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Associations Between Pro- and Anti-Inflammatory Cytokine Genes and Breast Pain in Women Prior to Breast Cancer Surgery

      Abstract

      The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain.

      Perspective

      In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain.

      Key words

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      References

        • Andersen K.G.
        • Kehlet H.
        Persistent pain after breast cancer treatment: A critical review of risk factors and strategies for prevention.
        J Pain. 2011; 12: 725-746
        • Barkhordari E.
        • Rezaei N.
        • Ansaripour B.
        • Larki P.
        • Alighardashi M.
        • Ahmadi-Ashtiani H.R.
        • Mahmoudi M.
        • Keramati M.R.
        • Habibollahi P.
        • Bashashati M.
        • Ebrahimi-Daryani N.
        • Amirzargar A.A.
        Proinflammatory cytokine gene polymorphisms in irritable bowel syndrome.
        J Clin Immunol. 2010; 30: 74-79
        • Baron R.H.
        • Fey J.V.
        • Borgen P.I.
        • Van Zee K.J.
        Eighteen sensations after breast cancer surgery: A two-year comparison of sentinel lymph node biopsy and axillary lymph node dissection.
        Oncol Nurs Forum. 2004; 31: 691-698
        • Bessler H.
        • Shavit Y.
        • Mayburd E.
        • Smirnov G.
        • Beilin B.
        Postoperative pain, morphine consumption, and genetic polymorphism of IL-1beta and IL-1 receptor antagonist.
        Neurosci Lett. 2006; 404: 154-158
        • Brunner F.
        • Bachmann L.M.
        • Weber U.
        • Kessels A.G.
        • Perez R.S.
        • Marinus J.
        • Kissling R.
        Complex regional pain syndrome 1–the Swiss cohort study.
        BMC Musculoskelet Disord. 2008; 9: 92
        • Campbell C.M.
        • Edwards R.R.
        • Fillingim R.B.
        Ethnic differences in responses to multiple experimental pain stimuli.
        Pain. 2005; 113: 20-26
        • Campbell C.M.
        • France C.R.
        • Robinson M.E.
        • Logan H.L.
        • Geffken G.R.
        • Fillingim R.B.
        Ethnic differences in diffuse noxious inhibitory controls.
        J Pain. 2008; 9: 759-766
        • Campbell C.M.
        • France C.R.
        • Robinson M.E.
        • Logan H.L.
        • Geffken G.R.
        • Fillingim R.B.
        Ethnic differences in the nociceptive flexion reflex (NFR).
        Pain. 2008; 134: 91-96
        • Chen R.H.
        • Chang C.T.
        • Chen W.C.
        • Tsai C.H.
        • Tsai F.J.
        Proinflammatory cytokine gene polymorphisms among Hashimoto’s thyroiditis patients.
        J Clin Lab Anal. 2006; 20: 260-265
        • Cheng K.K.
        • Lee D.T.
        Effects of pain, fatigue, insomnia, and mood disturbance on functional status and quality of life of elderly patients with cancer.
        Crit Rev Oncol Hematol. 2011; 78: 127-137
        • Cieza A.
        • Geyh S.
        • Chatterji S.
        • Kostanjsek N.
        • Ustun B.T.
        • Stucki G.
        Identification of candidate categories of the International Classification of Functioning Disability and Health (ICF) for a Generic ICF Core Set based on regression modelling.
        BMC Med Res Methodol. 2006; 6: 36
        • Cleeland C.S.
        • Gonin R.
        • Baez L.
        • Loehrer P.
        • Pandya K.J.
        Pain and treatment of pain in minority patients with cancer. The Eastern Cooperative Oncology Group Minority Outpatient Pain Study.
        Ann Intern Med. 1997; 127: 813-816
        • Conde L.
        • Vaquerizas J.M.
        • Dopazo H.
        • Arbiza L.
        • Reumers J.
        • Rousseau F.
        • Schymkowitz J.
        • Dopazo J.
        PupaSuite: Finding functional single nucleotide polymorphisms for large-scale genotyping purposes.
        Nucleic Acids Res. 2006; 34: W621-W625
        • Corry D.C.
        Pain in carcinoma of the breast.
        Lancet. 1952; 1: 274-276
        • Daut R.L.
        • Cleeland C.S.
        • Flanery R.C.
        Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases.
        Pain. 1983; 17: 197-210
        • Day M.A.
        • Thorn B.E.
        The relationship of demographic and psychosocial variables to pain-related outcomes in a rural chronic pain population.
        Pain. 2010; 151: 467-474
        • Edwards R.R.
        • Moric M.
        • Husfeldt B.
        • Buvanendran A.
        • Ivankovich O.
        Ethnic similarities and differences in the chronic pain experience: A comparison of African American, Hispanic, and white patients.
        Pain Med. 2005; 6: 88-98
        • Eisenberg E.
        • Pud D.
        • Koltun L.
        • Loven D.
        Effect of early administration of the N-methyl-d-aspartate receptor antagonist amantadine on the development of postmastectomy pain syndrome: A prospective pilot study.
        J Pain. 2007; 8: 223-229
        • Fillingim R.B.
        • Edwards R.R.
        The association of hormone replacement therapy with experimental pain responses in postmenopausal women.
        Pain. 2001; 92: 229-234
        • Gabriel S.B.
        • Schaffner S.F.
        • Nguyen H.
        • Moore J.M.
        • Roy J.
        • Blumenstiel B.
        • Higgins J.
        • DeFelice M.
        • Lochner A.
        • Faggart M.
        • Liu-Cordero S.N.
        • Rotimi C.
        • Adeyemo A.
        • Cooper R.
        • Ward R.
        • Lander E.S.
        • Daly M.J.
        • Altshuler D.
        The structure of haplotype blocks in the human genome.
        Science. 2002; 296: 2225-2229
        • Galer B.S.
        • Jensen M.P.
        Development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale.
        Neurology. 1997; 48: 332-338
        • Gan X.L.
        • Lin Y.H.
        • Zhang Y.
        • Yu T.H.
        • Hu L.N.
        Association of an interleukin-16 gene polymorphism with the risk and pain phenotype of endometriosis.
        DNA Cell Biol. 2010; 29: 663-667
        • Gartner R.
        • Jensen M.B.
        • Nielsen J.
        • Ewertz M.
        • Kroman N.
        • Kehlet H.
        Prevalence of and factors associated with persistent pain following breast cancer surgery.
        JAMA. 2009; 302: 1985-1992
        • Grivennikov S.I.
        • Karin M.
        Inflammatory cytokines in cancer: Tumour necrosis factor and interleukin 6 take the stage.
        Ann Rheum Dis. 2011; 70: i104-i108
        • Halder I.
        • Shriver M.
        • Thomas M.
        • Fernandez J.R.
        • Frudakis T.
        A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: Utility and applications.
        Hum Mutat. 2008; 29: 648-658
        • Hanahan D.
        • Weinberg R.A.
        Hallmarks of cancer: The next generation.
        Cell. 2011; 144: 646-674
        • Hickey O.T.
        • Burke S.M.
        • Hafeez P.
        • Mudrakouski A.L.
        • Hayes I.D.
        • Shorten G.D.
        Severity of acute pain after breast surgery is associated with the likelihood of subsequently developing persistent pain.
        Clin J Pain. 2010; 26: 556-560
        • Hoggart C.J.
        • Parra E.J.
        • Shriver M.D.
        • Bonilla C.
        • Kittles R.A.
        • Clayton D.G.
        • McKeigue P.M.
        Control of confounding of genetic associations in stratified populations.
        Am J Hum Genet. 2003; 72: 1492-1504
        • Iida A.
        • Saito S.
        • Sekine A.
        • Mishima C.
        • Kitamura Y.
        • Kondo K.
        • Harigae S.
        • Osawa S.
        • Nakamura Y.
        Catalog of 668 SNPs detected among 31 genes encoding potential drug targets on the cell surface.
        J Hum Genet. 2003; 48: 23-46
        • Janz N.K.
        • Mujahid M.
        • Chung L.K.
        • Lantz P.M.
        • Hawley S.T.
        • Morrow M.
        • Schwartz K.
        • Katz S.J.
        Symptom experience and quality of life of women following breast cancer treatment.
        J Womens Health. 2007; 16: 1348-1361
        • Jensen M.P.
        The validity and reliability of pain measures in adults with cancer.
        J Pain. 2003; 4: 2-21
        • Jensen M.P.
        • Gammaitoni A.R.
        • Olaleye D.O.
        • Oleka N.
        • Nalamachu S.R.
        • Galer B.S.
        The pain quality assessment scale: Assessment of pain quality in carpal tunnel syndrome.
        J Pain. 2006; 7: 823-832
        • Karam M.C.
        • Al-Kouba J.E.
        • Bazzi S.I.
        • Smith C.B.
        • Leung L.
        Interleukin-13 reduces hyperalgesia and the level of interleukin-1beta in BALB/c mice infected with Leishmania major with an up-regulation of interleukin-6.
        J Neuroimmunol. 2011; 234: 49-54
        • Karnofsky D.
        Performance scale.
        Plenum Press, New York, NY1977
        • Karnofsky D.
        • Abelmann W.H.
        • Craver L.V.
        • Burchenal J.H.
        The use of nitrogen mustards in the palliative treatment of carcinoma.
        Cancer. 1948; 1: 634-656
        • Kim E.
        • Jahan T.
        • Aouizerat B.E.
        • Dodd M.J.
        • Cooper B.A.
        • Paul S.M.
        • West C.
        • Lee K.
        • Swift P.S.
        • Wara W.
        • Miaskowski C.
        Changes in symptom clusters in patients undergoing radiation therapy.
        Support Care Cancer. 2009; 17: 1383-1391
        • Kim E.
        • Jahan T.
        • Aouizerat B.E.
        • Dodd M.J.
        • Cooper B.A.
        • Paul S.M.
        • West C.
        • Lee K.
        • Swift P.S.
        • Wara W.
        • Miaskowski C.
        Differences in symptom clusters identified using occurrence rates versus symptom severity ratings in patients at the end of radiation therapy.
        Cancer Nurs. 2009; 32: 429-436
        • Kim H.
        • Neubert J.K.
        • Rowan J.S.
        • Brahim J.S.
        • Iadarola M.J.
        • Dionne R.A.
        Comparison of experimental and acute clinical pain responses in humans as pain phenotypes.
        J Pain. 2004; 5: 377-384
        • Knudsen A.K.
        • Brunelli C.
        • Kaasa S.
        • Apolone G.
        • Corli O.
        • Montanari M.
        • Fainsinger R.
        • Aass N.
        • Fayers P.
        • Caraceni A.
        • Klepstad P.
        European Palliative Care Research Council, European Pharmacogenetic Study: Which variables are associated with pain intensity and treatment response in advanced cancer patients? Implications for a future classification system for cancer pain.
        Eur J Pain. 2011; 15: 320-327
        • Langford D.J.
        • Tripathy D.
        • Paul S.M.
        • West C.
        • Dodd M.J.
        • Schumacher K.
        • Miaskowski C.
        Trajectories of pain and analgesics in oncology outpatients with metastatic bone pain.
        J Pain. 2011; 12: 495-507
        • Li N.
        • Grivennikov S.I.
        • Karin M.
        The Unholy Trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment.
        Cancer Cell. 2011; 19: 429-431
        • Martin V.T.
        Ovarian hormones and pain response: A review of clinical and basic science studies.
        Gend Med. 2009; 6: 168-192
        • Nakki A.
        • Kouhia S.T.
        • Saarela J.
        • Harilainen A.
        • Tallroth K.
        • Videman T.
        • Battie M.C.
        • Kaprio J.
        • Peltonen L.
        • Kujala U.M.
        Allelic variants of IL1R1 gene associate with severe hand osteoarthritis.
        BMC Med Genet. 2010; 11: 50
        • Poleshuck E.L.
        • Katz J.
        • Andrus C.H.
        • Hogan L.A.
        • Jung B.F.
        • Kulick D.I.
        • Dworkin R.H.
        Risk factors for chronic pain following breast cancer surgery: A prospective study.
        J Pain. 2006; 7: 626-634
        • Portenoy R.K.
        • Thaler H.T.
        • Kornblith A.B.
        • Lepore J.M.
        • Friedlander-Klar H.
        • Coyle N.
        • Smart-Curley T.
        • Kemeny N.
        • Norton L.
        • Hoskins W.
        Symptom prevalence, characteristics and distress in a cancer population.
        Qual Life Res. 1994; 3: 183-189
        • Portenoy R.K.
        • Thaler H.T.
        • Kornblith A.B.
        • Lepore J.M.
        • Friedlander-Klar H.
        • Kiyasu E.
        • Sobel K.
        • Coyle N.
        • Kemeny N.
        • Norton L.
        The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptom prevalence, characteristics and distress.
        Eur J Cancer. 1994; 30A: 1326-1336
        • Price A.L.
        • Patterson N.J.
        • Plenge R.M.
        • Weinblatt M.E.
        • Shadick N.A.
        • Reich D.
        Principal components analysis corrects for stratification in genome-wide association studies.
        Nat Genet. 2006; 38: 904-909
        • Rahim-Williams F.B.
        • Riley III, J.L.
        • Herrera D.
        • Campbell C.M.
        • Hastie B.A.
        • Fillingim R.B.
        Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics.
        Pain. 2007; 129: 177-184
        • Reyes-Gibby C.C.
        • El Osta B.
        • Spitz M.R.
        • Parsons H.
        • Kurzrock R.
        • Wu X.
        • Shete S.
        • Bruera E.
        The influence of tumor necrosis factor-alpha -308 G/A and IL-6 -174 G/C on pain and analgesia response in lung cancer patients receiving supportive care.
        Cancer Epidemiol Biomarkers Prev. 2008; 17: 3262-3267
        • Reyes-Gibby C.C.
        • Shete S.
        • Yennurajalingam S.
        • Frazier M.
        • Bruera E.
        • Kurzrock R.
        • Crane C.H.
        • Abbruzzese J.
        • Evans D.
        • Spitz M.R.
        Genetic and nongenetic covariates of pain severity in patients with adenocarcinoma of the pancreas: Assessing the influence of cytokine genes.
        J Pain Symptom Manage. 2009; 38: 894-902
        • Reyes-Gibby C.C.
        • Spitz M.
        • Wu X.
        • Merriman K.
        • Etzel C.
        • Bruera E.
        • Kurzrock R.
        • Shete S.
        Cytokine genes and pain severity in lung cancer: Exploring the influence of TNF-{alpha}-308 G/A IL6-174G/C and IL8-251T/A.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 2745-2751
        • Reyes-Gibby C.C.
        • Spitz M.R.
        • Yennurajalingam S.
        • Swartz M.
        • Gu J.
        • Wu X.
        • Bruera E.
        • Shete S.
        Role of inflammation gene polymorphisms on pain severity in lung cancer patients.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 2636-2642
        • Rothman K.J.
        No adjustments are needed for multiple comparisons.
        Epidemiology. 1990; 1: 43-46
        • Sadeghnejad A.
        • Karmaus W.
        • Arshad S.H.
        • Kurukulaaratchy R.
        • Huebner M.
        • Ewart S.
        IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study.
        Respir Res. 2008; 9: 2
        • Sadeghnejad A.
        • Karmaus W.
        • Hasan Arshad S.
        • Ewart S.
        IL13 gene polymorphism association with cord serum immunoglobulin E.
        Pediatr Allergy Immunol. 2007; 18: 288-292
        • Sangha O.
        • Stucki G.
        • Liang M.H.
        • Fossel A.H.
        • Katz J.N.
        The Self-Administered Comorbidity Questionnaire: A new method to assess comorbidity for clinical and health services research.
        Arthritis Rheum. 2003; 49: 156-163
        • Serlin R.C.
        • Mendoza T.R.
        • Nakamura Y.
        • Edwards K.R.
        • Cleeland C.S.
        When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function.
        Pain. 1995; 61: 277-284
        • Seruga B.
        • Zhang H.
        • Bernstein L.J.
        • Tannock I.F.
        Cytokines and their relationship to the symptoms and outcome of cancer.
        Nat Rev Cancer. 2008; 8: 887-899
        • Siegel R.
        • Ward E.
        • Brawley O.
        • Jemal A.
        Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths.
        CA Cancer J Clin. 2011; 61: 212-236
        • Smith A.J.
        • Keen L.J.
        • Billingham M.J.
        • Perry M.J.
        • Elson C.J.
        • Kirwan J.R.
        • Sims J.E.
        • Doherty M.
        • Spector T.D.
        • Bidwell J.L.
        Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: Association with knee osteoarthritis.
        Genes Immun. 2004; 5: 451-460
        • StataCorp
        Stata Statistical Software: Release 9.
        Stata Corporation, College Station, Texas2005
        • Stephens M.
        • Smith N.J.
        • Donnelly P.
        A new statistical method for haplotype reconstruction from population data.
        Am J Hum Genet. 2001; 68: 978-989
        • Tasmuth T.
        • Estlanderb A.M.
        • Kalso E.
        Effect of present pain and mood on the memory of past postoperative pain in women treated surgically for breast cancer.
        Pain. 1996; 68: 343-347
        • Tasmuth T.
        • von Smitten K.
        • Hietanen P.
        • Kataja M.
        • Kalso E.
        Pain and other symptoms after different treatment modalities of breast cancer.
        Ann Oncol. 1995; 6: 453-459
        • Tasmuth T.
        • von Smitten K.
        • Kalso E.
        Pain and other symptoms during the first year after radical and conservative surgery for breast cancer.
        Br J Cancer. 1996; 74: 2024-2031
        • Tian C.
        • Gregersen P.K.
        • Seldin M.F.
        Accounting for ancestry: Population substructure and genome-wide association studies.
        Hum Mol Genet. 2008; 17: R143-R150
        • Torres R.
        • Macdonald L.
        • Croll S.D.
        • Reinhardt J.
        • Dore A.
        • Stevens S.
        • Hylton D.M.
        • Rudge J.S.
        • Liu-Bryan R.
        • Terkeltaub R.A.
        • Yancopoulos G.D.
        • Murphy A.J.
        Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis.
        Ann Rheum Dis. 2009; 68: 1602-1608
        • Uceyler N.
        • Valenza R.
        • Stock M.
        • Schedel R.
        • Sprotte G.
        • Sommer C.
        Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain.
        Arthritis Rheum. 2006; 54: 2656-2664
        • Utne I.
        • Miaskowski C.
        • Bjordal K.
        • Paul S.M.
        • Jakobsen G.
        • Rustoen T.
        Differences in the use of pain coping strategies between oncology inpatients with mild vs. moderate to severe pain.
        J Pain Symptom Manage. 2009; 38: 717-726
        • Vale M.L.
        • Marques J.B.
        • Moreira C.A.
        • Rocha F.A.
        • Ferreira S.H.
        • Poole S.
        • Cunha F.Q.
        • Ribeiro R.A.
        Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response in mice and zymosan-induced knee joint incapacitation in rats.
        J Pharmacol Exp Ther. 2003; 304: 102-108
        • Verri Jr., W.A.
        • Cunha T.M.
        • Parada C.A.
        • Poole S.
        • Cunha F.Q.
        • Ferreira S.H.
        Hypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?.
        Pharmacol Ther. 2006; 112: 116-138
        • Victor T.W.
        • Jensen M.P.
        • Gammaitoni A.R.
        • Gould E.M.
        • White R.E.
        • Galer B.S.
        The dimensions of pain quality: Factor analysis of the Pain Quality Assessment Scale.
        Clin J Pain. 2008; 24: 550-555
        • Wang X.M.
        • Hamza M.
        • Wu T.X.
        • Dionne R.A.
        Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain.
        Pain. 2009; 142: 275-283
        • Wang X.M.
        • Wu T.X.
        • Hamza M.
        • Ramsay E.S.
        • Wahl S.M.
        • Dionne R.A.
        Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain.
        Pain. 2007; 128: 136-147
        • Wang X.S.
        • Shi Q.
        • Williams L.A.
        • Mao L.
        • Cleeland C.S.
        • Komaki R.R.
        • Mobley G.M.
        • Liao Z.
        Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy.
        Brain Behav Immun. 2010; 24: 968-974
        • Wieseler-Frank J.
        • Maier S.F.
        • Watkins L.R.
        Central proinflammatory cytokines and pain enhancement.
        Neurosignals. 2005; 14: 166-174
        • Wolf G.
        • Livshits D.
        • Beilin B.
        • Yirmiya R.
        • Shavit Y.
        Interleukin-1 signaling is required for induction and maintenance of postoperative incisional pain: Genetic and pharmacological studies in mice.
        Brain Behav Immun. 2008; 22: 1072-1077