Women s Health Matters

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1 Wmen s Health Matters Nutritin & Breast Cancer Natalie Ledesma, MS, RD, CSO Ida & Jseph Friend Cancer Resurce Center UCSF Helen Diller Family Cmprehensive Cancer Center University f Califrnia, San Francisc Gd nutritin may reduce the incidence f breast cancer and the risk f breast cancer prgressin r recurrence. There are many studies in prgress t help further understand hw diet and cancer are related. We d knw, hwever, that imprved nutritin reduces risk f chrnic diseases, such as diabetes, besity, hypertensin and heart disease, and als enhances verall quality f life. It is estimated that ne third f cancer deaths in the U.S. can be attributed t diet in adulthd [1]. Guidelines fr a Healthy Diet Plant-based diet Plenty f fruits and vegetables High fiber beans/legumes, seeds, whle grains Include prtein with every meal - aim t include plant prtein daily Lw/mderate fat diet with emphasis n healthy fats Revised 07/15 Limit prcessed and refined grains/flurs/sugars Drink plenty f fluids Be physically active t help achieve and/r maintain a healthy weight Plant based diet A lifelng cmmitment t a plant based diet may lwer a wman s risk f develping breast cancer and may als reduce the risk f recurrent breast cancer. A plant based diet cnsists primarily f fruits, vegetables, beans/legumes, nuts/seeds and whle grains. A large chrt* study with ver 91,000 wmen shwed a plant-based diet was assciated with a 15% reductin in breast cancer risk; this effect was even mre significant fr thse with estrgen-receptr negative and prgesterne-receptr negative (ER-/PR-) tumrs [2]. Similarly, fllwing a Mediterranean dietary pattern f vegetables, fish and live il, legumes, and fruit was independently assciated with a decreased risk f breast cancer [3]. * All wrds nted with an asterisk ( * ) are defined in the glssary n page 54. Healthy Plate Diagram Fill yur plate with apprximately 50% (r mre) vegetables, 25% (r mre) prtein, and up t 25% starchy vegetable r whle grain. Find a Dctr: (888) Patient Educatin Library:

2 SUMMARY - HEALTHY BREAST CANCER DIET Eat 8 t 10 clrful fruit and vegetable servings daily Tw t three pieces f fruit One cup r mre f vegetables with lunch and dinner 8 fl z vegetable juice Cnsume 30 t 45 grams f fiber daily Yu will likely meet yur fiber gal if yu eat 8 t 10 servings f fruits and vegetables plus ne serving f beans/legumes, ne serving f chia and/r flax seed, r at least tw servings f whle grains daily. Avid prcessed and refined grains/flurs/sugar Keep WHITE ff yur plate: bread, pasta, rice, cream sauces, cakes, and mre. Lean prtein with every meal; plant prtein daily Limit fatty & prcessed meats, and dairy Include healthy fats like cld-water fish, chia seeds, flaxseeds, walnuts, sybeans, live il, avcads Eat chia seeds and grund flax daily 1-2 Tbsp daily Cnsume herbs and spices daily Limit alchl cnsumptin Drink 1 t 4 cups f green tea daily Ask yur dctr abut having a vitamin D bld test (serum 25 (OH)-vitamin D level). Maintain yur level abve 40 ng/ml thrugh diet and, if needed, supplements Drink plenty f fluids, water r nn-caffeinated beverages, daily t help meet fluid needs Engage in daily physical activity t help achieve and/r maintain a healthy weight FRUITS AND VEGETABLES Cntain vitamins, minerals, fiber, and varius cancer-fighting phytnutrients* (fr example: cartenids, lycpene, indles, isflavnes, flavnls). Vibrant, intense COLOR is ne indicatr f phytnutrient* cntent. There is extensive and cnsistent evidence that diets high in fruits and vegetables are assciated with decreased risks f many cancers, and while results fr breast cancer risk are nt yet cnclusive, they are prmising [2-26]. In a study f abut 3,000 pstmenpausal wmen, a prtective effect fr vegetables was bserved [4]. Wmen wh cnsumed 25 r mre servings f vegetables weekly had a 37% lwer risk f breast cancer cmpared with wmen wh cnsumed fewer than 9 vegetable servings weekly. 2

3 An epidemilgical* study reprted a significant prtective effect f vegetables against breast cancer when case-cntrl* and chrt* studies were cnsidered tgether [6]. A meta-analysis* lking at the data frm 17 studies [27] revealed that high vs. lw vegetable cnsumptin was assciated with a 25% reductin in breast cancer risk, but these findings were nt cnfirmed by data cllected frm 8 studies [28]. A study f ver 31,000 wmen shwed an inverse assciatin between vegetable cnsumptin and breast cancer risk [23]. Vegetables f nte were leafy vegetables, fruiting vegetables (peppers, tmates, eggplant), and raw tmates. In a chrt* study f nearly 21,000 participants, high cnsumptin f fruit and salad was assciated with a reduced risk f breast cancer, particularly in ER-/PR- tumrs [15]. A recent case-cntrl* study reprted wmen wh cnsumed mre than 3.8 servings f fruits and vegetables daily had a lwer risk f breast cancer when cmpared with wmen wh cnsumed fewer than 2.3 daily servings [29]. Japanese wmen fllwing a prudent dietary pattern (high in fruits and vegetables, lw in fat) had a 27% decreased risk f breast cancer [7]. A diet characterized by vegetables, fruit, and sy lwered risk f breast cancer amng pstmenpausal wmen by 30%; this effect was even strnger (43% risk reductin) fr thse fllwing this diet pattern fr 5 r mre years [17]. A Krean case-cntrl* study reprted that a high intake f certain fruits and vegetables resulted in a significantly lwer risk f breast cancer in premenpausal (tmates) and pstmenpausal wmen (grapes and green peppers) [8]. Pickled vegetables, hwever, may increase breast cancer risk [24]. A meta-analysis f 12 studies cncluded that the risk f breast cancer decreased significantly in wmen with a high flavnl and flavne intake [22]. Flavnl-rich fds include nins, kale, leeks, and brccli and flavne-rich fds include parsley, thyme, celery, regan, and chili peppers. A prspective analysis that included mre than 75,000 wmen ver a perid f 24 years, reprted the fllwing: 18% reduced risk f ER- breast cancer in wmen wh cnsumed 2 servings f berries weekly 31% reduced risk f ER- breast cancer in wmen wh cnsumed 1 r mre servings f blueberries weekly 41% risk reductin f ER- breast cancer in wmen wh cnsumed 2 servings f peaches/ nectarines weekly [19] Limnene, a biactive fd cmpnent frm citrus peel il may lead t cell-cycle arrest and reduced cell prliferatin in breast tissue [30]. While n effect was bserved fr vegetables, increasing ttal fruit intake significantly lwered the risk f breast cancer when cmparing thse in the highest t lwest tertile [31]. This effect was greater fr thse with ER+ tumrs. Eating a salad vegetable dietary pattern (high cnsumptin f raw vegetables and live il) exerted a significant prtective effect against HER-2-psitive cancers [12]. 3

4 This study fund that while specific vegetables (carrts and cruciferus vegetables) may be prtective fr all breast cancer types, ttal vegetable cnsumptin was assciated with a decreased risk f ER-/PR- breast cancer types nly [32]. In a case-cntrl* study f 6,917 Chinese wmen, ttal vegetable intake was inversely related t breast cancer risk, as were high intake f citrus and rsaceae fruits (apples, pears, quinces, apricts, plums, cherries, peaches, raspberries, lquats, and strawberries); n difference was bserved between different tumr types [16]. The Dietary Appraches t Stp Hypertensin (DASH) diet was assciated with a significantly lwer risk f ER- breast cancer; this effect was largely explained by higher intakes f fruits and vegetables [33]. A vegetable-based, lw-carbhydrate-diet was als assciated with a significantly lwer risk f ER- breast cancer. N assciatin was fund between ER+ tumrs and fruit and vegetable intakes. A study assessing plasma r bld cartenids as a marker fr fruit and vegetable intake reprted that individuals in the tp 1/4 had a 43% lwer risk f breast cancer recurrence when cmpared t thse in the lwest 1/4 [34]. Hwever, n assciatin was bserved between fruit and vegetable cnsumptin and breast cancer recurrence when wmen cnsumed five servings daily vs. eight servings daily [35]. Breast cancer survivrs significantly reduced mrtality by fllwing a diet lw in fat, high in vegetables, high in fiber, and high in fruit [36]. The cmbinatin f cnsuming five r mre daily servings f vegetables and fruits, and accumulating 540+ metablic equivalent tasks-min/wk (equivalent t walking 30 minutes 6 d/wk) decreased mrtality by nearly 50% [13]. The effect was strnger in wmen wh had ER+ r PR+ cancers. Vegetable intake has been inversely assciated with serum insulin-like grwth factr-i (IGF-I) levels [37]. IGF-I levels have been directly assciated with breast cancer. Beta-Cartene Beta-cartene is ne f the 600 cartenids that can be partially cnverted int vitamin A in the bdy. Cartenids have a prtective rle fr certain sites, including breast cancer [9, 38-41]. Cartenid intake was significantly assciated with reduced mrtality in breast cancer survivrs [36]. In varius studies, serum beta-cartene levels were lwer amng breast cancer patients cmpared t wmen withut cancer [38, 42-49]. One f these studies reprted the risk f breast cancer t be 221% greater fr wmen in the lwest quartile f serum beta-cartene cmpared t wmen in the highest quartile [29]. This inverse assciatin was strnger fr ER- tumrs than ER+ tumrs [48]. A case-cntrl* study reprted that increased plasma levels f beta-cartene, retinl, and ttal antixidant* status were assciated with abut a 50% reduced risk f breast cancer [45]. Cell studies indicate that cartenids may inhibit the prductin f breast cancer cells [50-51]. Beta-cartene may inhibit ER+ and ER- breast tumr develpment [39]. 4

5 Beta-cartene may hinder the develpment f breast cancer cells by inhibiting cell prliferatin [52], arresting cell cycle [52], and inducing apptsis* [52-53]. Research indicates that dietary surces f beta-cartene are likely much mre prtective than supplemental surces against the risk f cancer [54-56]. Cnsuming higher amunts f dietary beta-cartene, lycpene, and beta-cryptxanthin was assciated with a lwer risk f breast cancer amng Chinese wmen [40]. Carrt intake was inversely assciated with risk f breast cancer in the Black Wmen s Health Study [32]. Dietary cnsumptin f alpha-cartene, beta-cartene, beta-cryptxanthin, and lutein/zeaxanthin were all assciated with a lwer risk f breast cancer [57] in ER- breast cancer nly [58]. Lycpene, hwever, did nt result in a reductin f breast cancer risk. Dietary alpha-cartene, beta-cartene, and lycpene were inversely assciated with risk f ER+/ PR+ breast cancer [41]. Dietary beta-cartene intake was inversely assciated with IGF-I levels in a large case-cntrl study [37]. Cruciferus Vegetables Sme evidence suggests that the cruciferus vegetables, in particular, are assciated with a reduced risk f breast cancer [32, 59-65]. A recent meta-analysis* f 13 epidemilgic studies indicated that high cruciferus vegetable intake was significantly assciated with a reduced risk f breast cancer [66]. A Swedish study f pstmenpausal wmen reprted ne t tw daily servings f cruciferus vegetables reduced the risk f breast cancer, pssibly by as much as 20-40% [62]. Cruciferus vegetable intake was assciated with a significant decrease in risk f breast cancer in Japanese premenpausal wmen [60]. N significant assciatin was bserved fr pstmenpausal wmen and breast cancer. Wmen wh ate mre turnips and Chinese Cabbage (bth in the cruciferus vegetable family) significantly reduced the risk f pstmenpausal breast cancer [65]. Cnsumptin f cruciferus vegetables, particularly brccli, was inversely assciated, thugh nt statistically significant, with breast cancer risk in wmen [61]. The U.S. cmpnent f the Plish Wmen s Health Study fund that wmen wh cnsumed raw- r shrt-cked cabbage and sauerkraut 3 r mre times weekly had a significantly reduced risk f breast cancer [64]. Cabbage that was cked fr a lng time had n effect n breast cancer risk. Researchers suggested that glucsinlates, cmpunds in cabbage, may affect bth the initiatin phase f carcingenesis*, cell mutatin*, and inhibit apptsis*. Cruciferus vegetables appear t shift estrgen metablism in a favrable manner; increasing 2-hydrxyestrne:16-a-hydrxyestrne [67-68]. Fwke and clleagues [68] cncluded that cnsuming mre cruciferus vegetables acrss the ppulatin may have an impact n the incidence f breast cancer. 5

6 Several studies suggest that cmpunds fund in these fds, isthicyanates (sulfraphane), have inhibitry effects n breast cancer cells in bth cell studies and animal studies [59, 63, 69-71]. One mechanism appears t be thrugh ptent inhibitin f phase I and inductin f phase II detxifying enzymes, such as glutathine-s-perxidase [61, 65, 70]. Furthermre, these cmpunds reduced cell prliferatin and inhibited cyclxygenase-2 (COX- 2) expressin in breast cancer cells [72]. Inhibited cell grwth and induced apptsis has als been bserved [73]. Human breast cancer stem cells decreased significantly when benzyl isthicyanate was intrduced int the diet [69]. Indle-3-carbinl (I3C) is a cmpund fund in cruciferus vegetables that has anticancer prperties and anti-prliferative effects n breast cancer cells [74]. I3C may inhibit the grwth f bld vessels that the tumr needs t grw (anti-angigenesis) [75]. I3C and diindlylmethane (DIM) induce apptsis*, r cell death, in breast cancer cells [67,76] fr bth ER+ and ER- tumr cells [77]. Furthermre, I3C and tamxifen have been shwn t act separately and/r cperatively t inhibit the grwth f ER+ breast cancer cells [78]. Dietary I3C may have effects that blster immune functin [79]. Anther cmpund in cruciferus vegetables, calcium-d-glucarate, has been shwn t inhibit betaglucurnidase, an enzyme invlved in phase II liver detxificatin. Elevated beta-glucurnidase activity is assciated with an increased risk fr varius cancers, particularly hrmne-dependent cancers such as breast cancer [80]. Pmegranate (Punica granatum; Punicaceae) Varius parts f the pmegranate fruit (fr example: seed il, juice, fermented juice and peel extract) have expressed suppressive effects n human breast cancer cells in labratry research [81]. Pmegranate seed il and fermented juice blck the cancer cells xygen supply, slw cell grwth, and prmte cell death [82]. Fermented pmegranate juice plyphenls* appear t have twice the anti-prliferative effect as fresh pmegranate juice plyphenls* [83]. Pmegranate husk, rich in ellagitannins (plyphenls*), exhibited strng anti-prliferative activity against breast cancer cell lines and inhibits xidative DNA damage [84]. Pmegranate juice, r a cmbinatin f its cmpnents (lutelin, ellagic acid, punicic acid) increase cancer cell adhesin and decrease migratin, while leaving nrmal cells unaffected [85]. Furthermre, ne study suggests that pmegranate seed il may have the greatest preventive activity (87% reductin in lesins) cmpared t fermented pmegranate juice (42% reductin) [86]. Pmegranate peel extract has imprtant antixidant effects, and has been shwn t inhibit human breast cancer cells and hlds prmise as a pssible treatment against breast cancer [87-89]. 6

7 Nutrient Dietary Surces Recmmendatin Beta-cartene Carrts, sweet ptates, winter squash, cantalupe, and mang Include these fruits and vegetables daily. Cruciferus vegetables Arugula, brccli, Brussels Include these vegetables daily. spruts, cabbage, cauliflwer, cllard greens, hrseradish, kale, khlrabi, mustard greens, radishes, rutabaga, turnips and turnip greens, and watercress Pmegranate Pmegranate Cnsider including pmegranate r pmegranate cncentrate n a regular basis. Organic Prduce Organic fruits and vegetables have fewer pesticides, lwer levels f ttal pesticides, and less verall pesticide txicity than fruits and vegetables grwn with chemicals. Althugh mre research is needed, recent evidence indicates a significant increase in antixidants* in rganic and sustainably grwn fds versus cnventinally grwn fds [90-95]. Organic vegetables cntained a greater cncentratin f phytnutrients* (phenlic acids) when cmpared t cnventinally grwn vegetables [92, 93]. Organic fermented beetrt juices ffered strnger anticancer activity than the cnventinal juice [95]. Additinally, rganic fresh beets cntained mre vitamin C than the cnventinal beets. The extracts frm rganically grwn strawberries had a higher cntent f antiprliferative activity fr breast cancer cells, and displayed a 43% inhibitin [96]. Cnsuming rganic fds appears t increase salicylic acid, which may cntribute t a lwer risk f cancer [92]. Pesticides such as rganchlrine cmpunds (OCC), knwn as envirnmental pllutants, have been implicated in the etilgy f estrgen-related disrders due t their ptential estrgenic and anti-estrgenic prperties [94]. Results f sme studies [94, 97-98], but nt all [99] suggest that envirnmental expsure t rganchlrine pesticide residues r PCBs may cntribute t multifactrial pathgenesis f breast cancer. In a study f wmen living n Lng Island, New Yrk, breast cancer risk was assciated with lifetime residential pesticide use [100]. Organchlrine pesticide residues, including DDTs and HCHs, may increase wmen s risk f breast cancer, particularly in premenpausal wmen in China [97]. In mice, expsure t beta-hch, an rganchlrine pesticide residue, bth accelerated the appearance and incidence f breast cancer tumrs when cmpared t cntrls mice [98]. 7

8 The level f expsure may be integral in determining the effects f these OCC. One study fund that when breast adipse tissue reached levels higher than 2600 ppb, wmen with pstmenpausal ER+ breast cancer exhibited high prliferatin [101]. Chsing rganic prduce will help yu reduce yur levels f pesticide expsure and will mst likely increase yur phytnutrient* cnsumptin. Althugh washing and peeling yur nn-rganic fruits r vegetables may help t reduce pesticide residues, it will nt eliminate them. Listed belw are prduce with the mst and least pesticide cntaminatin, bth in terms f number f pesticides used and the level f pesticide cncentratin n an average sampling. Thus, fr the fruits and vegetables shwn n the mst cntaminated list, it is wise t buy rganic. Alternatively, if rganic chices are nt available, yu may want t cnsider substituting with prduce that tends t cntain the least amunt f pesticides. Prduce mst cntaminated by pesticides: Apples Peaches Nectarines Strawberries Grapes Celery Spinach Sweet bell peppers Cucumbers Cherry tmates Snap peas - imprted Ptates Prduce least cntaminated by pesticides: Avcads Sweet crn Pineapple Cabbage Sweet peas Onins Asparagus Mangs Papayas Kiwi Eggplant Grapefruit **Adapted frm Envirnmental Wrking Grup A Shpper s Guide t Pesticides in Prduce It is mst imprtant, hwever, t eat fruits and vegetables rganic r cnventinal. If the availability r cst f rganic prduce is a barrier, yu may wish t avid thse fruits and vegetables that have the highest pesticide residue cntent. FIBER A PLANT-BASED DIET IS NATURALLY HIGH IN FIBER A diet rich in natural fiber btained frm fruits, vegetables, legumes (fr example: lentils, split peas, black beans, pint beans), and whle-grains may reduce cancer risk and/r reduce risk f cancer prgressin. Fiber binds t txic cmpunds and carcingens, which are then later eliminated frm the bdy [102]. Varius mechanisms have been prpsed fr the prtective effects f dietary fiber against cancer. These include: Increased fecal bulk and decreased intestinal transit time, which allw less pprtunity fr fecal mutagens t interact with the intestinal epithelium [103]. Binding t bile acids, which are thught t prmte cell prliferatin [104]. 8

9 Fermentatin in the gut, prducing shrt-chain fatty acids (SCFA). SCFA imprve the gut envirnment and may prvide immune prtectin beynd the gut [103, 104]. Additinally, whle grains are rich in antixidants*, including trace minerals and phenlic cmpunds, which have been linked t disease preventin [104]. Furthermre, a high fiber diet wrks t reduce hrmne levels that may be invlved in the prgressin f breast cancer [103, ]. A high-fiber, lw-fat diet interventin fund that fiber reduced serum estradil* (estrgen breaks dwn int estradil* in the bdy) cncentratin in wmen diagnsed with breast cancer, the majrity f whm did nt exhibit weight lss. Thus, increased fiber intake was independently related t the reductin in serum estradil* cncentratin [107]. This decrease in estrgen levels in the bld thereby may ptentially reduce the risk f hrmne-related cancers, such as breast cancer. Reduced levels f serum estrne* and estradil* were bserved in premenpausal wmen with a greater intake f dietary fiber [106]. Similarly, a high intake f dietary fiber was significantly assciated with lw serum levels f estradil in pstmenpausal breast cancer survivrs [108]. Dietary fiber intake increases the amunt f estrgen excreted in the stl [109]. A high fiber diet is als assciated with less besity [105] - a risk factr fr pstmenpausal breast cancer. A high fiber diet may als lwer cancer risk via reduced inflammatin. Breast cancer survivrs wh cnsumed >15.5 g/day f insluble dietary fiber had a 49% reductin in the likelihd f having an elevated C-reactive prtein (CRP) cncentratin, a bimarker that assesses inflammatin [110]. A meta-analysis* f 10 prspective chrt studies and 16,848 cases shwed that fr every 10 g fiber/day increase, there was an assciated 7% reductin in breast cancer risk [111]. In a study f 11,576 breast cancer cases, risk was inversely linked t ttal dietary fiber intake and fiber frm vegetables [112]. The risk reductin was even mre prnunced in ER-/PR- wmen. Similarly, sluble fiber intake was assciated with a significantly reduced risk f breast cancer in pre-menpausal wmen; this effect was greatest in wmen with ER- tumrs [113]. A high fiber diet was assciated with a lwer risk f breast cancer in bth pre- and pstmenpausal wmen [114]. In a study f wmen with primary breast cancer, a significant inverse assciatin (69% reduced risk) was fund between dietary fiber and breast cancer risk in ER+, ER-, PR+, ER+PR+, and ER-PR+ tumrs [115]. Ttal dietary fiber intake, particularly frm cereals and fruit, was fund t significantly reduce the risk f breast cancer in pre-menpausal, but nt pst-menpausal wmen [116]. A recent chrt* study reprted that high fiber intake was assciated with a 42% lwer risk f pstmenpausal breast cancer, when cmparing wmen in the highest quintile f fiber intake cmpared t the lwest quintile [117]. 9

10 An earlier prspective chrt* study, hwever, reprted n prtective effect f fiber against breast cancer when cmparing wmen wh cnsumed fewer than 26 grams dietary fiber cmpared t thse wh cnsumed even less [118]. This finding is nt surprising given that the ttal grams f fiber cnsumptin was less than 30 grams. Similarly, anther study that reprted n significant findings cmpared wmen cnsuming less than 25 g fiber daily [119]. Overall, case-cntrl* studies have reprted the greater the fiber intake, the lwer the incidence f breast cancer [10, 114, ]. Data frm prspective studies is mixed, reprting prtective effects [117, ] r n effect bserved [118, 119]. Wmen wh ate beans and lentils at least twice a week had a 24% lwer risk f develping breast cancer than wmen wh ate them less than nce a mnth [126]. Mre recently, cnsumptin f legumes was fund t be inversely assciated with breast cancer [16]. High-Fiber Surces FRUITS: Fd Serving Size Fiber Grams/ Serving Apple 1 medium 3.7 Banana 1 medium 2.8 Blackberries 1/2 cup 1.9 Blueberries 1 cup 1.3 Cantalupe 1/2 cup 6.0 Figs (dried) 1/4 cup 6.0 Grapefruit 1 medium 3.4 Grapes 1 cup 1.6 Guava 1 medium 4.9 Kiwi 1 medium 2.6 Orange 1 medium 3.1 Pear 1 medium 4.0 Persimmn 1 medium 6.0 Prunes 1/4 cup

11 GRAINS & OTHER PRODUCTS: Fd Serving Size Fiber Grams/ Serving Amaranth 1/4 cup dry 7.4 Barley 1/2 cup cked 3.0 Beans, black 1/2 cup cked 8.3 Beans, red kidney 1/2 cup cked 8.2 Beans, garbanz 1/2 cup cked 5.0 Bran cereals 3/4 cup Check labels ( ) Brwn rice 1/2 cup cked 1.4 Bulgur 1/2 cup cked 4.0 Oatmeal 1/2 cup cked 2.0 Peanuts 1/4 cup 2.9 Quina 1/4 cup dry 2.5 VEGETABLES: Fd Serving Size Fiber Grams/ Serving Artichkes 1 medium 6.9 Beets 1/2 cup cked 1.7 Brccli 1/2 cup cked 2.3 Brussel spruts 1/2 cup cked 2.0 Carrts 1/2 cup cked 2.6 Kale 1/2 cup cked 1.3 Lima beans 1/2 cup cked 4.5 Peas, green 1/2 cup cked 4.4 Spinach 1/2 cup cked 2.2 Squash, winter-type 1/2 cup cked 3.4 Sweet ptates (yams) 1/2 cup cked 2.7 SUGARS AND THE ROLE OF INSULIN* High sugar fds are usually highly prcessed and refined, lw in nutrient value, and als lw in dietary fiber. In additin, these fds appear t increase serum insulin* and serum insulin-like grwth factr (IGF-I) levels [127], which stimulate cancer cell grwth. Overexpressin, r high amunts, f IGF increases mammary tumrs in mice [128]. IGF s may wrk by stimulating cell cycle prgressin and prevent cells frm premature death [ ]. IGF-I may prmte tumr grwth via upregulatin f varian sterid secretin [ ]. Research indicates a synergistic effect between IGF-I and estrgen [134] as well as IGF-I and insulin* resistance [135] in breast cancer. 11

12 Wmen in the highest quintile f IGF-I level had a 310% increased risk f all-cause mrtality [136]. A prspective chrt* study bserved a significant 310% increased risk f breast cancer in premenpausal wmen wh had the highest quartile f IGF-I cmpared t wmen with the lwest quartile [132]. A weaker assciatin was fund with fasting insulin* levels where premenpausal wmen in the tw highest quartiles had a 70% greater risk fr breast cancer. In premenpausal wmen, wmen in the highest quartile f serum glucse had a 280% increased risk f breast cancer cmpared with wmen in the lwest quartile. In pstmenpausal wmen, the assciatins f glucse, insulin*, and IGF-I were assciated with breast cancer risk in heavier subjects (BMI>26 1 ). Overall, these findings indicate that chrnic change f glucse/sugar metablism is related t breast cancer develpment. Other studies supprt a strnger link between IGF-I and breast cancer in premenpausal wmen [131, 137]. Additinally, a case-cntrl* study in China fund that IGF-I significantly increased the risk f breast cancer [135]. IGF-I levels were psitively assciated with the risk f ER+ breast tumrs (pre- and pstmenpausal wmen cmbined) and amng wmen wh were diagnsed with breast cancer at 50 years r lder [138]. Nnetheless, a meta-analysis* review f 18 studies reprted n verall statistically significant assciatin between circulating IGF-I levels and risk f breast cancer althugh the levels were greater in breast cancer patients than cntrls [130]. Hwever, IGF-I levels did appear t increase breast cancer risk in premenpausal wmen by almst 40%. Similarly, a large prspective trial reprted IGF-I significantly increased risk f breast cancer in premenpausal wmen under the age f 50; n significant relatinship was nted fr pstmenpausal wmen [139]. It has been suggested that decreasing IGF-I levels may be ne factr that cntributes t tamxifen s anti-tumr activity in breast cancer therapy [140]. While nt all studies [141] agree, a chrt* study reprted that higher insulin* levels significantly increased risk f breast cancer fr bth pre- and pst-menpausal wmen [142]. Recent studies indicate that high insulin* levels, increased cncentratin f IGF-I, and greater abdminal fat are assciated with increased risk fr breast cancer [143]. One study nted a direct assciatin, thugh nt statistically significant, between nn-fasting serum insulin* levels and 10-year mrtality in pstmenpausal breast cancer wmen [144]. Amng ther factrs, a diet lw in fiber may favr the develpment f insulin* resistance and hyperinsulinemia [127]. Hyperinsulinemia may cntribute t the develpment f breast cancer in verweight r bese wmen [145]. 1 BMI refers t bdy mass index, which is calculated by bdy weight (kg)/height2(m2). 12

13 Additinally, besity and fasting hyperinsulinemia have been assciated with a prer prgnsis in wmen with established breast cancer [146]. A case-cntrl* study reprted that carbhydrate intake significantly increased risk f breast cancer; sucrse (table sugar) imparted the greatest risk [147]. This risk was lessened cnsiderably with a higher fiber intake. A significant tw fld increased risk f breast cancer was assciated with wmen cnsuming the highest amunt f sugar in the diet [114]. Sugar and dessert intake was assciated with an increased risk f breast cancer [18]. Furthermre, an Italian case-cntrl* study fund that wmen wh cnsumed the highest tertile f desserts and sugars had a 19% increased risk f breast cancer cmpared with wmen in the lwest tertile [148]. A crss-sectinal study f wmen shwed that fr increasing amunts f sugar-sweetened beverages, higher mammgraphic density ccurs--a strng breast cancer risk factr [149]. A case-cntrl* study f 1,434 cases shwed that cnsumptin f sweet beverages, added sugars, and desserts was psitively assciated with breast cancer risk [150]. The risks f distant metastasis and breast cancer deaths were significantly higher in wmen with higher fasting glucse levels cmpared t wmen in the lwest glucse quintile (reference <87 mg/ dl) [152]. Breast cancer mrtality was significantly greater in ER+/PR+ wmen with a higher bld glucse (> 94 mg/dl) cmpared with thse with nrmal glucse levels [153]. The cnsumptin f sweet fds with a high glycemic index* (GI) and glycemic lad* (GL) have been implicated as a risk factr fr breast cancer due t their effects n insulin and IGF-I [ ]. Wmen wh cnsumed the greatest intake f desserts (including biscuits, briches, cakes, puffs and ice-cream) and sugars (including sugar, hney, jam, marmalade and chclate) had a 19% increased risk f breast cancer cmpared with wmen wh cnsumed the least desserts and sugars [153]. Adding credence t the idea that bld sugar levels may affect disease prgressin, wmen wh cnsumed a high GI and GL diet had a 57% and 253% increased risk f breast cancer, respectively [154]. This effect was mst prnunced in premenpausal wmen and thse wmen at a healthy bdy weight. GI and GL were bth assciated with an increased risk f breast cancer amng pstmenpausal verweight wmen; this effect was mst prnunced fr wmen with ER- breast cancer [155]. GL was psitively assciated with verall breast cancer risk in tw chrt* studies [ ]. This evidence was further supprted by a meta-analysis* that reprted GI t mdestly increase the risk f breast cancer [156]. 13

14 INSULIN HIGH TIDE. The bserved link between besity and cancer may be explained by the grwthprmting activities f insulin and IGF-1. One thery psits that excess weight sets ff a bichemical cascade that increases insulin and, in turn, IGF-1 levels. Bth hrmnes may activate IGF-1 receptrs n cells, which can spur cell grwth and inhibit cell death pathways that usually prtect against tumr develpment. E. Rell/Surce: Nature Reviews Cancer, 2004 Sugars & Insulin* Bttm Line T help cntrl yur insulin* level: Eat a high-fiber diet with limited refined/prcessed fds Fllw a lw/mderate fat diet rich in mega-3 fatty acids When yu eat fds rich in carbhydrates, include prtein at same meal/snack Limit r avid alchl Exercise Maintain a healthy bdy weight LOW FAT DIET Many studies have investigated the relatinship f fat and the risk f breast cancer, but the results remain incnsistent. Hwever, several trials shwed sme prmise in the area. The Wmen s Interventin Nutritin Study (WINS) fund that a reduced fat intake imprves relapse-free survival by 24% in pstmenpausal wmen with breast cancer cmpared with wmen fllwing a standard diet [159]. The risk f recurrence fr wmen with ER- breast cancer decreased by 42%. Later, the Eurpean Prspective Investigatin int Nutritin and Cancer (EPIC) Study reprted that eating a higher fat diet significantly increased the risk f breast cancer; wmen wh had a 35% and 39% fat diet were at a greater risk than thse eating a 31% fat diet [160]. While this diet wuld nt be cnsidered lw fat, a significant effect was still bserved. While the Nurses' Health Study fund that ttal fat intake was nt assciated with breast cancer risk [161], a systematic review and meta-analysis* reprted that increased fat in the diet was assciated with an increased risk f breast cancer [21]. Furthermre, a prspective trial suggested that a high fat diet was assciated with increased risk in ER+/PR+ disease, but nt ER-/PR- tumrs [162]. 14

15 The ptential elevated cancer risk may be, in part, due t the fact that a high fat diet stimulates increased estrgen levels, which is assciated with breast cancer grwth. A study f adlescent females fund that mdest reductins in fat intake during puberty resulted in significantly lwer cncentratins f sex hrmnes (estradil*, estrne*, prgesterne) [163]. Further research is needed t determine if in fact these lwer levels lead t a reduced risk f breast cancer. Aim fr clse t 20-30% f yur ttal calries frm fat, with less than 8% f ttal calries frm saturated fat. Likely mre imprtant, research indicates that the type f fat may be f paramunt significance. Saturated Fats Several studies indicate a psitive assciatin between saturated fat intake frm meat and dairy prducts (animal surces) and cancer [ ]. While breast cancer research is incnclusive, it is grwing [161, ]. A systematic literature review cncluded that higher saturated fat intake prediagnsis was assciated with an increased risk f breast cancer-specific mrtality [170]. Ttal saturated fatty acid intake was significantly assciated with breast cancer risk in chrt* studies in pstmenpausal wmen, but nt premenpausal wmen [171]. Based n a seven-day diary fr evaluating saturated fat intake, a high intake f saturated fat was reprted t increase the risk f breast cancer [166]. A meta-analysis* bserved a 19% increased risk f breast cancer with greater intake f saturated fats [172]. A prspective evaluatin cncluded that high ttal and saturated fat intake was assciated with a greater risk f ER+PR+ disease, but nt ER-PR- disease. High saturated fat was significantly assciated with greater risk f HER2- disease [162]. High-fat dairy intake, a significant surce f saturated fats, was psitively assciated with breast cancer recurrence, breast cancer mrtality, and verall mrtality [169]. N assciatin was bserved between lw-fat dairy and breast cancer. 0.5 t <1.0 dairy servings/day increased breast cancer mrtality by 20%. 1.0 dairy servings/day increased breast cancer mrtality by 49%. Other studies, hwever, have nt fund a significant assciatin between saturated fats and breast cancer [ ]. Trans-Fatty Acids Preliminary research indicates that these fatty acids may be assciated with an increased risk f cancer [170, ]. Minimal research exists n the relatinship between trans-fatty acids and risk f breast cancer, thus, mre research is needed fr cnclusive evidence. Hwever, evidence pints t a psitive assciatin between these fats and breast cancer risk [178, 180]. These fats may disrupt hrmnal systems that regulate healing, lead t the destructin f defective membranes, and encurage the develpment f cancer. 15

16 One study reprted a 40% increased risk f breast cancer in pstmenpausal wmen wh had higher tissue levels f trans-fatty acids [181]. Wmen wh cnsumed greater amunts f trans-fatty acids significantly increased their risk f breast cancer [179]. Wmen in the highest quintile f trans-fatty acid cnsumptin had a 75% increased risk cmpared with wmen in the lwest quintile. Pstdiagnstic trans fat intake was assciated with 45% and 78% increased risk f all-cause mrtality [170]. Omega-9 Fatty Acids (Mnunsaturated Fats) Mst research at this time indicates a neutral relatinship [173, 179] r a slightly prtective effect [175, ] between these fats and risk f breast cancer. Several case-cntrl* studies reprted that live il cnsumptin, rich in mega-9 fats, resulted in a 13-34% reductin in breast cancer risk [ ]. One study fund that wmen wh cnsumed 8.8 g/day f live il had a 73% lwer risk f breast cancer [184]. Oleic acid, an mega-9 fatty acid fund in live il, has been bserved t synergistically enhance the efficacy f trastuzumab (Herceptin) [189, 190]. A meta-analysis*, hwever, that included three chrt* studies reprted ttal mnunsaturated fatty acids and leic acid, t significantly increase breast cancer risk [171]. That said, in a meta-analysis f 13,800 patients, it was fund that the highest categry f live il cnsumptin was assciated with lwer dds f having any type f cancer [191]. These results were further supprted by this meta-analysis shwing thse with the greatest cnsumptin f live il having a 48% lwer risk f breast cancer cmpared with the lwest intake [192]. A prspective study, hwever, fund n relatinship between live il and breast cancer risk [193]. Plyunsaturated fats have a clear stimulating influence n mammary carcingenesis, whereas extravirgin live il diets mainly have a negative mdulatry effect n breast cancer develpment [194]. Oleurpein, the main live il plyphenl, has anti-prliferative effects. It was fund that treatment f breast cancer cells with leurpein culd help in preventin f breast cancer metastasis [195]. Olive il induces apptsis in sme cancer cells due t phenlic cmpunds like leurpein [196]. Essential Fatty Acids (EFA) Essential fatty acids are necessary fr the frmatin f healthy cell membranes, the prper develpment and functining f the brain and nervus system, and fr the prductin f hrmnelike substances called eicsanids* (thrmbxanes, leuktrienes, prstaglandins). Amng ther bdy functins, these chemicals regulate immune and inflammatry respnses. Eicsanids* frmed frm the mega-6 fatty acids have the ptential t increase bld pressure, inflammatin, platelet aggregatin, allergic reactins and cell prliferatin. Thse frmed frm the mega-3 fatty acids have ppsing affects. Current research suggests that the levels f essential fatty acids and the balance between them may play a critical rle in the preventin and treatment f cancer. 16

17 Omega-3 Fatty Acids Research is grwing supprting a prtective relatinship between mega-3 fatty acids [alpha linlenic acid (ALA), eicsapentanic acid (EPA), and dcsahexanic acid (DHA)] against the risk f breast cancer [ , 173, , ]. Studies shw that mega-3 fatty acids inhibit breast cancer tumr grwth and metastasis. Additinally, these fats are immune enhancing. Mechanisms prpsed fr their prtective effects include: Suppressin f eicsanid synthesis frm arachidnic acid (mega-6 fatty acid), which impedes immune functin [198, ]. Inhibit cell grwth and differentiatin via effects n gene expressin and signal transductin pathways [198, 203]. Alter estrgen metablism, which reduces estrgen-stimulated cell grwth [198, 203, 205]. Effects n insulin* sensitivity and membrane fluidity [203]. Anti-prliferative effects in breast cancer cells [206]. Inhibit prliferatin and induce apptsis [201]. A prspective study reprted that wmen wh cnsumed 44 g r mre f dietary marine surces f mega-3 fatty acids ver a 12 mnth perid reduced their risk f breast cancer by 26% when cmpared with wmen wh cnsumed 25 g r less [173]. Wmen with the greatest EPA, DHA, and ttal mega-3 fatty acids in their red bld cell membranes frm fish had a 73%, 94%, and 89% lwer risk f breast cancer, respectively [199]. In a prspective chrt* study, wmen with a lwer intake f marine-derived mega-3 fatty acids and a higher intake f mega-6 fatty acids had a significantly higher risk fr breast cancer; the researchers suggested that the balance between mega-6 and mega-3 fats may be f greater imprtance than the amunts f specific fatty acids [207]. High intake f fatty fish (mre than g f EPA and g f DHA) was assciated with a significantly reduced risk fr breast cancer in bth pre- and pstmenpausal wmen [208]. An inverse relatinship was fund between mega-3 fatty acids in breast tissue and the risk f breast cancer [190]. When cmparing wmen in the highest tertile f ALA and DHA t the lwest tertile, cancer risk was reduced by 61% and 69%, respectively. While n verall effect was bserved between mega-3 fatty acids and risk f breast cancer, mega-3 fatty acid intake significantly decreased the risk f breast cancer in bese wmen [209]. In a multivariate analysis f Greek wmen, elevated ttal plyunsaturated fatty acids in breast adipse tissue and mega-3 in buttck adipse tissue were assciated with reduced risk f breast cancer [210]. Mderate intake f fats (saturated fatty acids, mega-3 fatty acids, and mega-6 fatty acids) frm freshwater fish may decrease the risk f breast cancer amng premenpausal wmen [211]. Interestingly, the type f fish had varying effects with black carp (>500 g/m) and silver carp (>1000 g/m) significantly reducing risk while crutian carp (>1000 g/m) increased breast cancer risk. 17

18 Preliminary research indicates that DHA may synergistically enhance taxane cyttxicity [212]. Mre research is needed, but these findings wuld indicate that DHA during taxane administratin may imprve the effects f chemtherapy fr breast cancer patients. Fish and plant-based fds, hwever, cntain different types f mega-3 fatty acids. Fish cntains EPA and DHA, tw specific fatty acids that have shwn prmising results in the research literature [188, 199, 208, ]. Fish cnsumptin in general has been assciated with a prtective effect against breast cancer [189, 197, 199, 208, 213, 215]. The plant-based mega-3 fatty acid surces, such as flaxseed and thers listed in the table belw, cntain ALA. In an ideal envirnment, ALA is cnverted t EPA and DHA, hwever, this prcess is inefficient [102, 203, 216]. On the psitive side, the cnversin prcess is enhanced by fllwing a diet that is lw in saturated fats and lw in mega-6 fatty acids [203, 217]. Research suggests that higher intake f mega-3 fatty acid is related t decreased inflammatin and decreased physical aspects f fatigue amng breast cancer survivrs [218]. Survivrs with a high CRP, a marker f systemic inflammatin, had 1.8 times greater dds f fatigue. Omega-3 fat intake suggested an inverse assciatin with all-cause mrtality [170]. Fish il may ffset negative effects f armatase inhibitrs (AI) t bne; 4 g EPA and DHA daily fr 3 mnths reduced bne resrptin in breast cancer survivrs [219]. In a randmized duble blind placeb cntrlled trial, 70% f patients wh tk an mega-3 supplement during chemtherapy did nt develp peripheral neurpathy cmpared with 40.7% in the placeb grup [220]. Omega-6 Fatty Acids Recent studies indicate that a high intake f mega-6 fatty acids (linleic acid, which can be cnverted t arachidnic acid) prmte breast tumr develpment and metastasis [167, 190, 197, ]. A meta-analysis* f 3 chrt* studies fund palmitic acid, a type f mega-6 fatty acid, t be significantly assciated with an increased risk f breast cancer [171]. Additinally, researchers reprted that arachidnic acid, an mega-6 fatty acid almst exclusively frm meat, significantly increased xidative damage as measured by urinary bimarkers [222]. It is knwn that cyclxygenase is the rate-limiting enzyme that catalyzes the cnversin f arachidnic acid t prstaglandins. Furthermre, COX-2 is knwn t be verexpressed in varius human cancers. In this breast cancer study, COX-2 verexpressin was significantly crrelated with larger tumr size and advanced clinical stage, which indicates a prer prgnsis [221]. A very interesting finding was reprted in a prspective study that fund n verall assciatin between mega-6 fatty acids and risk f breast cancer [173]. Hwever, mega-6 fat cnsumptin increased risk by 87% in wmen wh cnsumed 25 g r less f marine mega-3 fatty acids. This effect was even greater fr advanced breast cancer. Thus, the balance between mega-6 and mega-3 fatty acids may be f paramunt imprtance. This was further supprted by ther studies [190, 197, ]. In this study, higher intake f mega-6 fatty acids t mega-3 fatty acids was assciated with significantly higher CRP values and these patients were significantly mre likely t experience fatigue [218]. 18

19 Fat Bttm Line Aim fr lw t mderate fat; fcus n type and quality. Nte that all fats are equally high in calries. Limit animal fats. Avid hydrgenated fats. Fcus n extra-virgin live il, avcads, and nuts/seeds as healthy fat surces. Increase mega-3 fatty acids. Fatty Acid Dietary Surces Recmmendatin Saturated fatty acids Meats, pultry skin, baked gds, ccnut il, and whle milk dairy prducts, including butter, cheese, and ice cream Reduce r eliminate meat and whle milk dairy prducts. Trans fatty acids Omega-9 fatty acids Omega-3 fatty acids: EPA and DHA ALA Margarine, fried fds, cmmercial peanut butter, salad dressings and varius prcessed fds including breads, crackers, cereals, and ckies Extra-virgin live il, almnd il, canla il, macadamia nut il, almnds, and avcads Cld-water fish (fr example: salmn, sardines, black cd, trut, herring), and DHAenriched eggs Flaxseeds, chia seeds, walnuts, hempseeds, and pumpkin seeds Avid trans r hydrgenated fats. Prducts may be labeled trans fat free if they cntain less than 0.5 mg per serving. Include these healthy fats daily. Limit cnsumptin f nuts t n mre than ¼ cup with meal r snack t limit ttal fat and calries. Include these healthy fats daily thrugh diet and/r supplements. It may be wise t cnsume cld water fish r fish il supplements at least twice weekly t btain an adequate amunt f EPA and DHA. Omega-6 fatty acids: Arachidnic acid Linleic acid Meats, butter, egg ylks, whle milk, and whle milk dairy prducts Cmmn vegetable ils, such as crn il, safflwer il, sunflwer il, and cttnseed il, and prcessed fds made with these ils 19 If yu chse t use a supplement, pt fr ne that is highest in EPA and DHA cncentratin. Reduce r eliminate meat and whle milk dairy prducts. Limit cnsumptin f linleic acid-rich ils. Substitute an mega-9 fatty acid-rich il fr yur current cking il r fat.

20 Meat Animal fat [26, 161, 225] and meat appear t increase the risk f breast cancer in recent studies [16, 168]. Cnversely, plant fat has been negatively assciated with breast cancer [225]. In a study f ver 35,000 wmen, meat cnsumptin significantly increased the risk f breast cancer in bth premenpausal and pstmenpausal wmen [226]. Wmen eating 1.75 z f prcessed meat daily increased the risk f breast cancer by 64% in pstmenpausal wmen cmpared t wmen wh did nt eat meat. Cnsumptin f red and fried meat quadrupled the risk f breast cancer in a case-cntrl study in Brazil [14]. Meat cnsumptin increased the risk f breast cancer risk by 56% fr each additinal 100 g (3.5 z) daily f meat cnsumptin in a French case-cntrl study [190]. Regular cnsumptin f fatty red meat and prk fat increased the risk f breast cancer by 348% and 632%, respectively in a small Brazilian study [227]. A large case-cntrl* study fund that wmen wh cnsumed very well-dne meat fr hamburger, bacn, r steak had a 54%, 64%, and 221% increased risk fr breast cancer, respectively [228]. Frequent cnsumers f these well-dne meats had a 462% greater risk f breast cancer. High intake f red meat is assciated with a significantly higher breast cancer risk, especially fr well-dne red meat [229]. This is slightly strnger fr pstmenpausal wmen than premenpausal wmen. Fd Categry Summary Recmmendatin Fruits and vegetables One serving = ½ cup fruit r vegetable 1 cup raw leafy greens ¼ cup dried fruit r vegetable 6 z fruit r vegetable juice At least 5, preferably 8-10 ttal servings daily [230] 5 r mre vegetable servings 3 fruit servings Fiber Eat 1 cup r mre vegetables with lunch and dinner. Chse breads with 3 r mre grams f fiber per slice. First ingredient n the label shuld be whle r spruted grain flur, nt white flur, unbleached white flur, r enriched wheat flur. Whle grains include ats, barley, brwn rice, quina, amaranth, bulgur, millet, buckwheat, spelt, wild rice, whle wheat, and teff grams daily This gal can be achieved by meeting yur fruit and vegetable gal plus ne serving f chia/ flax seeds r ne serving f legumes r at least tw servings f whle grains. 20

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