiveness to conventional therapy independently of HER2/neu amplification status.

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“…The differences in HER-2 status found in core biopsy, mastectomy and metastasis specimens, and the heterogeneous HER-2 protein expression (HER-2 phenotypic heterogeneity, PH) found in a primary tumour from mastectomy specimen in the case described by Wu et al, 6 from this point of view, are paradigmatic.…”

Section: Her-2 Intratumoral Heterogeneitymentioning

confidence: 99%

“…Cases whose results are at or near the cutoff point and that, therefore, 'should be interpreted with caution', 3,6 can become a real interpretative nightmare. Furtheremore, we believe that also HER-2 PH should be taken into due consideration when reporting a HER-2 characterization test.…”

Section: Her-2 Intratumoral Heterogeneitymentioning

confidence: 99%

HER-2 intratumoral heterogeneity

et al. 2013

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Intratumoral heterogeneity of HER-2 gene amplification and protein overexpression in breast cancer

Cited by 41 publications

References 13 publications

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

HER-2 intratumoral heterogeneity

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