METFORMIN

A substantial number of clinical trials in various cancers have results that have not confirmed the pre-clinical promise of metformin, beyond those recorded in diabetic patients for instance in lung cancer. To the contrary, some studies show increased rates of progression in several cancers when metformin is administered to non diabetics. Reports show both an increase in tumor aggressiveness and in resistance to therapy, for instance in digestive cancers.

In breast cancer, a recent canadian large scale phase III clinical study of breast cancer recurrence found no evidence that metformin improved patient outcomes. Concerningly, the data published even shows a tendency to increased relative risk levels in the 30% range among those taking metformin. Additionally in this population of non diabetics, metformin did not reduce the usual markers of metabolic health and inflammation such as insulin, HOMA-IR, leptin and c-reactive protein. (Highlight 1). Where metformin might show benefit in ER+ breast cancer appears to be in diabetic patients with particularly >70 years old. A large meta-analysis from 2023 shows a halving of relative risks in this group (Highlight 2). On the other hand, there was a notable increased risk even in this group for subtype ER-

Another 2021 canadian study in locally advanced lung cancer progression in non-diabetics had even more alarming findings. Both progression free disease survival and even relative overall mortality rates were drastically lower in the patients recieving metformin. For patients with type 2 diabetes there are studies showing significantly reduced risks during oncology with metformin added to TKI therapy. (see References). And in liver cancer, there is a large negative effect reported in patients due to metformin which increased tumor growth and treatment resistance. The same team have shown how low dose aspirin has protective actions there.

Multiple summary reviews have sought to explain the unexpected lack of benefits seen in metformin clinical trials, and speculate that more selective targeting to specific cases particularly with immunotherapy remain promising.One more positive finding is in localized prostate cancer treatment, finding almost a 50% longer progression free period but this is not confirmed elsewhere and did not change overall survival times.

The concept of using multiple re-purposed drugs for so called metabolic cancer therapy has included mebendazole with metformin, atorvastatin, dipyridamole and doxycycline. This has been withdrawn from its phase 3 trials, due to a lack of benefit and high burden from side effects in patients; https://clinicaltrials.gov/study/NCT02201381

The MA.32 trial provided a unique opportunity to examine the effects of metformin on the risk of developing new primary invasive cancers in a population without diabetes. Metformin did not affect the risk of new contralateral breast cancer, any invasive cancer, cancers outside of the breast, obesity, or tobacco-associated cancers…. Furthermore, metformin did not reduce cancer risk in subgroups defined by BMI, metabolic factors (insulin, HOMA, leptin, hsCRP), smoking history, or rs11212617 SNP status, factors that could potentially be associ...

We found evidence supporting an association of post-diagnostic use of statins and metformin with survival in patients with BC….The Hazard Ratio for the association between metformin use, compared to use of non-metformin antidiabetics, and BC-specific survival was estimated at 0.70 (ER+: HR = 0.67 ER−: HR = 1.62). An association with longer BC-specific survival was found among patients aged ≥ 70 years (HR = 0.57, 95% CI 0.36–0.92) and those not using chemotherapy (HR = 0.46).

Treatment failure was detected in 18 [Lung cancer] patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients. The 1-year progression-free survival rate was 34.8%) in the metformin arm and 63.0% in the control arm (hazard ratio, 2.42) The overall survival rates were 47.4% in the metformin arm and 85.2% in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event.

The concomitant use of metformin with systemic anticancer therapy did not increase tumor response (the pooled OR of ORR = 1.23), compared with anticancer therapy alone. In terms of survival, metformin added to anticancer agents failed to prolong PFS (HR = 0.95) and Overall Survival (HR = 0.97). In conclusion, this meta-analysis of randomized clinical trials indicates that the addition of metformin to systemic anticancer therapy has no clinical benefits in patients with advanced or metastatic cancer…The addition of metformin to anticancer ag...

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URL	Rating	Highlight	Highlight 2
https://ascopubs.org/doi/10.1200/JCO.23.00296	N/A	The MA.32 trial provided a unique opportunity to examine the effects of metformin on the risk of developing new primary invasive cancers in a population without diabetes. Metformin did not affect the risk of new contralateral breast cancer, any invasive cancer, cancers outside of the breast, obesity, or tobacco-associated cancers. Point estimates of risk were all above 1, making it unlikely that additional power would have identified a clinically important reduction in risk. Furthermore, metformin did not reduce cancer risk in subgroups defined by BMI, metabolic factors (insulin, HOMA, leptin, hsCRP), smoking history, or rs11212617 SNP status, factors that could potentially be associated with metformin benefit.	The effect of metformin versus placebo on the risk of developing a new invasive cancer did not differ by hormone receptor status (positive HR, 1.19[ 95% CI, 0.83 to 1.69] v negative HR, 1.44 [95% CI, 0.86 to 2.41]) or HER2 status (positive HR, 0.83 [95% CI, 0.39 to 1.81] v negative HR, 1.36 [95% CI, 0.99 to 1.86]) of the primary tumor (interaction P values .53 and .25, respectively) or by receipt of adjuvant hormonal therapy (tamoxifen HR, 1.23 [95% CI, 0.73 to 2.08]; aromatase inhibitor HR, 1.34 [95% CI, 0.80 to 2.24]; none HR, 1.21 [95% CI, 0.75 to 1.95; interaction P value .96). Metformin effects were similar for obesity-associated cancers (invasive breast, colorectal, pancreatic, gastric cardia, ovary, uterus, kidney, thyroid, and myeloma)26 and other cancers
https://pmc.ncbi.nlm.nih.gov/articles/PMC7532491/	4.5	The concomitant use of metformin with systemic anticancer therapy did not increase tumor response (the pooled OR of ORR = 1.23), compared with anticancer therapy alone. In terms of survival, metformin added to anticancer agents failed to prolong PFS (HR = 0.95) and Overall Survival (HR = 0.97). In conclusion, this meta-analysis of randomized clinical trials indicates that the addition of metformin to systemic anticancer therapy has no clinical benefits in patients with advanced or metastatic cancer...The addition of metformin to anticancer agents was not associated with increased incidence of AEs [Adverse Events] in most studies	Several possibilities may explain the reasons why the addition of metformin to anticancer agents failed to show clinical benefits in patients with advanced or metastatic cancer. First, the impressive effect of metformin in reducing the incidence of and mortality from cancer might be associated with time-related biases (e.g., immortal time bias) in some observational studies 49. Second, the dose of metformin used in the clinical trials might be insufficient. The optimal dose of metformin to display anticancer effects is not known. The metformin in the included trials were administered at the same dosage as usually used in the treatment of diabete
https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-023-01697-2	4	We found evidence supporting an association between post-diagnostic use of statins and metformin and survival, in patients with BC. Our findings indicate potential differences according to ER status.	The HR for the association between metformin use, compared to use of non-metformin antidiabetics, and BC-specific survival was estimated at 0.70 (ER+: HR = 0.67; ER−: HR = 1.62. An association with longer BC-specific survival was found among patients aged ≥ 70 years (HR = 0.57) and those not using chemotherapy (HR = 0.46).
https://pubmed.ncbi.nlm.nih.gov/26341687/	3.5	The median progression-free survival (PFS) and median overall survival (OS) in Group A were significantly longer than those in Group B (19.0 months vs. 8.0 months, P = .005; 32.0 months vs. 23.0 months, P = .002). The objective response rate (ORR) and disease control rate (DCR) in Group A were significantly higher than those in Group B (70.5% vs. 45.7%, P = .017; 97.7% vs. 80.4%, P = .009). Secondary data analysis showed that metformin use significantly prolonged the median PFS in subgroups using either first-line EGFR-TKI or second-line EGFR-TKI.	Metformin and EGFR-TKI have a synergistic effect in the treatment of DM2 NSCLC patients harboring EGFR-activating mutations. Metformin use is associated with improved survival and delayed onset of acquired resistance to EGFR-TKI. Studies have shown that the antidiabetic drug metformin could effectively increase the sensitivity of TKI-resistant lung cancer cells to EGFR-TKI. This study aimed to evaluate the effect of metformin in combination with EGFR-TKI on the prognosis of non-small cell lung cancer (NSCLC) patients with diabetes mellitus type 2 (DM2).
https://www.sciencedirect.com/science/article/abs/pii/S1078143921002283?via%3Dihub	3	A total number of 124 patients underwent randomization where 62 patients were allocated in each arm. Over a median follow up of 22 months, the CRPC-FS was significantly improved with metformin (29 months, 95% CI 25-33 vs. 20 months 95% CI 16-24; P = 0.01). After subgroup analysis, the addition of metformin improved the CRPC-FS in patients with high risk localized disease	Metformin is a safe and low-cost drug. Combining with androgen deprivation therapy improves the outcome in locally advanced or metastatic prostate cancer. Patients with low volume metastatic prostate cancer seem to drive more benefit.
https://pubmed.ncbi.nlm.nih.gov/34323924/	N/A	Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients. The 1-year progression-free survival rate was 34.8%) in the metformin arm and 63.0% in the control arm (hazard ratio, 2.42) The overall survival rates were 47.4% in the metformin arm and 85.2% in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event.	In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC [unoperable locally advanced lung cancer] who are candidates for chemoradiotherapy.
https://www.nature.com/articles/s41416-023-02204-2	N/A	Most notably, the MA.32 study was a Phase III randomised trial that recruited over 3600 patients with high-risk operable breast cancer randomised to 850 mg metformin or placebo for 5 years. The investigators concluded that the addition of adjuvant metformin did not lead to an improvement in disease-free survival for either oestrogen receptor-positive or negative breast cancer [19]. An exploratory analysis did suggest that there might be some benefit in patients with HER2-positive disease and who genotyped for the C allele of the rs11212617 single-nucleotide polymorphism although the authors concluded that this would need to be confirmed with further prospective study	In summary, outcomes from late-phase efficacy studies testing metformin as a repurposed cancer therapeutic have been disappointing. In a rush to establish its potential utility, such trials were designed prior to due diligence with regard to patient selection, mechanism of action and appropriate combination. New avenues of investigation in selected populations including the assessment of combination with immunotherapy, and potential as a cancer preventative agent still warrant well-designed clinical investigation.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04263-8	N/A	There is a discrepancy in the antitumor effect of metformin between clinical research and preclinical studies, although metformin has shown notable benefits for cancer prevention and treatment in preclinical research, and the related molecular mechanisms have been extensively studied. The challenges mainly include (1) simulating pharmacokinetics consistent with clinical settings, including appropriate metformin concentrations and dosing time; (2) exploring suitable synergetic therapies and patients who are more sensitive to metformin; and (3) utilizing other forms of biguanides, such as phenformin	Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin’s modes of action can be divided into two broad, non-mutually exclusive categories: “direct effects”, which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and “indirect effects” that arise from systemic metabolic changes depending on blood glucose and insulin levels.
https://diabetesjournals.org/care/article/46/5/904/148773/Metformin-and-Cancer-Solutions-to-a-Real-World	N/A	Soon after the signals of a potential benefit of metformin as a cancer treatment, calls were made for randomized therapeutic trials in several cancers (25–27). However, these trials that assessed metformin as adjuvant therapy for the treatment of various cancers did not find clinical benefits on cancer outcomes. A recent meta-analysis of nine phase 2 randomized trials of metformin as an adjuvant to standard of care for different advanced or metastatic cancers found no increase in tumor response (OR 1.23), progression-free survival (HR 0.95), or overall survival (HR 0.97) compared with standard of care alone	Randomized trials were also conducted to assess metformin in the treatment of other cancers. A phase 2 trial of 54 patients with unresected locally advanced non–small-cell lung cancer found that metformin in combination with chemoradiotherapy was associated with a higher incidence of locoregional disease progression (HR 2.42) and a higher mortality (HR 3.80) than no metformin. A meta-analysis of four randomized trials in patients with non–small-cell lung cancer also did not find that metformin improved overall survival (risk ratio [RR] 0.86) or progression-free survival (RR 0.92)
https://www.nature.com/articles/s41598-024-70928-z	N/A	Our study encompassed a larger patient sample receiving first-line treatment for advanced HCC (Atezolizumab plus Bevacizumab or Lenvatinib), whereas the previous study focused exclusively on patients who received immunotherapy in either the first or subsequent lines of treatment. However, our findings provide substantial support, based on a larger patient cohort, to the notion that individuals receiving immunotherapy for advanced HCC and using metformin as a chronic medication exhibit inferior survival outcomes when compared to those not taking metformin chronically	...the present study represents the first analysis focusing on the role of metformin in a large cohort of patients with advanced HCC, who underwent first-line therapy with either Lenvatinib or Atezolizumab plus Bevacizumab. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group. Our findings corroborated in a larger sample size the earlier study by Kang and colleagues adding a crucial piece to the complex puzzle of the interaction between metformin and immunotherapy for patients dealing with advanced HCC.
https://aacrjournals.org/clincancerres/article/25/8/2424/82360/PRE-surgical-Metformin-In-Uterine-Malignancy	N/A	Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.	These results are contrary to those of earlier window studies in endometrial cancer, which had almost universally described a significant reduction in cell proliferation with short-term metformin treatment of a similar dose and duration (13–15, 17, 18). These studies had, however, been small, unblinded, nonrandomized and often lacked a control arm for comparison. The major strength of the current trial is its rigorous study design, which included a placebo arm, blinding of participants
https://www.ejcancer.com/article/S0959-8049(17)31274-1/abstract	N/A	In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin	Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin...We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%,) .

METFORMIN

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