Topoisomerase IIalpha topo IIa expression

The topoisomerase II alpha gene (topo IIa) is located adjacent to the HER2 oncogene at chromosome 17q12-q21. Topo IIa is thought to be the primary molecular target of anthracyclines, as the exposure of cells to topo II inhibitors results in stabilization of covalently bound cleavable complexes and subsequent DNA double-strand breaks (106) and sensitivity to topo II inhibitors including anthracyclines was associated with topo IIa expression (75, 107-109). Furthermore, amplification of the topo IIa gene has been found in breast cancers with HER2 amplification.

In small studies, coamplification of erbB-2 and topo IIa was found to be significantly associated with favorable local response to anthracycline based therapy in locally advanced breast cancer (110, 111). In a larger retrospective study from the Danish Breast Cancer Cooperative Group, topo IIa amplification was found to have increased recurrence-free and overall survival, respectively, if treated with epirubicin-based regimes compared to non-epirubicin-based regimens (112). A Scandinavian Breast Group trial (9401) in women with high-risk breast cancer found topo IIa coamplification in 37% of HER2-amplified tumors (113). Topo IIa amplification was associated with better relapse-free survival in patients treated with tailored FEC (fluorouracil, epirubicin, and cyclophosphamide) (113).

A more recent study has further suggested an important role for topo IIa as a predictive marker. As the anthracyclines and trastuzumab have been associated with cardiac toxicity, BCIRG 06 addressed the question of whether an anthracycline could be omitted in patients with HER2 over-expressing breast cancer. A combination of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel and trastuzumab were compared to six cycles of docetaxel, carboplatin, and trastuzumab in patients with HER2 positive early-stage breast cancer (114). While the two trastuzumab-containing arms did not differ statistically, there was a numerical benefit towards the anthracycline-containing arm. Preliminary analyses suggested that in particular those patients with topo IIa and HER2 co-amplification appeared to benefit from the anthracycline-containing regimen (114, 115). These findings are currently being evaluated. A standardized test of topo IIa expression is not yet currently available.

3.9. Breast cancer (BRCA) gene mutation

BRCA1 or BRCA2 gene germ-line mutations can be identified in 5-10% of all patients with a newly diagnosed breast cancer. They are associated with a 50%-85% lifetime risk of developing breast cancer (116, 117).

Breast cancer patients with germ-line mutations in BRCA1 or BRCA2 have a high risk of developing ipsilateral and contralateral second primary tumors (118).

Prophylactic mastectomy was associated with a reduction in the incidence of breast cancer of at least 90% in a retrospective study of women with a family history of breast cancer (119). In a prospective cohort of women with germ-line mutations in BRCA 1 or BRCA2 and no previous cancer diagnosis, bilateral prophylactic salpingo-oophorectomy improved overall survival and cancer-specific survival (120). While the emotional and social implication of carrying a gene mutation have to be considered, the potential to prevent further cancers in the patient and possibly also in the patient's relatives by prophylactic measures should warrant a discussion about genetic testing in patients with suspected BRCA mutations.

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