Molecular subtypes of breast cancer and amplification of topoisomerase IIα: predictive role in dose intensive adjuvant chemotherapy

Abstract

Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase IIa (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose -response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.

Familial Breast Cancer Registry Program in Patients Referred to the Cancer Institute of Iran

“…TNBC is a more invasive cancer with higher degree of recurrence. About 14 to 20 percentages of breast cancers are triple negative (Carey et al, 2006;Hannemann et al, 2006;Lund et al, 2010). Similar to our study, the significant increase of the triple negative tumors with decrease of cancer onset age has been shown in many other studies in different countries that TNBC has been more frequent in younger ages (Dobi et al, 2011;Salami et al, 2011).…”

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors

“…This has been confirmed in various ethnic populations [25][26][27][28][29][30]. Therefore, they can be used to estimate the prevalence of the five intrinsic subtypes in epidemiological studies without loss of their prognostic significance [22,25,31]. IHC of receptors for female steroid hormones and HER-2 remains the most common practice in the primary evaluation of breast cancer.…”

Assessment of Topoisomerase II α Status in Breast Cancer by Quantitative PCR, Gene Expression Microarrays, Immunohistochemistry, and Fluorescence in Situ Hybridization

“…[41][42][43] Because of this coincidence, many researchers have hypothesized that TOP2A amplification might become the gold standard predictive factor for anthracyclines, rather than ERBB2; and many retrospective studies have been conducted to assess its predictive value. However, although several studies 19,39,42,44 have shown that TOP2A alterations are associated with an increased responsiveness to anthracycline-containing regimens, others 20,45 have been inconclusive.…”