HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer.
OBJECTIVE
Heterogeneity of HER2 gene amplification is found in a subset of breast cancers. We investigated the impact of HER2 heterogeneity on trastuzumab responses and clinical outcomes in 112 patients with HER2-positive metastatic breast cancer.


METHODS
Regional and genetic heterogeneity of HER2 gene amplification was determined in three different areas of each tumor by immunohistochemistry and silver in situ hybridization. We also assessed the overall levels of HER2 amplification and the proportion of tumor cells with a HER2/CEP17 ratio of more than 2.2 or strong and complete membranous (3+) expression of HER2 protein.


RESULTS
HER2 regional and genetic heterogeneity based on the HER2/CEP17 ratio was confirmed in 8.7% and 2.7% of cases, respectively. Poor response to trastuzumab was associated with overall low-level or equivocal amplification, HER2 regional heterogeneity by the HER2/CEP17 ratio, the HER2/CEP17 ratio of more than 2.2 in less than 80% of tumor cells, and HER2 immunohistochemical expression of 3+ in less than 75% of tumor cells. In survival analyses, low-level or equivocal HER2 amplification, HER2 regional heterogeneity based on the HER2/CEP17 ratio, and the HER2/CEP17 ratio of more than 2.2 in less than 80% of tumor cells were associated with shorter time to progression and lower overall survival in univariate and multivariate analyses.


CONCLUSIONS
These results suggest that accurate assessment of HER2 status, including HER2 heterogeneity, is important in predicting trastuzumab responses and outcomes in patients with HER2-positive metastatic breast cancer.
From the Departments of Pathology and Departments of Pathology and.
Hee Jin
HJ
Lee
From the Departments of Pathology and.
An Na
AN
Seo
From the Departments of Pathology and.
Eun Joo
EJ
Kim
From the Departments of Pathology and.
Min Hye
MH
Jang
Medical Oncology, Seoul National University Hospital, Seoul, South Korea;
Koung Jin
KJ
Suh
Departments of Pathology and.
Han Suk
HS
Ryu
Medical Oncology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, South Korea; Medical Oncology, Seoul National University College of Medicine, Seoul, South Korea; and.
Yu Jung
YJ
Kim
Medical Oncology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, South Korea; Medical Oncology, Seoul National University College of Medicine, Seoul, South Korea; and.
Jee Hyun
JH
Kim
Medical Oncology, Seoul National University Hospital, Seoul, South Korea; Medical Oncology, Seoul National University College of Medicine, Seoul, South Korea; and.
Seock-Ah
SA
Im
Departments of Pathology and.
Gyungyub
G
Gong
Medical Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Kyung Hae
KH
Jung
Departments of Pathology and Departments of Pathology and.
In Ae
IA
Park
From the Departments of Pathology and Departments of Pathology and sypmd@snu.ac.kr.
So Yeon
SY
Park
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab
Breast carcinoma; Gene amplification; HER2; Heterogeneity; Trastuzumab