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Back to Journal »Cancer Management and Research» Volume 13

The ketogenic diet and its therapeutic potential for breast cancer: a systematic review

Author Jemal M, Molla TS, Asmamaw Dejenie T 

Published on December 14, 2021, the 2021 volume: 13 pages 9147-9155

DOI https://doi.org/10.2147/CMAR.S339970

Single anonymous peer review

Editor approved for publication: Professor Harikrishna Nakshatri

Mohammed Jemal, Tewodros Shibabaw Molla, Tadesse Asmamaw Dejenie Department of Biochemistry, School of Medicine and Health Sciences, Gondar University, Gondar, Amhara, Ethiopia Communication: Tadesse Asmamaw Dejenie Phone +251 967913355 Email [email protected] Abstract: Breast Cancer is still the main cause of female morbidity and mortality, and there is still a lack of complementary methods to significantly improve the efficacy of standard therapies. For many types of cancer, the usual standard treatment is a combination of surgery, radiotherapy and chemotherapy. However, this standard treatment is not effective alone. Therefore, there is an urgent need for new methods to improve the therapeutic effect. Some preclinical and clinical evidence suggests that the ketogenic diet is a new way to treat certain types of cancer. The ketogenic diet consists of a high-fat, low-carbohydrate diet that contains enough protein. It seems to make most cancers sensitive to standard treatments by using the reprogramming metabolism of cancer cells, making them promising candidates for adjuvant cancer treatments. Most preclinical and clinical studies believe that the combination of a ketogenic diet with standard therapies is based on its potential to improve the anti-tumor effects of conventional chemotherapy, its overall good safety and tolerability, and the improvement of quality of life. According to new evidence, a ketogenic diet reduces blood glucose and insulin levels, which are necessary for tumor growth. Therefore, the ketogenic diet has become a potential treatment option for a variety of cancers, including breast cancer. In addition, the implementation of a ketogenic diet in the clinic can improve the progression-free survival and overall survival rate of breast cancer patients. This review summarizes the composition and metabolism of the ketogenic diet and its underlying mechanisms in breast cancer, as well as their therapeutic potential for breast cancer. Keywords: ketogenic diet, breast cancer, breast cancer adjuvant therapy

Breast cancer is a malignant tumor that starts in breast cells and spreads to other parts of the body. 1 It is still an important cause of female morbidity and mortality. According to data from the American Cancer Society, the estimated number of new cases and deaths of female breast cancer in the United States in 2019 is 268,600 and 41,760, respectively. 2 In fact, 30% of all female cancers will be caused by breast cancer alone. Although the incidence of breast cancer in black women is lower than that of white women, the mortality rate of black women is 41% higher than that of white women, which may be related to diet and lifestyle. 3 In view of lifestyle factors, epigenetic regulation and gene mutations, it is clear that the heterogeneous population is represented by individuals with breast cancer. Increased obesity, estrogen or hormone axis transfer, and epigenetic signals significantly modulate the risk of breast cancer, all of which, in turn, are driven or significantly changed by dietary factors. 4 At present, most nutritional cancer work focuses on low-fat diet patterns or research on single anti-cancer foods/nutrients, but the experience or experimental evidence supporting these cancer management methods is very inconsistent. When the energy expenditure provided by carbohydrate and protein intake is less than 20% of the total energy expenditure (that is, the ketogenic diet (KD)), insulin levels and glucose utilization are reduced, and the production of liver ketones accelerates, leading to a state of nutritional ketosis. 5

In cancer cells, even in the presence of oxygen and fully functional mitochondria, the glucose uptake rate will increase dramatically and lactic acid will be produced. This process is called the Warburg effect. 6 Increased glycolysis, reduced tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) activity can be seen in the early stages of tumorigenesis and form one of the hallmarks of cancer. 7 Consistent with the Warburg effect, it has been shown that breast cancer has a high level of glycolytic activity. 8

Several studies have tested the effects of supplements and dietary elements as cancer preventives. However, limited research has focused on the use of diet as an adjuvant treatment for cancer. The ketogenic diet is one of these complementary therapies. This diet includes high fat, very low carbohydrates, and moderate levels of protein. 9 This diet shifts the body's metabolism to burn fat instead of carbohydrates. After consuming a ketogenic diet, fatty acids are oxidized in the liver to ketone bodies (β-hydroxybutyrate (BHB), acetoacetate and acetone), and then transported through the circulation to various tissues of the body, where they are converted into acetyl-coenzymes A. The end result of consuming KD is a moderate reduction in blood sugar, high levels of ketones and better blood sugar control. 10

Several studies have been conducted to evaluate the efficacy of KDs on various cancers. In animal models of malignant glioma, 11 breast cancer, 12 and colon cancer, 13 diet reduces tumor size and improves survival. In clinical studies, the tumor volume of advanced malignant astrocytoma after KD was reduced by 21.8%. Combining KD with standard treatment improves the condition of female patients with glioblastoma multiforme. 14 In this review, the basic knowledge of KD, its anti-tumor mechanism proposed in breast cancer, and current evidence of effectiveness from preclinical and clinical studies are summarized.

KD is mainly composed of high fat, medium protein and very low carbohydrates. It can be divided into four main types, namely classic KD, medium-chain triglyceride diet, modified Atkins diet and low glycemic index treatment. 15 Various dietary methods can produce a metabolic ketosis state, such as classic KD, fasting periods, or high calorie restriction. Ketosis can be achieved through fasting-based interventions called fasting ketosis (FK). 16 FK is used as an indicator of weight loss effect. 17 In addition, ketosis can also occur when total energy expenditure equals calorie intake; especially in diets that contain a high percentage of fat (> 60%) and/or low carbohydrates. This state of ketosis is called nutritional ketosis (NK). 16

NK has been studied as a treatment for epilepsy because it is believed that ketones can provide energy to the brain, thereby reducing seizures. In addition, the ability to accumulate ketosis produced by the combination of NK and FK is associated with effective weight loss and positive health outcomes. 18

Recently, KD has become more and more interested in the treatment of various diseases, whether as a standalone metabolic therapy or as part of a broader treatment approach. Chronic systemic diseases with strong metabolic characteristics, such as cancer, are theoretically ideal targets for ketogenic metabolism therapy. 19

The anti-tumor effects of ketone bodies (such as acetoacetate and BHB) have been observed in several breast cancer cell lines in vitro. However, it seems unlikely that the anti-tumor properties of KDs can be entirely attributed to the anti-proliferative effects of ketone bodies and low blood sugar levels. 20,21

Current in vitro cancer cell culture methods usually use 25 mM (450 mg/dL) high glucose in the growth medium. Although high glucose media creates an optimal environment for cancer cell proliferation, these glucose levels may complicate the interpretation of drug efficacy studies. twenty two

Many preclinical studies have shown that KDs have anti-tumor effects, although in some cancer models, some studies have reported tumor-promoting effects or serious side effects. 22,23 In most preclinical studies, KD slowed tumor growth, prolonged survival, delayed tumorigenesis, and reversed the cachexia process caused by cancer. 24,25

In addition, studies on various mouse cancer models (including pancreatic cancer, bladder cancer, endometrial cancer and breast cancer, and acute myeloid leukemia) have shown that KD improves the effectiveness of targeted therapies, especially PI3K inhibitors. And overcome the resistance. 26 This shows that KD can be part of a multi-modal treatment plan to improve the efficiency of classic cancer treatments.

In addition, studies on mouse breast cancer models have shown that the blood glucose and insulin concentrations of mice that ingest KD are significantly reduced. Strict insulin inhibition can lead to two main effects, both of which may induce the programmed death of cancer cells and reduce the proliferation of cancer cells. First, the reduction of blood insulin levels on the cancer cell membrane leads to reduced binding to the insulin receptor, which leads to downstream inhibition of the mammalian target of rapamycin (mTOR) signaling cascade 25 and the mitogen-activated protein kinase (MAPK) pathway. 27

Therefore, the decrease in insulin concentration caused by the ketogenic diet helps to enhance programmed cell death by inhibiting the mTOR cascade and reducing the proliferation of both pathways. 28 Secondly, ketogenesis in the liver caused by insulin inhibition increases the blood levels of BHB and acetoacetone, both of which have demonstrated the effect of histone deacetylase inhibitors at the cellular level, and are known to reduce the risk of cancer cells. Proliferate and improve programmed cell death. 29,30 Based on preclinical observations; in mouse models of breast cancer, a ketogenic diet can inhibit the growth of primary breast tumors and lung metastases, and extend the life of mice. In addition, when KD is used in combination with rapamycin, KD can enhance the effect of rapamycin, thereby more effectively controlling cancer. 12,31 According to the results of these preclinical studies, KD has a beneficial effect on breast cancer models. Therefore, many clinical studies are currently being conducted on breast cancer patients.

For many types of cancer, the usual standard treatment is a combination of surgery, radiation therapy, and chemotherapy. 32 However, there is no effective standard treatment for highly aggressive cancer types with poor prognosis, such as triple-negative breast cancer. 33 Therefore, there is an urgent need for new methods to improve the effectiveness of treatment. Preclinical evidence suggests that KD is a new type of treatment for certain types of cancer. 34

Table 1 shows the summary of clinical trial studies evaluating the ketogenic diet as an adjuvant treatment for breast cancer. Compared with the control group, the ketogenic diet resulted in a significant reduction in staging and tumor size. Compared with the baseline, the tumor size in the KD group showed a significant reduction; compared with the 6 mm in the control group, the tumor size in the intervention group was reduced by 27 mm. Similarly, the lymph node scores (N1, N2, N3) of the KD group decreased from baseline to the end of the study. No such trend was observed in the control group. 35 Table 1 A clinical trial study evaluating the ketogenic diet as an adjuvant treatment for breast cancer

Table 1 A clinical trial study evaluating the ketogenic diet as an adjuvant treatment for breast cancer

In addition to its direct impact on tumor growth, KD also has the potential to improve patients' overall health and quality of life. A randomized controlled trial study for breast cancer patients reported that MCT-based KD led to a decrease in FBS (fasting blood glucose) and an increase in blood ketone levels in the intervention group. Positive effects on lipid profile and kidney and liver markers were also observed. In addition, it can be speculated that KD, which is high in fat and limited in carbohydrates, may affect the body's composition. In this regard, it has been shown that the weight, BMI (body mass index) and body fat percentage of the intervention group have shown a significant downward trend, indicating that KD based on MCT is beneficial to breast cancer patients. 36

According to the results of breast cancer randomized controlled trials, the level of compliance with KD intervention indicates that diet is a viable option for women with breast cancer undergoing chemotherapy. 35,36 However, some discomforts, such as weakness, starvation and lack of energy and proper tolerance of KD were observed in some patients, which may be attributed to the following reasons. First, combining KD with chemotherapy may lead to possible side effects such as weakness and the possibility of non-compliance. Secondly, this may be due to a greasy diet and limited/eliminated carbohydrate-containing foods such as fruits, milk, bread, rice and candy. Therefore, patients are not allowed to eat more than the prescribed diet, especially if they feel hungry during the first two weeks of follow-up. 36 However, some studies have reported that KD is well tolerated by patients who adhere to the diet and have concluded that it is feasible and safe to use KD in breast cancer patients. 35

A woman with triple-negative breast cancer provided a combination of KD and metabolically supported chemotherapy, hyperthermia, and hyperbaric oxygen, showing a complete clinical, radiological, and pathological response. 33

In addition, compared to the control group, KD resulted in a significant reduction in staging and tumor size. Compared with the baseline, the tumor size in the KD group showed a significant reduction; compared with the 6 mm in the control group, the tumor size in the intervention group was reduced by 27 mm. Similarly, the lymph node scores (N1, N2, N3) of the KD group decreased from baseline to the end of the study. No such trend was observed in the control group. 35

In addition to its direct impact on tumor growth, KD also has the potential to improve patients' overall health and quality of life. A randomized controlled trial study for breast cancer patients reported that MCT-based KD led to a decrease in FBS (fasting blood glucose) and an increase in blood ketone levels in the intervention group. In this regard, it has been shown that the weight, BMI (body mass index) and body fat percentage of the intervention group have shown a significant downward trend, indicating that KD based on MCT is beneficial to breast cancer patients. 36

In the following section, the potential mechanism of KD in breast cancer is discussed.

Most solid cancers have metabolic characteristics such as increased glucose uptake and dependence on glycolysis. 39 In breast cancer, aerobic fermentation (Warburg effect) is a common metabolic phenotype, regardless of histopathological type, grade or gene expression profile. 40 In the Warburg effect, cancer cells mainly use glycolysis to produce energy and lactic acid at the same time, but the paradox is that even if there is enough oxygen to breathe. 39 Therefore, it can be hypothesized that the Warburg effect in cancer cells is at least partly caused by the glucose supply caused by KD and/or calorie-restricted dietary interventions caused by chronic metabolic stress. 41 KD reduces the activity of insulin-like growth factor-1 (IGF-1)/insulin-PI3K-Akt-mTOR signaling pathway, which is closely related to growth. 35,42 Insulin activating enzyme PI3K is often enhanced in various types of cancer The activity, including breast cancer, is due to mutations in the PI3 K gene. Therefore, PI3K inhibitors are considered to be effective anticancer drugs. However, clinical trials have shown that drugs targeting PI3K usually cause hyperglycemia, leading to increased insulin levels and reactivation of the PI3K pathway, ultimately leading to treatment resistance. 43

Recently, KD has been shown to increase the efficacy and resistance of anti-PI3K therapy by limiting the acute glucose-insulin feedback of PI3K inhibitors, thereby blocking this cycle. 24 In addition, there have been reports of reduced levels of lactate and transketolase-1 in patients strictly using KD. 44

Emerging evidence suggests that most cancers exhibit abnormal metabolic energy. There is ample evidence that tumor cells, including breast cancer tissues, have abnormalities in the number, structure and function of mitochondria in most cancer tissues, and this abnormality affects the effective production of energy. 45 Breast cancer cells also express abnormal membranes related to mitochondrial membrane abnormalities in mitochondria, which will further reduce the energy produced by OXPHOS. In order to maintain sufficient energy for the survival and growth of breast cancer, it is necessary to increase fermentation metabolism to make up for the lack of OXPHOS. 46,47 Replacing glucose with ketone bodies requires tumors to have functional mitochondria so that they can effectively use ketone bodies for growth and survival. 42 The ketogenic diet is a non-drug method that induces the transition from glycolysis to mitochondrial respiration. Increased β-oxidation and mitochondrial biosynthesis, increased antioxidant signals through nuclear factor erythrocyte 2 related factors, and upregulation of manganese-dependent superoxide dismutase, catalase and mitochondrial uncoupling protein 2 are among the effects. 49,50

Damaged OXPHOS leads to the accumulation of active oxygen and compensatory fermentation. ROS is carcinogenic and mutagenic, and is the main cause of tumor cell genome instability and mutation. In other words, mutations in tumor cells stem from impaired energy metabolism. 51

Hypoxia-inducible factor 1-α (HIF-1α), myelomatosis (Myc), rat sarcoma and other oncogenes promote the dependence of tumor cells on glucose and glutamine, while the defects of p53 and pRb tumor suppressor genes will damage Functional OXPHOS, which leads to additional growth dependence on fermentation. These gene mutations are related to breast cancer and other cancers through mitochondrial dysfunction. 52 The ketogenic diet may reduce the induction and effectors of the Myc pathway, which is responsible for the transcription of lactate dehydrogenase A (LDH-A). The LDH-A enzyme is responsible for converting pyruvate into lactic acid and forcing the cell to produce a Warburg-like effect. 52,53

In addition, a clinical study reported that KD, hyperthermia and hyperbaric oxygen therapy (HBOT) also target the defective energy metabolism of tumor cells. Hyperthermia produces therapeutic effects by helping drug uptake, increasing the production of oxygen free radicals, and inhibiting the repair of deoxyribonucleic acid (DNA) in cancer cells, leading to the death of cancer cells. 54 HBOT targets tumor hypoxia related to tumor aggressiveness and resistance 55 tumor cells are dependent on glycolysis, which is a major factor in the up-regulation of antioxidant activity, leading to tumor resistance to pro-oxidative chemotherapy and radiotherapy Increased and also used by hyperthermia and HBOT. Therefore, high temperature and HBOT in tumor cells can selectively increase oxidative stress. The metabolism of the main circulating ketone body BHB protects normal cells from this stress by reducing the production of reactive oxygen species (ROS), while increasing the oxidative stress of tumor cells. 19 In general, the mechanism of the ketogenic diet in cancer suppression and anti-cancer mechanisms is described in (Figure 1). Figure 1 The pleiotropic mechanism associated with the ketogenic diet and related tumors and patient outcomes. Abbreviations: CHO, carbohydrate; HDAC, histone deacetylase; ROS, reactive oxygen species.

Figure 1 The pleiotropic mechanism associated with the ketogenic diet and related tumors and patient outcomes.

Abbreviations: CHO, carbohydrate; HDAC, histone deacetylase; ROS, reactive oxygen species.

As explained in this review, KD appears to create an unfavorable metabolic environment for breast cancer cell proliferation, and therefore, it represents a promising adjuvant for multi-factor treatment regimens for patients. One obvious benefit of KD is that it has the potential to increase the response to therapeutic drugs, which has been widely demonstrated in vitro and in vivo. 22,26,48 Therefore, combining KD with standard therapies or even new treatments to improve treatment response should be the focus of research in this field. 56

KD has been used in combination with low-dose chemotherapy and other treatments to control tumor growth in women with stage IV triple-negative breast cancer. The woman responded well and initially reported a complete response to the combination therapy. Although the overall survival exceeded the expected median of her stage and grade, she eventually died of cancer. The failure to continue the KMT regimen is believed to be part of the reason for her tumor recurrence. 30 In addition, a case study of a woman with metastatic breast cancer (bone and lung metastases) showed that a one-year ketogenic diet was combined with a standard diet. Her care treatment resulted in complete remission, and no visible tumor was assessed by FGD-positron emission tomography. 57

KD started shortly after diagnosis and before surgery, and may prove to be a non-toxic adjuvant treatment that can reduce the aggressiveness and aggressiveness of cancer, thereby increasing the efficiency of subsequent treatment. 58 Selection, dosage, timing, medications, diet, follow-up treatment, and the arrangement and arrangement of procedures when used as a complementary or alternative treatment strategy with standard care will provide survival and quality of life benefits for patients with advanced metastatic breast cancer. 52

The compression pulse therapy strategy for cancer management is demonstrated by the use of a calorie-restricted ketogenic diet (KD-R) in combination with drugs and procedures that produce chronic and intermittent acute stress on the energy metabolism of tumor cells, while protecting and Enhance the energy metabolism of tumor cells in normal cells. By optimizing the dosage, timing and scheduling of KD used with synergistic drugs and procedures, it will help eradicate breast tumor cells with minimal patient toxicity. This treatment can be used as a framework for designing clinical trials for non-toxic treatments for most cancers, including breast cancer. 19 In light of this evidence, nutritional ketosis may be beneficial for breast cancer patients, including direct treatment. The impact on tumor pathways and survivability requires more strictly controlled interventions. However, it is necessary to understand and implement carefully formulated ketogenic diet principles to ensure maximum safety and effectiveness in reducing tumor burden, managing comorbidities, and ensuring long-term quality of life. 57

Most preclinical and some clinical trials support the use of KD as an adjuvant treatment for breast cancer. Based on convincing evidence that the ketogenic diet is related to a wide range of health promotion outcomes through various mechanisms of action, a broader view has now emerged. The ketogenic diet reduces dependence on the glucose/insulin axis and leads to significant changes in substrate usage, such as increased fatty acid oxidation and decreased glucose flux, which may be a therapeutic mechanism for the treatment of breast cancer.

The ketogenic diet can also restore the host's hormonal and inflammatory environment, which is thought to inhibit tumor growth. As insulin concentration and signal transduction decrease, the activation of growth factors and oncogenic pathways involving PI3K/Akt and mTOR should also decrease. The ketogenic diet encourages an anti-inflammatory phenotype, which may result in less aggressive and longer progression-free survival. Generally speaking, breast cancer patients can benefit from a ketogenic diet because it can improve biochemical parameters and body composition.

In order to better understand the mechanism behind KD treatment and its application in breast cancer treatment, more molecules and well-designed randomized controlled trials are needed. In addition, large-scale clinical trials will be conducted, focusing on implementing a carefully formulated ketogenic diet for various types of breast cancer. In addition, additional clinical trials are needed to clarify whether calorie restriction or combination with other treatments (such as radiotherapy or anti-angiogenesis therapy) can improve the efficacy of the ketogenic diet.

BMI, body mass index; CHO, carbohydrates; FBS, fasting blood glucose; FK, fasting ketosis; HBOT, hyperbaric oxygen therapy; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factor 1-α; IGF-1 , Insulin-like growth factor-1; KD, ketogenic diet; KD-R, calorie-restricted ketogenic diet; KMT, ketogenic metabolism therapy; MCT, medium-chain triglycerides; NK, nutritional ketosis; OXPHOS, oxidized phosphoric acid Chemical; PI3K, phosphatidylinositol-3 kinase; Ras, rat sarcoma; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Upon reasonable request, the corresponding author may provide supporting data. 

Ethical approval does not apply because the publication is based on data from previously published articles rather than its investigation.

All authors have made significant contributions to the work of the report, whether in terms of concept, research design, execution, data acquisition, analysis, and interpretation, or in all these areas; participating in drafting, revising, or critically reviewing articles; final approval requirements Published version; agreed on the journal to which the article was submitted; and agreed to be responsible for all aspects of the work.

The author did not receive any funding for this review from any funding agency.

The authors declare that they have no conflicts of interest in this work.

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