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. 2015 Oct;144(4):570-8.
doi: 10.1309/AJCP51HCGPOPWSCY.

Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab

Hee Jin Lee  1 , Joo Young Kim  2 , So Yeon Park  3 , In Ah Park  1 , In Hye Song  1 , Jong Han Yu  4 , Jin-Hee Ahn  5 , Gyungyub Gong  6
Affiliations

Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab

Hee Jin Lee et al. Am J Clin Pathol. 2015 Oct.

Abstract

Objectives: Although intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been associated with a poor prognosis for primary HER2-positive breast cancer and metastatic HER2-positive breast cancer treated with trastuzumab, the clinicopathologic significance in a setting involving trastuzumab treatment as an adjuvant treatment has not been studied in patients.

Methods: We retrospectively investigated 443 patients with HER2-positive breast cancer treated with surgery, adjuvant chemotherapy, and 1 year of trastuzumab. Three areas that showed different levels of HER2 protein expression were chosen, and silver in situ hybridization was performed.

Results: HER2 regional and genetic heterogeneity was found in 6.2% and 6.8% of tumors, respectively. Both types of heterogeneity were significantly associated with hormone receptor positivity, HER2 immunohistochemistry score of 2+, a low level of HER2 gene amplification, and absence of an extensive intraductal component. Genetic heterogeneity also showed strong correlation with a lower histologic grade. In the hormone receptor-positive group, the regional heterogeneity affected disease-free survival of patients (hazard ratio, 4.869; 95% confidence interval, 1.424-16.646; P = .005), whereas genetic heterogeneity did not.

Conclusions: Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.

Keywords: Adjuvant chemotherapy; Breast carcinoma; Gene amplification; HER2; Heterogeneity; Trastuzumab.

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