Crcinogenesis, 2015, Vol. 36, No. 2, 243 248 doi:10.1093/crcin/bgu247 Advnce Access publiction December 18, 2014 Originl Mnuscript originl mnuscript Prognostic significnce of pretretment serum levels of lbumin, LDH nd totl bilirubin in ptients with nonmetsttic brest cncer Xion Liu 1,2, Qing H.Meng 3, Yunqing Ye 1, Michelle A.T. Hildebrndt 1, Jin Gu 1 nd Xifeng Wu 1, * 1 Deprtment of Epidemiology, The University of Texs MD Anderson Cncer Center, Houston, TX 77030, USA, 2 Deprtment of Brest Surgery, The First Affilited Hospitl with Nnjing Medicl University, Nnjing 210029, Chin nd 3 Deprtment of Lbortory Medicine, The University of Texs MD Anderson Cncer Center, Houston, TX 77030, USA *To whom correspondence should be ddressed. Tel: 713 745 2485; Fx: 713 792 2145; Emil: xwu@mdnderson.org Abstrct Liver function tests (LFTs) hve been reported s independent predictors of non-liver disese-relted morbidity nd mortlity in generl popultion nd cncer ptients. In this study, we evluted the reltionship between pretretment serum LFTs nd overll survivl (OS) in non-metsttic Cucsin brest cncer ptients. Seven LFTs, including lbumin, lnine minotrnsferse, sprtte minotrnsferse, lkline phosphtse, lctte dehydrogense (LDH), totl bilirubin nd totl protein, were mesured in pretretment serum from 2425 femle Cucsin ptients with newly dignosed, histologiclly confirmed non-metsttic invsive brest cncer. Multivrite Cox model ws used to estimte hzrd rtio (HR) nd 95% confidence intervl (CI) for the ssocition of individul LFTs with 5-yer OS while djusting for ge, smoking sttus, pthologicl chrcteristics nd tretment regimen. We found tht serum lbumin, LDH nd totl bilirubin were significntly ssocited with 5-yer OS in multivrite Cox nlyses. Ptients with higher lbumin level exhibited 45% reduced risk of deth (HR = 0.55, 95% CI: 0.40 0.75) compred with those with lower lbumin level. Ptients with higher totl bilirubin level hd nerly 40% reduction in the risk of deth (HR = 0.62, 95% CI: 0.45 0.85) nd ptients with higher LDH levels hd 1.42-fold incresed risk of deth (HR = 1.42, 95% CI: 1.08 1.88). Furthermore, cumultive nlysis showed significnt dose response trend of significntly incresing risk of deth with incresing number of unfvorble LFT levels. Our result highlighted the potentil of using pretretment serum levels of lbumin, LDH nd totl bilirubin s prognostic fctors for OS in ptients with non-metsttic brest cncer. Introduction Brest cncer is the most frequently occurring cncer in women worldwide. The 5-yer overll survivl (OS) for non-metsttic stge brest cncer ptients rnged from 72 to 100%; however, the 5-yer survivl for stge IV ptients ws disml 22%. Most ptients with non-metsttic brest cncer will receive locoregionl tretment, i.e. surgery with djuvnt rdiotherpy on indiction, nd djuvnt systemic therpy which my consist of chemotherpy, endocrine therpy, trget therpy or combintion of these tretments (1), wheres the primry tretment for metsttic brest cncer is systemic therpy. Modern brest cncer tretment cn be tilored to individul tumor chrcteristics, therefore, being ble to predict ptients prognosis will hve tremendous clinicl benefits by identifying most optionl therpeutic options for certin subgroups of ptients. Trditionl prognostic vribles, including tumor size, grde nd lymph node sttus, hve been integrted into the tumor, node nd metstsis stging system nd Nottinghm prognostic index (2,3). Recently, severl tumor-bsed moleculr mrkers, such s the expression of estrogen receptor lph, progesterone receptor nd humn epiderml growth fctor receptor-2, hve been strongly ssocited with OS (4). Furthermore, tumor-bsed gene expression profiling provided gret promise in predicting Received: September 19, 2014; Revised: November 26, 2014; Accepted: December 15, 2014 The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, plese emil: journls.permissions@oup.com. 243
244 Crcinogenesis, 2015, Vol. 36, No. 2 Abbrevitions CI HR LDH LFT OS confidence intervl hzrd rtio lctte dehydrogense liver function test overll survivl. brest cncer outcome (5,6). For exmple, the PAM50 gene signture ws pproved by the U.S. Food nd Drug Administrtion to ssess ptient s risk of distnt recurrence in postmenopusl women with node negtive (stge I or II) or node positive (stge II), hormone receptor-positive brest cncer. However, the discrimintory ccurcy with the ddition of PAM50 to the clinicl vribles ws still moderte with concordnce index of 0.78 (7). There is n urgent need to identify dditionl biomrkers which could improve the prediction of ptient s prognosis. Since blood re esily ccessible nd minimlly invsive, the identifiction of blood-bsed biomrkers re ppeling nd pose the gret potentil to enble ccurte prediction of individul s clinicl outcome nd clssify ptients into differentil prognostic subgroups. Liver function tests (LFTs), group of blood tests, usully consist of bilirubin, lbumin, totl protein, lnine minotrnsferse, sprtte minotrnsferse, gmm-glutmyltrnsferse, lkline phosphtse nd lctte dehydrogense (LDH). These tests re frequently included s bseline tests for mny different clinicl presenttions nd often obtined t initil consulttion since they re ssocited with mny spect of liver function including cellulr integrity, functionlity nd conditions relted to biliry trct. There is incresing interest for using LFT vribles s independent predictors of non-liver disese-relted morbidity nd mortlity in generl popultion nd cncer ptients (8,9). A few studies hve investigted the ssocitions of LFTs with mortlity in brest cncer (10 13). In this study, we collected dt from the lrge brest cncer ptient popultion t the University of Texs MD Anderson Cncer Center nd investigted the ssocition of selected pretretment LFTs with mortlity in non-metsttic brest cncer ptients. To our knowledge, this is the first study to ssess pnel of LFTs in lrge non-metsttic brest cncer ptient popultion. Mterils nd methods Ptient popultion nd dt collection This study included 2425 femle Cucsin ptients with newly dignosed, histologiclly confirmed, non-metsttic invsive brest cncer (stge I III). All ptients were recruited t the University of Texs MD Anderson Cncer Center. All ptients signed n informed consent before tking prt in the study. There were no other recruitment restrictions on ge, pthologicl fetures nd tretments. Informtion on ethnicity, smoking history nd fmily history of brest cncer ws ssessed by selfdministered questionnires. Clinicl nd pthologicl dt, tretment regimen nd follow-up informtion were bstrcted from medicl chrts. Albumin, lkline phosphtse, sprtte minotrnsferse, lnine minotrnsferse, totl bilirubin, LDH nd totl protein were mesured s prt of stndrd pnel of tests evluting ptients overll condition before tretment t the bseline visit. These tests were performed within 30 dys fter the dignosis nd before ny tretment by the Deprtment of Lbortory Medicine t MD Anderson Cncer Center. The study ws pproved by the MD Anderson Cncer Center Institutionl Review Bord. Sttisticl nlysis The endpoint of this study ws OS, which ws defined from the dte of dignosis to the dte of deth or the ltest follow-up. In this study, we presented the results for the 5-yer OS. STATA softwre, version 10 (SttCorp, College Sttion, TX) ws used for sttisticl nlyses. Chi-squre test or Fisher s exct test ws used to nlyze the differences in ptients host chrcteristics. Ptient ge ws ctegorized into <50 nd 50 yers of ge. Tumor size ws ctegorized into 1 cm, <1 cm to 2 cm, >2 cm to 3 cm, >3 cm to 4 cm, >4 cm to 5 cm nd >5 cm. Axillry lymph node positivity ws ctegorized into 0, 1 or 2, 3 or 4, 5 8, 9 19 nd 20. Nucler grde ws ctegorized into grde I, II nd III. Smoking sttus ws ctegorized into never, former nd current. Other strtified fctors, including first-degree reltive brest cncer history, lymph vessels invsion nd tretment regimens, were divided into two ctegories (yes versus no).the LFTs were dichotomized using cut-off points derived from spline modeling procedure which identified the optiml ctegoriztion through minimizing the distnce between estimted nd observed outcome vlues mong subjects in the sme ctegory s described in detil by O Brien (14), since over 90% of mrker levels were within norml rnge. The ssocition of the three significnt mrkers, lbumin, LDH nd totl bilirubin, were non-liner s illustrted by the spline curves shown in Supplementry Figure 1, vilble t Crcinogenesis Online. Multivrite Cox proportionl hzrds model ws used to ssess the effect of ech LFT vrible on 5-yer OS. Hzrd rtios (HRs) nd 95% confidence intervls (CIs) were estimted by fitting the multivrite Cox model while djusting for ge, smoking sttus, pthologicl fetures, first-degree reltive brest cncer history nd tretment regimens. Kpln Meier survivl nlysis nd log-rnk tests were used to ssess the differences in OS by individul LFTs. The cumultive effects of multiple unfvorble LFT levels were evluted for the three tests tht showed sttisticl significnce in the min nlysis. For ll nlyses, P vlue of <0.05 ws considered sttisticlly significnt. Results Ptient chrcteristics This study included 2425 femle Cucsin ptients with non-metsttic invsive brest cncer. The medin ge of ll ptients ws 54 yers (rnge: 22 98). There were 1030 ptients hving stge I tumor (42.47%), 1011 (41.69%) nd 384 ptients (15.84%) hving stge II nd III tumor, respectively. A totl of 1,281 ptients hd negtive xillry lymph nodes (52.82%), nd 644 hving lymph vessel invsion (26.56%). Estrogen receptor sttus included positivity (n = 1872, 77.20%), negtivity (n = 538, 22.19%) or unknown (n = 15, 0.62%). About 64.6% (n = 1566) of ll ptients were positive for progesterone receptor sttus, 34.64% (n = 840) negtive nd 0.78% (n = 19) unknown. As for Her2 sttus, 81.20% (n = 1969) ws negtive, 14.93% (n = 362) positive nd 3.88% (n = 94) unknown. The mjority of ptients hd djuvnt hormone therpy (n = 1709, 70.47%), nd 653 hd neodjuvnt chemotherpy (26.93%). Totlly, 1159 ptients (47.79%) received djuvnt chemotherpy (Tble 1). Assocition of pretretment LFT with OS We nlyzed the ssocition of the seven routine pretretment serum LFTs with 5-yer OS. Three LFTs including lbumin, LDH nd totl bilirubin were significntly ssocited with 5-yer OS in multivrite Cox nlyses, djusting for ge, smoking sttus, pthologicl chrcteristics, first-degree reltive brest cncer history nd tretment regimens (Tble 2, Figure 1). Ptient with higher lbumin level (>3.9 g/dl) were t 45% reduced risk of deth (HR = 0.55, 95% CI: 0.40 0.75, P = 0.0002) compred with those with lower lbumin level ( 3.9 g/dl). For bilirubin, ptients with totl bilirubin level >0.2 mg/dl hd better 5-yer OS nd their risks of deth reduced nerly 40% compred with tht of ptients with totl bilirubin level 0.2 mg/dl (HR = 0.62, 95% CI: 0.45 0.85, P = 0.003). The lbumin nd bilirubin remined significnt t P < 0.007 (= 0.05/7) fter the Bonferroni correction for multiple comprisons. Ptients with higher LDH levels (>469 U/l) hd 1.42-fold incresed risk of deth compred with ptients with lower LDH levels ( 469 U/l) (HR = 1.42, 95% CI: 1.08 1.88,
X.Liu et l. 245 Tble 1. Host chrcteristics of brest cncer ptients Vribles Clss Ded N (%) Alive N (%) P vlue Age, medin (rnge) 54 (22 98) Smoking sttus Never 124 (8.95%) 1262 (91.05%) Former 51 (6.68%) 712 (93.32%) Current 37 (13.41%) 239 (86.59%) 0.003 First-degree reltive brest cncer history N 190 (9.55%) 1799 (90.45%) Y 22 (5.05%) 414 (94.95%) 0.002 TNM stge I 37 (3.59%) 993 (96.41%) II 87 (8.61%) 924 (91.39%) III 88 (22.92%) 296 (77.08%) <0.001 Nucler grde I 6 (3.26%) 178 (96.74%) II 50 (4.58%) 1042 (95.42%) III 156 (13.58%) 993 (86.42%) <0.001 Tumor size 0 1 cm 41 (6.56%) 584 (93.44%) 1 2 cm 48 (5.13%) 888 (94.87%) 2 3 cm 39 (9.26%) 382 (90.74%) 3 4 cm 26 (14.69%) 151 (85.31%) 4 5 cm 16 (16.49%) 81 (83.51%) 5+ cm 42 (24.85%) 127 (75.15%) <0.001 Node positivity 0 64 (5.00%) 1217 (95.00%) 1 or 2 47 (7.83%) 553 (92.17%) 3 or 4 21 (9.59%) 198 (90.41%) 5 8 33 (20.89%) 125 (79.11%) 9 19 29 (23.02%) 97 (76.98%) 20 18 (43.90%) 23 (56.10%) <0.001 Lymph vessels invsion N 109 (6.12%) 1672 (93.88%) Y 103 (15.99%) 541 (84.01%) <0.001 Neodjuvnt chemotherpy N 92 (5.19%) 1680 (94.81%) Y 120 (18.38%) 533 (81.62%) <0.001 Adjuvnt chemotherpy N 145 (11.45%) 1121 (88.55%) Y 67 (5.78%) 1092 (94.22%) <0.001 Adjuvnt hormone therpy N 111 (15.50%) 605 (84.50%) Y 101 (5.91%) 1608 (94.09%) <0.001 TNM, tumor, node nd metstsis. P vlue for the differences in ptients host chrcteristics between ded nd live. P = 0.01). In subgroup nlysis strtified by stge, we found tht lbumin levels were ssocited with OS regrdless of stges. LDH ppered to only influence OS in stge II nd III ptients. The ssocition of bilirubin with OS ppered to the strongest in stge I ptients (Tble 3). In subgroup nlysis strtified by moleculr subtypes, we observed similr estimted HRs for lbumin nd totl bilirubin while the estimtes for LDH were more evident in HR-positive nd humn epiderml growth fctor receptor-2-enriched subgroups. Cumultive effects of unfvorble LFT levels We then conducted joint nlysis to test whether ptients with more unfvorble pretretment LFT levels hd worse OS compred with those with fewer unfvorble LFT levels (Tble 4, Figure 2) Compred with ptient without ny unfvorble LFT level, ptients with 1, 2 nd 3 unfvorble LFT levels exhibited progressively incresed risks of deth with HRs of 1.39 (95% CI: 1.00 1.94), 2.56 (95% CI: 1.72 3.79), nd 3.34 (95% CI: 1.61 6.93), respectively. The 5-yer OS rtes were 94.11, 91.30, 83.96 nd 72.73% for ptients with 0, 1, 2 nd 3 unfvorble LFT levels, respectively (log-rnk P < 0.0001). Discussion In this study, we demonstrted tht pretretment serum lbumin, totl bilirubin nd LDH levels were ssocited with 5-yer OS in ptients with non-metsttic invsive brest cncer, nd the results remined significnt for lbumin, LDH nd bilirubin fter djusting for multiple comprisons using the stringent Bonferroni method, wheres lkline phosphtse, sprtte minotrnsferse, lnine minotrnsferse or totl protein levels were not ssocited with OS. Furthermore, there ws cumultive effect of those three unfvorble mrkers (lower lbumin level, higher LDH level nd lower totl bilirubin level) on ptients survivl. To illustrte the improvement of the three mrkers on the prediction of brest cncer survivl, we clculted re under the time-dependent receiver operting chrcteristic curves (AUC) for censored survivl dt using two models. The clinicl model included the trditionl prognostic fctors (ge, nucler grde, tumor size, number of positive lymph nodes, detection mode, lymphom or vsculr invsion), wheres the clinicl + mrker model included the three mrkers in ddition to the clinicl vribles described bove. The AUC incresed from 0.748 for the clinicl model to 0.766 for the clinicl + mrker model. Serum lbumin is one of the mostly commonly used mrkers for ssessing ptients nutritionl sttus. Albumin is produced by the liver nd is the mjor protein in blood, cting s key ntioxidnt, detoxifier nd trnsporter of importnt nutrients. In dvnced cncer ptients, the levels of serum lbumin fll shrply, becuse mlnutrition nd systemtic inflmmtory response to tumors both suppress lbumin synthesis (15). The prevlence of mlnutrition mong brest cncer ptients
246 Crcinogenesis, 2015, Vol. 36, No. 2 Tble 2. Assocition of biomrker levels with 5-yer OS Lb test Ded (N) Alive (N) Adjusted HR (95% CI) P vlue Albumin (g/dl) 3.9 56 363 1 (reference) >3.9 156 1850 0.55 (0.40 0.75) 0.0002 ALP (IU/l) 79 108 1296 1 (reference) >79 104 913 1.25 (0.95 1.65) 0.11 ALT (IU/l) 19 120 1075 1 (reference) >19 92 1138 0.79 (0.59 1.04) 0.09 AST (IU/l) 37 121 1377 1 (reference) >37 28 222 1.40 (0.91 2.15) 0.12 LDH (IU/l) 469 100 1319 1 (reference) >469 112 894 1.42 (1.08 1.88) 0.01 Totl bilirubin (mg/dl) 0.2 51 330 1 (reference) >0.2 159 1868 0.62 (0.45 0.85) 0.003 Totl protein (g/dl) 6.9 15 180 1 (reference) >6.9 118 1152 1.02 (0.57 1.81) 0.96 ALP, lkline phosphtse; ALT, lnine minotrnsferse; AST, sprtte minotrnsferse. Adjusted for ge, smoking sttus, first-degree reltive brest cncer history, pthologicl chrcteristics nd tretment. reported by two French studies ws 20.5% (16) nd 18.3% (17), respectively. A Koren study lso showed over 51% of femle brest cncer ptients hd moderte to high risk of mlnutrition (18). Mlnutrition cn cuse mny clinicl consequences, including decresed life qulity, reduced tretment response nd incresed tretment-relted toxicity. Serum lbumin hs been used to ssess severity of disese, disese progression nd prognosis. Numerous studies hve evluted the ssocition of serum lbumin levels with the survivl of cncer ptients nd the results re firly consistent: lower serum lbumin levels re n independent indictor of worse survivl of vrious cncers (8). Severl studies with reltively smll smple sizes hve consistently reported the prognostic vlue of serum lbumin in brest cncer ptients. Heys et l. (12) reported tht pretretment serum lbumin, lymph node involvement nd dvnced stge were independent prognostic fctors of worse survivl using 77 lrge nd loclly dvnced brest cncer ptients treted with neodjuvnt chemotherpy. In nother study of 180 consecutively treted brest cncer ptients, Lis et l. (13) found tht norml levels of bseline serum lbumin levels reduced the risk of deth by 72% compred with low levels. Only tumor stge hd lrger impct on survivl thn serum lbumin levels. In the third study of 145 ptients with heptic metstses from brest cncer, Wyld et l. (11) identified low lbumin, dvnced ge nd estrogen receptor negtivity s independent predictors of poor survivl. To our knowledge, this current study is the lrgest study to evlute pretretment serum lbumin levels in brest cncer ptients nd is the only study tht hs sufficient smple size to exclusively focus on erly stge ptients. Our results re consistent with previous finding for other cncer sites (19 22) nd provide the strongest evidence tht lower serum lbumin level ws prognostic fctor for poor survivl in erly stge brest cncer ptients regrdless of stges. LDH is key enzyme in the conversion of pyruvte to lctte during nerobic conditions. LDH is ssocited with metbolic Figure 1. The Kpln Meier curves showing 5-yer OS mong brest cncer ptients ccording to pretretment lbumin levels (A), LDH levels (B) nd totl bilirubin levels (C). ctivities, inflmmtion, tissue injury nd neoplsms. Hypoxi in tumor microenvironment leds to high LDH levels. Mny studies hve shown tht LDH level could be used to estimte tumor bulk nd ctivity nd predict tretment response nd prognosis. High serum LDH levels hve been reported to be prognostic mrker for poor survivl in severl different cncer types (23 27). Few studies with reltively smll smple sizes nd focusing on metsttic brest cncer ptients hve ssessed the prognostic role of serum LDH level. Ymmoto et l. (28) found tht n elevtion of serum LDH significntly contributed to poorer survivl mong metsttic brest cncer ptients in Jpn. A recent study reported tht serum LDH level correlte strongly with survivl in ptients with bone metstsis from brest cncer (10). Our study showed tht higher levels of LDH predicted worse 5-yer OS in non-metsttic brest cncer ptients which ws consistent with previous reports. Furthermore, it ppered tht the prognostic effect of LDH ws only evident in stge II nd III ptients, but not in stge I ptients. It is likely tht higher LDH levels indicte high tumor ctivities nd occult metstsis, which my not be evident in stge I tumors. It is lso possible tht stge I brest cncer ptients hd excellent survivl, nd the 5-yer follow-up is not long enough to see the OS difference in stge I ptients.
X.Liu et l. 247 Tble 3. Assocition of biomrker levels with 5-yer OS strtified by stge nd moleculr subtypes Stge I Stge II Stge III Lb test Ded (N) Alive (N) HR (95% CI) Ded (N) Alive (N) HR (95% CI) Ded (N) Alive (N) HR (95% CI) Albumin (g/dl) 3.9 8 153 26 167 22 43 >3.9 29 840 0.62 (0.28 1.38) 61 757 0.60 (0.37 0.96) 66 253 0.46 (0.27 0.80) LDH (IU/l) 469 22 597 39 547 39 175 >469 15 396 0.98 (0.50 1.92) 48 377 1.44 (0.91 2.26) 49 121 1.59 (1.02 2.50) Totl bilirubin (mg/dl) 0.2 12 113 19 171 20 46 >0.2 25 871 0.25 (0.12 0.51) 67 749 1.02 (0.60 1.74) 67 248 0.51 (0.30 0.88) HR positive HER2 enriched Triple negtive Lb test Ded (N) Alive (N) HR (95% CI) Ded (N) Alive (N) HR (95% CI) Ded (N) Alive (N) HR (95% CI) Albumin (g/dl) 3.9 28 242 11 61 16 44 >3.9 78 1280 0.54 (0.34 0.86) 26 264 0.58 (0.27 1.29) 51 228 0.68 (0.35 1.33) LDH (IU/l) 469 50 930 16 188 33 151 >469 56 592 1.66 (1.11 2.47) 21 137 2.00 (0.97 4.11) 34 121 0.89 (0.51 1.54) Totl bilirubin (mg/dl) 0.2 25 228 7 58 19 37 >0.2 79 1282 0.65 (0.41 1.03) 30 265 0.84 (0.32 2.22) 48 234 0.51 (0.28 0.93) HR positive: ER+ or PR+, HER2 ; HER2 enriched: HER2+, regrdless of ER nd PR; Triple negtive: ER, PR, HER2. ER, estrogen receptor; HER2, humn epiderml growth fctor receptor-2; PR, progesterone receptor. Adjusted for ge, smoking sttus, first-degree reltive brest cncer history, pthologicl chrcteristics nd tretment. Tble 4. Cumultive effect of unfvorble LFT levels ssocited with 5-yer OS Number of dverse tests Ded (N) Alive (N) Adjusted HR (95% CI) P 0 57 910 1 (reference) 1 97 1018 1.39 (1.00 1.94) 0.0535 2 47 246 2.56 (1.72 3.79) <0.0001 3 9 24 3.34 (1.61 6.93) 0.0012 Adjusted for ge, smoking sttus, first-degree reltive brest cncer history, pthologicl chrcteristics nd tretment. Oxidtive stress contributes to crcinogenesis. Bilirubin is potent ntioxidnt nd hs been shown to protect ginst cncer development. Lower serum bilirubin level hs been linked to incresed risk of crdiovsculr diseses nd cncer (29,30). The reltionship of serum bilirubin level with survivl hs been evluted in metsttic brest cncer ptients (11,31), nd the results showed tht hyperbilirubinemi ws ssocited with worse survivl. However, our study reveled tht non-metsttic brest cncer ptients with higher totl bilirubin levels hd better OS compred with those with lower bilirubin levels. This discrepncy my be due to the differences in ptient popultion. The bove two mentioned studies focused on hevily pretreted dvnced brest cncer ptients or brest cncer ptients with liver metstsis. Therefore, serum bilirubin level my hve different predictive effect in metsttic nd non-metsttic brest cncer ptients. Serum biomrkers re promising clinicl prognostic fctors in cncer ptients. However, single biomrker my not hve sufficient predictive power for clinicl ppliction. The combintion of Figure 2. Kpln Meier cumultive survivl plots for 5-yer OS ccording to unfvorble mrker score. multiple biomrkers through the cumultive nlysis cn improve the predictive power (19,32), s evidenced by previous ttempts of clculting prognostic scores (33). In our study, we found the ptients with the most unfvorble LFT levels hd worst 5-yer OS (5-yer OS rtes for ptients without unfvorble LFT versus ptients with three unfvorble LFTs: 94.11 versus 72.73%), supporting the potentil of combining multiple prognostic fctors. The mjor strength of this study is the lrge smple size of non-metsttic brest cncer ptients who received tretment t single institution. The follow-up time ws reltively long. Our study provides strong evidence supporting tht pretretment serum levels of lbumin, LDH nd bilirubin re prognostic fctors for OS in non-metsttic brest cncer. These results
248 Crcinogenesis, 2015, Vol. 36, No. 2 suggest tht evlution of these three biomrkers my be useful for predicting prognosis in non-metsttic brest cncer. This study hs couple of limittions. Our study focused on Cucsin ptients; therefore, dditionl studies re needed before it cn be generlized to other ethnic groups. In ddition, vlidtion of our findings in n independent popultion is wrrnted. In conclusion, our study ws bsed on the lrge ptient cohort of 2425 non-metsttic brest cncer ptients. These results suggest tht evlution of serum lbumin, bilirubin nd LDH my be useful for predicting prognosis in non-metsttic brest cncer. Supplementry mteril Supplementry Figure 1 cn be found t http://crcin.oxfordjournls.org/ Funding The University of Texs MD Anderson Cncer Center support for the Center for Trnsltionl nd Public Helth Genomics. Conflict of Interest Sttement: None declred. References 1. Erly Brest Cncer Trilists Collbortive Group. 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