Soyfood Consumption and Breast Cancer Survival Xiao Ou Shu, M.D., Ph.D. Ingram Professor of Cancer Research Vanderbilt University, U.S.A.
Objectives Brief summary of the health benefits of soyfood consumption on breast cancer risk Potential health concerns for soyfood consumption after breast cancer diagnosis Epidemiological evidence on the association of soyfood consumption and breast cancer outcomes Current recommendations for breast cancer survivors
Breast Cancer Most common cancer diagnosed among women in the US and in many countries the world over 5-year survival rates: Average, 89%; Distant stage, 27%; Localized stage, 98% Over 2.9 million breast cancer survivors in the US; 4.4 million worldwide 10-15% of tumors recur within 3 years, 36-49% recur by year 10, and 41-57% by year 15 after diagnosis 63-96% of pre-menopausal breast cancer patients experience ovarian failure <1 year after chemotherapy
Factors Influencing Breast Cancer Outcomes cancer Progression death cancer free recurrence second primary cancer Comorbidities Lifestyle Diet Psychosocial factors Germline genetic variance Clinical characteristics: age, stage, grade Intrinsic tumor characteristics: genetic & epigenetic changes Tumor microenvironment Immune response Treatments Surgery, chemotherapy, radiotherapy, immune therapy Non-cancer related treatment
Soyfood Excellent Nutrition Source High quality protein Rich in essential fatty acids, low in saturated fat and high in unsaturated fat High calcium, folate, and other nutrients High dietary fiber (extremely fermentable) Richest dietary source of isoflavones
Proposed targets for beneficial effects of a high soy diet on human health Phytochemistry 2002; 60:205-211
Chemical Structures of 17 ß-estradiol and Soy Isoflavones HO 7 O HO 7 O HO 7 O 3 O Daidzein 4' OH 5 OH O Genistein 3 4' OH H 3 CO 6 O Glycitein 3 4' OH 17 ß-estradiol HO 7 O 3 O Dihydro-daidzein 4' OH HO 7 O 3 5 OH O Dihydro-genis tein 4' OH HO 7 O 3 HO 7 OH CH 3 3 Equol 4' OH O O-Desmethylangolensin (DMA) 4' OH
Anti-Estrogenic Effect of Isoflavones Compete for estrogen receptor-binding sites Increase synthesis of sex hormone binding globulin (SHBG) Inhibit estrogen synthesis enzymes Increase clearance of steroids Inversely related to estrogen level Prolong menstrual cycle
Deposition of Isoflavones in Breast Tissue Isoflavones can reach breast tissue, although with a lower level in breast tissue than in blood Breast adipose/glandular tissue distribution is 40:60 Isoflavone-derived E 2 β equivalents are, on average, 21 and 40 times more abundant than endogenous E 2 in adipose and glandular breast tissue Levels in breast tissue are potentially capable of producing a biological effect
Trock B J et, al. JNCI 2006
. Trock B J et al. JNCI; 2006
Soy Intake and Breast Cancer Risk: 8 Studies Conducted in Asia and in Asian Americans Description No. of studies Odds ratio 95% confidence interval Highest (~20 mg or more isoflavone per day) vs lowest (~5 mg or less isoflavone per day) All studies a 8 0.71 (0.60 0.85) All studies in Asia b 7 0.73 (0.61 0.89) Case control studies c 7 0.75 (0.62 0.89) Premenopausal women d 6 0.65 (0.50 0.85) Postmenopausal women d 6 0.63 (0.46 0.85) Moderate (~10 mg isoflavone per day) vs lowest (~5 mg isoflavone or less per day) All studies 8 0.88 (0.78 0.98) Wu A, BJC, 2008
Soy Intake and Breast Cancer Risk: 11 Studies Conducted in Western Populations Description No. of studies Odds ratio 95% confidence interval Highest (~0.8 mg or more isoflavone per day) vs lowest (~0.15 mg or less isoflavone per day) All 11 1.04 (0.97 1.11) Cohort/nested case control 4 1.08 (0.95 1.24) Case control studies 7 1.02 (0.95 1.11) Wu A, BJC, 2008
Dietary Isoflavone Intake by Ethnicity and Country The After Breast Cancer Pooling Project
Recent Case-Control Studies on Soyfood and Breast Cancer Risk by ER Status Study Location No. Cases/ Controls Amount of Intake ER+/ER+ PR+ ER-/ER- PR- Japan (2003-2005) 678/3390 SF <27.4 vs >51.2 g/d (T) Korea (2007-2008) 358/360 SF <45.7 vs 122.2 g/d (Q) China (2007-2008) 438/438 SP <0.93 vs 4.66 g/d (Q) China (2004-2005) 756/1009 SI <7.78 vs >25.4 mg/d (Q) 0.74 (0.58-0.94) 0.95 (0.58-1.57) 0.39 (0.22-0.68) 0.30 (0.11-0.82) 0.54 (0.32-0.91) 0.46 (0.23-0.92) 0.39 (0.27-0.58) 0.32 (0.21-0.49)
Shanghai Women s Health Study SWHS 1997-2012 75,000 women aged 40-70 enrolled between 1987-2000 Two dietary assessments at baseline recruitment and 2 years after enrollment Biennial in-person follow-up and record linkage with tumor registry 1034 incident cases identified for analysis during 13.2 years of follow-up
Risk of Breast Cancer by Adulthood Soyfood Intake SWHS 1997-2012 Intake level (by quintile) 1 (low) 2 3 4 5 P for trend All women 1.00 1.01 1.00 0.88 0.80 0.01 Premenopausal 1.00 0.99 0.85 0.98 0.46 0.003 Postmenopausal 1.00 1.03 1.07 0.86 0.93 0.26 Baglia et al, Int J Cancer, 2016
Soyfood Intake and Breast Cancer Risk by Receptor and Menopausal Status SWHS 1997-2012 PREMENOPAUSAL Adulthood Soyfood Intake Tertile 1 Tertile 2 Tertile 3 median=4.5g/day median=8.2g/day median=13.5g/day P trend ER+/PR+ (N(cases)=103) 1.00 (ref) 0.92 (0.58, 1.48) 0.91 (0.54, 1.52) 0.72 ER-/PR- (N(cases)=68) 1.00 (ref) 0.85 (0.50, 1.44) 0.46 (0.22, 0.97) 0.04 ER+/PR- (N(cases)=30) 1.00 (ref) 1.32 (0.56, 3.12) 1.04 (0.38, 2.83) 0.97 HER2+ (N(cases)=49) 1.00 (ref) 1.07 (0.56, 2.05) 0.73 (0.33, 1.61) 0.44 HER2- (N(cases)=122) 1.00 (ref) 0.90 (0.58, 1.38) 0.93 (0.58, 1.51) 0.78 POSTMENOPAUSAL ER+/PR+ (N(cases)=306) 1.00 (ref) 0.90 (0.69, 1.19) 0.72 (0.53, 0.96) 0.02 ER-/PR- (N(cases)=178) 1.00 (ref) 1.44 (1.00, 2.08) 1.04 (0.69, 1.58) 0.91 ER+/PR- (N(cases)=94) 1.00 (ref) 1.14 (0.66, 1.94) 1.35 (0.78, 2.33) 0.28 HER2+ (N(cases)=109) 1.00 (ref) 1.02 (0.65, 1.61) 0.81 (0.49, 1.36) 0.40 HER2- (N(cases)=312) 1.00 (ref) 0.94 (0.71, 1.23) 0.80 (0.60, 1.08) 0.14 Baglia et al, Int J Cancer, 2016
Non-estrogenic Tumor Inhibitory Effect of Isoflavones and Other Soy Components Inhibit tumor cell growth and proliferation Inhibit tyrosine kinases Inhibit DNA topoisomerase II Inhibit angiogenesis, increase apoptosis Enhance immune system Anti-oxidation, anti-inflammation Decrease chemically induced mammary cancer and increase the latency of tumorigenesis in animal models
Pre-diagnosis Soyfood Intake and Expression Level of mrna and mirna in Triple Negative Breast Cancer Tissue
Take Home Message Soyfood consumption at the level of a traditional Asian diet is inversely associated with breast cancer risk. The inverse association does not appear to be restricted to ER/PR positive breast cancer, and may depend on menopausal status. Multiple biological mechanisms may be involved.
Safety Concerns Estrogen-like effects: soy phytoestrogens induce a genomic fingerprint that is indistinguishable from the transcriptional effects of the endogenous hormone 17β-estradiol in cell lines with no ER-β Biomodel effect on some breast cancer cell lines Increase in mammary tumors among ovariectomized rats Induction of chromosome aberrations in human peripheral blood lymphocytes Increase in serum insulin-like growth factor-1 levels Short-term (7-30 days) soy protein supplementation immediately prior to cancer surgery was associated with increased expression of cell-cycle genes in breast cancer tissue
Influence of Soy on Breast Cancer Treatment and Survival Breast cancer is hormone-dependent cancer Breast cancer adjuvant therapies: Inhibition of estrogen action Reduction of estrogen production Soy isoflavones and other constituents: Weak estrogenic or anti-estrogenic effects Interaction with tamoxifen Other cancer inhibitory/promoting effects
Shanghai Breast Cancer Survival Study Baseline(6-m), 18-m, 36-m, 5-y and 10-y questionnaires Validated FFQ Assessed habitual intake of soyfoods Soy beans, tofu, soy milk, etc Estimate nutrient intake (soy protein and isoflavone intake) Based on Chinese Food Composition Tables 2002 Baseline, cumulative weighted average http://veganerliv.com/wp-content/uploads/2011/01/tofu.jpg
Soyfood Intake & Mortality Among Breast Cancer Survivors 1 1.0 0.77 0.72 0.71 1.0 0.77 0.69 0.68 1 0.5 0.5 0 0 Low Q2 Q3 High Low Q2 Q3 High Total Mortality Recurrence/Specific Mortality Soy Food Intake Shu XO et al., JAMA (2009)
Soy Intake in Association with Overall and Disease-Free Survival by ER Status SBCSS Women With ER-Negative Breast Cancer Soy protein 5.31 424 54 1[Reference] 65 1[Reference] 5.32-9.45 446 46 0.82(0.57-1.18) 64 0.93(0.67-1.29) 9.46-15.31 445 60 0.63(0.42-0.94) 66 0.67(0.47-0.97) >15.31 457 64 0.78(0.54-1.14) 72 0.77(0.54-1.09) Women With ER-Positive Breast Cancer Soy protein 5.31 808 55 1[Reference] 67 1[Reference] 5.32-9.45 797 47 0.79(0.53-1.18) 69 0.71(0.50-1.01) 9.46-15.31 794 49 0.88(0.61-1.30) 60 0.79(0.56-1.10) >15.31 781 51 0.67(0.45-1.00) 59 0.69(0.50-0.98) Soyfood intake was treated as a time dependent variable. Hazard ratios were adjusted for age at diagnosis, TNM stage, chemotherapy, radiotherapy, type of surgery received, BMI, menopausal status, ER and progesterone receptor status, tamoxifen use, education level, income, cruciferous vegetable intake, meat intake, any vitamin supplement use, tea consumption, and physical activity.
Risk of Breast Cancer Recurrence or Specific Mortality by Soy Intake & Tamoxifen Use (for ER+ BC only) 1.2 1 0.8 0.6 0.4 0.2 0 NO YES Shu XO et al., JAMA (2009)
Challenge to Investigate Soy Food Intake on Breast Cancer Outcomes Among US women Few soyfood consumers Low amount of intake Healthy life bias Hidden exposures Among Chinese Women High intake Lifestyle exposure Generalizability
Breast Cancer Recurrence among Postmenopausal Women using Tamoxifen, According to Daidzein Intake Life After Breast Cancer Epidemiology (LACE) Study Gaha, N, et al. BCRT, 2009
The After Breast Cancer Pooling Project Cohort Characteristics (N=18,314) SBCSS WHEL LACE NHS n=4,886 n=3,088 n=2,265 n=8,075 Study Design Prospective cohort Prospective follow-up Prospective cohort Prospective cohort of participants of a randomized controlled clinical trial Location Shanghai, China Seven sites in the western United States California, Utah, and WHEL sites United States Age at diagnosis, range 20-75 26-70 25-79 30-83 Year of diagnosis, range 2002-2006 1991-2000 1997-2000 1976-2004 Year of baseline recruitment, range 2002-2006 1995-2000 2000-2002 1976 Months between diagnosis and baseline survey/first survey after diagnosis, mean (range) 6.5 (3.6 to 11.4) 23.5 (1.9 to 48.3) 22.7 (11.1 to 38.9) 12.3 (0.91-45.9) Years of follow-up, mean (range) Major Endpoints, n Deaths Breast Cancer Deaths Recurrence* 4.2 years (0.5-6.2) 485 423 624 9.3 years (0.35-15.2) 452 356 583 7.8 years (0.10-10.3) 376 207 366 10.7 years (0.08-30.0) 2,423 1,628 1,991 *Defined as a local/regional recurrence, distant recurrence/metastasis or development of a new primary breast cancer.
Post-diagnosis Isoflavone Intake and Breast Cancer Outcomes by Country and Ethnicity ABC Pooling Project, N=9,514 Isoflavones (mg/day) All-Cause Mortality Breast Cancer-Specific Mortality Breast Cancer Recurrence Cohort Events HR (95% CI) Events HR (95% CI) Events HR (95% CI) Shanghai, China (SBCSS, n=4,856) <4.0 198 20 1.00 (reference) 19 1.00 (reference) 28 1.00 (reference) 4.0-10.0 328 36 1.07 (0.62, 1.86) 32 0.98 (0.56, 1.75) 41 0.91 (0.56, 1.47) 10.0 4,330 410 0.84 (0.54, 1.33) 354 0.75 (0.47, 1.20) 464 0.69 (0.47, 1.01) US cohorts (LACE and WHEL) All US Women (n=4,658) <4.0 3,933 615 1.00 (reference) 412 1.00 (reference) 702 1.00 (reference) 4.0-10.0 285 37 1.02 (0.73, 1.42) 28 1.10 (0.74, 1.62) 51 1.03 (0.77, 1.37) 10.0 440 53 0.93 (0.69, 1.24) 36 0.84 (0.59, 1.19) 62 0.76 (0.58, 0.99) Non-Asian US Women (n=4,458) <4.0 3,810 607 1.00 (reference) 408 1.00 (reference) 692 1.00 (reference) 4.0-10.0 250 34 1.00 (0.71, 1.42) 26 1.06 (0.71, 1.59) 41 0.87 (0.63, 1.20) 10.0 398 48 0.89 (0.66, 1.20) 33 0.80 (0.55, 1.15) 57 0.74 (0.56, 0.97) Baseline intake; ABC Pooling Project (unpublished) Nechuta SJ et al., AJCN (2012
Post-diagnosis Isoflavone Intake and Breast Cancer Outcomes by Tamoxifen Use among Women with ER+ tumors ABC Pooling Project, N=6,690 Isoflavones (mg/d) All-Cause Mortality Breast Cancer-Specific Mortality Breast Cancer Recurrence Event HR (95%CI) Event HR (95%CI) Event HR (95%CI) No Tamoxifen Use <4.0 66 1.00 (reference) 42 1.00 (reference) 89 1.00 (reference) 4.0-10.0 15 1.37 (0.76, 2.46) 12 1.54 (0.78, 3.02) 15 0.99 (0.56, 1.75) 10.0 82 0.98 (0.65, 1.47) 69 1.16 (0.71, 1.90) 100 0.79 (0.55, 1.14) Tamoxifen Use <4.0 422 0.83 (0.63, 1.09) 265 0.96 (0.68, 1.35) 448 0.78 (0.62, 0.99) 4.0-10.0 37 0.85 (0.56, 1.29) 27 1.05 (0.63, 1.74) 48 0.80 (0.56, 1.16) 10.0 149 0.74 (0.52, 1.07) 119 0.84 (0.54, 1.31) 184 0.63 (0.46, 0.87) Baseline intake; ABC Pooling Project (unpublished) Nechuta SJ et al., AJCN (2012
Recommendations for Breast Cancer Survivors Current evidence does not suggest that consuming soy foods is likely to have adverse effects on risk of recurrence or survival. ~Nutrition and Physical Activity Guidelines for Cancer Survivors American Cancer Society (2012) Soy is safe for breast cancer survivors. ~American Institute for Cancer Research (2012) Determining whether it is safe for breast cancer survivors to eat soy has been one of the big research questions, and now we know it is safe ~Karen Collins, AICR Nutrition Advisor (2012)
Association of Soy Food Intake After Cancer Diagnosis and Breast Cancer Outcomes (SBCSS) Shu XO, et al: JAMA, 2009
Soy Food Intake in Association with Inflammation Biomarkers in the SWHS Wu SH, et al; J Acad Nutr Diet, 2012
Soyfood consumption during the first 36 months postbreast cancer diagnosis and menopausal symptoms SBCCS Quartiles of isoflavone intake No. Hot flashes Night sweats Vaginal dryness (mg/day) All women 3472 1904 (54.8%) 966 (27.8%) 471 (13.6%) 27.28 868 1.00 1.00 1.00 27.28-42.22 825 1.11 (0.93-1.40) 1.09 (0.87-1.35) 1.05 (0.79-1.39) 42.23-62.86 912 1.06 (0.92-1.37) 1.03 (0.82-1.28) 1.02 (0.77-1.35) >62.86 867 1.18 (1.00-1.50) 1.10 (0.88-1.37) 0.89 (0.67-1.19) P trend 0.18 0.52 0.43 Premenopausal 742 407 185 65 27.28 195 1.00 1.00 1.00 27.28-42.22 176 1.40 (0.90-2.17) 1.54 (0.94-2.53) 0.87 (0.42-1.81) 42.23-62.86 193 1.16 (0.75-1.78) 1.15 (0.69-1.90) 0.82 (0.39-1.70) >62.86 178 1.59 (1.02-2.48) 1.60 (0.97-2.62) 0.87 (0.42-1.79) P trend 0.09 0.16 0.67 Postmenopausal 2730 1497 781 406 27.28 673 1.00 1.00 1.00 27.28-42.22 649 1.05 (0.82-1.34) 1.00 (0.78-1.27) 1.10 (0.81-1.50) 42.23-62.86 719 1.09 (0.85-1.38) 1.01 (0.79-1.28) 1.07 (0.79-1.46) >62.86 689 1.08 (0.84-1.38) 0.99 (0.78-1.27) 0.90 (0.65-1.24) P trend 0.50 0.99 0.50
Bone Mineral Density Measurement Bone Mineral Density 60 months post-diagnosis 1707 participants Duel energy x-ray absorptiometry Forearm 3 sites Distal (radius and ulna) Proximal (radius and ulna) Proximal (radius only)
Soyfood Consumption in Association with Bone Mineral Density
Take Home Message In general, moderate soyfood consumption after breast cancer diagnosis is safe and is associated with lower recurrence rates. Some but not all benefits from soyfood are related to its antiestrogenic property. The soyfood survival association does not follow a linear pattern. The beneficial effect of moderate levels of soyfood consumption on survival may be more evident among tamoxifen users.
Acknowledgements Vanderbilt Epidemiology Center and Vanderbilt- Ingram Cancer Center Shanghai Cancer Institute Shanghai Center for Disease Control and Prevention DOD Breast Cancer Research Program National Cancer Institute Research Team Members and Study Participants