This review article explains the urgent need to understand liver metastatic breast cancer, a condition where breast cancer spreads to the liver and carries a median survival of only 2–3 years (or as little as 4–8 months without treatment). Researchers at the University of Illinois explored how diet—particularly the Western diet and the fasting-mimicking diet—affects tumor metabolism, growth, and treatment effectiveness. The review highlights emerging evidence that dietary interventions could enhance anti-cancer therapies, though no standard evidence-based diet recommendations currently exist for cancer patients. Key findings include how sugar-driven metabolic pathways fuel tumor growth, while fasting-mimicking diets may slow cancer progression and even enhance the effectiveness of chemotherapy and hormone therapy.
Breast cancer remains the most common cancer among women in the United States, accounting for a staggering 30% of all new cancer cases. The American Cancer Society estimated that in 2021 alone, there would be 281,550 newly diagnosed breast cancer cases and 43,600 deaths from the disease. In total, an estimated 1.9 million new cancer cases and 608,570 cancer deaths were projected in the US that year.
As of 2018, approximately 3.7 million women in the US were living with a breast cancer diagnosis. Globally, the picture is equally concerning. Breast cancer mortality is rising substantially, particularly in developing regions such as Latin America and the Caribbean, where deaths are increasing by an estimated 7 million every five years.
These numbers reflect a serious public health challenge. But there is renewed hope emerging from an unexpected area: the food we eat. Accumulating research suggests that targeted dietary interventions—such as the ketogenic diet and the fasting-mimicking diet—may improve the effectiveness of anti-cancer therapies and potentially extend survival.
When breast cancer is caught early, the outlook is generally good. Approximately 63% of breast cancer patients are diagnosed with local-stage disease (confined to the breast), and 27% with regional-stage disease (spread to nearby lymph nodes). Only about 6% are diagnosed with distant, metastatic disease at the time of initial diagnosis.
Yet it is the metastatic disease that poses the greatest danger. In 2020, more than 168,000 women in the US were living with metastatic breast cancer. Although metastatic cases represent a small percentage of breast cancer diagnoses, metastatic tumors are responsible for more than 90% of all cancer-related deaths.
The survival statistics tell a sobering story:
About one-third of women diagnosed early with non-metastatic breast cancer will eventually develop metastatic disease, which often becomes resistant to therapies over time.
Among stage IV breast cancer patients, the sites of distant metastasis are:
Liver metastasis deserves special attention because of its dire outcomes and limited treatment options. Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database—a network of tumor registries covering about 30% of the US population with data from 1975 to 2017—revealed that among 2.4 million cancer patients, 5.14% presented with synchronous liver metastases (meaning the liver spread was found at the same time as the primary diagnosis).
Half of all breast cancer patients will eventually develop liver metastases at some point in their disease course. If left untreated, survival can be as short as 4–8 months. Interestingly, liver metastasis is observed more frequently in younger women, occurring in 34.2% of breast cancer patients under 50 years of age, compared to only 8.9% of patients aged 50 and older.
The type of breast cancer also matters. Patients with hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer with liver metastasis have a longer median survival than patients with HR+/HER2-negative or triple-negative breast cancer—largely due to the introduction of HER2-targeted therapy.
Liver metastasis may initially produce no symptoms at all. When symptoms do appear, they can include:
Liver metastasis is often identified through liver function tests, which detect signs of liver disease or damage. Diagnosis may also be confirmed through imaging techniques such as MRI (magnetic resonance imaging), CT (computed tomography), PET (positron emission tomography), or combined PET/CT scans. In some cases, a biopsy (tissue sample) is performed to confirm the diagnosis.
Most patients with breast cancer liver metastasis are treated with either systemic medications (which travel through the bloodstream) or local treatments (which target the liver directly).
Systemic treatments include:
Local treatments for breast cancer liver metastasis include:
Liver metastatic estrogen receptor-positive (ERα-positive) breast cancer is currently considered incurable, and persistent tumor cells frequently develop resistance to endocrine therapies. However, several promising small molecule therapies are being investigated:
Several oral selective estrogen receptor degraders (SERDs) and other pathway inhibitors are also in clinical investigation:
Dietary factors account for about 30% of all cancer cases, making diet one of the most modifiable causes of cancer. High consumption of red meat, animal fats, and refined carbohydrates is associated with increased risk and severity of diseases such as breast cancer.
For postmenopausal women, Western diets that promote weight gain, fat redistribution, abnormal blood lipids (dyslipidemia), high blood pressure, and insulin resistance are particularly concerning. These factors are all components of what doctors call metabolic syndrome, and they increase the risk of developing obesity-related breast cancer.
The statistics are striking: for overweight or obese postmenopausal women, the risk of developing estrogen receptor-positive (ER+) and progesterone receptor-positive (HR+) breast cancer is about 1.5 to 2 times higher than for women with normal body weight. This increased risk is likely due to higher levels of estrogen produced by extra fat tissue, as well as elevated insulin levels and other mechanisms.
The Western diet is characterized by high amounts of fat and sugar—specifically saturated fats and sucrose—with a low intake of fiber. This eating pattern plays a role in inflammatory disease and negatively affects both the immune system and the gut microbiota. Western diets are strongly associated with obesity and metabolic effects such as weight gain, and they are often blamed for what experts call "the obesity epidemic" as well as rising rates of type 1 and type 2 diabetes.
Glucose (sugar) is central to the Western diet, and understanding how cancer cells behave when glucose is abundant is critical. The Western diet directly promotes tumor cell proliferation through mechanisms involving the insulin/IGF1/PI3K signaling pathway.
Here is what happens in simple terms:
Insulin also stimulates the release of inflammatory molecules called IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha), which can further promote cancer growth.
Research has shown that many aggressive tumors overexpress glucose transporters 1 and 3, which correlates with elevated glucose uptake. In laboratory experiments:
Reducing glucose concentrations significantly decreases the proliferation of MCF-7 and T47D breast cancer cells (both estrogen receptor-positive) and MCF-10A breast epithelial cells. Conversely, high glucose levels (25 mM) significantly block the therapeutic effects of metformin (a common diabetes drug with anti-cancer properties) on triple-negative breast cancer cells, affecting cell proliferation, death, and cell cycle arrest. High glucose also contributed to metastatic progression and the development of resistance to chemotherapy and radiation therapy.
Animal studies reinforce this picture. Mice with breast cancer liver metastasis that were fed sugar-rich diets had high metastatic burden, while mice fed high-fat/low-sugar diets had low tumor burden—despite being obese. In other mouse studies, liver tumor burden was positively correlated with hepatic fat accumulation, insulin levels, and liver IL-6 levels, and inversely correlated with adiponectin (a protective hormone) levels. These results indicate that dietary sugar intake may stimulate liver tumor growth.
At the molecular level, researchers found that reduced extracellular glucose can stimulate an enzyme called CARM1 (coactivator-associated arginine methyltransferase 1) to modify a key metabolic protein, GAPDH, at a specific site (arginine 234). This modification inhibits GAPDH's enzymatic activity and represses glycolysis, which delays liver cancer cell growth—since cancer cells depend on glycolysis for proliferation.
There is also a higher incidence of breast cancer among diabetic and obese populations, supporting the theory that a low-carbohydrate diet may limit or prevent tumor growth.
The fasting-mimicking diet (FMD) is a specific dietary approach that is low in calories from sugars and protein but high in unsaturated fats. It is important to note that the FMD is not the same as water-only fasting—it provides food but in a form and quantity that mimics the effects of fasting on the body.
This diet is widely studied in relation to disease prevention and treatment. While it has low levels of toxicity, it may have limitations in terms of how well people can stick to it, and it may not be appropriate for individuals with pre-existing nutritional deficiencies.
Unlike the Western diet, low-carbohydrate diets slow cancer growth by inhibiting the insulin/IGF pathway and its downstream intracellular signaling pathways—specifically PI3K/Akt/mTOR. Here is what happens in the body:
When cancer cells metastasize to the liver, they undergo metabolic reprogramming. Liver cancer cells become dependent on glucose or fructose as energy sources to fuel high rates of glycolysis or fructolysis. This process generates NADPH and pyruvate through the pentose phosphate pathway.
To give a concrete example: in colon cancer that has spread to the liver, dietary fructose provides fuel for major pathways of central carbon metabolism during tumor cell proliferation by activating an enzyme called aldolase B (ALDOB) or its upstream regulator GATA6.
Cancer cells become dependent on ATP (the cell's energy currency) produced by the less efficient process of glycolysis. Additionally, tumor cells have more mitochondrial DNA mutations than normal cells, producing an increased number of reactive oxygen species (ROS) during respiration—which can damage cells and promote cancer progression.
The FMD cleverly exploits the fact that tumor cells depend on glucose. When glucose is limited, the body produces an alternative form of energy: ketones. Cancer cells are forced to use mitochondrial oxidative metabolism, which causes metabolic oxidative stress. The liver produces ketone bodies that benefit normal cells—but cancer cells cannot effectively use them for energy.
This approach is effective because of a phenomenon known as the Warburg effect: even in the presence of oxygen, cancer cells preferentially use glycolysis (which produces lactate in excess) to compensate for dysfunctional mitochondrial oxidative phosphorylation. High-fat, low-carbohydrate diets like the FMD are able to restrict the availability of glucose and limit this Warburg-type metabolism.
Several animal studies across various cancer types have shown that the FMD effectively limits tumor growth—either by itself or in combination with other therapies—without causing the rebound hyperglycemia (high blood sugar) and hyperinsulinemia (high insulin levels) seen with other approaches.
Key findings include:
One of the most exciting findings is that the FMD enhances the anti-cancer efficacy of endocrine therapeutics, including tamoxifen and fulvestrant, and delays endocrine resistance. In mouse models of hormone-receptor-positive breast cancer, the FMD achieved this by:
Importantly, the first-in-human clinical trial of the FMD (trial number NCT03340935) has been reported in patients with different tumor types, including 56 breast cancer patients (26 with luminal tumors, 19 with triple-negative breast cancer, and 11 with HER2-positive tumors) who were treated with concomitant anti-tumor therapies. The results showed that the FMD favorably modulates systemic and intratumoral immunity and activates several anti-tumor immune programs by significantly reducing:
Additional molecular targets of the FMD include the NLRP3 inflammasome, RNA-binding proteins, and G protein-coupled receptors.
When on a high-fat, low-carbohydrate diet, the liver produces ketone bodies through a process called ketogenesis. When the supply of carbohydrates is low, acetyl-CoA is broken down into acetoacetate (AcAc) and then further reduced to β-hydroxybutyrate (βHB), one of the most abundant and principal ketone bodies.
Interestingly, although βHB is produced in the liver from the breakdown of free fatty acids, the liver itself does not use ketone bodies for energy because it lacks the necessary enzyme thiophorase (beta ketoacyl-CoA transferase). This means the ketones produced by the liver are released into the bloodstream for other organs to use.
In most people, the plasma βHB concentration typically reaches at least 2 mM (a measure of concentration) on a low-carbohydrate, high-fat diet.
βHB has several beneficial properties:
In laboratory studies, βHB effectively inhibits S2-013 cells—a cell line derived from a liver metastasis of a human pancreatic tumor. High levels of βHB (25 mM) do not stimulate breast cancer cell proliferation, suggesting that breast cancer cells cannot use βHB as fuel to proliferate.
In an animal study involving mice implanted with VM-M3 tumors, dietary ketone supplementation (either 1,3-butanediol or a ketone ester, both of which are metabolized to βHB and acetoacetate) prolonged survival and reduced tumor burden in mice with metastatic cancer. The supplementation also lowered blood glucose, elevated blood ketones, and decreased overall body weight.
In another study, βHB enhanced the cancer-killing effects of cisplatin (a chemotherapy drug) in hepatocellular carcinoma (liver cancer) through a specific cell death pathway involving histone deacetylase (HDAC) 3/6 inhibition.
Clinical trials at the University of Würzburg tested low-carbohydrate, high-fat diets in 16 patients with advanced or metastatic solid malignant tumors. After 3 months of ketogenic diet therapy, patients experienced stable physical condition, lower body mass index (BMI), somewhat better quality of life, and/or slowed tumor growth.
However, some studies link βHB to tumor progression, metastasis, and clinical failure. This has given rise to what researchers call the "β-hydroxybutyrate paradox."
The paradox is explained by the concept that βHB's effect on cancer growth depends on the tumor's energetic phenotype:
In a spontaneous mouse mammary tumor model, βHB at low concentration (less than 1 mM) increased tumor growth by acting as an oxidative energy source rather than as an epigenetic factor. An in vitro (test tube) study determined that βHB can change the energetic phenotype of breast cancer cells but not their glucose consumption and lactate production.
A similar paradox surrounds another common ketone body called butyrate. Like βHB, butyrate can mediate histone acetylation and inhibit cell proliferation in cells that follow the Warburg effect (preferentially using glucose). However, in cancer cells that do not follow the Warburg effect and instead oxidize butyrate as fuel, butyrate fails to reach inhibitory concentrations and can actually stimulate tumor growth.
In vitro studies showed that sodium butyrate (NaBu), an HDAC inhibitor, inhibits breast cancer cell growth in a time- and dose-dependent manner. This anti-cancer effect is due to NaBu triggering a process called apoptosis (programmed cell death) through elevated levels of reactive oxygen species, increased caspase activity, and reduced mitochondrial membrane potential. Another study demonstrated that NaBu induces autophagy (a cellular self-digestion process that can suppress tumors) in colorectal cancer cells through a pathway involving phosphorylated liver kinase B1 (LKB1) and AMPK signaling.
The scientific community has not reached a consensus on the benefits or detriments of high-fat, low-glucose diets. The effects of ketone bodies appear to be highly context-dependent—what helps one patient might harm another, depending on the metabolic characteristics of their specific tumor.
Although dietary recommendations are not yet standardized, the emerging evidence has several practical implications for breast cancer patients, particularly those with liver metastases.
First, the FMD can reduce the toxic effects of chemotherapy and enhance therapeutic efficacy beyond chemotherapy alone. When used alongside chemotherapy, the FMD delays breast cancer and melanoma progression in mice by reducing a protein called HO-1, which sensitizes tumors to the chemotherapy. In patients with HER2-negative early breast cancer receiving chemotherapy, the FMD increased tumor cell death and significantly slowed chemotherapy-induced DNA damage in T-lymphocytes (a type of immune cell). This suggests the diet might protect healthy cells while making cancer cells more vulnerable—a promising combination.
Second, lowering blood sugar may improve survival. The evidence that metastatic triple-negative breast cancer patients with lower glycemia (blood sugar) survive longer suggests that dietary strategies to control blood glucose could have direct clinical benefits.
Third, individual tumor biology matters. The β-hydroxybutyrate paradox teaches us that the same diet could theoretically help or harm depending on whether a tumor uses oxidative phosphorylation or glycolysis. This means "one-size-fits-all" dietary advice is unlikely to be effective—personalized approaches based on tumor metabolic phenotyping would be ideal.
The authors of this review are clear about the limitations of current research:
Based on the current evidence, here are some practical considerations for patients with breast cancer—especially those with liver metastasis:
This review suggests that the future of breast cancer treatment will likely involve combining standard therapies with personalized dietary interventions designed to exploit the metabolic weaknesses of individual tumors. While we are not there yet, the scientific foundation is being built.
Liver metastasis from breast cancer is serious. Without treatment, survival can be as short as 4–8 months. With treatment, median survival from a metastatic breast cancer diagnosis is about 18–24 months, and five-year survival is 28%. Treatments include chemotherapy, hormonal therapy, targeted therapy, surgery, and radiation.
The Western diet is high in saturated fat and sugar and low in fiber. It promotes weight gain and metabolic syndrome. High sugar intake raises insulin and IGF-1, which can fuel tumor growth. In mouse studies, sugar-rich diets led to high liver tumor burden, while high-fat/low-sugar diets had low burden.
The FMD is a low-calorie, low-sugar, low-protein, high-unsaturated-fat eating plan that mimics fasting. It restricts glucose, curbs glycolysis, activates AMPK, and lowers insulin and IGF-1. Studies show it can slow tumor growth and improve the effectiveness of chemotherapy and hormone therapy, though more human research is needed.
β-hydroxybutyrate is a ketone produced on low-carbohydrate diets. It can fight cancer by reducing inflammation and inhibiting tumor growth. However, in tumors that rely on oxygen-based energy, βHB may act as fuel and promote growth. Its effect depends on the tumor's metabolic phenotype, so one diet may not fit all.
No standard dietary guidelines exist for cancer patients. The FMD is promising but not proven therapy. Discuss any dietary changes with your oncology team first. Avoid high-sugar diets, as sugar may stimulate liver tumor growth. Do not replace standard treatments like chemotherapy or hormone therapy with diet alone.
Treatments include systemic therapies such as chemotherapy, hormonal therapy (tamoxifen, aromatase inhibitors, fulvestrant), and targeted therapies like everolimus, palbociclib, and ribociclib. Local treatments include surgery and radiation techniques such as SBRT and Y-90 radioembolization. Newer drugs like SERDs are being studied in clinical trials.
In some studies, metastatic triple-negative breast cancer patients with lower blood sugar survived longer than those with higher blood sugar. A low-carbohydrate diet may limit tumor growth by reducing insulin and IGF-1. However, evidence is not definitive, and dietary changes should be coordinated with your medical team.
Original Article Title: Liver Metastatic Breast Cancer- Epidemiology, Dietary Interventions, and Related Metabolism
DOI: 10.3390/nu14122376
Authors: Qianying Zuo, Nicole Hwajin Park, Jenna Kathryn Lee, and Zeynep Madak Erdogan
Journal: Nutrients, 2022, Volume 14, Issue 12, Article 2376
DOI: 10.3390/nu14122376
Publication Date: June 8, 2022
Affiliations: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign; Department of Neuroscience, Northwestern University; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign; Cancer Center at Illinois; Beckman Institute for Advanced Science and Technology; Carl R. Woese Institute of Genomic Biology; Department of Biomedical and Translational Sciences, Carle-Illinois College of Medicine.
This patient-friendly article is based on peer-reviewed research. The original article is an open-access review published under the Creative Commons Attribution (CC BY) license.
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