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Background: [18F]ICMT-11 is an isatin analogue which has been developed by our group as a novel PET radiotracer for studies of apoptosis in vivo. Preclinical studies have demonstrated subnanomolar affinity to caspase 3, and validated the potential for imaging apoptosis in xenograft models. A first-in-man study showed that the agent was well tolerated with acceptable dosimetry. This is the first study of this agent to measure the effect of chemotherapy on radiotracer uptake in patients. As apoptosis is a dynamic process, one of the main objectives of the study was to determine the optimal time-point for imaging post-chemotherapy and compare the results with immunohistochemistry assessments at the same time-points. The study was approved by a regional ethics committee and ARSAC. Methods: 7 patients with breast tumour lesions measuring 15mm or more, due to undergo neoadjuvant chemotherapy with FEC (5FU, Epirubicin, Cyclophosphamide) had dynamic PET scans for 66mins 30seconds following intravenous injection of [18F]ICMT-11 with a mean activity of 340.82 Mbq±20.76 and Specific Activity range of 447.014-5128.34 Gbq/µmol prior to chemotherapy and 24h-2 weeks post-chemotherapy. A breast biopsy was also obtained within a few hours of the 2nd PET scan to correlate apoptosis in the breast tissue utilising TUNEL and Caspase 3 staining by immunohistochemistry. Volumes of interest were drawn manually and analyzed using Analyze software®. Results: The scans were well tolerated in all patients. Uptake of [18F]ICMT-11 was demonstrated in all tumor lesions. The tumours studied included ER positive and PR positive, HER2 positive and triple negative patients. The first cohort patients were imaged pre-chemotherapy and 24-48h post chemotherapy. Tumour to Breast ratio (TBR) showed an increase from 1.42±0.21(pre) to 1.71±0.33 (post). Tumour to muscle ratio (TMR) was not increased, 1.52±0.30(pre) and 1.22±0.09 (post). In addition, an increase the SUV was noted in the lymph nodes of patients, at both 24 and 48h. (SUVav 0.39±0.02 (pre), 0.45±0.03 (post), and SUVmax 0.87± 0.02(pre) ,1.22±0.12 (post). The lymph nodes were however not sampled for immunohistochemistry. A further cohort of patients had the follow-up scan 2 weeks post chemotherapy, TBR and TMR were both increased in this cohort 1.50±0.22 (pre), 2.52±0.48 (post),and 1.82±0.10 (pre), 2.08±0.0.04 (post), respectively. Caspase and TUNEL labelling with immunohistochemistry also showed increased in apoptosis in the breast biopsies at 2 weeks compared to baseline in keeping with the PET data. Conclusion: These preliminary data suggest that [18F]ICMT-11 is a promising marker for chemotherapy induced apoptosis in vivo, and correlates with findings in tumor biospsies using TUNEL and immunostaining for caspase 3. Further work is underway to study a larger cohort of patients, and identify the optimal PET pharmacokinetic parameter to describe [18F]ICMT-11 uptake and retention. Citation Format: Shairoz Merchant, Eric O Aboagye, Adrian Lim, Kasia Kozlowski, Naina Patel, Jennifer Steel, Susan Cleator, Sami Shousha, Vidhya Varghese, Raoul C Coombes, Laura Kenny. Evaluation of apoptosis in breast cancer using the novel PET probe [18F]ICMT-11 in patients treated with neoadjuvant FEC chemotherapy: Initial assessment of optimum imaging time and relation to caspase-3 immunostaining [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-01-02.

Background: Triple negative breast cancer (TNBC) has been associated with a high glycolytic rate. As a surrogate measure, the SUV of FDG uptake is found to be higher both in the TNBC and her2 positive phenotypes. Tumour lesion glycolysis (TLG) is a product of the mean SUV value and tumour volume. We wished to evaluate the role of combined volume and metabolic measurements of glycolysis in patients with TNBC. Methods: 300 FDG-PET scans were performed in patients with breast cancer, of whom 25 were found to have TNBC over a 4 year period, in 19 patients there were suitable lesions identified for analysis. Patients were scanned on the same Siemens PET/CT scanner in the local hospital, static images were acquired 60 minutes post-injection. SUV was corrected for injected activity and body weight, TLGMAX50 was also calculated considering SUV50 isocontour instead of SUV mean. ∑TLG was the sum of TLG for an individual patient. Results: 117 lesions in total from 19 different patients were analyzed (mean = 6.15 lesions per patient). SUVMEAN, TLG mean, SUVMAX and TLGMAX were calculated for each lesion. SUVMEAN per patient varied from 2.69 to 15.48 while SUV50 varied from 5.45 to 48.23. ∑TLGMEAN and ∑TLGMAX ranged from 13.06 to 364.072 and 18.29 to 575.627, respectively. There was significant variation between patients and within different tumor lesions within patients. SUVPEAK for all lesions of patients ranged from 4.8 to 36.4. Conclusions: TLG varies widely in patients with triple negative breast cancer, further studies are required to determine if this will be a useful prognostic/predictive measure in the future. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-22.

Background; Glycolysis is one of the major metabolic pathways in cancer cells. The conversion of glucose to lactate in the presence of oxygen is a critical aerobic pathway that allows cancer cells to proliferate rapidly and the amount of lactate produced is correlated with tumor aggressiveness. Moreover, the increase in glycolysis is partially mediated by hypoxia-inducible transcription factor (HIF-1) and a metabolic enzyme, lactate dehydrogenase B (LDHB). However, the mechanism behind this metabolic shift is not well understood. Metformin reduces the overall risk of cancer incidence by 31%, improves cancer-related mortality and enhances response to chemotherapy in diabetic patients pre-operatively. This study aimed to evaluate metabolism in triple negative breast cancer. Methods; Breast cancer cell lines (estrogen receptor positive MCF7 and triple negative MDA-MB 231 and MDA-MB468) were analysed for protein expression by western blotting and mRNA expression by qRT-PCR with or without cisplatin and metformin. To study the biological mechanism, we evaluated cell growth using proliferation assay in the presence of metformin and cisplatin. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and MDA-MB468 cell lines. Results; We first examined the basal expression levels of LDHB and HIF1a in these cancer cell lines. LDHB expression was high in MDA-MB 231, and HIF1α was high in MDA-MB468. Both metformin and cisplatin treatment resulted in the down-regulation of LDHB and HIF1α in MDA-MB231, metformin led to downregulation of LDHB in MDA-MB 468, while MCF7 demonstrated no significant changes. Inhibition of cell proliferation was dose-dependent and significant at low concentrations of cisplatin and metformin in only MDA-MB468 but not in MCF7 and MDA-MB231. The combination of cisplatin in with metformin had an added inhibitory effect on cell proliferation in these MD-MB231 cells. Conclusion; These studies suggest that combination treatment of metformin and cisplatin have potent anticancer activity in LDHB highly expressed triple negative breast cancer cells. Identification of a new targeted therapeutic approach could contribute to the new therapy to the breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-07.