Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracyclin based therapy: influenced by the HER2- and Topoisomerase IIα-status of the primary tumor?

Abstract

HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.

Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial

“…Other studies have previously attempted to examine the value of topo 2a expression in predicting responsiveness to anthracycline based chemotherapy. These studies were either not randomized and therefore unsuitable for determining predictive value [19][20][21][22][23][24][25][26] and/or did not choose a clinical outcome and could therefore not assess prognosis or prediction [27] or examined responses in locally advanced or metastatic breast cancer [23,28]. Press et al [29] recently published results examining HER2 amplification and topo IIa co-amplification in a 'test set' of women treated with doxorubicin and cyclophosphamide (AC) ± trastuzumab in the metastatic setting.…”

Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIα (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

“…In the adjuvant studies, only those HER-2 amplified breast cancer patients, who also had a simultaneous amplification of T O P 2 A , derived benefit from the anthracycline-chemotherapy [186,190,192], whereas the coamplification of HER-2 and TOP2A predicted good response to preoperative topoII-inhibitor chemotherapy [193]. The results of the latest trial showed that the breast cancer patients who received topoII-inhibitor chemotherapy and had TOP2A amplification tended to stay or became negative of circulating tumor cells in their bone marrows´ [194]. Furthermore, the patients with TOP2A amplification showed prolonged disease-free survival as none of them niether developed distant metastasis nor died during the follow-up [194].…”

“…The results of the latest trial showed that the breast cancer patients who received topoII-inhibitor chemotherapy and had TOP2A amplification tended to stay or became negative of circulating tumor cells in their bone marrows´ [194]. Furthermore, the patients with TOP2A amplification showed prolonged disease-free survival as none of them niether developed distant metastasis nor died during the follow-up [194]. These results suggest that TOP2A amplification and deletion account for both relative chemosensitivity and resistance to topoII-inhibitor-therapy (anthracycline) depending on the specific genetic defect at the TOP2A locus in HER-2 amplified breast tumors [168,170,195] (Fig.…”

“…The preliminary results on T O P 2 A amplification and deletion strongly point out that a TOP2A screening test together with a HER-2 test could ensure that the combination of Herceptin and topoII-inhibitor is optimal, i.e. it is given just for the patients with the simultaneous amplification of both genes [168,170,[185][186][187][188][189][190][191][192][193][194][195] (Figs. 9 and 10).…”

“…The predictive values of HER-2 amplification and TOP2A gene copy number aberrations have not only been assessed from six large, multi-center trials [186][187][188][189][190][191] as well as from three small trials with limited number of patients [192][193][194]. In all of these nine trials, primary or advanced breast cancer patients received anthracyclines (topoIIinhibitor), as their chemotherapy for the disease [186][187][188][189][190][191][192][193][194].…”