Tumor diversity may cause therapeutic resistance and HER2 heterogeneity have been reported to associate with poor prognosis in esophageal adenocarcinomas. We focused on the correlation between HER2 heterogeneity and prognosis in breast cancer.
To determine the characteristics of heterogeneous overexpression of HER2 in breast cancer, we established two types of HER2-expressing cells, HER2-60 contains 63.2% of HER2-positive cells, and HER2-90 contains 92.4%, by introducing the HER2 gene into a human triple-negative breast cancer cell line, MDA-MB 231. We also investigated correlation between HER2 heterogeneity and tumor malignancy in human breast cancer specimens.
When we inoculate the HER2-60 into the mammary fat pads of nude mice, heterogeneous HER2-expressing tumors developed, while HER2-90 consists mostly of HER2-expressed cells, and developed monotonous HER2-expressing tumors. We found that HER2-60 mice showed shorter survivals than HER2-90 mice, the median survival days after intracardiac injections were 24 (n = 22) and 30 (n = 13), respectively. Next we investigated the correlation between HER2 expression and prognosis in human breast cancer. There were 73 HER2-positive breast cancer patients who received neoadjuvant chemotherapy with trastuzumab and underwent surgery between January 2004 and December 2010 in our hospital. Fifty-five patients showed HER2 3+ by immunohistochemistry and 18 patients showed HER2 2+ and FISH-positive. HER2 2+ patients were divided into 2 groups by the staining pattern, overall and partially stained cases. We defined as HER2 monotonous-type (HER2 mono) and HER2 heterogeneous-type (HER2 hetero), respectively At the median follow-up of 69.1 months, recurrent diseases were found in 25% (14/55) in HER2 3+ cases, and 30% (3/10) in HER2 hetero cases, while no recurrence was found in HER2 mono cases.
Intratumoral HER2 heterogeneity is associated with aggressive breast cancers. Additional therapy should be considered for HER2 hetero breast cancers because HER2-positive breast cancers are all treated with chemotherapy with trastuzumab.
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All authors have declared no conflicts of interest.