Metformin and breast cancer: an opportunity for pharmacogenetics.
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ABSTRACT:
SUBMITTER: Cuyas E
PROVIDER: S-EPMC9365564 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Metformin and breast cancer: an opportunity for pharmacogenetics.
Cuyàs Elisabet E Martin-Castillo Begoña B Menendez Javier A JA
Aging 20220718 14
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Project description:Despite its widespread use as the first-line agent for the treatment of type 2 diabetes, it has become clear that metformin does not work optimally for everyone. Elucidating who are the likely metformin responders and non-responders is hampered by our limited knowledge of its precise molecular mechanism of action. One approach to achieve the related goals of stratifying patients into response subgroups and identifying the molecular targets of metformin involves the deployment of agnostic genome-wide approaches in cohorts of appropriate size to attain sufficient statistical power. While candidate gene studies have shed some light on the role of genetic variation in influencing metformin response, genome-wide association studies are beginning to provide additional insight that is unconstrained by prior knowledge. To fully realise their potential, much larger samples need to be assembled via international collaboration, preferably involving the academic community, government and the pharmaceutical industry.
| S-EPMC5709222 | biostudies-literature
Project description:The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMP-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor (IR)-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown.We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ?2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment.Levels of IR expression decreased significantly in tumors (P?=?0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) (P?=?0.0001, P?<?0.0001, P?<?0.005 and P?=?0.02, respectively). All tumors expressed organic cation transporter 1, with 90% (35 of 39) exhibiting an Allred score of 5 or higher.Reduced PKB/Akt and ERK1/2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies.ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.
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Project description:PurposeReverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC).MethodsIn an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m2. For RPPA, formalin-fixed paraffin-embedded (FFPE) samples were probed with 160 antibodies. Paired and two-sample t-tests were performed (p ≤ 0.05). Multiple comparisons were adjusted for by fixing the false discovery rate at 25 %. We evaluated whether pre- and post-metformin changes of select markers by RPPA were identified by immunohistochemistry (IHC) in these samples. We also assessed for these changes by western blot in metformin-treated BC cell lines.ResultsAfter adjusting for multiple comparisons in the 32 tumors from metformin-treated patients vs. 34 untreated historical controls, 11 proteins were significantly different between cases vs.Controlsincreases in Raptor, C-Raf, Cyclin B1, Cyclin D1, TRFC, and Syk; and reductions in pMAPKpT202,Y204, JNKpT183,pT185, BadpS112, PKC.alphapS657, and SrcpY416. Cyclin D1 change after metformin by IHC was not observed. In cell lines, reductions in JNKpT183 and BadpS112 were seen, with no change in Cyclin D1 or Raptor.ConclusionsThese results suggest that metformin modulates apoptosis/cell cycle, cell signaling, and invasion/motility. These findings should be assessed in larger metformin trials. If confirmed, associations between these changes and BC clinical outcome should be evaluated. CLINICALTRIALS.Gov identifierNCT00930579.
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Project description:There is wide individual variability in the pharmacokinetics, pharmacodynamics, and tolerance to anticancer drugs within the same ethnic group and even greater variability among different ethnicities. Pharmacogenomics (PG) has the potential to provide personalized therapy based on individual genetic variability in an effort to maximize efficacy and reduce adverse effects. The benefits of PG include improved therapeutic index, improved dose regimen, and selection of optimal types of drug for an individual or set of individuals. Advanced or metastatic breast cancer is typically treated with single or multiple combinations of chemotherapy regimens including anthracyclines, taxanes, antimetabolites, alkylating agents, platinum drugs, vinca alkaloids, and others. In this review, the PG of breast cancer therapeutics, including tamoxifen, which is the most widely used therapeutic for the treatment of hormone-dependent breast cancer, is reviewed. The pharmacological activity of tamoxifen depends on its conversion by cytochrome P450 2D6 (CYP2D6) to its abundant active metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the coadministration of other drugs that inhibit CYP2D6 function, produce little endoxifen and hence derive limited therapeutic benefit from tamoxifen; the same can be said about the different classes of therapeutics in breast cancer. PG studies of breast cancer therapeutics should provide patients with breast cancer with optimal and personalized therapy.
| S-EPMC3513214 | biostudies-literature
Project description:BackgroundMetformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa.MethodsMETAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London.DiscussionThis randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place.Trial registrationEudraCT number 2014-005193-11 . Registered on September 09, 2015.
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Project description:Patients with breast cancer often receive many drugs to manage the cancer, side effects associated with cancer treatment, and co-morbidities (i.e., polypharmacy). Drug-drug and drug-gene interactions contribute to the risk of adverse events (AEs), which could lead to non-adherence and reduced efficacy. Here we investigated several well-characterized inherited (germline) pharmacogenetic (PGx) targets in 225 patients with breast cancer. All relevant clinical, pharmaceutical, and PGx diplotype data were aggregated into a single unifying informatics platform to enable an exploratory analysis of the cohort and to evaluate pharmacy ordering patterns. Of the drugs recorded, there were 38 for which high levels of evidence for clinical actionability with PGx was available from the US FDA and/or the Clinical Pharmacogenetics Implementation Consortium (CPIC). These data were associated with 10 pharmacogenes: DPYD, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, G6PD, MT-RNR1, SLCO1B1, and VKORC1. All patients were taking at least one of the 38 drugs and had inherited at least one actionable PGx variant that would have informed prescribing decisions if this information had been available pre-emptively. The non-cancer drugs with PGx implications that were common (prescribed to at least one-third of patients) included anti-depressants, anti-infectives, non-steroidal anti-inflammatory drugs, opioids, and proton pump inhibitors. Based on these results, we conclude that pre-emptive PGx testing may benefit patients with breast cancer by informing drug and dose selection to maximize efficacy and minimize AEs.
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Project description:Breast cancer is the most frequent cause of cancer death in low- and middle-income countries, in particular among sub-Saharan African women, where response to available anticancer treatment therapy is often limited by the recurrent breast tumours and metastasis, ultimately resulting in decreased overall survival rate. This can also be attributed to African genomes that contain more variation than those from other parts of the world. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to specific available treatments and the known genetic variabilities associated with metabolism and/or transport of breast cancer drugs, and treatment outcomes when possible. The emphasis is on the African genetic variation and focuses on the genes with the highest strength of evidence, with a close look on CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, CYP19A1, UGT1A4, UGT2B7, UGT2B15, SLC22A16, SLC38A7, FcγR, DPYD, ABCB1, and SULT1A1, which are the genes known to play major roles in the metabolism and/or elimination of the respective anti-breast cancer drugs given to the patients. The genetic variability of their metabolism could be associated with different metabolic phenotypes that may cause reduced patients' adherence because of toxicity or sub-therapeutic doses. Finally, this knowledge enhances possible personalized treatment approaches, with the possibility of improving survival outcomes in patients with breast cancer.
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Project description:Tamoxifen is the most used hormonal therapy for oestrogen receptor-positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N-desmethyl-tamoxifen ratios (P = 0.0006).
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Project description:Breast cancer is one of the most common malignancies in females. It is an etiologically complex disease driven by a multitude of cellular pathways. The proliferation and spread of breast cancer is intimately linked to cellular glucose metabolism, given that glucose is an essential cellular metabolic substrate and that insulin signalling has mitogenic effects. Growing interest has focused on anti-diabetic agents in the management of breast cancer. Epidemiologic studies show that metformin reduces cancer incidence and mortality among type 2 diabetic patients. Preclinical in vitro and in vivo research provides intriguing insight into the cellular mechanisms behind the oncostatic effects of metformin. This article aims to provide an overview of the mechanisms in which metformin may elicit its anti-cancerous effects and discuss its potential role as an adjuvant in the management of breast cancer.
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