Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities

Mary C Playdon; Sheetal Hardikar; Prasoona Karra; Rachel Hoobler; Anna R Ibele; Katherine L Cook; Amanika Kumar; Joseph E Ippolito; Justin C Brown

doi:10.1093/jncimonographs/lgad003

. 2023 May 4;2023(61):68–76. doi: 10.1093/jncimonographs/lgad003

Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities

Mary C Playdon ^1,², Sheetal Hardikar ^3,⁴, Prasoona Karra ^5,⁶, Rachel Hoobler ^7,⁸, Anna R Ibele ⁹, Katherine L Cook ^10,^11,¹², Amanika Kumar ¹³, Joseph E Ippolito ¹⁴, Justin C Brown ^15,^16,^17,^✉

¹ Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA

² Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA

³ Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA

⁴ Department of Population Health Sciences, School of Medicine, University of Utah, Salt Lake City, UT, USA

⁵ Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA

⁶ Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA

⁷ Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA

⁸ Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA

⁹ Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT, USA

¹⁰ Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA

¹¹ Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA

¹² Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA

¹³ Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, USA

¹⁴ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA

¹⁵ Pennington Biomedical Research Center, Baton Rouge, LA, USA

¹⁶ Louisiana State University Health Sciences Center New Orleans School of Medicine, New Orleans, LA, USA

¹⁷ Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA

^✉

Correspondence to: Justin C. Brown, PhD, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA (e-mail: Justin.Brown@pbrc.edu).

Roles

Mary C Playdon: PhD, MPH, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing - original draft, Writing - review & editing

Sheetal Hardikar: MBBS, PhD, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing - review & editing

Prasoona Karra: PhD, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing - original draft, Writing - review & editing

Rachel Hoobler: RD, BS, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing - original draft, Writing - review & editing

Anna R Ibele: MD, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing - review & editing

Katherine L Cook: PhD, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing - review & editing

Amanika Kumar: MD, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing - review & editing

Joseph E Ippolito: MD, PhD, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing - review & editing

Justin C Brown: PhD, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing

PMCID: PMC10157771 PMID: 37139980

Abstract

Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. This report provides a concise review of the current state of the science regarding metabolic and bariatric surgery and obesity pharmacotherapy related to cancer risk. Meta-analyses of cohort studies report that metabolic and bariatric surgery is independently associated with a lower risk of incident cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.

Obesity is a chronic, relapsing, progressive disease of excess adiposity (1). More than 40% of adults in the United States have a body mass index (BMI) of at least 30 kg/m², consistent with a diagnosis of obesity (2). Obesity increases the risk of developing at least 13 types of cancer [Figure 1 (3,4)]. These obesity-related cancers account for 40% of all malignancies diagnosed in the United States each year (5).

Figure 1. — Thirteen cancers have been convincingly linked with obesity.

The precise biological mechanisms by which obesity increases cancer risk are incompletely understood but likely multifactorial. The metabolic causes and consequences of obesity include insulin resistance and hyperinsulinemia, alterations in adipokines and sex steroid hormones, systemic inflammation, abnormal lipid metabolism, oxidative stress, and gut microbiome dysfunction (6-13). These metabolic changes can activate intracellular pathways that promote malignant transformation by stimulating cell growth, cell migration and invasion, angiogenesis, and resistance to apoptosis (7).

Interventions to break the obesity-cancer link remain elusive. Intensive lifestyle interventions that include dietary modification, physical activity, and behavioral support are the foundation of obesity treatment (14). Intensive lifestyle interventions induce a 5%-7% weight loss at 1 year (15-17). Observational and randomized studies demonstrate that intentional weight loss may reduce cancer risk (18-20). However, weight loss achieved exclusively by intensive lifestyle intervention is challenging to sustain long-term (21). This may be due, in part, to physiologic mechanisms of appetite and metabolic adaptation that occur in the weight-reduced state and counter an individual’s efforts to sustain long-term weight loss (22).

Additional interventions that produce substantial and sustained weight loss are needed to convincingly break the obesity-cancer link. Two obesity treatment modalities that produce substantial and sustained weight loss are metabolic (bariatric) surgery and obesity pharmacotherapy. Metabolic and bariatric surgery (MBS) often yields 25%-30% weight loss at 10 years, a magnitude of weight loss substantially larger than intensive lifestyle interventions, with low operative morbidity (5%) and mortality (0.2%) (23,24). Moreover, there are currently 5 medications approved by the US Food and Drug Administration for weight management in adults with obesity (25,26). The American Association of Clinical Endocrinologists and the American College of Endocrinology have published algorithms that guide the initiation and selection of obesity treatment modalities (eg, lifestyle, pharmacotherapy, surgery) (27).

This report provides a concise review of the current state of the science regarding MBS and obesity pharmacotherapy related to cancer risk (Box 1). The report concludes with a look to the future by identifying research gaps and opportunities to determine the potential for MBS and obesity pharmacotherapy to represent an evidence-based cancer prevention strategy.

Box 1. Practice points for the clinical care provider.

Obesity is a chronic, relapsing, progressive disease of excess adiposity.
Obesity increases the risk of developing at least 13 types of cancer.
Metabolic and bariatric surgery is associated with a lower risk of invasive cancer.
Less is known regarding the cancer-preventive effects of obesity pharmacotherapy.
There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.

Metabolic and bariatric surgery

MBS is an effective weight-loss treatment for patients with a BMI of at least 35 kg/m², a BMI of at least 30 kg/m² with type 2 diabetes, or a BMI of at least 30 kg/m² and at least 1 or more adiposity-based chronic diseases (eg, hypertension, sleep apnea, nonalcoholic fatty liver disease, osteoarthritis, hyperlipidemia, and cardiovascular disease) who have been unable to achieve and sustain durable weight loss or comorbidity improvement with nonsurgical weight loss previously (28). Currently, the most common MBS procedures include Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (29). Other procedures, such as adjustable gastric banding (AGB), vertical banded gastroplasty, and biliopancreatic diversion with duodenal switch, are less commonly used because of poor durability of weight loss (AGB), long-term complication rates (ABG, vertical banded gastroplasty), and concern for malnutrition (biliopancreatic diversion with duodenal switch) (30,31).

MBS and cancer risk

More than 49 reports have examined the association between MBS and cancer risk (or cancer precursor lesions) (Supplementary Table 1, available online). A meta-analysis of 21 cohort studies that included 304 516 patients with obesity treated with MBS and 8.49 million patients with obesity who were not treated with surgery reported that MBS reduced cancer risk by 44% (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.48 to 0.66) (32).

Few studies have stratified by MBS procedure type. One meta-analysis reported that RYGB was associated with lower cancer mortality but not cancer risk (OR = 0.39, 95% CI = 0.11 to 1.33) (32). In another recent study conducted using data from more than 300 000 women, those treated with RYGB had a lower risk of developing female-specific cancer than vertical sleeve gastrectomy (hazard ratio [HR] = 0.66, 95% CI = 0.51 to 0.87) and AGB (HR = 0.83, 95% CI = 0.69 to 0.99), revealing potential opportunities to interrogate the mechanisms underlying female-specific cancer risk reduction (33).

There is also evidence that patient sex, the control group used (eg, hospital vs population based), and the cancer type examined modify the association between MBS and cancer risk (34). In a meta-analysis stratified by sex, receipt of MBS was associated with a reduced rate of obesity-related cancer among females but not males (35). More recent studies have replicated these findings (36,37).

Several studies have examined the association of MBS on cancer death (38-43) and prognostic factors among cancer survivors (44); however, these studies were beyond the scope of the current review.

MBS and the risk of site-specific cancers

Because of the heterogeneity of the associations between MBS and cancer risk, several meta-analyses have pooled estimates for specific cancer types (45,46).

A meta-analysis of 11 studies among 1.1 million women reported that MBS reduced the risk of breast cancer by 50% (relative risk [RR] = 0.50, 95% CI = 0.37 to 0.67); however, substantial heterogeneity persisted (I² = 88%) (47). MBS reduced the risk of stage III or IV breast cancer (RR = 0.50, 95% CI = 0.28 to 0.88) and was not modified by the hormone receptor status of the breast tumor (47).

Uterine cancer is strongly related to obesity; for each 5 kg/m² increase in BMI, the relative risk of uterine cancer increases by 50% (48). A meta-analysis of 5 studies among 7.4 million women reported that MBS reduced the risk of uterine cancer by 59% (OR = 0.41, 95% CI = 0.22 to 0.74) (49).

The association between MBS and colorectal cancer risk has been somewhat inconsistent in the literature. For example, individual studies have reported that bariatric surgery increases (50,51), decreases (37,52), and has no effect on colorectal cancer risk (53). However, a recent meta-analysis of 7 studies among 1.2 million men and women reported that MBS reduced the risk of colorectal cancer by 36% (RR = 0.64, 95% CI = 0.42 to 0.98) (54). This finding has been recently corroborated in a retrospective analysis of 30 000 adults with severe obesity, where RYGB reduced colorectal cancer risk by 53% (OR = 0.47, 95% CI = 0.30 to 0.75) (55). However, the effects of MBS on colorectal cancer risk may differ by patient sex and surgery type (37,56) and thus require further study (32). Bariatric procedures that alter intestinal continuity (eg, RYGB) vs those that only affect the stomach (eg, AGB) may differentially impact bile salt absorption and the microbiome, potentially influencing colorectal cancer risk.

Another notable example of divergent findings in the literature is the observation that MBS may increase (57) or decrease kidney cancer risk (58).

Biological mechanisms of MBS and cancer risk

The chronic stimulation of estrogen by aromatization of androgens in adipose tissue to estradiol and modulated levels of sex hormone–binding globulin convincingly link obesity with hormonally driven cancers (eg, cancers of the breast, prostate, and endometrium). However, other important pathways include insulin-like growth factors, inflammation, and adipokine metabolism. The Women’s Health Initiative Observational Study concluded that leptin, C-reactive protein, fasting insulin, and estradiol mediate the association between BMI and cancer risk, particularly for endometrial cancer (59).

In the Longitudinal Assessment of Bariatric Surgery 2, a prospective, multicenter cohort study, the degree of surgically induced weight loss statistically significantly correlated with the magnitude of cancer risk reduction (60). In the Longitudinal Assessment of Bariatric Surgery 2 analysis, biomarkers that predicted cancer risk independent of weight loss included glucose, proinsulin, insulin, leptin, and ghrelin (60). This analysis highlights the multifactorial biological mechanisms by which obesity increases cancer risk and underscores the important roles of hyperinsulinemia, hyperglycemia, adipokine signaling, and inflammation.

The immune microenvironment of the uterus is modulated with bariatric surgery, which reduced systemic inflammation and recruitment of protective immune cells to the uterus in one study (61). Other cancer risk biomarkers modulated in target tissues with MBS include Ki-67, pAKT, reduction in hormone receptor status (estrogen receptor, progesterone receptor), PTEN expression, glycated hemoglobin, insulin resistance, C-reactive protein, and interleukin-6 (62). Rearrangement of neurohormonal feedback loops linked to inflammation and metabolism (eg, adiponectin, orexin-A) and oxidative DNA damage have also been implicated (63,64).

Pathophysiological examination of colorectal tissue has demonstrated reduced rectal crypt cell proliferation and systemic and mucosal inflammation in one study (65). Other studies, albeit small (n < 100), showed that rectal epithelial cell mitosis and crypt size were elevated after RYGB compared with presurgery (66). Fecal markers of increased inflammation were also observed after RYBG (eg, fecal calprotectin, active lipopolysaccharide concentration, Saccharomyces cerevisiae immunoglobulin A antibodies, and methylglyoxal-hydro-imidazolone) protein adducts values increased statistically significantly, whereas fecal short-chain fatty acids, especially acetate and butyrate, were reduced (67).

Obesity pharmacotherapy

There are currently 5 medications approved by the US Food and Drug Administration for long-term weight management in adults with a BMI of at least 30 kg/m² or BMI of at least 27 kg/m² and a weight-related chronic condition (eg, type 2 diabetes, hypertension, dyslipidemia, sleep apnea, cardiovascular disease) (68,69). The comparative effectiveness of these medications for weight loss has been reviewed (25,26). In contrast to the rapidly expanding evidence on MBS and cancer risk, the evidence on obesity pharmacotherapy and cancer risk are smaller and more limited in scope. Herein we review the key phase III randomized clinical trials that contributed to the regulatory approval of these agents for obesity management (70).

Orlistat

Orlistat is a reversible inhibitor of gastrointestinal lipases that induces weight loss by reducing the hydrolyzation of triglycerides into absorbable free fatty acids and monoglycerides (71). In a 52-week study of 228 participants, the mean placebo-subtracted weight loss of orlistat was −3.1% (−8.5% vs −5.4%; P = .016); 35% of participants randomly assigned to orlistat lost at least 5% of body weight compared with 21% of participants randomly assigned to placebo, respectively (P < .05) (72). Patients with a history of cancer at baseline were excluded from this 52-week study (72). The efficacy and safety of orlistat have been summarized (73). Orlistat reduces waist circumference, the risk of progression to type 2 diabetes, fasting and postprandial glucose and insulin, inflammation, and lipids (74). Concern was raised that colorectal cancer risk may be elevated because of the increased triglyceride content in the large intestine (75). However, a retrospective matched cohort study demonstrated that orlistat was not associated with a higher risk of colorectal cancer (HR = 1.11, 95% CI = 0.84 to 1.47) (76). The effect of orlistat on cancer risk of noncolorectal origin is not known.

Phentermine with topiramate

Phentermine with topiramate extended-release is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release, an antiepileptic drug that induces weight loss, in part, by appetite suppression and satiety enhancement (77). In a 56-week trial, 2487 participants were randomly assigned to placebo, once-daily phentermine 7.5 mg with topiramate 46 mg, or once-daily phentermine 15 mg with topiramate 92 mg in a 2:1:2 ratio (78). The mean placebo-subtracted weight loss of phentermine 7.5 mg with topiramate 46 mg was −7.8%, and the mean placebo-subtracted weight loss of phentermine 15 mg with topiramate 92 mg was −8.6% (both P < .001 vs placebo); 62% and 70% of participants randomly assigned to phentermine 7.5 mg with topiramate 46 mg and phentermine 15 mg with topiramate 92 mg lost at least 5% of body weight compared with 21% of participants randomly assigned to placebo, respectively (both P < .05 vs placebo) (78). Patients with a history of cancer at baseline were not excluded from this 56-week study; however, the number of randomly assigned participants with a history of cancer is unknown (78). The efficacy and safety of phentermine with topiramate have been summarized (79). Phentermine with topiramate reduces waist circumference, fasting glucose and insulin, and lipids (79). The effect of phentermine with topiramate on cancer risk is not known.

Naltrexone with bupropion

Naltrexone with bupropion extended-release is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, which induces weight loss, in part, by suppressing food intake, food craving, and other aspects of eating behavior in the hypothalamic and mesolimbic dopamine circuits of the brain (80). In a 56-week study, 1742 participants were randomly assigned to placebo, once-daily naltrexone 16 mg with bupropion 360 mg or once-daily naltrexone 32 mg with bupropion 360 mg in a 1:1:1 ratio (81). The mean placebo-subtracted weight loss of naltrexone 16 mg with bupropion 360 mg was −3.7%, and the mean placebo-subtracted weight loss of naltrexone 32 mg with bupropion 360 mg was −4.8% (both P < .0001 vs placebo); 39% and 48% of participants randomly assigned to naltrexone 16 mg with bupropion 360 mg and naltrexone 32 mg with bupropion 360 mg lost at least 5% of body weight compared with 16% of participants randomly assigned to placebo, respectively (both P < .0001 vs placebo) (81). Patients with a history of cancer within the past 5 years (except nonmelanoma skin cancer and surgically cured cervical cancer) were excluded from this 56-week study (81). The efficacy and safety of naltrexone with bupropion have been summarized (82). Naltrexone with bupropion reduces waist circumference, fasting glucose and insulin, inflammation, and lipids (81). The effect of naltrexone with bupropion on cancer risk is not known.

Liraglutide

Liraglutide 3.0 mg is a glucagon-like peptide-1 (GLP-1) receptor agonist that induces weight loss, in part, by the hypothalamic suppression of appetite and energy intake (83). In a 56-week study of 3731 participants, the mean placebo-subtracted weight loss of liraglutide 3.0 mg was −5.4% (−8.0% vs −2.6%; P < .0001); 63.2% of participants randomly assigned to liraglutide 3.0 mg lost at least 5% of body weight compared with 27.1% of participants randomly assigned to placebo, respectively (P < .001) (84). Patients with a history of cancer (except basal or squamous cell skin cancers) at baseline were excluded from this 56-week study (84). The efficacy and safety of liraglutide 3.0 mg have been summarized (85). Liraglutide 3.0 mg reduces waist circumference, the risk of progression to type 2 diabetes, fasting glucose and insulin, inflammation, and lipids (84). Liraglutide 1.8 mg is indicated for treating type 2 diabetes, and an exploratory analysis of the cardiovascular outcome study demonstrated that liraglutide 1.8 mg did not increase cancer risk (86). A recent meta-analysis of incretin-based therapies, including liraglutide 1.8 mg, demonstrated no increased risk of pancreas cancer (87).

Semaglutide

Semaglutide 2.4 mg once weekly is a GLP-1 receptor agonist that induces weight loss, in part, by the hypothalamic suppression of appetite and energy intake (88). Semaglutide has a lower GLP-1 receptor affinity than liraglutide but an increased serum albumin affinity. In a 68-week study of 1961 participants, the mean placebo-subtracted weight loss of semaglutide 2.4 once weekly was −12.4% (−14.9% vs −2.4%; P < .0001); 86.4% of participants randomly assigned to semaglutide 2.4 mg once weekly lost at least 5% of body weight compared with 31.5% of participants randomly assigned to placebo, respectively (P < .0001) (89). Patients with a history of cancer within the past 5 years (except basal cell or squamous cell skin cancers) were excluded from this 68-week study (89). The efficacy and safety of semaglutide 2.4 mg once weekly have been summarized (90). Semaglutide 2.4 mg once weekly reduces waist circumference, the risk of progression to type 2 diabetes, fasting glucose and insulin, inflammation, and lipids (89). The ongoing Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity cardiovascular outcome study in 17 500 subjects with obesity may provide preliminary data on the effects of semaglutide 2.4 mg once weekly on cancer risk (91,92).

Withdrawn obesity medications relevant to cancer prevention and control

Between 1964 and 2009, 25 obesity medications were withdrawn because of adverse events, including psychiatric disturbances, cardiotoxicity, and drug abuse or dependence (93). Most recently, the US Food and Drug Administration requested that the manufacturer of lorcaserin voluntarily withdraw the drug from the market because of increased cancer risk (94). Lorcaserin is a serotonin 2C receptor agonist that induced a mean placebo-subtracted weight loss of −3.6% (−5.8% vs −2.2%; P < .001) at week 52 (95). During the cardiovascular outcome study in 12 000 participants, a potential signal of increased cancers and cancer-related mortality was identified (96). Rates were higher in the lorcaserin group than in the placebo group for colorectal, pancreatic, and lung cancers; the rate ratio of cancer, excluding common skin cancers, was 1.16 (95% CI = 0.98 to 1.36) and increased with time, consistent with a drug effect manifested after a latency period (94). In an observational study of 17 900 subjects, lorcaserin did not increase cancer risk compared with phentermine with topiramate (HR = 0.91, 95% CI = 0.76 to 1.09) (97).

Obesity medications in the pipeline

The next generation of obesity pharmacotherapy will leverage the synergy of dual agonists, such as glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist (eg, tirzepatide) or amylin agonists coupled with GLP-1 receptor agonists (eg, cagrilintide with semaglutide 2.4 mg) (69,98). In a 72-week phase 3 study of tirzepatide that included 2539 participants, the placebo-subtracted weight loss was −11.9%, −16.4%, and −17.8% for doses of 5 mg, 10 mg, and 15 mg, respectively; 15.3%, 32.3%, and 36.2% of participants randomly assigned to tirzepatide 5 mg, 10 mg, and 15 mg lost at least 25% of body weight compared with 1.5% of subjects randomly assigned to placebo, respectively (all P < .001) (99). Tirzepatide (once weekly 5 mg, 10 mg, and 15 mg) is approved by the US Food and Drug Administration for type 2 diabetes (100). A phase 1 b trial has demonstrated promising safety, tolerability, and preliminary efficacy of cagrilintide with semaglutide 2.4 mg (101). The pipeline of obesity pharmacotherapy will continue to expand over the next decade, as a recent phase I trial established the safety and tolerability of a triple agonist of glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors (102). Moreover, the recent discovery of a monoclonal antibody that inhibits activin type II receptor producing increases in muscle mass and decreases in fat mass in humans with obesity and type 2 diabetes (103) will further expand therapeutic opportunities in obesity pharmacotherapy.

Unanswered questions

To advance the field of obesity management and cancer prevention in a transformative manner will require the assembly of diverse teams of scientists, such as that made possible by the National Cancer Institute–sponsored Transdisciplinary Research on Energetics and Cancer Consortium (104,105). These looming questions pertain to study design, population subgroups, the synergy of multiple obesity modalities, the timing of obesity treatment to reduce cancer risk, and mechanisms of action.

Study designs

Because of the diverse causes of obesity and cancer, observational and randomized study designs will offer unique and complementary evidence to advance the field. The evidence supporting the cancer-preventive effects of MBS is derived from observational studies, primarily retrospective cohort analyses with or without a parallel BMI-matched control group. Many observational studies have not adjusted for sociodemographic characteristics, diet and physical activity, family history of cancer, chronic health conditions, or cancer screening history, which often prognostically favor patients who undergo MBS. Consequently, uncertainty persists about whether the observed associations are attributable to confounding from other factors (106). A randomized trial, or prospective studies that comprehensively measure sociodemographic and health history information, may be necessary to provide more definitive evidence regarding the cancer-preventive effects of MBS (PAR-21-331). Studies with follow-up duration necessary to detect rare cancer outcomes are also needed (eg, >10-year follow-up).

The US Food and Drug Administration generally requires randomized, double-blind, placebo-controlled trials to evaluate the safety and efficacy of obesity drugs. However, these studies are often too small (eg, within a development program, approximately 3000 subjects are treated with drug and approximately 1500 treated with placebo) to examine cancer risk. However, the conduct of large cardiovascular safety studies, such as Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (91), provides an unprecedented opportunity to examine cancer risk as a secondary objective. Investigators, sponsors, and regulators should consider collecting detailed cancer incidence data on study participants.

Population subgroups

It is not known if MBS and obesity pharmacotherapy reduce cancer risk in subgroups at high risk for developing cancer. For example, it is uncertain if patients with established precancerous lesions, such as endometrial hyperplasia or colorectal polyps, when treated with MBS or obesity pharmacotherapy, experience a resolution or regression of the precancerous lesions. A recent study suggested that MBS may be associated with a lower incidence of colorectal adenomas (107); however, the effect on recurrent polyps is unknown. Obesity increases the relative risk of uterine cancer by sevenfold, the largest relative risk of all obesity-associated malignancies (48). Polycystic ovary syndrome is a risk factor for metabolic syndrome and uterine cancer (108), yet this population remains understudied.

Among population subgroups with hereditary cancer predisposition, such as BRCA1/2 or Lynch syndrome, it is not known if MBS or obesity pharmacotherapy reduces cancer risk or delays the time to cancer onset. Findings from the MBS literature point toward biological sex differences in the association with cancer risk, where benefits may be experienced predominantly among females. Yet, most MBS patients tend to be female, and thus statistical power of existing studies may be limited to evaluating effect modification by sex. Moreover, studies powered to evaluate surgery type-specific associations (particularly malabsorptive vs restrictive procedures) with cancer incidence will clarify some conflicting existing evidence and further illuminate potential etiological mechanisms. Finally, among studies that collected demographic information, a lack of racial and ethnic diversity has been noted. Given the stark disparities in cancer risk among racial and ethnic minorities and other minority groups (eg, rural, lower socioeconomic status), considering their inclusion in future studies is warranted (105).

Synergy of multiple therapies

Obesity treatment has evolved to resemble comprehensive cancer care that integrates distinct treatment modalities to improve the probability of a successful treatment outcome. For example, MBS has been combined with obesity pharmacotherapy (109,110), and obesity pharmacotherapy has been combined with intensive lifestyle modification (111) to generate synergy to reduce body weight and excess adiposity. It remains uncertain if combining obesity treatment modalities synergistically impact cancer risk. The effect of endoscopic procedures and devices for weight loss (eg, Gelesis100 absorbent hydrogels) on cancer risk also requires investigation (112,113).

Timing of obesity treatment delivery to reduce cancer risk

Adolescent obesity predicts midlife cancer risk and is hypothesized as a potential cause of the increase in early onset cancer (cancers occurring before the age of 50 years) (114,115). More than half of all children today will have obesity at age 35 years (116). The long latency period of cancer creates uncertainty regarding the optimal time to deploy obesity therapy for cancer prevention. Studies that integrate life-course approaches may provide unique data to clarify the optimal timing of intervention. Conversely, many studies that have examined the association between MBS and cancer risk have examined younger patients, which does not represent older adults with obesity who are at high risk of cancer, particularly given the median length of follow-up in existing studies.

Mechanisms of action

Distinct MBS procedures may have divergent effects on metabolism, such as appetite hormones that regulate food intake, energy expenditure, and insulin metabolism (60). It is also plausible that different procedures with different effects on bile salt absorption have varying effects on intestinal microbiota linked to carcinogenesis (117), which may be modulated by dietary changes postsurgery. Recent work suggests that diet-responsive lipid metabolism plays a central role in controlling tumor growth and progression (PAR-21-331), and this may be relevant to MBS (118,119).

Relevant to MBS and obesity pharmacotherapy, it will be critical to determine if a cancer preventive effect is mediated exclusively by weight loss or via weight-independent mechanisms.

Discussion

Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. Meta-analyses of cohort studies observe that MBS is independently associated with a lower relative risk of cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs that induce an average of at least 10% reduction in body weight will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. Policy reform will be necessary to reduce barriers to delivering comprehensive obesity treatment promptly and cost-effectively to patients at high risk of developing obesity-related cancers. There are myriad research opportunities to advance our understanding of how MBS and obesity pharmacotherapy may be used for cancer prevention.

Supplementary Material

lgad003_Supplementary_Data

Click here for additional data file.^{(103.7KB, docx)}

Contributor Information

Mary C Playdon, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA; Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Sheetal Hardikar, Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA; Department of Population Health Sciences, School of Medicine, University of Utah, Salt Lake City, UT, USA.

Prasoona Karra, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA; Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Rachel Hoobler, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA; Cancer Control and Population Sciences Program, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Anna R Ibele, Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT, USA.

Katherine L Cook, Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Amanika Kumar, Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, USA.

Joseph E Ippolito, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Justin C Brown, Pennington Biomedical Research Center, Baton Rouge, LA, USA; Louisiana State University Health Sciences Center New Orleans School of Medicine, New Orleans, LA, USA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Data availability

No new data were generated or analyzed in support of this research.

Author contributions

MCP, SH, PK, RH, ARI, KLC, AK, JEI, and JCB contributed to the conception and design of the article and interpretation of the relevant literature; MCP and JCB drafted the initial manuscript; MCP, SH, PK, RH, ARI, KLC, AK, JEI, and JCB provided critical and important intellectual revisions to the initial draft.

Funding

Dr Brown is supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R25 CA203650, R00 CA218603, R01 CA270274, and U01 CA271279, the National Institute of General Medicine Sciences of the National Institutes of Health under Award Number U54 GM104940, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number P30 DK072476, and the American Institute for Cancer Research. All other authors disclose no relevant financial support.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

None.

Role of the funder: No funding agencies were involved in the preparation or decision to publish this manuscript.

Prior presentations: None.

References

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Associated Data

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Supplementary Materials

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Data Availability Statement

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PERMALINK

Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities

Mary C Playdon, PhD, MPH

Sheetal Hardikar, MBBS, PhD

Prasoona Karra, PhD

Rachel Hoobler, RD, BS

Anna R Ibele, MD

Katherine L Cook, PhD

Amanika Kumar, MD

Joseph E Ippolito, MD, PhD

Justin C Brown, PhD

Roles

Abstract

Figure 1.

Box 1. Practice points for the clinical care provider.

Metabolic and bariatric surgery

MBS and cancer risk

MBS and the risk of site-specific cancers

Biological mechanisms of MBS and cancer risk

Obesity pharmacotherapy

Orlistat

Phentermine with topiramate

Naltrexone with bupropion

Liraglutide

Semaglutide

Withdrawn obesity medications relevant to cancer prevention and control

Obesity medications in the pipeline

Unanswered questions

Study designs

Population subgroups

Synergy of multiple therapies

Timing of obesity treatment delivery to reduce cancer risk

Mechanisms of action

Discussion

Supplementary Material

Contributor Information

Data availability

Author contributions

Funding

Conflicts of interest

Acknowledgements

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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