High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer.
Subgroup analysis showed no significant differences of OS and DFS either between TOP2A-positive and TOP2A-negative groups or between TOP2A amplification and control group in population of patients with HER-2 amplification, triple negative breast cancer, or hormone-positive breast cancer.
Correlation between ER, PR, HER-2, Bcl-2, p53, proliferative and apoptotic indexes with HER-2 gene amplification and TOP2A gene amplification and deletion in four molecular subtypes of breast cancer.
During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status.
TOP2A gene alterations were found in 22.6% (21.0% of cases with amplification and 1.6% with deletion), and these tumors were biologically more aggressive, with higher nuclear grade, more frequently with HER2 amplification and inflammatory type.
Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1 immunoreactive and HER2 negative) and anthracycline responsive (all other cases).
HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A.
This study suggests that CEP17 duplication has a borderline association with clinical responsiveness to anthracycline containing chemotherapy similar to previous results seen with HER2 amplification and TOP2A alteration in MA.5.
C-myc and HER2 amplification were examined by FISH, and oestrogen receptor (ER), progesterone receptor (PR), Ki67, and topoisomerase 2α (TOP2A) expression were examined immunohistochemically.
Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours.
In multivariate analysis, TOP2A amplification (odds ratio [OR] 3.04, P = 0.021), but not HER2 amplification (OR 1.74, P = 0.170) was associated with a significantly higher pCR rate.
In univariate analyses, only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free (hazard ratio [HR] 1.59, 95% CI 1.32-1.92, p<0.0001; and 1.52, 1.20-1.92, p=0.0006, respectively) and overall survival (1.79, 1.47-2.19, p<0.0001; and 1.62, 1.26-2.08, p=0.0002 respectively).
Simultaneous amplification of both genes was found in 28% of the abnormal tumors (12% of all patients) while TOP2A deletion and ERBB2 amplification was observed in 16% of the abnormal cases (8% of all patients).
This led to the suggestion that HER2 amplification was acting as a surrogate for the gene encoding topoisomerase IIα (TOP2A), a direct cellular target of anthracyclines.
TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.
HER-2 amplification was detected in 11 patients (22%) and TOP2A changes were seen in 6 patients (12%); two amplifications and two deletions were observed in HER-2-amplified cases and two deletions in HER-2-nonamplified cases.
Assessment of HER-2 gene amplification and TOP2A gene amplification/deletion was made by FISH analysis using the LSI TOP2A/HER-2/CEP 17 multicolor probe or the LSI HER-2/CEP dual color probe (Vysis, Downers Grove, IL, USA) in formalin-fixed and paraffin-embedded tissue sections of 54 breast cancer patients who were grouped into stages 1+, 2+ or 3+ based on IHC (HercepTest; DakoCytomation, Carpinteria, CA, USA) observations.