Obesity, cancer risk, and time-restricted eating

Obesity has reached epidemic proportions globally, with nearly 39% of adults being classified as overweight and, of these, over 600 million being categorized as clinically obese in 2020 [1]. At the current pace, nearly half of the world’s population will be overweight or obese by 2030. Currently in the USA, 60% of the population is overweight and 30% is obese [2, 3]. The implications of this epidemic on the USA and global population health are enormous, as obesity has been linked to several metabolic, cardiovascular, and neurodegenerative diseases [4]. Furthermore, obesity is associated with an increased risk for developing cancer and predicts worse outcomes for a variety of malignancies [5‐7]. Obesity may also worsen several aspects of cancer survivorship, including quality of life, cancer progression and recurrence, and disease-free survival [8]. Globally, 481,000 new cancer cases are attributed to overweight and obesity according to United Nations news report in 2014, establishing excessive body adiposity as a strong risk factor for cancer development [9]. The American Cancer Society reported in 2014 that 7.8% (122,536) of all cancers and 6.5% (38,188) of all cancer deaths in the USA were attributed to excess body weight [10]. After cigarette smoking, obesity represents the second greatest modifiable risk factor in the USA. The increased risk of cancer incidence and mortality is multi-factorial, but likely related to both the innate pro-inflammatory environment, dysregulation of growth factor and hormone expression, and altered circadian rhythms that occur in obesity. For instance, chronic low-level inflammation in viral hepatitis (a disease of the liver causing inflammation), obesity, or alcohol abuse is a risk factor for liver cancer [11]; increased levels of insulin and insulin-like growth factor-1 (IGF-1) may promote the development of colon, kidney, prostate, and endometrial cancers [12]; high levels of estrogen have been associated with increased risk of endometrial, breast, and ovarian cancer [13‐15]; and circadian deregulation in night shift workers or in obesity has been connected with increased risk of breast cancer [10]. Given the common co-occurrence of obesity-related risk factors in many cancer patients that affect overall survival and increases risk of death, it is logical that strategies for weight control would be beneficial for both prevention and to improve cancer outcomes. Therefore, there is an urgent need to improve cancer care beyond novel therapeutics by elucidating the effects of different weight management strategies in cancer prevention and treatment. In this regard, many observational studies have provided consistent evidence that individuals with lower weight gain or weight loss have lower risk of colon cancer, kidney cancer, and breast, endometrial, and ovarian cancer [16‐19]. Weight loss through dietary interventions such as caloric restriction (CR), intermittent fasting (IF), and fasting-mimicking diets (FMD) have beneficial metabolic effects and decrease cancer risk but are difficult to maintain. Surgical approaches such as gastric bypass are also beneficial in the short-term but long-term improvements are rare. Time-restricted eating (TRE) is a popular new intervention for improved metabolic health and weight control that does not involve calorie reduction. This method is a potentially easier way to maintain optimal body weight and health over a long period as it does not require reducing total food intake, calculating daily calorie intake, or changing diet. Small clinical studies have confirmed the effectiveness of this strategy to improve overall metabolic heath [20‐22]. Preclinical studies have also reported the therapeutic benefits of TRE in mouse models of cancer [23‐25]. Clinical trials are just starting to explore the role of TRE in cancer so it is too early to assess whether TRE has encouraging outcomes in cancer prevention and treatment. Although TRE is a promising dietary intervention for controlling weight and improving metabolic dysfunction in overweight or obese individuals, large-scale clinical trials are still needed to confirm the benefit of TRE for metabolic health and cancer prevention. In this review, we will give an overview of obesity as risk factor for cancer and the potentially useful role of time-restricted eating in cancer prevention and treatment.

Obesity is defined by a body-mass index (BMI) of > 30 and over-weight as a BMI of 25–29.9. These cutoffs have been developed based on Caucasian data and it is important to recognize that they may not hold for other groups. For example, the Asia–Pacific classification uses a BMI 23–24.9 for over-weight and > 25 as obese. Obesity has been associated with an increased incidence of a variety of cancers such as colorectal, kidney, esophagus, endometrium, breast, pancreas, thyroid, liver, ovary, gallbladder, and prostate cancer, as well as non-Hodgkins lymphoma [26, 27]. In addition, obesity is increasingly recognized as an indicator of poor prognosis as data show that obesity is associated with higher rates of cancer progression and recurrence, reduced progression-free survival, and increased mortality, especially for breast, prostate, and colon cancer [28‐33]. Cancer metastasis accounts for over 90% of cancer mortality and obesity increases distal metastasis, thereby increasing the severity of the disease and mortality [34, 35]. Unfortunately, weight gain after diagnosis is common in cancer patients, especially among breast cancer patients receiving systemic adjuvant therapy [36, 37]. In a study of 535 women with newly diagnosed breast cancer, 84.1% of the patients gained weight during the first year after diagnosis and the weight gain was significantly greater in patients on chemotherapy [37]. Obesity also increases the risk of complications from cancer treatment and the risk of several comorbidities. For example, obesity is associated with an increased risk of both treatment-related lymphedema in breast cancer survivors [38] and incontinence in prostate cancer survivors who have undergone radical prostatectomy [39]. Thus, obesity represents a significant modifiable risk factor affecting cancer health worldwide.

The mechanisms underlying the cancer-promoting effect of obesity are complex and likely multifactorial. There are several potential explanations for the link between increased adiposity and worse cancer prognosis, including hormonal, inflammatory, and immune system effects. Studies have documented links between obesity and elevated levels of free circulating hormones (e.g., insulin and estradiol) and their impact on hormone-dependent cancers [15, 40‐42] such as breast and prostate cancer. These differences likely underlie the reported differential effects of obesity on cancer subtypes. A large meta-analysis of breast cancer studies reported that obesity in premenopausal women is a positive risk factor for triple-negative breast cancers (TNBC, odds ratio (OR) 1.4–3.7) but a negative risk factor in estrogen receptor (ER) positive breast cancers (OR 0.35–0.81) [43]. In contrast, obesity in postmenopausal women is a positive risk factor for ER-positive breast cancer (OR 1.2–2.7) when endogenous estrogen levels are low. The detrimental effect of obesity is not limited to cancer risk however the American Cancer Society Prevention Study II of 495,977 women reported an association of BMI and BrCa mortality. Women with BMI > 30 kg/m² had > 65% increase in mortality [5]. In the UK Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) study of 2,956 young (aged < 41 yrs) breast cancer survivors, obesity was associated with larger tumors, positive lymph node status, and higher percentage of TNBC. Overall (8-year) survival and disease-free interval were significantly shorter [44]. Lastly, a meta-analysis of 82 studies including 213,075 breast cancer survivors found a 40% increased risk of mortality due to obesity in both pre- and post-menopausal women [45]. These observations might indicate that dietary interventions to reduce obesity may only be beneficial in selected cancer subtypes, but obesity has a detrimental effect on mortality in all subtypes of breast cancer, so one cannot be guided by cancer risk analyses alone.

Obesity has been linked to increases in estradiol due to aromatase expression in adipose tissue [46]. In the HEAL study of 505 postmenopausal women with stage 0-IIIA breast cancer, adiposity was positively associated with circulating levels of estrone and estradiol [47]. A combined meta-analysis of nine cohort studies, which included data from 663 breast cancer cases and 1,765 women without breast cancer, found that postmenopausal women with serum hormone concentrations in the top quintile for androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate were nearly twice as likely to develop breast cancer in comparison to women with serum hormones in the bottom quintile [48]. In the same analysis, a doubling of androgen concentration resulted in a 20% to 40% increase in risk for breast cancer. Other hormones have also been implicated. One of the best documented effects of obesity is to cause hepatic insulin resistance that triggers a compensatory increase in insulin secretion to maintain normoglycemia. This results in fasting hyperinsulinemia. Other tissues including tumors do not become insulin resistant so are exposed to elevated insulin levels. Hence, increased signaling via insulin and IGF-1 receptors, and the downstream phosphatidylinositol 3-kinase pathway, are observed in diverse cancers [49]. For example, in non-diabetic breast cancer patients, higher levels of fasting insulin have been associated with a 2–threefold increased risk of mortality [50‐54]. Similarly, the Women’s Health Initiative Observational Study (WHI-OS) of 93,676 postmenopausal women, insulin levels were associated with a > 2.4-fold increase in breast cancer risk in women not on hormone-replacement therapy [55]. The increased risk may be restricted to postmenopausal women as the Nurse’s Health Study II of 29,611 women did not show an association of insulin with breast cancer incidence [56]. Elevated insulin levels may also be associated with cancer progression. Additionally, fasting insulin levels were significantly associated with both distant recurrence and death. In a study, women in the highest quartile of insulin levels had a 2.1 times increased risk of distant recurrence compared to those in the lowest quartile (95% CI = 1.2–3.6, P = 0.01) and a 3.3 times greater risk of death (95% CI = 1.5–7.0, P = 0.002) [52]. Similar findings are reported for colorectal cancer [57]. A meta-analysis of all cancer deaths in non-diabetics reported that fasting serum insulin was associated with increased mortality (HR 1.92) in men [58] and the French TELECOM study reported that elevated fasting insulin posed increased risk of cancer death (HR 2.30) in men over a 28-year follow-up [59].

Chronic tissue inflammation is a feature of obesity. Inflammation in itself makes individuals susceptible to many forms of cancer as it has been linked to different steps involved in tumorigenesis, including transformation of normal cells to cancerous cells, survival, proliferation, promotion, invasion, angiogenesis, and metastasis [60]. Immune cells such as tumor-associated macrophages, tumor-associated dendritic cells, and pro-inflammatory cytokines and chemokines are key players in initiating inflammation creating a pro-cancer microenvironment [61]. Obesity is associated with inflammatory markers including C-reactive protein, serum amyloid A, interleukin-6, interleukin-1, and tumor necrosis factor alpha, and importantly some of these are higher in patients with metastatic cancer compared with patients without cancer and with those with early cancer [2].

Several methods for weight loss or control have been tested in the general population [106], including diets, exercise, and bariatric surgery [107‐110]. Dietary interventions have received a lot of attention in both the scientific and lay community as a result of successful results in experimental animal models [111, 112]. The limited human data are consistent with the animal data. Sustained weight-loss after the age of 50 measured over 10 years reduces the risk of breast cancer (HR 0.68–0.82), whereas stable weight or short-term weight loss over one 5-year interval does not reduce risk [17]. This observation underscores the need for an intervention that is sustainable over a long period. Strong evidence for a causal link between obesity and cancer comes from bariatric surgery studies. Weight loss through bariatric surgery reduces the risk of colon, endometrial, pancreas, and pre-menopausal ER-negative and post-menopausal ER-positive breast cancer [113, 114]. Dieting or caloric restriction for weight loss can also prevent cancer. Experimentally, CR involves a 30% reduction in the daily caloric intake with the usual timing of meals [111] and CR without malnutrition remains the most robust intervention to date for cancer prevention in rodents, monkeys, and humans [111]. CR promotes anti-carcinogenic adaptations such as decreased production of inflammatory cytokines, growth factors, and anabolic hormones as well as decreased oxidative stress and DNA damage [115]. Despite of an abundance of the literature on the mechanisms and impact of CR, its clinical applicability remains limited because of challenges in long-term sustainability as most people regain weight lost during CR. Considering difficulties maintaining weight loss with CR, adopting a healthy diet to promote weight loss has been tested. A healthy diet, either with or without physical activity, however, does not alter disease-free survival or mortality in breast cancer [116]. Although physical activity does not alter cancer outcomes, there is evidence for a beneficial effect on quality-of-life, depression, anxiety, lymphedema, and fatigue [117].

There has been growing interest in intermittent fasting as an alternative to CR because of promising results in experimental animal models [112]. According to a survey by the International Food Information Council Foundation, IF has become the most popular dietary intervention and many cancer patients are seeking advice from oncologists about its beneficial effect for cancer prevention and treatment [118]. IF can take various forms, including alternate day fasting with 0–25% of normal daily calories on the fasting days, the 5:2 method with 2 days of 25% calorie intake every 5 days of normal eating, periodic fasting (calorie intake is restricted for multiple consecutive days, such as 5 days, once a month, and unrestricted on all other days), Sunnah fasting (fasting every Monday and Thursday), and many other variations. Preclinical studies have shown beneficial effect of IF on tumor growth. In p53-deficient cancer mouse model, a 1 day per week IF regimen delayed tumor onset, significantly reduced tumor metastasis, and improved overall survival [119]. A study in a human xenograft prostate cancer model, an IF regimen comprised of 2 separate 24-h fasting periods per week exhibited similar trends toward delayed tumor growth and improved survival compared to an iso-caloric control group [120]. When combined with a fasting-mimicking diet, IF blocks TNBC and cancer stem cell escape in mice [121]. Interestingly, several short-term randomized clinical trials have indicated promising effects of alternate day fasting or a 5:2 diet in improving some cancer risk factors, including decreased fasting glucose, insulin, and leptin levels and increased adiponectin [22]. A small nonrandomized study of 23 women at increased risk for breast cancer found that IF for 2 days per weeks resulted in 4.8% reduction in body weight, an 8.0% reduction in body fat, and an improvement in insulin resistance over 4 to 5 weeks [122]. Similarly, IF of a ketogenic diet in patients with grade 2–4 astrocytoma decreased body mass and insulin levels [123]. IF for 24 h before and after chemotherapy reduced hematologic toxicity and promote recovery of chemotherapy-induced DNA damage [124]. IF also improved quality of life in cancer patients undergoing chemotherapy [125, 126].

While IF emphasizes the ratio of fasting/feeding durations, time-restricted eating emphasizes the timing of eating within a limited window without involving CR. TRE is a type of intermittent fasting, which involves consuming all calories within a consistent 8–12 h daily window based on the normal circadian rhythm of eating (Fig. 1) [62, 67, 127]. TRE (also called time-restricted feeding or TRF in mice) improves metabolic health in animal models and potentially in humans and may facilitate adherence and long-term weight loss maintenance as it doesn’t involve calorie counting [22, 23, 128‐130].

Given that TRE improves metabolic health in obese animals and humans, it might be expected to have anti-cancer effects in obesity-driven cancers. This has been borne out in a few rodent studies that evaluated the effect of TRE in modulating cancer risk or progression. In a recent study using mouse postmenopausal breast cancer models, our group reported that TRE, in the absence of caloric restriction or weight loss, could effectively inhibit the accelerated tumor initiation, progression, and metastasis due to obesity in comparison with mice with 24-h access to food. This beneficial effect of TRE was mediated, in part, by reduced insulin signaling as systemic insulin infusion through implanted pumps reversed the TRE-mediated protection and reducing insulin secretion mimicked the protection [23]. Sundaram and Yan have also shown that TRE of high-fat diet prevented cancer in the same transgenic MMTV-PyMT model of spontaneous breast cancer [24]. This group also demonstrated that TRE prevented high-fat diet enhanced metastasis in a subcutaneously injected Lewis lung cancer mouse model [25]. Aging increases the risk of cancer, and it has been proposed that the aged tissue microenvironment provides a pro-neoplastic niche. A recent study demonstrated that TRE could prevent the aging-associated changes in microenvironment and consequently decreases the growth of transplanted pre-neoplastic hepatocytes [176]. Colorectal cancer is also sensitive to the intestinal microenvironment and dysregulation of the gut microbiome has been connected to the pathogenesis of colorectal cancer. TRE was recently shown to improve the gut microbiota and prevent colon cancer [177]. Not all cancers respond to TRE however. Turbitt et. al. tested whether TRF alone or combined with anti-CTLA-4 immunotherapy would reduce tumor growth a murine model of kidney cancer. They found that TRF alone did not reduce tumor growth or metastasis in lean chow-fed or obese HFD-fed mice. Immune-checkpoint therapy had no effect in chow-fed mice but did reduce tumor growth in normal weight and obese mice on HFD irrespective of TRF [178]. Similarly, mice harboring LAPC-4 prostate cancer tumors did not show decreased tumor growth or increased survival [179].

As large prevention studies are lacking, most human studies to date have been epidemiological studies or small studies focused on assessing cancer biomarkers. In the Women’s Healthy Eating and Living study on a cohort of 2413 women with breast cancer, there was a significant increase in the risk of breast cancer recurrence with fasting < 13 h per night compared to fasting > 13 h per night (hazard ratio, 1.36; 95% CI, 1.05–1.76) [180]. An analysis of the NHANES data showed that each 3-h increase in night-time fasting was associated with improved glucose regulation and a decrease in hemoglobin A1c [181]. A case–control study in 922 Chinese women with incident BrCa and 913 controls [182] reported that eating after 10 pm was significantly associated with increased risk of breast cancer (OR 1.50). The association was strongest in women who had > 20 year history of eating after 10 pm (OR 2.28). A population case–control study of 1205 breast cancers and 621 prostate cancers in 1321 women and 872 men in Spain reported that a longer interval between the last meal and sleep was associated with lower cancer risk (prostate OR 0.74, breast OR 0.64)[183]. Similar protection was reported if meal eaten before 9 pm vs after 10 pm (OR 0.75 & 0.85) and in morning chronotypes (OR 0.65 & 0.67). As mentioned earlier, obesity causes hyperinsulinemia that can drive tumor growth and reducing insulin levels in mouse models inhibits tumor growth. Indeed, most of the obesity-associated increased risk for breast cancer can be accounted for by the increased risk due to the hyperinsulinemia [184‐186]. Several small TRE studies have reported reductions in insulin resistance, and by inference insulin levels, that would be expected to reduce cancer risk [20, 187]. Breast cancer risk is also linked with hypertension, with several studies reporting a 7–38% higher risk of breast cancer among women with hypertension [188]. A meta-analysis of six TRE studies with 97 participants showed clinically significant decreases in systolic and diastolic blood pressure [128, 189]. All these epidemiological and observational studies support the potential beneficial role of TRE in cancer. Nonetheless, these findings strongly suggest that more TRE studies are needed to better understand the underlying mechanisms and differences in outcomes before clinicians may start to consider safely and confidently prescribing TRE for the treatment of cancer in humans.

As discussed earlier, obesity is tightly linked to the metabolic syndrome which is a collection of metabolic disturbances including hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension, many of which have been linked to cancer [190]. In a recent review, Mattson et al. discussed the metabolic and physiological responses to CR, IF, and TRE, and highlighted the importance of four mechanisms including the adaptive stress response to oxidative damage, the bioenergetics or normal and cancer cells, suppression of inflammation, and induction of autophagy to remove or repair damaged organelles [191]. Many of these pathways also have relevance to cancer development. Post-prandial hyperglycemia may provide excess glucose to cancer cells to support their rapid growth since many cancer cells are more glycolytic than normal cells [12, 192]. Hyperglycemia can cause overproduction of advanced glycation end-products and reactive oxygen species, which can cause DNA damage and may initiate cancer. Obesity can also cause oxidative stress through increased mitochondrial oxidation of lipids [193‐196] and preliminary evidence suggests that TRE may reduce oxidative stress in men [20]. At the metabolic level, hyperinsulinemia increases the risk of both cancer incidence and death [197, 198]. This increase of cancer mortality is also observed in non-obese people with hyperinsulinemia [199]. Indeed, we recently demonstrated that TRF acts by correcting insulin resistance to prevent and inhibit breast tumor growth in mouse models of breast cancer [23]. Furthermore, obesity and diabetes alters the production of endotrophin, leptin, adiponectin, angiopoietins, bone morphogenic proteins, and other adipokines, which can also affect cancer cell growth and survival [200‐204]. For example, endotrophin, which is a carboxy-terminal proteolytic cleavage product of collagen 6α3, is overexpressed in obesity, enhances progression of breast and liver cancer, enhances epithelial-mesenchymal transition, and causes chemoresistance [205‐207]. As discussed earlier, obesity creates a state of sub-clinical, chronic tissue inflammation with immune cell infiltration due to elevated adipocyte inflammatory cytokine production [208, 209]. Such local inflammatory changes in the microenvironment have been shown to accelerate tumor initiation and growth [60, 61]. TRE reduces tissue macrophage infiltration and inflammation in mouse models [23, 131, 135, 210, 211]. Some human studies have shown that restricting food intake to 8 h, or a longer nighttime fast, significantly decreases proinflammatory markers [157] but other studies have not seen any changes in these markers [174, 212, 213].

In addition to the above-mentioned metabolic/inflammatory mechanisms, another mechanism to consider is circadian realignment. Most time-restricted eating protocols involve limiting food intake to a prescribed window, usually 6–10 h, but the timing of this window is also important. TRE during the normal active phase is more beneficial than TRE during the inactive phase in both animal and human studies. In-phase TRE reinforces the normal circadian rhythms of nutrient dependent clock genes, but out-of-phase TRE causes a phase shift in the normal oscillations. The circadian clock is essential for normal metabolic regulation and disruption of the clock causes obesity and insulin resistance [214‐217]. Disruption of the clock also causes abnormal cellular division and promotes tumorigenesis [62, 69]. Indeed, clock genes have been implicated in cancer as many tumors are acyclic with deficient endogenous clocks [93, 218, 219], circadian gene variants are associated with cancer [89, 220], clock genes regulate oncogene expression and suppresses oncogenic signaling [221‐223], and oncogenes regulate clock gene expression [224]. Our group has demonstrated that many of the disrupted tumor circadian rhythms were restored by TRE to patterns found in the normal tissues suggesting that TRE might suppress tumorigenesis by regulating tumor clock genes [23]. Despite the strong connection between circadian clock genes and cancer, no studies have shown a causative link between TRE-induced clock gene rhythms and tumor inhibition.

Fasting has been safely practiced by individuals in various religious practices. For instance, over the 30 days of Ramadan, individuals fast from dawn-to-dusk which varies up to 21 h per day depending on latitude, and in Judaism individuals routinely undertake 25 h fasts [212, 225‐227]. TRE is distinct from these religious fasts as the long fasting period is overnight rather than during the day, so is less associated with hunger. TRE also does not require total withdrawal from food and drink, as water and other zero-calorie beverages are allowed. Importantly, TRE has been reported not to cause major adverse events or negatively impact eating disorder symptoms among adults with obesity, metabolic syndrome, diabetes [128, 140], or pre-diabetes [20, 129], and TRE with a daytime feeding time window of 8 h does not cause occurrences of hypoglycemia, nor cause depression, anxiety or stress [228]. TRE has proven to be a more effective, safe, and convenient strategy than CR diet to lose weight [229, 230]. In obese individuals, TRE preserves healthy muscle in contrast to CR that causes 20–35% muscle loss [231‐234]. This is an important finding, because weight loss interventions typically result in concomitant decreases in both fat and lean body mass [156, 157]. However, safety studies of longer duration are needed before recommending TRE as a healthy lifestyle intervention for body weight control. Furthermore, TRE may not be suitable for everyone, especially those with underlying metabolic conditions. Adhering to a TRE diet is likely not wise for type 1 diabetics, since metabolic switching, which can occur with TRE, may lead to diabetic ketoacidosis [235]. Similarly, the potential use of TRE in pediatric intensive care units may be complicated by the susceptibility of newborns and infants to fasting-induced ketogenesis [236]. People with impaired liver function may also be particularly sensitive to TRE [237, 238].

TRE is a new treatment strategy for weight control, metabolic improvement, and diverse disease prevention without calorie reduction [190]. This method is an easier approach to maintain optimal body weight and health for a longer time because patients do not need to reduce total food intake, or calculate total daily calorie intake, or change the composition of their diet. Clinical studies have confirmed the effectiveness of this strategy. Dorothea et al. have reported that, 86% of participants achieved their weight target during the 3-month study period and TRE was well accepted by participants [152]. Studies in humans and animal models have reported the beneficial effects of TRE on obesity, diabetes, fatty liver, cardiometabolic dysfunctions, and lifespan [155, 239]. Several key features of TRE promote adherence relative to CR or other forms of IF. As TRE follows a cycle of fasting during the night with an 8–10 h eating window during the day with no calorie restriction, it may require less cognitive effort and facilitate dietary satisfaction. Additionally, TRE may reduce conflict with the homeostatic drive to eat and prevent dietary lapses resulting from prolonged negative energy balance [240]. In a large, randomized controlled trial of TRF in 116 overweight and/or obese men and women, high adherence to the TRF protocol (8-h feeding window) was reported [241]. Follow-up data from two small TRE trials reported promising data that subjects continued TRE even after the trial period had ended. In one study, long-term follow-up ~ 16 months after the end of the study reported that > 60% of the participants were still practicing some form of TRE [130]. In another study, it was reported that all participants were still doing TRE and maintained their weight loss one year after the end of the study [159]. While these observations are anecdotal, they do support the idea that TRE is easy to adopt and maintain. Long term adherence is very important if TRE is to have any preventative value for cancer, as Teras et al. found that sustained weight loss over two successive 5-year periods was needed to show a decreased risk of breast cancer, weight loss of a single 5-year period did not show a protective effect [17]. Although TRE may be easy to maintain once adopted, there are potential barriers to trying TRE in the general population. Work and family schedules may make adherence to a strict eating window difficult. Luckily, the animal data has shown that the benefits of TRE are maintained even if performed only during the week. Human data are lacking, but if this finding holds true, a five day "weekends-off" TRE regimen may prove attractive allowing participation in social events while maintaining adherence to TRE [242].

In conclusion, TRE is a promising therapeutic strategy for controlling weight and improving metabolic dysfunctions in those who are overweight or obese. As obesity represents a potential risk factor in cancer development and outcome, strategies that effectively modify obesity could potentially be harnessed as a means of cancer control. Preclinical studies support the potential beneficial effect of TRE in cancer prevention and growth. While definitive clinical trials showing the long-term effect of TRE on cancer prevention, treatment, and outcome are under investigation (Table 2), short-term TRE strategies for weight control may be helpful for some cancer patients and survivors. On a note of caution, TRE should still be regarded as a new dietary intervention with limited studies that have given mixed outcomes. For instance, small TRE studies have found significant decreases in weight and associated metabolic parameters, however, a large, randomized controlled trial of TRE in 116 overweight/ obese men and women for 12 weeks did not show a significant change in weight compared with the control group, although there were no measurements of energy intake or expenditure [241]. Therefore, large randomized clinical trials showing efficacy of TRE in obese individuals for 5-years or longer are needed before the adoption of TRE in the cancer clinical setting.