Body Mass Index Influences the Salutary Effects of Metformin on Survival After Lobectomy for Stage I NSCLC

Yendamuri, Sai; Barbi, Joseph; Pabla, Sarabjot; Petrucci, Cara; Punnanitinont, Achamaporn; Nesline, Mary; Glenn, Sean T.; DePietro, Paul; Papanicalou-Sengos, Antonios; Morrison, Carl; Dy, Grace K.; Elkin, Peter L.

doi:10.1016/j.jtho.2019.07.020

Cited by 26 publications

(32 citation statements)

References 15 publications

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“…Our clinical findings are not only in line with the effects of obesity and tumor progression found in many murine lung cancer models but they also reflect the logical outcome of the roundly pro-tumor alterations that obesity triggers in human and murine gene expression (Fig. 2 and Supplementary Tables 4 and 6) and its effects on the immune cell composition of the TME reported by us 65 (Fig. 3) and others.…”

Section: Discussionsupporting

confidence: 90%

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Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Barbi

Patnaik

Pabla³

et al. 2021

Journal of Thoracic Oncology

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Introduction: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC.Methods: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity.Results: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche.Conclusions: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

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Section: Discussionsupporting

confidence: 90%

“…52,63,64 We recently linked metformin use to significantly better survival outcomes specifically in obese patients with early stage lung cancer. 65 It is possible that the contextspecific benefit of this drug may account at least partially for the better lung cancer outcomes found in patients with high BMI.…”

Section: Discussionmentioning

confidence: 99%

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Barbi

Patnaik

Pabla³

et al. 2021

Journal of Thoracic Oncology

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“…As an independent prognostic indicator of tumor-related diseases, BMI has got more and more concern by researchers in recent years. BMI was related with the prognosis of breast carcinoma, non-small-cell lung cancer, and so on [20,21]. In this paper, we found that BMI was signi cantly correlated with the prognosis of AEG patients.…”

Section: Discussionmentioning

confidence: 51%

A simple model established by blood markers predicting overall survival after radical resection of type II and III Adenocarcinomas of the Esophagogastric Junction

Zhang

Wei

2020

Preprint

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Background. The prognostic prediction after radical resection of Adenocarcinomas of the esophagogastric junction (AEG) has not been well established. We aimed to establish a prognostic model for AEG(type II and III) based on routine markers. Methods. 355 patients who underwent curative AEG at the first affiliated Hospital of Anhui Medical University from January 2010 to January 2011 were included in this study. Univariate and multivariate analysis were used to screen for risk factors. The construction of the nomogram was based on Cox proportional hazard regression models. The new score models was analyzed by C index and Calibration curves. Results. Multivariate analysis showed that TNM stage, NLR and BMI were independent prognostic factors. The new score system had a higher C-index, and the Calibration curves of the nomogram were reliable. Conclusions. Based on the serum markers and other clinical indicators, we developed a precise model to predict the prognosis of patients with AEG(type II and III). This score system can provide effective help for surgeons and patients.

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“…Several studies observed favorable treatment outcomes (objective response rate, disease control rate, median progression-free survival, and median overall survival) in patients who received metformin in combination with ICIs without reaching a statistically significant trend ( 1 , 11 , 37 ). The subgroup analysis found a statistically significant association between metformin use and OS in obese patients with a BMI >25 kg/m 2 ; the strength of the association was higher in patients with a BMI >30 kg/m 2 ( 31 ). However, one study found worse treatment outcomes in patients who took metformin plus ICIs with a nonsignificant trend ( 32 ).…”

Section: Metformin Influences the Antitumor Efficiency Of Icismentioning

confidence: 95%

“…In contrast, according to a recently published study, metformin may increase the expression level of PD-L1 in liver kinase B1 (LKB1) wild-type NSCLC via AMPK-LKB1 signaling (71). Moreover, the results of a clinical study showed that metformin use was associated with significantly decreased expression of six (CTLA4, PDCD1, ICOS, BTLA, CD27, and LAG3) of the seven immune checkpoint genes in only those patients who had a high BMI; opposite results were found in the low BMI group (31). The expression levels of four (CTLA4, CD28, BTLA, and CD27) immune checkpoint genes were significantly increased in patients administered metformin.…”

Section: Metformin Exposure Decreases the Expression Levels Of Immune Checkpoint Genesmentioning

confidence: 99%

Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

et al. 2021

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Cancer is an important threat to public health because of its high morbidity and mortality. In recent decades, immune checkpoint inhibitors (ICIs) have ushered a new therapeutic era in clinical oncology. The rapid development of immune checkpoint therapy is due to its inspiring clinical efficacy in a group of cancer types. Metformin, an effective agent for the management of type 2 diabetes mellitus (T2DM), has shown beneficial effects on cancer prevention and cancer treatment. Emerging studies have suggested that metformin in combination with ICI treatment could improve the anticancer effects of ICIs. Hence, we conducted a review to summarize the effects of metformin on ICI therapy. We also review the pleiotropic mechanisms of metformin combined with ICIs in cancer therapy, including its direct and indirect effects on the host immune system.

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Body Mass Index Influences the Salutary Effects of Metformin on Survival After Lobectomy for Stage I NSCLC

Cited by 26 publications

References 15 publications

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

A simple model established by blood markers predicting overall survival after radical resection of type II and III Adenocarcinomas of the Esophagogastric Junction

Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors

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