PROTEIN ANABOLIC RESISTANCE IN CANCER

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1 PROTEIN ANABOLIC RESISTANCE IN CANCER Dr. Barbara van der Meij CRICOS CODE 00017B

2 CONTENTS Obesity and body composition Metabolic alterations in cancer Protein anabolic resistance Implications for clinical practice

4 % O b e s i t y The obesity epidemic in cancer O b e s i t y t r e n d s i n t h e U S, G e n e r a l P o p u l a t i o n C a n c e r S u r v i v o r s N S C L C Y e a r Engelen et al. Curr Opin Clin Nutr Metab Care. 2015

5 Correlation BMI and FFMi Correlation between BMI and FFMI in 186,975 healthy white individuals R = 0.62, P < Franssen et al. J Am Med Dir Assoc. 2014;15(6):448 e1-6

6 Metabolic alterations in cancer

7 Argiles, Nat Rev Cancer 2014

8 Muscle and fat loss in cancer n=368 lung, colorectal, pancreatic and cholangiocarcinoma Prado, AJCN 2013

9 Protein metabolism in cancer Studies in different types of cancer: Changes in plasma amino acids (e.g. decreased arginine, glutamine, citrulline) Increased protein turnover Increased muscle protein breakdown Lai Sem Cancer Biol 2005, Miyagi et al. PLoS One. 2011, Fukutake et al. PLoS ONE. 2015, van Dijk, J Cach Muscle Wasting 2015, van der Meij, unpublished data

10 Weight loss / muscle wasting in cancer: Associated with Fatigue and apathy Hospital length of stay Increased susceptibility to infection Postoperative complications and mortality Delay in return to work Poor quality of life Response to chemo/radiotherapy Treatment toxicity Komurcu, SO, 2000, Rosenbaum, JPEN, 2000, Curt, Oncol, 2000; Grossmann, Surg, 2002; Spelten, EJC, 2003, Argiles, Eur J Oncol Nurs, 2005, Gordon, QJM, 2005, Prado, Appl Physiol Nutr Metab, 2014, Barret, Nutr Cancer, 2014

11 Sarcopenia and toxicity Breast cancer, n=55 Sarcopenia: n=14 (25.5%) Sarcopenic patients: more dose limiting toxicity Prado, Clin Cancer Res 2009

12 Can cancer patients have an anabolic response to food?

14 n=16 cancer patients and n=16 healthy subjects T=-1h T=0h T=1h T=2h T=3h T=4h T=5h T=6h T=7h T=7.5h Primed and constant continuous stable isotope infusion: 2 H 5 -Phe, 13 C 9 15 N-Tyr, D5-Trp Stable isotope pulse: 2 H 3 -Leu, [ 2 H 3 ]-3-MetHis, 2 H 2 -Gly, 2-D-OHPro, 1-13 C-KIC, 15 N 2 -ARG, 2 H 2 -CIT, 13 C-Urea, 1,2-13 C 2 Taurine X X Intake of complete high protein meal and 13 C-Phe, 13 C 3 -Tripalmitin, 2 H 2 -Palmitic acid, 15 N-Spirulina X DXA (wb, hip and spine) & BIA Respiratory and handgrip muscle function X X Kin Com one leg exercise X Questionnaires (wellbeing, diet, and cognition) Blood sampling

15 Maximum Inspiratory Pressure (MIP) Maximum Expiratory Pressure (MEP) Leg extension (KinCom) Hand grip strength

Body composition Cancer (n=16) Healthy (n=16) P-value Gender n (%) M / F 9 / 7 9 / 7 1.00 Age y 60.1 (16.6) 59.8 (15.9) 0.97 Weight kg 72.7 (16.1) 77.3 (12.9) 0.38 BMI Overweight n (%) Obesity n (%) kg/m² 26.

16 Body composition Cancer (n=16) Healthy (n=16) P-value Gender n (%) M / F 9 / 7 9 / Age y 60.1 (16.6) 59.8 (15.9) 0.97 Weight kg 72.7 (16.1) 77.3 (12.9) 0.38 BMI Overweight n (%) Obesity n (%) kg/m² 26.8 (5.4) 4 (25) 4 (25) 26.7 (3.2) 7 (43.8) 4 (25) FFM-i kg/m² 17.7 (2.2) 18.1 (2.4) 0.56 Arms FFM kg 5.2 (1.8) 5.8 (1.7) 0.30 Legs FFM kg 15.0 (3.2) 16.7 (3.5) 0.14

17 Myofibrillar protein breakdown - fasted van der Meij, unpublished data

18 MEAL: BOOST High Protein drink (237 ml) 15g protein, 6g fat, 33 g carbohydrates van der Meij, unpublished data

19 Muscle function Mean (SD) Unit Healthy controls (n=16) Muscle function Cancer patients (n=16) P-value Maximal inspiratory pressure cmh2o (40.2) 72.2 (30.6) 0.17 Maximal expiratory pressure cmh2o (41.7) 96.2 (33.9) 0.45 Handgrip strength N 292 (66) 236 (96) 0.06 /FFM 5.5 (1.0) 4.8 (1.3) 0.08 Handgrip endurance % lost 25.4 (6.8) 23.5 (13) 0.61 Leg extension strength N 374 (140) 253 (118) 0.01 N/FFM 42.6 (10.2) 32.6 (10.8) 0.01 Leg extension endurance % lost 25.4 (13.3) 29.3 (11.4) 0.42

20 High-protein supplement anabolism n=8 pancreatic cancer and n=7 healthy controls FORTISIP High Protein drink (200 ml) 12g protein, 6g fat, 37 g carbohydrates van Dijk, J Cach Muscle Wasting 2015

21 Net protein anabolism Essential Amino Acids (EAA) anabolism 14 g EAA/leucine mixture Engelen, Ann Oncol 2015 EAA intake (umol/kg FFM)

22 Conclusion: Not enough solid evidence for protein supplements in cancer HMB, arginine and glutamine: Increase in lean body mass after 4 weeks in advanced solid tumour patients No benefits in lung cancer after 8 weeks L-carnitine in pancreatic caner: increase of BMI and survival Mochamat, J Cachexia Sarcopenia Muscle 2016

23 Summary Body composition in cancer is relevant: Obesity and aging epidemic High body fat and low muscle mass: associated with toxicity, muscle weakness, impaired quality of life and mortality Cancer patients have a higher protein turnover than healthy subjects Higher muscle protein breakdown Similar anabolic potential Protein supplementation works (short-term) Limitation: small sample sizes Where to go from here?

Recommendations ESPEN guidelines on Nutrition in Cancer Patients: Aim: 1.2 1.

24 Recommendations ESPEN guidelines on Nutrition in Cancer Patients: Aim: g protein/kg body weight Higher quality protein is recommended Promote physical exercise throughout cancer treatment Future research: Effects of long-term protein supplementation (>1.2 g/kg) Effects on muscle mass, muscle function, quality of life Additional effect of physical exercise and pharmaceutics (multimodal interventions) Arends, Clin Nutr 2017

25 ACKNOWLEDGEMENT Dr. Mick Deutz Dr. Marielle Engelen Department of Health and Kinesiology Center for Translation Research on Aging and Longevity Texas A&M College Station, TX, USA

26 THANK YOU VERY MUCH CRICOS CODE 00017B

ANABOLIC RESPONSE IN CANCER: DOES IT REALLY EXIST?

ANABOLIC RESPONSE IN CANCER: DOES IT REALLY EXIST? Dr. Barbara van der Meij CRICOS CODE 00017B CONTENTS Body composition Metabolic alterations in cancer Anabolic resistance Implications for clinical practice