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SummaryLate-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.

CCND1 encodes for the cyclin D1 protein involved in G1/S cell cycle transition. In breast cancer the mechanism of CCND1 amplification, relationship between cyclin D1 protein expression and the key clinical markers estrogen receptor (ER) and HER2 requires elucidation. Tissue microarrays of primary invasive breast cancer from 93 women were evaluated for CCND1 amplification by fluorescent in-situ hybridization and cyclin D1 protein overexpression by immunohistochemistry. CCND1 amplification was identified in 27/93 (30%) cancers and 59/93 (63%) cancers had overexpression of cyclin D1. CCND1 amplification was significantly associated with cyclin D1 protein overexpression (p < 0.001; Fisher's exact test) and both CCND1 amplification and cyclin D1 protein expression with oestrogen receptor (ER) expression (p 5 0.003 and p < 0.001; Fishers exact test). Neither CCND1 amplification nor cyclinD1 expression was associated with tumor size, pathological node status or HER2 amplification, but high CCND1 amplification (Copy Number Gain (CNG) ! 8) was associated with high tumor grade (p 5 0.005; chi square 7.915, 2 df) and worse prognosis by Nottingham Prognostic Index (p 5 0.001; 2 sample t-test). High CCND1 amplification (CNG ! 8) may identify a subset of patients with poor prognosis ER-positive breast cancers who should be considered for additional therapy.

Background The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

Bile duct injury incurred during LC remains a serious hazard for patients. The resulting complications have led to litigation that has caused a huge financial drain on the health care system. Delayed recognition appears to correlate with more costly litigation.

Objective: To evaluate clinical outcomes of using acellular dermal matrix (ADM) with implant based breast reconstructions (IBBRs) in a randomized controlled trial. Summary Background Data: The use of ADMs in IBBRs is widespread, but link between ADM and complications remain a controversial topic. In view of reports concerning harm, we present 6-months safety data of ADM-assisted IBBR in the setting of breast cancer treatment. Methods: An open-label, randomized, controlled trial recruiting patients from 4 centers in Sweden and 1 in UK. Eligible were women with breast cancer planned for mastectomy with immediate IBBR. Participants were randomly allocated to IBBR with or without ADM (Strattice, Branchburg, NJ), with stratification by center in blocks of 6. Main primary endpoint was number of unplanned reoperations at 24 months, and safety expressed as the incidence of adverse events with a 6-month follow-up time for all participants. Analysis were done per protocol using Fisher exact test for complications and reoperations. Results: From start of enrolment on April 24, 2014, to close of trial on May 10, 2017, 135 women were enrolled, of whom 64 with ADM and 65 without ADM were included in the final analysis. Four patients (6%) in each group had reconstructive failure with implant loss, but IBBR with ADM exhibited a trend of more overall complications and reoperations (difference 0·16, 95% CI, −0·01 to 0·32, P = 0·070), and with higher risk of wound healing problems (P = 0·013). Conclusions: With 6-months follow-up for all participants, immediate IBBR with ADM carried a risk of implant loss equal to conventional IBBR without ADM, but was associated with more adverse outcomes requiring surgical intervention. Further investigation of risk factors and patient selection in a long-term follow-up is warranted.

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.

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