Association of Metformin Use and Survival Outcome in Women With Cervical Cancer

Takiuchi, Tsuyoshi; Machida, Hiroko; Hom, Marianne S.; Mostofizadeh, Sayedamin; Frimer, Marina; Brunette, Laurie L.; Matsuo, Koji

doi:10.1097/igc.0000000000001036

Cited by 17 publications

(16 citation statements)

References 42 publications

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“…A total of five studies from four articles involving 149,742 participants were finally included in the meta-analysis, two studies were RCTs and three were retrospective cohort studies, published between 2010, and 2017. Of these, two studies were conducted in the UK [11], one in Taiwan [14], one in USA [15] one in Thailand [16], and the sample size ranged from 248 to 139,911 all of which are outlined in.…”

Section: Resultsmentioning

confidence: 99%

A systematic review and meta-analysis on the effects of metformin on survival outcomes and risk in women with cervical cancer

2020

European Journal of Gynaecological Oncology

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Objective: A systematic review and meta-analysis was conducted to quantitatively assess the effects of metformin on both the treatment and risk of cervical cancer in women. Materials and Methods: A search was conducted in a number of databases including CNKI, VIP, Wanfang Digital Journal Full-text Database, PubMed, Cochrane, and Web of Science. In accordance with inclusion and exclusion criteria screening in the literature, Newcastle-Ottawa scale and RevMan 5.3 software were employed to perform the meta-analysis. Results: A total of five studies taken from four articles involving 149,742 participants were finally included in meta-analysis,two random clinical trials (RCTs) and three retrospective cohort studies. Evaluation of metformin usage in two of the studies did not show significant association with five-year overall survival (OS) of patients receiving adjuvant whole-pelvic radiation therapy (WPRT) as a primary therapy compared to those. not using metformin (RR = 1.08, 95% CI 1.00-1.18, p = 0.06). In the three other studies metformin use was associated with a significant reduction in cervical cancer risk in diabetes mellitus patients (RR = 0.60, 95% CI 0.44-0.82, p = 0.001). Conclusion: Merformin use is associated with a reduction in cervical cancer risk in patients with diabetes mellitus, but is not associated with five-year OS of patients receiving WPRT. Further studies are required to confirm survival outcomes for use of metformin in cervical cancer.

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Section: Resultsmentioning

confidence: 99%

A systematic review and meta-analysis on the effects of metformin on survival outcomes and risk in women with cervical cancer

2020

European Journal of Gynaecological Oncology

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“…Recently, researchers investigated the potential anticancer role of metformin in non-diabetic patients with cancer, such as lung cancer, breast cancer and prostate cancer; however, the results are controversial [ 7 ]. The role that metformin may play in non-diabetic women with cervical cancer remains unclear since metformin is typically given to only diabetic patients and the typical cervical cancer population is young and nondiabetic [ 8 ]. In Takiuchi et al’s study [ 8 ], the authors examined the association of metformin use and survival outcome in women with cervical cancer by stratifying patients into diabetic metformin users, 68; diabetic metformin nonusers, 42; nondiabetic patients, 673.…”

Section: Introductionmentioning

confidence: 99%

“…The role that metformin may play in non-diabetic women with cervical cancer remains unclear since metformin is typically given to only diabetic patients and the typical cervical cancer population is young and nondiabetic [ 8 ]. In Takiuchi et al’s study [ 8 ], the authors examined the association of metformin use and survival outcome in women with cervical cancer by stratifying patients into diabetic metformin users, 68; diabetic metformin nonusers, 42; nondiabetic patients, 673. There were two metformin users, among the 673 nondiabetics, excluded in that study for not being diabetic.…”

Section: Introductionmentioning

confidence: 99%

“…However, not all the studies are in progress are on the prognostic significance of metformin in cervical cancer patients. Takiuchi et al demonstrated no association between metformin use and the survival outcome of women with cervical cancer [ 8 ]. An epidemiologic study evaluated the association between metformin use and oncological outcomes in patients with cervical cancer and type 2 diabetes, and revealed that patients receiving metformin had a lower recurrence rate than those not receiving metformin [ 18 ]; moreover, non-use of metformin (hazard ratio, 1.89; p = 0.037) was an independent adverse prognostic factor of 5-year disease-free survival, but not of overall survival [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Metformin may reduce the risk of cancer in patients with type 2 diabetes [ 20 , 21 ], and several studies have demonstrated an association between metformin use and prognosis or mortality in patients with cancer. Among older women with diabetes and cervical cancer, cumulative doses of metformin may be associated with a significant decrease in mortality [ 22 ]; however, a recent study indicated that the survival outcome in women with cervical cancer was not associated with metformin use [ 8 ], while another study showed that metformin may reduce the risk of gynecological cancers [ 23 ]. Metformin significantly reduced the risk of cancer (RR = 0.27, 95% CI = 0.17–0.41) and the overall risks of ovarian (RR = 0.18, 95% CI = 0.12–0.28) and cervical cancer (RR = 0.60, 95% CI = 0.43–0.83) in an Asian population [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Chen

Wang

Chen

et al. 2021

Cancers

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Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

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Effects of Metformin on the virus/host cell crosstalk in human papillomavirus‐positive cancer cells

Hoppe‐Seyler

Herrmann

Däschle

et al. 2021

Intl Journal of Cancer

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Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The viral E6/E7 oncogenes maintain the malignant growth of HPV-positive cancer cells. Targeted E6/E7 inhibition results in efficient induction of cellular senescence, which could be exploited for therapeutic purposes. Here we show that viral E6/E7 expression is strongly downregulated by Metformin in HPV-positive cervical cancer and head and neck cancer cells, both at the transcript and protein level. Metformininduced E6/E7 repression is glucose and PI3K-dependent but-other than E6/E7 repression under hypoxia-AKT-independent. Proteome analyses reveal that Metformin-induced HPV oncogene repression is linked to the downregulation of cellular factors associated with E6/E7 expression in HPV-positive cancer biopsies. Notably, despite efficient E6/E7 repression, Metformin induces only a reversible proliferative stop in HPV-positive cancer cells and enables them to evade senescence. Metformin also efficiently blocks senescence induction in HPV-positive cancer cells in response to targeted E6/E7 inhibition by RNA interference. Moreover, Metformin treatment enables HPV-positive cancer cells to escape from chemotherapyinduced senescence. These findings uncover profound effects of Metformin on the virus/host cell interactions and the phenotype of HPV-positive cancer cells with implications for therapy-induced senescence, for attempts to repurpose Metformin as an anticancer agent and for the development of E6/E7-inhibitory therapeutic strategies.

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Association of Metformin Use and Survival Outcome in Women With Cervical Cancer

Abstract: In this study population, metformin use was not associated with survival of women with cervical cancer.

Cited by 17 publications

References 42 publications

A systematic review and meta-analysis on the effects of metformin on survival outcomes and risk in women with cervical cancer

A systematic review and meta-analysis on the effects of metformin on survival outcomes and risk in women with cervical cancer

Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Effects of Metformin on the virus/host cell crosstalk in human papillomavirus‐positive cancer cells

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