Brief Communications

Patient Nutrition: An Overlooked Yet Emerging

Variable in the Precision Oncology Equation
Ashley E. Holly,1* Karla A. Lee,2,3* Carrie R. Daniel,4 Timothy D. Spector,2 Jennifer L. McQuade1
1
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA
2
Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
3
Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London, United Kingdom
4
Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD

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Anderson Cancer Center, Houston, TX, USA

Address correspondence to Jennifer McQuade (jmcquade@mdanderson.org)

*Co-first authors
Source of Support: Dr. Holly reports personal fees from the Applied Science and Performance Institute, personal fees and other
from Myogin, LLC, and Ketogenic.com, nonfinancial support from BioTRUST Nutrition; the other authors have nothing to
disclose. Conflict of Interest: None.
Received: February 28, 2020; Accepted: June 9, 2020
Holly AE, Lee KA, Daniel CR, Spector TD, McQuade JL. Patient nutrition: An overlooked yet emerging variable in the precision
oncology equation. J Immunother Precis Oncol. 2020; 3:108–112. DOI: 10.36401/JIPO-20-7.
& Innovative Healthcare Institute
Keywords: precision medicine, oncology, metabolism, immunotherapy, targeted therapy

Increased understanding of the molecular biology and
immunology of cancer has led to development of rational
targeted and immune therapies that have dramatically
improved outcomes for cancer patients across multiple
tumor types. While the interaction between diet and
cancer risk and prevention is well-established in some
malignancies (eg, colorectal),[1] the ability of diet to
impact outcomes in patients with established cancer has
not been well-established. Thus, we provide this brief
commentary highlighting the impact of nutrition on
various molecular targets, expected potential synergies
with distinct therapies based on emerging preclinical or
observational data, and ongoing clinical trials designed to
test the impact of prospective precision nutrition inter-
ventions in cancer (Table).
Interestingly, many oncogenic pathways are classic
nutrient-sensing pathways, with recent provocative data
showing that host metabolic phenotype can in turn
influence tumor biology, shaping a new direction for
precision nutrition.[2] Strong evidence for the gut micro-
biome influencing response to immune checkpoint
inhibition (ICI)[3] and the role of diet, a key determinant
of the microbiome,[1,4] has similarly paved a new path
forward for nutrition interventions in this space. The
work of oncology dieticians has conventionally been
primarily focused on issues of malnutrition rather than
optimizing treatment outcomes. Otherwise, nutritional
guidelines for patients on active anti-cancer therapy are
largely extrapolated from cancer prevention and are
homogenous across tumor types, stages, and therapies.
However, targeted research is required to determine
where nutritional intervention fits into precision cancer
treatment.
Select precision nutrition interventions currently
being explored in the oncology setting are summarized
in Table. These include modulation of the gut micro-
biome with fiber, targeting oncogenic signaling path-
ways and host metabolism with the use of ketogenic
diets, caloric restriction, and fasting. It is unlikely that
one singular nutritional intervention or treatment will
provide benefit to all. Future nutrition targets are likely
to differ based on histology, stage, and treatment, and
they may develop as synergistic partners or adjuncts to
contemporary therapy. In addition to the incorporation
of diet assessments into clinical trials of systemic agents,
rationally designed controlled prospective diet interven-
tion studies are urgently needed to provide sufficient
data to answer these pressing questions.
FIBER AND THE GUT MICROBIOME
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 respond-
ers versus nonresponders to ICI.[3] Preclinical evidence
extends the correlative relationship between the gut
microbiome and therapeutic response to support a causal

Journal of Immunotherapy and Precision Oncology 2020 | Volume 3 | Issue 3 | 108

jipoonline.org
Table.—Clinical trials employing diet as cancer therapy
Planned
Recruitment,
Study n Intervention Patients Location Citation
NCT02843425 80 Addition of beans History of CRC and BMI .25 not on United States, The University of
to diet daily treatment Texas MD Anderson Cancer Center
NCT03950635 20 Fiber-rich (group 1) History of melanoma (currently with United States, The University of
or ketogenic NED) Texas MD Anderson Cancer Center
(group 2) diet
NCT02983942 50 KD Methotrexate for primary CNS China, Beijing Tiantan Hospital
lymphoma
NCT03451799 20 KD RT and temozolomide for United States, Cedars-Sinai Medical
glioblastoma Center
NCT03535701 15 KD Paclitaxel for stage 4 breast cancer United States, Ohio State University
NCT01716468 17 KD Advanced/metastatic colorectal, United States, Pittsburgh Tan-Shalaby JL, Carrick J, Edinger K,
prostate, brain, breast, pancreatic, et al. Modified Atkins diet in
hepatobiliary, melanoma, sarcoma, advanced malignancies–Final results
lung, genitourinary cancers. of a safety and feasibility trial
Participants must not be receiving within the Veterans Affairs
chemotherapy. Pittsburgh Healthcare System. Nutr
Metab. 2016;13:61.
NCT03285152 30 KD Newly diagnosed overweight or obese United States, Memorial Sloan
endometrial cancer patients Kettering Cancer Center
NCT03962647 30 KD Estrogen receptor positive breast United States, Vanderbilt-Ingram
cancer receiving letrozole Cancer Center
NCT03194516 12 KD Prostate cancer on active surveillance United States, University of Maryland
NCT03171506 57 KD Ovarian or endometrial cancer United States, University of Alabama Cohen CW, Fontaine KR, Arend RC, et
receiving ‘‘usual care’’ at Birmingham al. A ketogenic diet reduces central
obesity and serum insulin in
women with ovarian or endometrial
cancer. J Nutr. 2018;148:1253–1260.
NCT04316520 20 KD Renal cell carcinoma and SOC France, University Hospital/Vitaflo
immune or targeted therapy International, Ltd
NCT01535911 16 KD Surgery followed by chemo and United States, Michigan State Schwartz K, Chang HT, Nikolai M, et
radiotherapy for brain tumors University al. Treatment of glioma patients
with ketogenic diets: report of two
cases treated with an IRB-approved
energy-restricted ketogenic diet
protocol and review of the
literature. Cancer Metab. 2015;3:3.
NCT02768389 18 Modified Atkins Bevacizumab for glioblastoma United States, Case Comprehensive
Diet Cancer Center
NCT02516501 85 KD Chemoradiation for breast, rectal, or Germany, MVZ Leopoldina GmbH Klement RJ, Schäfer G, Sweeney RA. A
head and neck cancer ketogenic diet exerts beneficial
effects on body composition of
cancer patients during radiotherapy:
An interim analysis of the
KETOCOMP study [published
online ahead of print March 21,
Brief Communications

2019]. J Tradit Complement Med.

https://doi.org/10.1016/j.jtcme.
2019.03.007.
109

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 110

Table.—Continued.
Holly et al: Precision Nutrition

Planned
Recruitment,
Study n Intervention Patients Location Citation
NCT03075514 12 Modified KD or Chemotherapy and/or RT for United Kingdom, University of Martin-McGill KJ, Marson AG, Tudur
medium-chain glioblastoma Liverpool Smith C, Jenkinson MD. Ketogenic
triglyceride KD diets as an adjuvant therapy in
glioblastoma (the KEATING trial):
study protocol for a randomised
pilot study. Pilot Feasibility Stud.
2017;3:67. doi:10.1186/s40814-017-
0209-9.
NCT03278249 30 Modified Atkins KD Temozolomide and RT for malignant United States, University of
glioma Cincinnati
NCT01175837 12 Short-term starvation Chemotherapy for any cancer United States, Mayo Clinic
NCT02710721 60 FMD Chemotherapy for prostate cancer Germany, Charite University Berlin
NCT03162289 150 FMD or vegan diet Chemotherapy for breast or ovarian Germany, Charite University Berlin
cancer
NCT03340935 85 FMD SOC for any malignancy except Italy, Fondazione IRCCS Istituto De Braud FG, Milano M, Fuca G, et al.
small-cell neuroendocrine tumors Nazionale dei Tumori Safety and metabolic effects of
cyclic fasting mimicking diet (FMD)
in cancer patients. J Clin Oncol.
2018; 36(suppl): e14549–e14549.
NCT03700437 40 FMD Chemo-immunotherapy for NSCLC United States, Indiana University
Hospital & Eskenazi Hospital
RT, radiotherapy; KD, ketogenic diet; FMD, fasting-mimicking diet; CNS, central nervous system; SOC, standard of care; BMI, body mass index; NED, no evidence of disease; CRC,
colorectal cancer; NSCLC: non-small-cell lung cancer

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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 influen-
tial 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 inten-
sive 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 second-
ary 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 micro-
biome 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.
KETOGENIC DIET
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
Brief Communications 111
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
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global regulator of insulin and glucose homeostasis.
PI3Ka 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
PI3Ka inhibitors has piqued curiosity regarding investi-
gating this approach in other settings where the PI3K
pathway has been shown to mediate therapeutic resis-
tance. 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]
FASTING AND NUTRIENT RESTRICTION
AND TIMING
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 selec-
112 Holly et al: Precision Nutrition
tive 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-chemother-
apy 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] Re-
cent work has further demonstrated that the FMD can
epigenetically regulate AKT/mTOR/HIF1a 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 favor-
able clinical outcomes.[14]
CONCLUSIONS
Mirroring the larger scale work in normal popula-
tions,[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 as-
sessments 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.
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