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Conventional mainstays of breast cancer treatment, including surgery, radiation, chemotherapy, hormone therapy, and targeted therapy, may not be as effective when they stand alone.¹ To this end, scientists continue to study novel treatments, including complementary lifestyle approaches, which may help reduce the side effects of cancer treatment, improve physical and emotional well-being, and improve recovery from cancer.²

“What integrative cancer care should be doing is integrating knowledge from all aspects of medicine and health—epidemiology and public health, nutritional medicine, endocrinology, as well as oncology and complementary medicine—into the care of cancer patients. The key is not to think ‘outside the box’ but to create a ‘bigger box,’” says Dr. D. Barry Boyd, MD, MS, a pioneer in the field of integrative cancer care with a targeted focus on nutritional support for cancer patients.

For the purposes of this article, we will look at some new clinical evidence behind two dietary patterns that may support conventional treatment: the fasting-mimicking diet and the ketogenic diet. “When I went to medical school, we spent an hour on nutrition, and in my oncology training, not a single minute was spent discussing diet,” says Dr. Boyd. “But when I went into practice, patients were always asking me about nutrition, which further propelled me to investigate what role it plays in cancer.”

The Fasting-Mimicking Diet

Preclinical evidence suggests that short-term fasting and fasting-mimicking diets (FMD) are associated with immunological regeneration³ and may protect healthy cells from the stressors of chemotherapy.^4,5 Research suggests that fasting causes healthy cells to switch from a proliferative state toward a state of maintenance and repair.⁴ However, malignant cells may be unable to enter this protective state because of oncoprotein activity and therefore fail to adapt to conditions where nutrients are scarce. Because fasting deprives proliferating cancer cells of nutrients, growth, and other factors, this may render them more sensitive to cancer therapy and increase cell death. A 2020 randomized phase 2 DIRECT trial of 131 patients by de Groot et al is the first randomized controlled study evaluating the effects of FMD on toxicity and efficacy of chemotherapy in patients with cancer. The results suggest that FMD cycles are safe and effective as an adjunct to chemotherapy in women with early breast cancer.⁴

Writing in Nature Communications, de Groot et al explain that declines in plasma levels of insulin-like growth factor-1 (IGF-1), insulin, and glucose are among the mediators of the effects of fasting on cancer cells, as these factors can promote growth and prevent apoptosis.⁴ Fasting periods of at least 48 hours may be required to induce a robust decrease in circulating glucose, IGF-1, and insulin levels. In this randomized study, a low calorie, low protein FMD was developed for its ability to cause metabolic effects on various starvation response markers similar to those caused by water-only fasting while reducing the burden often associated with a water-only fast. However, the authors stress that their data should be cautiously interpreted for potential selection bias.⁴

A clinical trial in 2021 observed better adherence to the FMD than the DIRECT study mentioned above; it was less calorie-restricted than the one used by de Groot et al.⁵ This trial also accrued patients who were treated with different types of therapies, including chemotherapy, endocrine therapies, proteasome inhibitors, and more. In these patients, the FMD was also found to be feasible and safe. Overall, when combined with dietary and muscle training instructions to promote weight and lean body mass re-gain in the periods between FMD cycles, even multiple administrations of this dietary regime were safe in cancer patients. The FMD decreased fat mass and effectively lowered circulating insulin, IGF-1, and leptin levels.⁵

More recently, scientists studied the metabolic and immunomodulatory effects of a calorie-restricted, five-day FMD regimen in patients with cancer, finding that FMD cycles may decrease the side effects and increase the effectiveness of chemotherapy.⁵ More specifically, FMDs broadly reshaped intratumor immunity within 7-10 days in patients with limited-stage breast cancer, reducing biomarkers associated with immune suppression and promoting tumor infiltration by activated and cytotoxic immune cell populations.⁶

The Ketogenic Diet

A novel therapeutic approach for certain types of cancer, the ketogenic diet consists of a high-fat, low-carbohydrate diet with adequate protein and may sensitize most cancers to standard therapy by utilizing the reprogrammed metabolism of cancer cells, making it a candidate for adjuvant cancer treatment.¹ Preclinical and clinical studies suggest that the use of a ketogenic diet, in combination with standard therapies, may improve the antitumor effects of conventional chemotherapy and improve quality of life. New evidence suggests a ketogenic diet lowers the level of glucose and insulin in the blood, which are necessary for tumor growth. A 2021 systematic review by Jemal et al specifically studying ketogenic diets and their therapeutic potential on breast cancer found that the ketogenic diet improves biochemical parameters and body composition. Specifically, it causes less reliance on the glucose/insulin axis and significant changes in substrate use, such as increased fatty acid oxidation and decreased glucose flux, which could be a therapeutic mechanism for the treatment of breast cancer.¹

While the data above suggest that a ketogenic diet could be an important therapeutic approach for breast cancer, another systematic review conducted in 2021 by Römer et al points out that such diets may be considered controversial treatments for cancer patients.⁷ This review found that there was no conclusive evidence that ketogenic diets had anti-tumor effects or improved overall survival. While their findings are not specific to breast cancer only (as above), the authors noted that most studies of ketogenic diets for cancer conducted so far have been of low quality, included a high risk of bias, and were highly heterogeneous. The inability to find any effects may be related to these factors or perhaps that adherence to the diet was rather low in most studies. While Römer et al conclude that clinical evidence for the effectiveness of ketogenic diets in cancer patients is still lacking, and a randomized controlled trial with a well-designed control group and the ability to detect evidence for absence of anti-tumor effects is necessary,⁷ it is important to note that for highly motivated patients who are willing to adhere to the ketogenic diet, this therapeutic option should be a consideration.

Functional Medicine Considerations

As the nutritional research in this area continues,^8,9 functional medicine can play a much-needed role in oncology care. Digging deep into the antecedents, triggers, and mediators and addressing them may support a patient’s quality of life and impact their clinical outcomes.

Specifically, IFM’s Functional Medicine Matrix provides an outline for the clinician to organize a patient’s clinical imbalances in the following biological systems, called nodes: defense and repair, energy, biotransformation and elimination, transport, communication, structural integrity, and assimilation. The left section of the matrix is useful in retelling the patient’s story by tracking antecedents, triggering events, and mediators/perpetuators. The bottom of the matrix details lifestyle factors like sleep and relaxation, exercise and movement, nutrition and hydration, stress and resilience, and relationships and support networks.

The functional medicine approach prioritizes a collaborative patient-practitioner relationship to support patients and develop sustainable and effective personalized treatment strategies. IFM’s clinical tools, such as the matrix, are applied within the functional medicine framework of whole-person care and help organize what may seem to be disparate issues into a complete story that provides a comprehensive perspective of each individual patient and subsequently facilitates discussion of complex diseases such as breast cancer.

Related Articles

Type 2 Diabetes and the Ketogenic Diet

Fasting and Mitochondrial Health

The Fasting-Mimicking Diet: Impacts on Aging and Chronic Disease

References

1. Jemal M, Molla TS, Asmamaw Dejenie T. Ketogenic diets and their therapeutic potential on breast cancer: a systemic review. Cancer Manag Res. 2021;13:9147-9155. doi:2147/cmar.s339970
2. The American Cancer Society medical and editorial content team. Which complementary methods are likely safe? American Cancer Society. Reviewed August 25, 2021. Accessed October 22, 2024. https://www.cancer.org/cancer/managing-cancer/treatment-types/complementary-and-integrative-medicine/complementary-and-alternative-methods-and-cancer/which-methods-are-likely-safe.html
3. Tang D, Tang Q, Huang W, Zhang Y, Tian Y, Fu X. Fasting: from physiology to pathology. Adv Sci. 2023;10(9):e2204487. doi:1002/advs.202204487
4. de Groot S, Lugtenberg TR, Cohen D, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020;11(1):3083. doi:1038/s41467-020-16138-3
5. Valdemarin F, Caffa I, Persia A, et al. Safety and feasibility of fasting-mimicking diet and effects on nutritional status and circulating metabolic and inflammatory factors in cancer patients undergoing active treatment. Cancers. 2021;13(16):4013. doi:3390/cancers13164013
6. Vernieri C, Fucà G, Ligorio F, et al. Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in patients with cancer. Cancer Discov. 2022;12(1):90-107. doi:1158/2159-8290.CD-21-0030
7. Römer M, Dörfler J, Huebner J. The use of ketogenic diets in cancer patients: a systematic review. Clin Exp Med.2021;21(4):501-536. doi:1007/s10238-021-00710-2
8. Ligorio F, Lobefaro R, Fucà G, et al. Adding fasting-mimicking diet to first-line carboplatin-based chemotherapy is associated with better overall survival in advanced triple-negative breast cancer patients: a subanalysis of the NCT03340935 trial. Int J Cancer. 2024;154(1):114-123. doi:1002/ijc.34701
9. Son DS, Done KA, Son J, et al. Intermittent fasting attenuates obesity-induced triple-negative breast cancer progression by disrupting cell cycle, epithelial-mesenchymal transition, immune contexture, and proinflammatory signature. Nutrients. 2024;16(13):2101. doi:3390/nu16132101