Improving breast cancer treatments with diets enriched in omega-3 fatty acids : action on the tumor or on the host?

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Philippe Bougnoux INSERM U 169 Centre Henry S.

1 Improving breast cancer treatments with diets enriched in omega-3 fatty acids : action on the tumor or on the host? Philippe Bougnoux INSERM U 169 Centre Henry S. Kaplan University Hospital Tours France philippe.bougnoux@inserm.fr

2 There are multiple evidence that long chain omega-3 fatty acids may improve cancer treatments: Curr Opin Clin Nutr Metab Care 213, 16: Sapienza university, Roma, Italy University of Kansas Medical Center, USA For all that, there is still no consensus on a systematic use of these fatty acids during cancer treatment

3 The outcome of advanced cancers (such as breast, prostate and digestive cancers) depends on treatment efficacy Omega-3 FA supplements may improve treatment efficacy through: The physical condition of the patient = Increased tolerance of host patients to anticancer treatments by limiting muscle loss or cachexia An action on the tumor = Increased sensitivity of tumors to anti-cancer treatments Preclinical data on the action of DHA: Overview - sensitivity of breast cancer cell lines to anthracyclines or taxanes - response of rat mammary tumors to chemotherapy - ROS, lipid peroxidation and tumor antioxidant defenses - tumor neovascular architecture and drug diffusion Clinical trials carried out in metastatic breast cancer: - An open-label phase I-II study of DHA supplementation during chemotherapy - A randomized, double blind, phase III study, with high caloric diets comparing fish oil to coprah oil

Effect of DHA on chemosensitivity of MDA-MB 231 Breast cancer cell line MDA-MB 231 Culture medium enriched (5days) - in DHA or - oleic acid Conditions Control Docosahexaenoic acid (DHA) Prooxidants

4 Effect of DHA on chemosensitivity of MDA-MB 231 Breast cancer cell line MDA-MB 231 Culture medium enriched (5days) - in DHA or - oleic acid Conditions Control Docosahexaenoic acid (DHA) Prooxidants Antioxidants Oleic acid Doxorubicin, 1-7 M (Doxo) Doxo + DHA Doxo + DHA + Oxidants Doxo + Oxidants Doxo + DHA + Antioxidants Doxo+ oleic acid +Oxidants Cell Viability (%) * * DHA enhances doxorubicin efficacy depending on experimental conditions The effect is increased by prooxidant agents and abolished by antioxidants Germain et al., Int J Cancer, 1998

5 Cytotoxicity, % What about other PUFA? PUFA enhance cytotoxic efficacy of doxorubicin 1 % change in cell toxicity after doxorubicin LA n-6 * ALN n-3 * Fatty acids, 1µg/ml * * AA EPA n-6 n-3 * * GLA n-6 * * DHA n-3 Germain et al., Int J Cancer,1998 Fatty acids alone Fatty acids + oxidants Fatty acids + antioxidants R 2 =, hydroperoxides, pmol/µg proteins while producing lipoperoxides Doxorubicine is a quinone macromolecule which generates an oxidative stress

6 In vivo? Dietary DHA makes rat mammary tumors sensitive to anthracyclines

7 In-vivo dietary intervention with DHA Basal diet (7 % peanut/rapeseed) Control (addition of 8 % palm oil) DHA (addition of 8 % DHASCO) w or w/o antioxidants Adipose tissue Palm DHA.1 g DHA.3 g DHA.8 g Diet Dietary DHA is readily incorporated into adipose tissue

8 Change in size of Target tumor, % Epirubicin efficacy according to dietary supplementation Weeks DHA + anti-oxidants Palm oil DHA -4 Epirubicin injections Bougnoux et al, Lipids, 1999 Dietary DHA enhances the antitumor action of anthracyclins, depending on experimental conditions The effect is abolished by Vitamin E

9 Mechanisms other than ROS-induced lipid peroxidation? the antitumor action of docetaxel is amplified by DHA Docetaxel is a macrocyclic molecule without semi-quinone functions

variation % DHA sensitizes breast cancer cells to docetaxel Dietary DHA increases the antitumor action of docetaxel Mammary tumors in rats Cell

Docetaxel nm and the sensitizing effect of DHA to docetaxel is not abolished by vit E Chauvin L, PhD thesis, 215 Tumor Surface 2 Chemotherapy with

10 variation % DHA sensitizes breast cancer cells to docetaxel Dietary DHA increases the antitumor action of docetaxel Mammary tumors in rats Cell viability, % 4 2 Breast MDA-MB-231 cancer cell line MDA-MB Control DHA 8 Control +Vit E DHA+VitE Docetaxel nm and the sensitizing effect of DHA to docetaxel is not abolished by vit E Chauvin L, PhD thesis, 215 Tumor Surface 2 Chemotherapy with docetaxel Control DHA -7 weeks Docetaxel Kornfeld et al, Carcinogenesis, 212 DHA increases the activity of several drugs with distinct modes of action

11 Mechanisms of DHA effects on tumor chemosensitivity

12 The cancer cell Lipoperoxidation through amplified oxidative stress (Vibet et al, 28) Anthracyclins (Germain et al, 1998, Hardman et al, 21); Ionizing Radiations (Colas et al, 24) Cell cycle: CDK1-cyclin B1 (Barascu et al, 26). Tubulin kinetics: Vincristine (Ikushima et al, 1991), Vinorelbin (Menendez et al, 24), Signal transduction: Akt and ERK (Chauvin et al. 216) NF-kappa B pathway, PPARβ (Wannous et al, 215) Apoptotic pathways (balance pro- anti-apoptotic proteins Bcl-2) Lipid rafts, CD95 translocation, (Ewaschuk et al, 212); Ion channels: KCa/ClCa/Ca2+ (Guéguinou et al, 215) Drug uptake, MDR protein The host Mechanisms of DHA effects on tumor chemosensitivity Activation of reducing enzymes: Mitomycin C (Pardini et al, 1993) Alteration of drug metabolism through CYPs: Cyclophosphamide (Shao & Pardini, 1995) Inflammation: antagonist (Cox-2) and agonist of resolution (resolvins) The tumor microenvironment Generates cytotoxic oxidation products (cytotoxic intermediates, Siddiqui et al, 28) Alters immune response against tumor cells (Calder et al, 29) Remodels tumor neovascular architecture (Goupille et al, 216) Reduces tumor interstitial fluid pressure (Kornfeld et al, 212) - alters angiogenesis, through lipid peroxidation (Maheo et al, 212)

Investigating tumor neovascular architecture Using Power-Doppler sonography of rat mammary tumors, sensitized with microbubbles to quantify tumor vessels We found that dietary DHA led to

E (Colas et al, Clin Cancer Res 26) Denis et al, Clin Cancer Res, 23 Using polymer casts of tumor blood vessels, we found that fish oil diet induced remodeling of tumor vascularization with lower

13 Investigating tumor neovascular architecture Using Power-Doppler sonography of rat mammary tumors, sensitized with microbubbles to quantify tumor vessels We found that dietary DHA led to decreased tumor vascularization, prior to any chemotherapy, and that effect of DHA was abolished by dietary Vit. E (Colas et al, Clin Cancer Res 26) Denis et al, Clin Cancer Res, 23 Using polymer casts of tumor blood vessels, we found that fish oil diet induced remodeling of tumor vascularization with lower density and thinner blood vessels (Goupille et al, PLoS 216, in revision) This led to decreased interstitial pressure within mammary tumors and increased diffusion Maheo et al, Breast Cancer Res & Treat, 212 Remodelling tumor neovessels may account for the tumor specificity of DHA action

14 Clinical trials How to differentiate between the effects of DHA on the tumor and the host? Multiple non tumor effects of omega-3 PUFA: Improves quality of life during cancer treatment (de Aguiar Pastore Silva et al. Clinical Nutrition 215) Preserve muscle mass and function during chemotherapy (Laviano et al. Current Opinion Nutr Metab Care 213) Enhances pulmonary strength and endurance during chemotherapy (Suzumara et al. Nutr Cancer 216) Reduces inflammation, and cancer-associated cachexia (Calder et al, 26, 28 ; Mocellin et al, 216) Reduces cancer treatment toxicity (Laviano et al. Nature Reviews Clin Oncol, 212) Controls metabolic derangements (Molfino et al. Int. J. Mol. Sci. 216) Few clinical trials of dietary intervention during treatment of cancer patients are available: - 6 on NSCLC - 3 in colorectal or oeso-gastric cancers - 2 in breast cancer: Reviewed in: Vaughan et al, Marine polyunsaturated fatty acids and cancer therapy. Br J Cancer, 213; 18: Phase II Study - Open-label, single arm - Metastatic breast cancer patients (n=25) - Supplementation - DHASCO (DHA, 1.8g/d) 18 wks Bougnoux et al, Br J Cancer 29 - Phase III Clinical trial (DHALYA) - Randomized, double blind - Metastatic breast cancer patients (n=53) - Energy-rich supplementation (9kcal/j) 12 to 2 wks - E = Fish oil (EPA 2g/d + DHA 1.5g/d) vs - C = Coprah oil (EPA g/d, DHA g/d) ClinicalTrials.gov Identifier: NCT

15 Results of the phase II study 1) DHA was rapidly incorporated after dietary intervention Open-label, single arm phase II study Metastatic breast cancer patients 1.8g daily DHA, capsules, during 22 wks. 1 st line chemotherapy 2) Interindividual variability in DHA incorporation after dietary intervention Plasma level Red Blood Cells Stratification into 2 groups Low DHA incorporators High DHA incorporators

16 Time to progression and survival according to the incorporation status of DHA p<.2 Bougnoux et al, Br J Cancer, 29 p<.7 Median follow-up = 18.6 months (range 3 to 53 months) DHA should be evaluated during chemotherapy in an appropriate clinical trial taking into account its beneficial effects on the host patient Elevated DHA incorporation during first line chemotherapy is associated with better outcome Is the beneficial effect of DHA on metastatic breast cancer outcome via: - Increased tumor sensitivity to chemotherapy? - Improved condition of patients and their tolerance to treatments?

17 Design of the trial How to get around the variability in DHA incorporation? This may be circumvented by providing DHA within a food carrier and not as capsules Food supplements make possible randomized, double blind dietary intervention trials provide fish oil within blind supplemented food cans How to assess the presence of a specific effect of DHA on the tumor whilst taking into account its beneficial effects on the host patient? Provide in the control arm a high caloric food supplement - which preserves muscle mass - contains no long chain omega-3 PUFA Triglycerides with medium-size chain fatty acids (Coprah oil) - Ethical arm, since provided in standard nutritional interventions to lower cholesterol or triglycerides. - best lipids to improve the protein balance

18 DHALYA clinical trial

19 RANDOMIZE Aim of the study: To individualize a specific effect of marine omega-3 PUFA on the tumor, irrespective of its effects on the host patient A randomized, double-blind, phase III multicentric clinical trial comparing a high caloric supplementation with fish oil versus coprah oil during chemotherapy in metastatic breast cancer patients First line chemotherapy (anthracyclines, taxanes..) Metastatic breast cancer HER2 negative HR positive Funding : PHRC 211 Fish DHA oil, g g / day / day (Fish oil in food supplement) Dietary intervention, 4 to 6 months DHA g / day (Coprah oil in food supplement) Medium Chain FA, 9g / day Endpoints: Time to progression QoL ClinicalTrials.gov Identifier: NCT cancer centers involved Beginning: April patients available for analysis

High calories food supplement Control cans Experimental cans Rapeseed + Coprah 2mL cans 3kcal Proteins Carbohydrates Lipids 15 g 36 g 12 g Rapeseed oil* + Coprah* Rapeseed + Fish 2mL cans 3kcal

20 High calories food supplement Control cans Experimental cans Rapeseed + Coprah 2mL cans 3kcal Proteins Carbohydrates Lipids 15 g 36 g 12 g Rapeseed oil* + Coprah* Rapeseed + Fish 2mL cans 3kcal Proteins Carbohydrates Lipids 15 g 36 g 12 g Rapeseed oil* + Fish oil*** Nutrialys (Rennes, France) Recommandation 3 cans/day (9kcal/day) Saturates 6,6g (55%) C8: + C1: 5% Monounsaturates 3,8g (31%) C18:1n-9 28% Polyunsaturates 1,1g (9.2%) Omega6 (9.2%) 18/2n-6 (9%) Omega3 (4.4%) 18:3n-3,5g (4.4%) EPA DHA + Vitamins * TCM (SIO) ** (SIO) Saturates 3g (25%) C16: 1% Mono-unsaturates 5g (42%) C18:1n-9 3% Polyunsaturates 4g (33%) Omega6 (9.1%) 18/2n-6 (8%) Omega3 2,6g (22%) 18:3n-3,5g (4.4%) EPA,88g (7,3%) DHA,52g (4,3%) + Vitamins *** ROPUFA 3 (DSM Nutr Products) (17 % EPA, 1 % DHA) Control Cans (g/day) ALA 1.5 EPA DHA MCFA 9 Experimental Cans (g/day) ALA 1.5 EPA 2.1 DHA 1.5 MCFA <1

21 Demographic Data (n=53) Characteristics Coprah oil Fish oil p (n=28) (n=25) Age, median (years), [range] 57 [36-72] 58 [42-79] ns BMI median, [SD] 26. [ ] 25.2 [ ] ns Menopausal Status Yes 2 (69%) 19 (76%) No 3 (1.4%) 4 (16%) Pre-menopausal 3 (1.4%) 2 (8%),9 UK* 3 (1.4%) Stage (at diagnosis) T1-T2 16 (55.2%) 11 (44%) T3, T4a,b,c 5 (17.2%) 7 (28%) T4d 2 (6.9%) 6 (24%),48 Tx (UK)* 5 (17.2%) 1 (4%) Nodal Status (at diagnosis) N 8 (28.6%) 5 (2%) N1 11 (39.3%) 14 (56%) N2, N3 3 (1.7%) 3 (12%) Nx (UK)* 6 (21.4%) 3 (12%),57 Pathological Grade (SBR) 1 7 (25.%) 1 (4%) 2 * 16 (57.1%) 14 (56%) 3 Unknown 5 (17.9%) 8 (32%) UK* 2 (8%),2 No significant differences - in plasma FA composition -in plasma tocopherol level at baseline between the two dietary groups- In the Fish oil group, more patients larger tumor size, inflammatory and grade III BC

22 Tolerance to the Dietary Intervention 6 Dietary Intervention Continuation 1% 96% Weight loss during treatment? 5 83% Weight variation follow up n=54 Number of patients % Inclusion C1 C3-4 End Chemotherapy, cycles Weight variation % (/basal wt) ns Coprah FishOil Mean +/- SD Toxicity related to cans Fish oil N (%) Coprah oil N (%) Duration of supplementation (weeks) Gr I-II 14 (51.8) 16 (56.9) Gr II-III 1 (1.9) Gr unknown 13 (48.2) 11 (41.2) Dietary supplementation was safe and well tolerated In terms of prevention of muscle mass: the dietary intervention was successful: No weight loss in either arm during chemotherapy

23 FA, % FA, % FA, % FA, % Evolution of plasma PUFA level, by supplementation EPA Basal C1 (1 days) C3-4 X 4, End Linoleate Basal C1 (1 days) C3-4 End - 3% Coprah Oil Fish Oil Rapid (<1days) and sustained increase in DHA and EPA DHA Arachidonate Coprah Oil Fish Oil Commensurate decrease in omega-6 PUFA X % -15%. Basal C1 (1 days) C3-4 End 6 Basal C1 (1 days) C3-4 End In terms of lipid changes: the dietary intervention was successful: incorporation of DHA (and EPA) was achieved

24 Evolution of plasma antioxidants level, by supplementation a-tocopherol b-carotene 5 4 *** * 3 Vitamin E (µm) 3 2 Vitamin A (µm) C C1 C3-4 FT C C1 C3-4 FT C C1 C3-4 FT C C1 C3-4 FT Coprah Oil Fish Oil Coprah Oil Fish Oil Time-dependent increase in plasma vitamin E in the CO group Slight increase in vitamin A in both groups In terms of plasma antioxidant vitamins: No major differences among dietary intervention groups

25 Time to Progression (%) Chemotherapy outcome Progression-free Survival Median PFS: 1.7 months DHALYA : all patients n=53 Phase III trial, Time (months) Progresssion Free Survival (%) Time to Progression by Dietary Intervention Group (tentative results) 9.8 months 12 months Coprah oil (n=28) Fish oil (n=25) DHALYA, Phase III trial, 216 Median survival Fish oil Coprah oil ns months DHASCO, Phase II trial, 29 High DHA incorporators arm Progression-free survival by DHA incorporation Percent survival months 8.7 months Time Time (months) HIGH DHA High Low LOW DHA Legend HIGH DHA LOW DHA Legend In terms of clinical efficiency - Beneficial effect of the high caloric supplementation in both arms, compared to the phase II trial - No superiority of the fish arm on "coprah" arm Bougnoux et al, Br J Cancer Time Time to progression in the phase III trial similar to «high DHA incorporators» (phase II clinical trial)

26 Evolution of plasma cytokines IL-6 and TNF-a levels, by supplementation 8 IL-6 5 TNF-a * 4 IL-6 (pg/ml) 6 4 * (paired***) TNF (pg/ml) C C1 C3-4 FT C C1 C3-4 FT C C1 C3-4 Coprah Oil FT C C1 C3-4 FT Fish Oil Time-dependent decrease in IL-6 level Coprah Oil Fish Oil Slight (not significant) decrease in TNF-a In terms of inflammatory cytokines changes: the dietary intervention with FO was successful: diminution of IL-6

27 Evolution of acute-phase proteins, by supplementation 2 15 CRP CRP/Albumin CRP (mg/l) C C1 C3-4 FT C C1 C3-4 FT Coprah Oil Fish Oil Albumin CRP / Albumine Albumin (g/l) 45 C C1 C3-4 FT C C1 C3-4 FT 4 Coprah Oil Fish Oil C C1 C3-4 FT C C1 C3-4 FT Coprah Oil Fish Oil In terms of inflammation markers changes: trend for a diminution of CRP/Albumin ratio

28 Summary In pre-clinical studies, - in vitro, DHA increases the sensitivity of a variety of tumor cell lines to several types of anticancer drugs - In rat models, diets enriched in DHA: - Enhance the response of mammary tumors to anthracyclins or to taxanes (chemosensitivity) - The effect is abolished by antioxidants In clinical trials carried out during chemotherapy of metastatic breast cancer - DHA supplementation (DHASCO) during a phase II trial resulted in improved disease-free survival - In a randomized trial, fish oil supplementation compared to coprah oil - provided a similar beneficial effect, w/o additional benefice on DSF - induced a decrease on inflammatory markers

29 Need to define the proper conditions to obtain the chemosensitization effect of omega-3 FA gained in preclinical studies.... in order to add this tumor effect to the beneficial effect of dietary supplementation during chemotherapy

Participants Inserm U 169, Clinical oncology Biology CHU Tours, France Charles Couet Caroline Goupille Marie-Lise Jourdan Emmanuelle Germain Séverine Colas Karine

Tours Bruno Giraudeau Tumor imaging : Léandre Pourcelot François Tranquart Inserm U 93 Tours Thanks to all patients for their dedication to the studies Phase III

30 Participants Inserm U 169, Clinical oncology Biology CHU Tours, France Charles Couet Caroline Goupille Marie-Lise Jourdan Emmanuelle Germain Séverine Colas Karine Mahéo Nawale Hajjaji Pierre Weber Oncology & Radiotherapy Olivier Le Floch Agnès Reynaud-Bougnoux Surgical Gynecology Gilles Body Jacques Lansac CIC Inserm 22, Tours Bruno Giraudeau Tumor imaging : Léandre Pourcelot François Tranquart Inserm U 93 Tours Thanks to all patients for their dedication to the studies Phase III randomized clinical trial: Virginie Berger + CECO ICO-CPP, Angers France Supports : Région Centre, French Research Ministry, DHOS, Inserm (ATC), INCa, Canceropôle GO

The use of omega-3 fatty acids in the management of cancer cachexia. Rhys White Principal Oncology Dietitian Guys and St Thomas NHS Foundation Trust

The use of omega-3 fatty acids in the management of cancer cachexia Rhys White Principal Oncology Dietitian Guys and St Thomas NHS Foundation Trust Overview Cancer cachexia Clinical features Pathogenesis