Table 5.
Studies evaluating the relationship between topoisomerase IIa and response to anthracycline (all received anthracycline).
| Study | Ref | Regimen | Dz Setting | N | Outcomes | Topo2 test/definitions |
|---|---|---|---|---|---|---|
| Jarvinen, et al 1998 Tampere University Finland | Br J Cancer | Epirubicin | MBC | 55 |
TopoIIα expression stable from primary to metastatic sample. Validated IHC Ab test on FFPE. Expression TopIIα (at different levels) does not predict response to first-line epirubicin. FISH not done. HER2 overexpression, lower response to epirubicin. |
IHC only rabbit polyclonal Ab; Analyzed as a continuous variable; compared outcome for IHC > or <15% |
| Rush - Chicago (Retrospective series) Coon 2002 | 130 | Anthracycline | NAC | 35 | Eight HER2 amplified, six TOP2A amplified-all HER2+ favorable response if co-amplified. Expression of TopoIIα is also associated with a favorable response. |
FISH: Ratio >2.5 = amplified for HER2 and TOP2A IHC: Nuclear staining scored 0–4 using JH2.7 Ab |
| Bergonie Institute MacGrogan 2003 | BJC 89 666 | EVM-MTC | NAC | 125 | All received epirubicin based therapy; TopoIIα expression predictor of clinical response |
IHC HER2+ if 10% moderate- strong+ IHC KiS7 Ab for Topo2a, high >15% |
| Royal Marsden series Arriola 2007 | 138 | All anthracycline | Adj | 232 of 245 |
TOP2A amplification only on HER2+ (20/37 HER2+TOP2A+) In HER2+ tumors, TOP2A amplification associated with better OS and DFS Median DFS 115 mos vs 68 mos p = 0.026 Median OS 119 mos vs 94 mos, p = 0.028 No association with TopoIIa expression and outcome |
CISH TOP2A and HER2 Positive if >6 signals/nucleus in >50% cancer cells or when large gene copy clusters were seen IHC with Ki-S1 Ab |
| HeCOG pooled analysis HE10/97 and HE10/00 Fountzilas 2013 | 147 | E-CMF or E-T-CMF | Adj | 1031 of 1681 |
244 HER2 amplified, 102/244 (42%) co-amplified for TOP2A 102/104 TOP2A amplified were HER2 amplified. 40% had CEP17 gain HER2 amplification, TOP2A amplification and CEP17 gain and HER2/TOP2A co-amplification were not associated with TTR or time to death TOP2A deletions did not result in lower TopoIIa expression. No signif association between TOP2A amplification and expression 5% tumors TOP2A deleted |
HER2 >2.2 or copy number >6 TOP2A >2.0 or copy number >6 Deletion <0.8 CEP17 gain if >3 CEP signals in >30% nuclei |
| Milan case series Orlando 2008 | 171 | E or A | NAC | 23 (of 286) | TOP2A amplification predicts pCR after neoadjuvant anthracycline-based therapy (epirubicin or doxorubicin) in ER/PR negative, HER2 overexpressing. 22% (5/23) TOP2A amplified. 4/23 del. 1 chromosome 17 polysomy. pCR 60% (3/5) in TOP2A amp; 17% (3/18) in TOP2A non-amplified. 0/4 TOP2A deleted tumors pCR; Disease progression in one TOP2A deleted tumor. |
FISH Ratio >2 = positive Ratio <0.8 = del |
| CALGB 8541 Harris 2009 | 143 | CAF | ADJ | 624 |
HER2+ 117/624 = 19%. TOP2A amp 41 (7%), del 69 (11%); 39/41 HER2/TOP2 coamplified TOP2A amp does not predict benefit from CAF in HER2+. 41 patients TOP2A+ spread over three arms; All pts received anthracycline. No info regarding the distribution of patients across dose strata (very small numbers in each of three dose strata, underpowered). |
FISH HER2 & TOP2A Ratio >2 = positive Ratio <0.67 = del |
| SWOG S9313/INT0137 Tubbs 2009 | 142 | AC vs A→C | ADJ |
1729 Of 3125 |
1380 patients had both HER2 and TOP2 FISH done. 279/1483 (18.8%) patients HER2 amplified; 65/1626 TOP2A+; 64/65 TOP2+/HER2+. No association between TOP2 alteration and outcome to anthracycline therapy. Positive association with HER2. |
FISH HER2 and TOP2ARatio >2 = positive Ratio <0.7 = del |
| BCIRG005 Press 2011 | 136 |
AC-T TAC |
ADJ | 1614 | HER2 neg by FISH. 2.6% TOP2A deleted (42/1614). Not one had TOP2 amplification |
FISH HER2 and TOP2A Ratio >2 = positive <0.82 = deleted |
| TOP Trial Desmedt 2011 | 135 | Epirubicin all patients | NAC | 149 | ER negative treated with epirubicin monotherapy to look at predictive value of TOP2A. 10/106 samples TOP2A amplified, all HER2 amplified. 33/106 HER2 amplified: higher chance of pCR if HER2 amplified. TOP2A amplification (not expression) associated with pCR (p < 0.001). Developed anthracycline-based score (A-score) to combine Top2A gene signature with tumor invasiveness and immune response signatures |
FISH Ratio >2 = positive Ratio <0.8 = del |
| Chen 2013 | Eur J Surg Oncol 39:619-26 | Anthracycline | NAC | 99 | Topo2a expression associated with pCR with anthracycline-based neoadjuvant therapy | IHC 10% = positive |
A doxorubicin, Ab antibody, ADJ adjuvant, amp amplification, BCIRG Breast Cancer International Research Group, CALGB Cancer and Leukemia Group B, C cyclophosphamide, CEP17 chromosome enumeration probe 17, CISH chromogenic in situ hybridization, del deleted, DFS disease free survival, E epirubicin, ER estrogen receptor, F fluorouracil, FISH fluorescent in situ hybridization, FFPE fresh frozen paraffin embedded, HD high dose, HeCOG Hellenic Cooperative Oncology Group, HR hazard ratio, IHC immunohistochemistry, M methotrexate, MBC metastatic breast cancer, NAC neoadjuvant chemotherapy, NR not reported, OS overall survival, P melphalan, pac paclitaxel, pCR pathologic complete response, p-int p-value interaction test, PR progesterone receptor, RFS relapse-free survival, SWOG Southwest Oncology Group, T docetaxel, V vincristine.