Breast cancer recurrence is the greatest fear for those with breast cancer. While many survivors know that being overweight can contribute to recurrence of their cancer, the thought of dieting and how to go about it can be overwhelming. Dr. Nicholas Webster, Professor of Medicine, Chief of the Division of Endocrinology and Metabolism, and Associate Director for Shared Resources, Moores Cancer Center discusses his study that suggests a path that is easy to follow and produces the type of results that can be a matter of life and death for some breast cancer patients.

1. Time Restricted Eating: Can it reduce the risk of
breast cancer or recurrence?
Nick Webster, Ph.D., M.A.
Senior Research Career Scientist, VA San Diego Healthcare System;
Professor of Medicine and Chief, Division of Endocrinology and
Metabolism, University of California, San Diego

2. Obesity and cancer risk
Studies of circadian-synchronized feeding in
preclinical models of obesity-driven breast cancer
Is timed eating applicable to humans?
Talk outline

3. Take home message
When you eat matters as much as
what you eat

4. Obesity is a risk factor for several cancers
AACR Cancer
Progress Report
2020

5. Obesity (BMI >30) = 31.4%
Overweight (BMI 25-29.9) = 35.2%
Overweight or obese = 67%
Prevalence of Obesity Among U.S. Adults 2019

6. Obesity shows significant racial disparity
NHW Hispanics
African
Americans

7. Prevalence of Obesity Among Women in 2020
<24.7% 24.7-27.0% 27.1-31.5% 31.6-33.1% >33.2%

8. Rates of Breast Cancer in Women in US
109-124 124-129 129-135 135-145
Rate per 100,000

9. Prevalence of Obesity Worldwide

10. Prevalence of Overweight or Obese Worldwide

11. Global incidence of Breast Cancer

12. C. Kang, D. LeRoith, and E.J. Gallagher et al. Endocrinology, 159:3801–3812 (2018)
Potential mechanisms linking
obesity/diabetes and breast cancer

13. How do we treat obesity?
Current strategies
1. Dieting (caloric restriction)
2. Exercise
3. Bariatric surgery
4. Drugs targeting obesity (Xenical,
Phentermine-topiramate, Naltrexone-
buproprion, Liraglutide)

14. Weight loss after the age of 50 reduces risk
of breast cancer
Teras L.R., et al., Sustained Weight Loss and Risk of Breast Cancer in Women 50 Years and Older: A
Pooled Analysis of Prospective Data, Journal of the National Cancer Institute, 112(9): 929–937 (2020)

15. Changing diet alone does not work
Women’s Healthy Eating and Living (WHEL)
• 640 pre- and 2448 post-menopausal women (28% obese)
• Intervention: increased green vegetable/fruit/fiber
• No weight loss
Women’s Intervention Nutrition Study (WINS)
• 2347 post-menopausal women (27% obese)
• Intervention group: reduced fat intake to 15%
• Small weight loss (2.3 kg)
No reduction in cancer outcomes in either study
Pierce, J.P. Diet and breast cancer prognosis: making sense of the Women's Healthy Eating and Living and
Women's Intervention Nutrition Study trials. Curr Opin Obs Gyn 21(1): 86-91 (2009)

16. Diet and exercise also does not work
Rubinstein et al., Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01393-y
Ongoing

17. Physical activity can improve some cancer-
related health outcomes
Significant evidence exists for a beneficial effect of physical
activity (aerobic and/or resistance training) on cancer-related
anxiety, depressive symptoms, fatigue, quality-of-life,
lymphedema and physical function.
Campbell K.L. Exercise Guidelines for Cancer Survivors: Consensus Statement from International
Multidisciplinary Roundtable. Medicine & Science in Sports & Exercise 51(11), 2375-2390 (2019)

18. Bariatric surgery reduces cancer risk
Schauer D.N et al., Ann Surg 2019;260:95-101
All cancers Obesity-associated cancers

19. Effect on breast cancer risk
Fiegelson H.S. et al., Ann Surg 2020;272:1053-1059

20. How do we treat obesity?
Current strategies
1. Dieting (caloric restriction)
2. Exercise
3. Bariatric surgery
4. Drugs targeting obesity (Xenical,
Phentermine-topiramate, Naltrexone-
buproprion, Liraglutide)
But these strategies are not effective
in the long term
Is there another
solution?

21. Types of Intermittent Fasting
Hoddy K.K. et al., Obesity 28(1):S29-S37 (2020)
Ramadan fasting is out-of-phase version of time-restricted eating
Sunnah fasting is weekly fasting on Monday and Thursday

22. Physiology follows circadian rhythms
Patterson RE et al. J Acad Nutr Diet (2015) 115(8):1203-12.

23. What synchronizes the clock?
Gill and Panda, Cell 22:789-798 (2015)
Panda, Science 354:1008-1015 (2016)
Humans eat for ~18 h per day
Arble DM, Best Pract Res Clin Endocrinol Metab. 2010

24. Does disrupting the clock alter metabolism?

25. Frank A. J. L. Scheer et al. PNAS 2009;106:11:4453-4458
Forced circadian misalignment in humans
disrupts metabolism
aligned
misaligned

26. McHill A.W. et al., Am J Clin Nutr, 106(5), 1213–1219 (2017)
Eating earlier in the day results in lower body
fat
110 individuals aged 18-22 in a 30-day cross-sectional study with normal eating habits
No relation between caloric amount, meal macronutrients, activity or sleep duration
Timing of food intake relative to melatonin onset was associated with % body fat and BMI.

27. Arble D.M., et al., Obesity, 17(11):2100-
2102 (2009)
Swarmy S., et al., Hormones and Behavior 105:177-
184 (2018)
Out of phase eating alters activity and
causes obesity in mice

28. Circadian disruption and disease with aging
Gabriele Sulli, Emily N.C. Manoogian, Pam R. Taub, Satchidananda Panda. Training the Circadian
Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases.
Trends in Pharmacological Sciences, 39(9): 812-827, (2018)

29. Time Restricted Feeding
Ad libitum Feeding
Circadian Rhythms
Reinforced
Metabolism Corrected?
Synchronizing eating to circadian rhythms
Panda lab
Sassone-Corsi lab
Takahashi/Bass labs

30. Time-restricted feeding improves
metabolism
Chung H. et al., Metabolism 65:1743-1754, 2016; Das M. et al., Nature Commun 12:565, 2021
4 weeks 6 weeks 8 weeks

31. TRF can prevent weight regain after dieting
H – High-Fat Diet AL – 24h access to food
L – Low-Fat Diet TRF – Time-restricted feeding

32. TRF improves glucose metabolism
Overeat Low-Fat Diet Overeat
H – High-Fat Diet
L – Low-Fat Diet

33. Does this work in humans?

34. Sutton et al., Cell Metabolism 2018 27:1212-1221
Study of early TRF in 8 pre-diabetic men
5-week randomized,
cross-over design with 7-
week wash-out between
Calorie-matched
Enough calories to
maintain weight
Metabolic assessment
by glucose and insulin
response during GTT

35. Ten-Hour Time-Restricted Eating in
Patients with Metabolic Syndrome
19 participants with pre-
diabetes on statin or anti-
hypertensives who ate >14
h per day placed on TRE for
12 weeks.
No change in diet
Monitored by phone app,
Actiwatch, and CGM
Wilkinson M.J., et al., Cell Metabolism 31(1) 92-104 (2020)

36. Heathy Heroes study design
Pam Taub and Satchin Panda, BMJ Open 2021;11:e045537
150 Fire Fighters randomized to Mediterranean diet v.s. 10-h time-restricted eating for 3 mo.

37. Can circadian synchronization inhibit
obesity-induced cancer growth?
Ad libitum Feeding
Reduce
Tumor Growth
Time restricted Feeding
Accelerate
Das M. et al., Nature Commun 12:565, 2021

38. Obesity accelerates breast cancer in mice
Chung H.Y., et al., Oncogene 34(27):3504-13 (2014)
High-fat diet and genetic
models of obesity in post-
menopausal mice with tumor
cells implanted into mammary
fat pads

39. Study Design: Post-menopausal breast cancer
Postmenopausal Female Mouse Models
OVX mice 4-vinylcyclohexene diepoxide (VCD)
160 mg/kg body weight, IP
d0 d15 d110
follicle depletion
Up to 10 weeks
Body weight >40 g
10 wks
Harvest tumors
TCI (Py230 or E0771)
HFD
TRF
TRF (16 h fasting/day)
AL (continuous feeding)
NC AL (continuous feeding)
Feeding strategy
3 wks
X X
Das M. et al., Nature Commun 12:565, 2021
Py230: luminal A BrCa; ERa+/PR+/ERBB2-
E0771: luminal B BrCa; ERa-/PR+/ERBB2+/ERb+

40. TRF reduces obesity-driven breast tumor growth
OVX-Py230 VCD-Py230 OVX-E0771
OVX-PyMT
Das M. et al., Nature Commun 12:565, 2021

41. TRF reduces growth of existing tumor
Das M. et al., Nature Commun 12:565, 2021
TRF started after tumors were visible by ultrasound imaging at week 13

42. Insulin drives tumor growth in obese mice
Increasing insulin levels with an insulin pump reverses the TRF effect
Decreasing insulin levels with diazoxide mimics the TRF effect
Das M. et al., Nature Commun 12:565, 2021

43. Does prolonged nightly fasting reduce
cancer risk in humans?
2413 breast cancer survivors in the Women’s Healthy Eating and Living (WHEL)
Study (7-yr prospective); mean [SD] age, 52.4 [8.9] years; Marinac CR et al. (2016)
JAMA Oncology
• Fasting <13 h/night associated with 36% increased risk of cancer recurrence
(HR, 1.36; 95% CI 1.05-1.76) compared to fasting ≥13 h/night.
Case-control study in 922 patients with incident BrCa vs. 913 controls in China; Li Met
al. (2017) Breast Cancer Research
• Eating after 10 pm significantly associated with increased risk of breast cancer (OR
1.50). Association strongest in women who had >20 year history of eating after 10
pm (OR 2.28).
Population case-control study of 1205 BrCa and 621 PrCa in 1321 women and 872
men in Spain; Kogevinas et al., (2018) Int. J. Cancer
• Longer interval between last meal and sleep associated with lower cancer risk
(prostate OR 0.74, breast OR 0.64)
• Similar protection if meal eaten before 9pm vs after 10 pm (OR 0.75 & 0.85) and
in morning chronotypes (OR 0.65 & 0.67)

44. • Time-restricted feeding improves metabolism in obese mice
• TRF inhibits tumor growth in three mouse models of obesity-
driven post-menopausal breast cancer, and a model of
spontaneous breast cancer
• Epidemiological evidence suggests that time-restricted
eating would have similar beneficial effects in humans, but
large-scale randomized control trials are needed
Summary

45. Webster Lab
Manasi Das Deepak Kumar Emilie Gross
Consuelo Sauceda Tyler Mandt Alexis Oberg
Liping Zheng Heejun Jung Panyisha Wu
Amandip Bangar Mehak Kaur Karina Kuo
Purva Parwal Heekyung Chung Winjet Chou
Panyisha Wu Liping Zeng
Valeria Estrada, UCSD
Dorothy Sears, UCSD
Ruth Patterson, UCSD
Lesley Ellies, UCSD
Isabel Newton, UCSD
Acknowledgements
Collaborators
Funding
VA I01BX000130,
NIH R01 CA196853,
NIH U54 HD012303,
NIH U54 CA155435,
NIH R01 HL141999,
NIH U01 AI125860

46. Circadian rhythms are driven by transcription
Core clocks regulate biological processes in 24-h cycles
Bmal1
Asher and Sassone-Corsi, Cell 161, March 26, 2015

47. Obesity alters circadian rhythms
Mammary
Fat Pad
Tumor