The impact of metformin on clinical outcomes of metastatic colorectal cancer with known molecular profile treated with cytotoxic chemotherapy or immune checkpoint inhibitor.
Authors: Bicer Fuat , Ozluk Ahmet Anil , Malla Midhun , Sadeghipour Negar , Elliott Andrew , Lou Emil , Khushman Moh'd M. , Vanderwalde Ari M. , El-Rayes Bassel F. , Akce Mehmet 
Published: June 2024

e15580

Background: Colorectal cancer (CRC) is the third most common cancer in the US, with a dismal 5-year OS of 13% in mCRC. Concomitant metformin with chemotherapy or immune checkpoint inhibitors (ICIs) revealed improved outcomes in various cancers. Metformin's anti-cancer effects stem its effects on cancer metabolism, cell cycle modulation, cancer stem cells, gut microbiota, immunomodulatory properties. The aim of this retrospective study was to study the impact of concomitant metformin use with the type of systemic therapy (chemotherapy or ICIs) in CRC. Methods: CRC tumors were analyzed by NGS of DNA (592-gene) and RNA (whole transcriptome) at Caris Life Sciences. MSS was assessed by NGS, with MSI-H and MSS patients subcategorized by concomitant metformin use with ICI or with chemotherapy, respectively. Real-world OS, derived from insurance claims data, was calculated from the time of CRC sample collection to the last contact. Hazard ratio (HR) was calculated using the Cox proportional hazards model, with p values calculated using the log-rank test. Results: The study cohort included 31,083 CRC cases (male: female = 1.2, age: 80% > = 50 years). Common molecular alterations included TP53 (73.6%), APC (77.6%), KRAS (47.4%), CTNNB1 (2.0%), and HER2 amplification (1.7%). 1,503 patients were MSI-H (4.83%), 21,330 as MSS (68.6%), and 8,250 indeterminate. MSI-H patients receiving concurrent ICI/metformin had similar OS (52.7 vs. 55.4 months, HR = 0.78, 95% CI: 0.41 – 1.51, p = 0.462). Conversely, OS was increased in MSS patients on concomitant chemotherapy and metformin (38.1 vs 31.1 months, HR = 0.77, 95% CI: 0.69 – 0.86, p < 0.00001). In comparing real-world OS between left-sided and right-sided colorectal cancer (CRC), regardless of metformin use, multivariate analysis incorporating molecular alterations revealed longer OS for left-sided MSS CRC compared to right-sided (HR = 0.80, 95% CI: 0.76 – 0.84, p < 0.00001). However, further improvement in OS was associated with concurrent metformin use in both right-sided and left-sided tumors. Conclusions: In this retrospective analysis of real-world clinical outcomes, patients receiving concomitant metformin and cytotoxic chemotherapy had improved clinical outcomes in MSS CRC compared to those not on concurrent metformin. However, the concurrent use of metformin with ICIs in MSI-H CRC did not show an impact on clinical outcomes given low sample size. These results add to the existing body of literature on the potential benefits of metformin in the context of MSS CRC and underscore the importance of a prospective controlled study of concurrent metformin use with systemic chemotherapy in metastatic CRC. Limitations of this study involves the potential inclusion of cases with prior metformin use, small sample size, retrospective analyses, and the lack of control for the patients with type II DM.