**3. Deployment strategies for metformin in cancer**

Metformin can be used tactically under various scenarios against cancer. It can be used as standalone or in combination with other agents for the primary or secondary prevention of cancer [31], as neoadjuvant or adjuvant cancer therapy [32], as maintenance therapy or salvage therapy, or to reduce chemoresistance or enhance radiosensitivity [33] as well as for the reduction of side-effects or complications [34]. Notably, metformin is usually deployed as an adjunct but not as a sole agent except in the case of primary prevention. Since it has such low toxicity and multifaceted mechanisms of actions, it is usually integrated with other treatment agents and modalities under other scenarios besides primary prevention. The key feature of metformin that allows this combinatorial deployment is its low toxicity and its synergism with various other agents and modalities, as it has been demonstrated both *in vitro* and *in vivo*.

#### **3.1 Metformin synergies with other anticancer agents and modalities**

Notably, synergisms with metformin has been reported with numerous anticancer agents and modalities including chemotherapy [35], targeted drugs [36], and radiotherapy [37]. In the past ten years alone, metformin synergism with chemotherapies pemetrexed [38], temozolomide [39], cisplatin [40], gemcitabine [41], paclitaxel [42], 5FU [43], vincristine [44] with targeted agents erlotinib against non-small cell lung cancer [45], imatinib against colon cancer [46], gefitinib against bladder cancer [47], trastuzumab against human epidermal growth factor receptor 2 (HER2) positive breast cancer [48], celecoxib against NSCLC [49], regorafenib against liver cancer [50], with everolimus as neuroendocrine cancers [51]; and other anticancer agents such as with nelfinavir against cervical cancer [52], propranolol against breast cancer [53], 2-deoxyglucose against ovarian cancer [54], arsenic trioxide against cholangiocarcinoma [55], and with natural compounds epigallocatechin-3-gallate [56], curcumin [57], berberine [58], resveratrol [59].

What is interesting is that different biological mechanisms may be responsible for the efficacy of metformin's combinatorial effects depending on the specific combination. For example, regulation of lipid synthesis may underlie metformin enhancement of taxanes, pro-apoptotic mechanisms could account for its synergy with cisplatin, AMPK/mTOR signaling maybe significant when combined with hormonal drugs, and suppression of HIF-1, P glycoprotein (p-gp) and multidrug resistance-associated protein 1 (MRP1) expression is thought to be responsible for metformin's synergy with anti-metabolites [60]. In the case of targeted agents such as the epidermal growth factor receptor (EGFR) inhibitor gefitinib against NSCLC where a Chinese study on diabetic NSCLC patients on gefitinib demonstrated significantly improved response rate, disease control rate, median progression free survival (PFS) and median overall survival (OS) compared with patients controls (70.5% vs. 45.7%, *P* = 0.017; 97.7% vs. 80.4%, *P* = 0.009; 19 months vs. 8 months, *P* = 0.005; 32 months vs. 23 months, *P* = 0.002, respectively) [61]. Separately, metformin combination with m-TOR inhibitor everolimus in patients with advanced pancreatic neuroendocrine tumors showed improved median PFS of patients treated with the combination vs. control (median PFS, 20.8 months;

*Repurposing of Metformin as a Multifaceted and Multitasking Preventative and Treatment… DOI: http://dx.doi.org/10.5772/intechopen.96101*

hazard ratio, 0.49; 95% confidence interval (CI), 0.34–0.69; *P* < .0001), suggesting that metformin may sensitize everolimus in these patients [62]. As far as combination with antibody treatments go, a randomized phase II study of metformin plus bevacizumab-based chemotherapy in advanced or metastatic NSCLC patients resulted in a 47% (95% CI, 25%–88%) one-year PFS in patients on metformin, which is much improved over a historical control of 15%. Median overall survival of 15.9 months of metformin treated patients was also improved over control arm of 13.9 months [63]. Furthermore, metformin in combination with immune checkpoint inhibitors (ICI) has received much recent attention as ICI is increasingly being deployed in cancer treatments. A retrospective review of 50 NSCLC patients receiving ICIs as second or third line therapy with or without metformin showed higher overall response rate, disease control, median OS and PFS in the metformin group (41.1 vs. 30.7%, *P* = 0.4; 70.5 vs. 61.6%, *P* = 0.5; 11.5 vs. 7.6 months, *P* = 0.5 and 4.0 vs. 3.0 months, *P* = 0.6, respectively) [64]. Very recently, several significant trials have been launched to further investigate the role metformin may have in combination with ICI's, including a metformin-nivolumab combination in patients with NSCLC (NCT03048500), a phase I trial investigating the combined effect of metformin and another anti-PD-L1 antibody durvalamab in head and neck squamous cell carcinoma (NCT03618654), a phase I trial of metformin in combination of the anti-PD-1 antibody pembrolizumab in advanced melanoma (NCT03311308), and a phase II trial combining metformin with nivolumab in stage IV colorectal cancer that has not responded to previous treatment (NCT03800602).

The use of metformin under various scenarios against cancer has been best studied clinically for primary prevention and in the neoadjuvant setting and some of the relevant data is summarized below.

#### **3.2 Metformin for primary prevention of cancer**

Cancer prevention is the earliest role that metformin was hypothesized to play in the disease as it was Evans' original 2005 retrospective case–control study demonstrating metformin's involvement in reducing cancer risk in T2DM that highlighted its potential for cancer [4]. Subsequently, a confirmative cohort study of T2DM with metformin followed in which the frequency of cancer was significantly lower in patients receiving metformin versus controls who had never received metformin, after adjusting for body mass index, hemoglobin A1C, smoking and the use of other drugs [65], a finding that was subsequently repeatedly confirmed. Indeed, meta-analyses have demonstrated that metformin is associated with a decreased risk of breast, colon, liver, pancreas, prostate, endometrium and lung cancer across meta-analyses [31] suggesting that people with T2DM receiving metformin demonstrate a lower risk and improved outcomes with most common cancers; more specifically one meta-analysis found that metformin-treated T2DM patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index [66].

#### **3.3 Metformin in neoadjuvant treatment**

Neoadjuvant effects of metformin in combination or alone has been clinically explored in several cancers types. In one study of two hundred eighty-five patients with esophageal adenocarcinoma treated with concurrent chemoradiation followed by esophagectomy, complete remission (CR) was higher in T2DM patients taking metformin (34.5%) compared to those who are not (4.8%, *P* = 0.01) as well as nondiabetic patients who are not on the drug (19.6%, *P* = 0.05) and furthermore the CR rate was found to be related to metformin dose, with ≥1500 mg per day associated

with a higher CR rate [67]. In a separate study of diabetic rectal cancer patients undergoing neoadjuvant chemoradiotherapy, those on metformin experienced better tumor responses (*P* = 0.002), pathologic complete remission (p = 0.037), and N downstaging (*P* < 0.001) as well as experienced improved cancer specific survival and lower risk of recurrence [68]. Separately, women with endometrial cancer on neoadjuvant metformin 850 mg twice daily for an average of 20 days between diagnosis and surgery had reduced cell proliferation per Ki-67 expression, compared to the untreated [69]. A similar biomarker based on a "window of opportunity" assessment of metformin 500 mg three times daily for a median duration of 18 days in non-diabetic breast cancer also demonstrated that short-term preoperative metformin resulted in both clinical and cellular changes including a significant decrease in the Ki-67 proliferation index from 36.5 to 33.5% (*P* = 0.016) [70]. Separately and perhaps more significantly, a study involving early-stage breast cancer assessing remission rates after neoadjuvant therapy among metformin vs. non-metformin users found a significant difference in CR of 24% in the metformin group, 8.0% in the non-metformin group, and 16% in the non-diabetic group, with metformin use independently predictive of response (OR 2.95; *P* = 0.04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant chemotherapy use by multivariate logistic regression [71].
