Patient Nutrition: An Overlooked Yet Emerging Variable in the Precision Oncology Equation

The gut microbiome refers to the genetic makeup of all species contained within the gut. Independent groups in the United States and Europe have demonstrated that commensal gut microbiota play a significant role in shaping therapeutic response to cancers treated with ICI, with distinct microbiome profiles identified in responders versus nonresponders to ICI.^[3] Preclinical evidence extends the correlative relationship between the gut microbiome and therapeutic response to support a causal role, opening the exciting possibility of increasing ICI efficacy in humans by manipulating or modulating the gut microbiota. Possible intervention strategies being tested include fecal microbiota transplant, bacterial consortia, bacteriophages, and dietary intervention.^[3]

While a number of external factors may affect the composition of the gut microbiome, none are as influential a determinant as diet. Additionally, the favorable safety profile, cost, and accessibility of dietary intervention support diet as a potential scalable and noninvasive modality for microbiome modulation in cancer patient populations. The ability of the host's nutrient and supplement intake to modulate the gut microbiome and alter its structure and metabolic output is emerging in the context of cancer. More specifically, profound and intensive changes in diet can significantly alter the gut microbiota and its metabolic capacity as well as key cancer biomarkers within a period of days to weeks.^[1] A more focused view of microbial metabolism revealed that consumption of a diet predominated by fiber-rich plant-based foods can shift the microbiome to beneficially increase short-chain fatty acid (SCFA) production, while a diet largely composed of animal foods, including red and processed meats, shifts the community toward production of potentially harmful N-nitroso compounds and secondary bile acids.^[3] Interestingly, many of the bacteria that have been associated with response to ICI are fiber-fermenting bacteria, and provocative early data have suggested an association between fiber intake, the gut microbiome, and response to ICI, although this needs to be tested in a prospective fashion.^[5] This hypothesis was further supported by a small prospective cohort study that demonstrated an association between higher fecal SCFA levels and improved outcomes with ICI, with favorable response to ICI and longer progression-free survival.^[6] Such data are exciting given the significant problem of heterogeneity of response to ICI and the enormous efforts to identify a biomarker of response to ICI that are currently ongoing globally. Fiber consumption with the gut microbiome as a direct target has become a priority for larger and longer duration preclinical and clinical investigations, specifically those with focused efforts on systemic and tumoral immunity.^[3,4] Numerous questions relating to fiber dose, duration of high-fiber intervention, impact of confounding factors, and mechanism(s) remain.

Early investigations of the ketogenic diet in cancer were based on the Warburg hypothesis, an observation that even in aerobic conditions, cancer cells often favor metabolism via glycolysis rather than the much more efficient oxidative phosphorylation pathway.^[7] This hypothesis has led to investigating the therapeutic application of the ketogenic diet in brain diseases such as glioblastoma multiforme, given that glucose is the major fuel source of the brain as is readily apparent on positron emission tomography scans. Though we now know tumor metabolism to be significantly more complex and plastic than originally postulated, the ketogenic diet has remained relevant with not only glycolysis as a target but also alternative fuel source utilization (ketone bodies) and insulin/insulin-like growth factor 1 (IGF-1) signaling as potential areas of attention for this dietary intervention.^[8]

The identification and ubiquitous presence of the phosphoinositide 3-kinase (PI3K) pathway as a key oncogenic signaling pathway has made focusing efforts on insulin signaling in cancer quite relevant given the normal physiological function of the PI3K pathway as a global regulator of insulin and glucose homeostasis. PI3Kα inhibitors are now an approved therapy for some tumors with PI3K pathway alterations, but it can lead to reflexive hyperglycemia and hyperinsulinemia. This on-target toxicity, far from being benign, was recently shown in preclinical models to abrogate pathway inhibition within the tumor and decrease efficacy of these agents.^[2] To combat this disturbance in glucose metabolism, strict dietary interventions (eg, ketogenic diet) have been investigated in preclinical models with great success. More specifically, the insulin feedback mechanism that was provoked by PI3K inhibitors could be abrogated by the ketogenic diet (ie, lowering of systemic insulin) and thus improve pathway inhibition and tumor control.^[2] These profound results have led to ongoing clinical trials testing the synergistic effects of PI3K pathway inhibitors and the ketogenic diet. The clear synergistic relationship between insulin/IGF-1/PI3K pathway inhibition and ketogenic diet in the setting of PI3Kα inhibitors has piqued curiosity regarding investigating this approach in other settings where the PI3K pathway has been shown to mediate therapeutic resistance. For example, in melanoma, the PI3K pathway has been shown to drive resistance to both BRAF-directed targeted therapies and ICIs.^[9] Whether the ketogenic diet will also be relevant as a synergistic partner with these agents, which do not cause hyperinsulinemia and hyperglycemia, remains to be seen. Moreover, it remains unclear whether metabolic therapies through diet and/or drug are sufficiently specific and potent for targeting tumors and what unintended effects there may be on immune function or the host's normal cells. Moreover, the impact of the ketogenic diet on the gut microbiome/immunity in the context of immunotherapy has also not been well-studied to date, with concerns that pro-ICI response bacteria could be negatively impacted.^[10]

In addition to specific dietary interventions targeting the above, there is now emerging evidence suggesting that nutrient timing and quantity are not trivial in the precision nutrition equation. Preclinical work has shown that fasting or approaches that mimic the effects of fasting can limit chemotherapy toxicity through selective cell cycle arrest in normal cells, as well as enhance T cell–mediated cytotoxicity and modulate oncogenic signaling pathways and metabolism.^[11–13] Prospective human studies have demonstrated that peri-chemotherapy fasting (≤72 hours) is safe and feasible in specific populations. Fasting-mimicking approaches, in part, were designed to promote an impact similar to that which occurs when fasting (as defined by absence of any nutrient intake) without the lack of adherence and sustainability as associated with the latter (ie, zero nutrient intake). ^[11] The fasting-mimicking diet (FMD) has been shown to synergize with chemotherapy in preclinical models, inducing increases in lymphoid progenitors and tumor-infiltrating lymphocytes.^[13] Recent work has further demonstrated that the FMD can epigenetically regulate AKT/mTOR/HIF1α and tumor metabolism.^[12]

In human studies, the FMD has the ability to favorably modulate cancer-relevant metabolic and inflammatory biomarkers (eg, IGF-1, C-reactive protein, etc) and physiology (eg, reduction in adipose tissue).^[14] With shared, favorable, metabolic impact (eg, decrease in IGF-1 as with ketogenic diet), further exploration of the application of FMD in cancer may pave the way for patients to have several dietary intervention options, thus promoting adherence and sustainability for favorable clinical outcomes.^[14]

Mirroring the larger scale work in normal populations,^[15] nutrition as precision medicine represents an exciting area of oncology research and is an opportunity for benign, noninvasive, and inexpensive interventions to potentially and dramatically improve outcomes. Despite long-appreciated contributions of diet and nutrition to cancer risk, nutrition has historically been neglected in patients receiving active oncologic care, with only those patients experiencing significant weight loss, anorexia, or cachexia referred for nutritional consultation or intervention. For all other patients, the prescribed eat what you want approach remains the status quo among the majority of oncologists and clinicians, primarily due to a lack of strong evidence to the contrary, that is, data demonstrating improvements in response or survival outcomes following nutritional intervention. Thus, there is a growing need for improved nutritional education of all healthcare professionals along with a clear requirement for more specialist oncology dieticians. Prospective clinical trials incorporating nutritional assessments must pave the way for rigorously conducted interventional trials that have been designed and powered to determine dose and duration of intervention. Identification of key targets has just begun, and much work is required to select these targets based on synergy with other therapeutic agents, interaction with host metabolic phenotypes, and recognized tumor drivers.