Genotypic Intratumoral Heterogeneity in Breast Carcinoma With HER2/neu Amplification

Abstract

We evaluated intratumoral heterogeneity of 30 ductal breast carcinomas with HER2/neu amplification, scored by the American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) criteria, and 3+ immunoexpression. High-grade (ratio > or =4.0) vs low-grade amplification (ratio >2.2 to <4.0) and chromosome 17 polysomy were also evaluated. On whole tissue sections, 20 tumors (67%) showed high-grade and 10 (33%) showed low-grade HER2/ neu amplification. Of 20 tumors with high-grade amplification, 14 (70%) showed no intratumoral genotypic heterogeneity; 6 (30%) showed at least 1 core with low-grade amplification. Of 10 cases with low-grade amplification, 6 (60%) showed no intratumoral heterogeneity; 4 (40%) showed chromosome 17 polysomy without gene amplification in 2 of 3 cores per case. Of 30 cases with gene amplification, 4 (13%) showed a "not-amplified pattern" in other parts of the tumor. The routine assessment of HER2/neu amplification using the ASCO/CAP criteria on whole tissue sections is not significantly confounded by intratumoral heterogeneity in breast cancer with high-grade amplification; however, genetic heterogeneity exists in a subset of breast carcinomas with low-grade amplification. The clinical relevance and impact on treatment outcome of intratumoral heterogeneity in breast cancer with low-grade HER2/neu amplification or chromosome 17 polysomy need further investigation.

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

“…16,21,22 Our results confirmed these findings. The frequency of HER2 regional heterogeneity or HER2 genetic heterogeneity was significantly higher in the cases with low grade or equivocal amplification in whole sections than in those with high-grade amplification.…”

“…8,13,14 Intratumoral heterogeneity of HER2 gene amplification has been demonstrated in a subset of breast cancers. [15][16][17][18][19][20][21][22][23] However, as the previous studies targeted different sets of samples, the frequency of intratumoral HER2 heterogeneity was quite variable and was not comparable between the studies. Andersson et al 15 found HER2 heterogeneity within the invasive components of breast cancers in only 1 of 78 tumors.…”

Serial Changes in Expression of Proteins in Response to Neoadjuvant Chemotherapy in Breast Cancer

“…In fact such an issue already exists with regard to Her2 testing by FISH; the clinical significance of genetic heterogeneity (i.e. in certain tumours, only a fraction of the cells are positive for the oncoprotein) of Her2 is still being investigated (84,161).…”

Intratumoral heterogeneity of HER2 status in breast carcinoma

“…Meistens wird unter intratumoraler HER2-Heterogenität die regionale Variation des HER2-Status in Tumorzellen des gleichen Karzinoms verstanden [1,2,4,5,6,8,9,13,14,16]. Unterschiede hinsichtlich des Vorliegens oder des Grades einer HER2-Genamplifikation werden auch als genetische HER2-Heterogenität bezeichnet.…”