Tumour Topoisomerase II Alpha Protein Expression and Outcome After Adjuvant Dose-Dense Anthracycline-Based Chemotherapy

Abstract

There is a need for the selection of those breast cancers where benefit may be attained from the addition of an anthracycline to the adjuvant chemotherapy. The expression of topoisomerase II alpha (TOP2A) protein in 3 cohorts of breast cancers treated with adjuvant dose-dense anthracycline-based chemotherapy was determined retrospectively. The TOP2A status was analysed in relation with the other standard tumour features and the outcome. TOP2A IHC results were assessable in 106 patients: with a cut-off value of 15%, 48% of the tumours were classified as TOP2A-positive. The expression of TOP2A correlated with that of Ki67 (R = 0.532, p < 0.001) and a high grade (p = 0.04), but did not correlate with the proportion of ER- or PR-positive cells in the tumour. More tumors were TOP2A-negative among the ER- or PR-positive cancers than among the ER/PR-negative cancers (p = 0.021 and p = 0.002, respectively). After a median follow-up time of 64.5 months, 31 relapses (23.5%) and 23 deaths (17.4%) had occurred in 131 patients. The overall survival was longer in the TOP2A-positive cases than in the TOP2A-negative cases. The recurrence-free survival and the overall survival were significantly more favourable in the ER/PR-negative and TOP2A-positive tumours than in other subgroups. In a Cox proportional hazards model, the grade and TOP2A remained significant determinants in the ER/PR-negative subgroup. TOP2A positivity and grade 3 indicated a decrease in the risk of death with HR = 0.211 (95% CI: 0.042-1.05, p = 0.056) and HR = 0.216 (95% CI: 0.047-0.990, p = 0.048), respectively. A higher sensitivity to anthracycline-containing regimens is suggested in ER/PR-negative and TOP2A-positive cancers.

The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer

“…In consistent with previous studies [ 30 , 31 , 34 ], we found TOP2A protein was significantly associated with high tumor grade and Ki67 index, suggesting that tumors with high level of TOP2A expression were more aggressive. No association between TOP2A expression and age, menstrual status, tumor size, lymph node status, pathological type were observed.…”

“…However, no standard antibodies, staining procedure, and scoring system have been recommended. Various cut-off values such as 5% [ 29 ], 10% [ 30 ], 15% [ 31 ], 20% [ 26 ], and 30% [ 32 ] have been applied in different studies. Other studies took both the staining intensity and percentage of positive cells into consideration to defined TOP2A status [ 33 ].…”

Thymidine Kinase 1 Upregulation Is an Early Event in Breast Tumor Formation

“…These indicators, although well established, are all related to tumor aggressiveness. Recent evidence has shown that proliferation markers, such as Ki-67 and proliferating cell nuclear antigen (PCNA), may have independent prognostic value [1–3]. Although these proliferation markers have potential, recent studies indicate that thymidine kinase 1 (TK1), another marker associated with proliferation, may be a better prognostic marker than either Ki-67 or PCNA [4, 5].…”

Comprehensive Analysis of Candidate Diagnostic and Prognostic Biomarkers Associated with Lung Adenocarcinoma

“…Patients with TOP2A-positive breast cancer are more sensitive to anthracyclines than TOP2A-negative patients [38]. TOP2A is highly expressed in more advanced uterine leiomyosarcoma with a high mitotic index but not in nonmalignant uterine diseases [39].…”