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Background: T-DM1, an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1, is in development for the treatment of HER2−positive cancers. Single-agent T-DM1 3.6 mg/kg every 3 weeks (q3w) has demonstrated clinical activity in 2 phase II studies (TDM4258g and TDM4374g) in patients with pretreated HER2−positive MBC. The efficacy and safety of T-DM1 vs trastuzumab + docetaxel was investigated in patients with no prior MBC treatment in the randomized phase II study TDM4450g/BO21976. Here we report the PK of T-DM1 from that study and compare these data with those from studies that enrolled pretreated patients. Methods: In all 3 studies, PK parameters, including maximum concentration (Cmax), area under the concentration-time curve (AUC), terminal half-life (t½), steady-state volume of distribution (Vss), and clearance (CL) were estimated by noncompartmental analysis (NCA) for serum T-DM1, serum total trastuzumab (conjugated and unconjugated), and plasma DM1. The effects of baseline trastuzumab and HER2 extracellular domain (ECD) concentration on T-DM1 exposure were explored and the relationship between T-DM1 exposure and clinical response (objective response rate [ORR] and progression-free survival [PFS]) was modeled. Results: T-DM1 PK from evaluable patients enrolled in 3 studies are shown in Table 1. No significant correlations were observed between efficacy (as measured by ORR) and T-DM1 exposure (AUC, Cmax) after administration of T-DM1 to pretreated patients; efficacy-exposure analyses (ORR and PFS) for previously untreated patients will be presented. Patients with measurable concentrations of trastuzumab at baseline had a greater AUC during cycle 1; however, this did not impact ORR. Baseline circulating HER2 ECD concentrations also had no effect on ORR for pretreated patients. The impact of baseline trastuzumab and HER2 ECD concentrations on ORR and PFS in previously untreated patients will be presented. Conclusions: Single-agent T-DM1 has similar PK in patients who have received prior therapy for MBC and in those who have not. The PK of T-DM1 was not affected by prior trastuzumab treatment or by circulating HER2 ECD, and no significant correlations were observed between efficacy (ORR) and T-DM1 exposure (AUC, Cmax) or HER2 ECD for pretreated patients. The relationships between efficacy and T-DM1 exposure and HER2 ECD concentrations will be presented for patients without prior MBC treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-13.

Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes drives tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones. Although the role of CA in cancer progression is well-defined, no studies have yet discussed how CA is induced in tumor cells. We report here that intra-tumoral hypoxia, which is considered one of the major contributors to intratumor heterogeneity, induces CA via HIF-1α. Methods: We first immunohistochemically labeled 24 breast carcinoma and uninvolved adjacent normal tissue samples for HIF-1α and calculated weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were also immunofluorescently labeled for γ-tubulin and CA was calculated. Using public microarray datasets (Kao dataset, n=327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to determine the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) and knocked out (KO) HIF-1α in TNBC cells and quantitated CA. Additionally, to discern the biological pathway through which HIF-1α induces CA we performed ChIP assay and in silico analyses to identify the possible targets of HIF-1α. Results: A strong positive correlation between nuclear HIF-1α WI and CA was found in breast tumor samples (Spearman's rho p=0.722, p<0.001). In addition, we found that higher nuclear HIF-1α was associated with worse overall survival (p=0.041; HR=1.03). Our in silico findings suggest that breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. In addition, cells cultured in hypoxic conditions exhibited ˜1.5 fold higher (p<0.05) CA when compared to the cells cultured in normoxic conditions. Interestingly level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia and it increased when HIF-1α OE TNBC cells were culture in normoxic conditions. Furthermore, we discovered that HIF-1α induced CA by directly regulating the expression of Plk4 which was confirmed by performing ChIP assay. Our results indicated HIF-1α interaction with the motif in the PLK4 promoter from genomic DNA of MDA-MB 231 cells under hypoxic conditions, was significantly (p=0.04) higher when compared with the cells cultured under normoxic conditions. Plk4 mRNA expression was assessed using the online BC gene expression data sets (n=25). We found significantly higher expression of Plk4 in TNBC (n=374) when compared with non-TNBC (n=4098) and it was associated with poor overall survival (HR=1.76; p=0.054) in TNBC. Conclusion: Collectively our findings suggest that hypoxia drives CA in TNBC via HIF-1α and contribute to poor outcomes. Thus, determination of CA and HIF-1α can help risk stratification in TNBC patients for more personalized treatments. Citation Format: Mittal K, Choi DH, Maganti N, Ogden A, Melton BD, Kaur J, Gupta MV, Jonsdottir K, Janseen EAM, Aleskandarany MA, Rakha EA, Rida PCG, Aneja R. Hypoxia induced centrosome amplification via HIF-1α/Plk4 signaling axis associates with poorer overall survival in TNBC [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-23.

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