Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment.

Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms. In a window-of-opportunity study in 35 ductal breast cancer patients for 2weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCE-MRI], transcriptomic and pathology. Initial treatment response showed significant overall decrease in DCE-MRI median K(trans), angiogenic factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations. These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high K(trans), and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment.

Slip imaging: reducing ambiguity in breast lesion assessment.

Ultrasound elasticity imaging (elastography) is gaining popularity as an adjunct to B-mode ultrasound for breast cancer diagnosis. Cancerous masses are usually stiffer than normal tissue, hence, using elasticity imaging should lead to better differentiation between benign and malignant masses than using B-mode alone. Clinicians assess the mobility of masses on palpation; cancers usually being less mobile. We introduce a method to estimate mobility, called slip imaging and combine it with conventional B-mode and elasticity data. In the reported evaluation on 70 women recalled to a breast assessment clinic, images were scored by three breast radiologists independently. Diagnostic accuracy increased from 75.7% with B-mode alone, to 78.1% when including elasticity imaging, to 80.0% when further including slip imaging. Specificity increased (74.6%:75.4%:82.5% respectively), with an apparent trade-off in sensitivity (77.1%:81.3%:77.1%). We conclude that Slip imaging is potentially a useful adjunct to B-mode and elasticity imaging and should undergo further research and development.

Radiologic characteristics and management of screen-detected metastatic carcinoid tumor of the breast: a case report.

Carcinoid tumors are known to metastasize to the breast, but their appearance can mimic a primary breast carcinoma, making biopsy essential in order to give the correct preoperative diagnosis. It has been suggested that core biopsy might precipitate a carcinoid crisis and should be avoided. We describe a case of screen-detected carcinoid tumor metastasis in the breast safely diagnosed by core biopsy and present the imaging findings, including magnetic resonance imaging and elastography. This case illustrates the importance of preoperative histologic diagnosis in enabling the appropriate surgical or medical management of these patients. Review of the literature also supports the policy that biopsy of nonhormonally active tumors may be safely performed.