**4.3 Colon cancer**

Ng et al. from Singapore found 58 studies that provided incidences of colorectal adenoma and cancer and cancer survival outcomes and found that metformin significantly lowered the risk of colorectal adenoma (RR 0.77, CI 0.67–0.88, *P* < 0.001), advanced adenoma (0.61, CI 0.42–0.88, *P* = 0.008) and colorectal cancer (RR 0.76, CI 0.69–0.84, *P* < 0.001) respectively. Overall cancer survival (HR 0.6, CI 0.53–0.67, *P* < 0.001), even among metastatic cases was also higher among metformin users (HR 0.77, CI 0.68–0.87, *P* < 0.001), and it was concluded that metformin significantly reduces colorectal adenoma and cancer incidence as well as enhanced colorectal cancer survival at all stages [78].

#### **4.4 Endometrial cancer**

In 19 studies reviewed in 2017, metformin used reversed atypical endometrial hyperplasia to normal, and decreased cell proliferation from 51.94% (CI = 36.23% to 67.46%) to 34.47% (CI = 18.55% to 52.43%) [79], while separately, a review of seven studies showed that metformin could significantly improve overall survival of in endometrial cancer (HR = 0.61, 95% CI 0.48–0.77, P < 0.05) and reduce their recurrence risk (OR = 0.50, 95% CI 0.28–0.92, *P* < 0.05) [80], whereas another review of six retrospective cohorts if 4723 endometrial cancer cases demonstrated that metformin use was associated with a significant reduction in overall mortality in comparison with not using metformin (adjusted HR 0.64, 95% CI 0.45–0.89, *P* = 0.009) irrespective of diabetic status [81], and these results corroborated the improved overall (HR, 0.58; 95% CI, 0.45–0.76; *P* = 0.207) as well as progression free survival (HR, 0.61; 95% CI, 0.49–0.76; *P* = 0.768) found in another review of 6242 patients from fourteen studies [82].

#### **4.5 Lung cancer**

An analysis of 13 observational studies found lung cancer incidence to be reduced in diabetic patients on metformin vs. no metformin (RR = 0.89; 95% CI, 0.83–0.96; *P* = 0.002) [83]. A separate meta-analysis found six studies comparing metformin usage and non-metformin usage significantly improved overall survival in diabetic patients with NSCLC [pooled HR =0.87 (0.77–0.99), *P* = 0.04] [84]. Especially noteworthy was an ambitious prospective clinical trial conducted by Marrone et al. which studied non-diabetics with advanced or metastatic NSCLC receiving platinum-based doublet chemotherapy and bevacizumab with or without metformin 1000 mg twice daily followed by maintenance therapy with bevacizumab and metformin combined or bevacizumab alone and showed a significant clinical benefit in PFS (9.6 vs. 6.7 months) with the addition of metformin [63].

#### **4.6 Pancreas cancer**

A review of seventeen studies involving 36791 participants study has evidenced a significant association of metformin adjuvant treatment in pancreas cancer with overall survival benefit (HR = 0.88, 95% CI = 0.80–0.97) especially in Asians, those with early stage disease and those undertaking surgery [85]. In terms of overall survival with metformin use in pancreas cancer, a study of 8 retrospective cohort studies and 2 randomized clinical trials representing 3,042 patients revealed overall survival to be improved with metformin (meta-HR = 0.79; 95% CI: 0.70, 0.92, *P* < 0.001) [86].

#### **4.7 Prostate cancer**

In a systematic review involving eleven studies with 877,058 patients, the odds ratio of metformin use for reducing prostate cancer was estimated at 0.89 (95%CI: 0.67–1.17) and it was concluded that metformin consumption reduced the risk of prostate cancer, although the result was not statistically significant [87]. Separately, a review of eight studies on diabetic patients with prostate cancer found no metformin use was associated with an increased risk of cancer recurrence (RR, 1.20; 95% CI, 1.00–1.44) [88], which concurs with another review of eight retrospective cohort studies and one nested-case–control study, metformin was found to be associated with a reduced risk of biochemical recurrence (pHR: 0.82, 95% CI 0.67, 1.01, *P* = 0.06) [89]. Finally, a large review of 30 cohort studies, including 1,660,795 prostate cancer patients revealed that metformin treatment compared with no treatment improved overall, prostate cancer specific, and recurrence free survival (HR = 0.72, 95% CI: 0.59–0.88, *P* = 0.001; HR = 0.78, 95% CI: 0.64–0.94, *P* = 0.009; and HR = 0.60, 95% CI: 0.42–0.87 *P* = 0.006, respectively) [90].

#### **4.8 Ovarian cancer**

*One review of 13 studies involving ovarian cancer incidence and prognosis revealed metformin use to be associated with* a lower incidence (pooled OR 0.76, 95% CI 0.62 to 0.93, *P* = 0.008) as well as improved prognosis (pooled OR 0.55, 95% CI 0.36 to 0.84, *P* = 0.006) [91].

#### **4.9 Other cancers**

Metformin is also increasingly studied or planned in less common cancers, such as glioblastoma, thyroid cancer, and non-Hodgkin's lymphoma. The recent study on newly diagnosed glioblastoma showed that temozolomide plus memantine, mefloquine, and metformin are feasible as an adjuvant therapy [92]. One planned phase 1b/2 clinical trial of metformin and chloroquine was recruiting patients with IDH1-mutated or IDH2-mutated solid tumors, including glioma [93]. In another recent retrospective study from Korea, cancer preventative effects of metformin on thyroid cancer were observed in individuals with T2DM on long duration or higher doses of the drug [94]. Separately, a trial in head and neck squamous cell cancer patients revealed metformin to inhibit cancer by enhancing apoptosis, and increasing cellular immune infiltration of the cancer [95]. In non-Hodgkin's lymphoma,

a retrospective analysis of looking at T2DM patients treated with standard therapy found improved progression-free survival and overall survival compared to control not taking metformin [96].
