Abstract P2-09-15: TOP2A and DARPP32 Are Associated with Response to Trastuzumab-Based Treatment of HER2-Positive Advanced Breast Cancer (ABC)
Authors: Kotoula V , Bobos M , Kalogeras KT , Timotheadou E , Skarlos DV , Pavlidis N , Koutras AK , Vlachodimitropoulos D , Pectasides D , Fountzilas G. 
Published: April 2011

Background: HER2 status (gene amplification, protein overexpression) is the hallmark for the selection of patients who will benefit from trastuzumab-based treatment. Except for HER2, however, the status of additional genes located at chromosome 17q seems to have an impact on disease biology and patients’ outcome. In this retrospective study, we investigated the impact of TOP2A (chr 17q21-q22, telomerically to ERBB2) and PPP1R1B (DARPP32, chr 17q12, centromerically to ERBB2) status on the outcome of patients with ABC treated with trastuzumab-based regimens. Materials and Methods: In a cohort of 199 patients with ABC treated with 1st or 2nd line trastuzumab-containing regimens, tumor tissues were assessed for HER2 and TOP2A gene amplification (by FISH), HER2, TOP2A and DARPP32 mRNA expression (by RTQ-PCR), and Her2 and TopoIIa protein expression (by IHC). Tumors were HER2 positive (FISH amplified and/or 3+ by IHC) (n= 137) or negative (n=62). Disease outcome was assessed as time to progression (TTP), survival from trastuzumab administration (survivalT) and survival from 1st metastasis (survivalM). Results: In comparison to patients with HER2-negative tumors, those with HER2-positive tumors exhibited a longer TTP (Median [95% CI] = 13.7 [10.7-16.7] vs 9.2 [7.5-10.9], p=0.037) and survivalT (Median [95% CI] = 47.4 [37.9-56.9] vs 34.8 [24.3-45.4], p=0.008), as expected. HER2 positivity was strongly associated with relatively high HER2 mRNA and protein expression (P&lt;0.001 for both) and with TOP2A amplification (P&lt;0.001), but not with relatively high TOP2A mRNA and protein expression. DARPP32 mRNA strongly correlated with HER2 mRNA (P&lt;0.001) and was associated with HER2 and TOP2A gene status (P&lt;0.001), it was not however related to TOP2A mRNA, and TopoIIa and Her2 protein expression. The relative expression of DARPP32 to HER2 mRNA was occasionally very high, with ratios of DARPP32/HER2 &gt;1 equally distributed among HER2-positive and negative tumors. In patients with HER2-positive tumors, TOP2A gene amplification was associated with longer survival, irrespectively of the chemotherapy regimen administered in addition to trastuzumab (survivalT: p=0.004, survivalM: p=0.003). Interestingly, in patients with HER2-negative tumors, DARPP32/HER2 ratios of &gt;1 were associated with a favorable outcome (survivalT: p=0.008 and survivalM: p=0.043). No association with disease outcome was observed for high DARPP32 expression or for DARPP32/HER2 ratios in HER2-positive tumors.

Discussion: This study shows that genes located peripherally to HER2 on the same chromosome arm, such as TOP2A and DARPP32, may be concomitantly altered in the same breast tumor, but may have a different impact on the course of the disease. A favorable outcome may be predicted for HER2-positive tumors with amplified TOP2A and for HER2-negative tumors expressing higher DARPP32 mRNA in comparison to HER2.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-15.