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Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer



Insulin-like growth factor 1 (IGF-1) stimulates mitosis and inhibits apoptosis. High circulating IGF-1 levels are linked with an increased risk of colorectal and breast cancer. Recently, IGF-1 single nucleotide polymorphisms (SNPs), especially variant rs2946834, have been associated with poor clinical outcome in patients with colorectal cancer. In the present study, we aimed to investigate the influence of IGF1 polymorphisms associated with IGF-1 plasma levels on event-free survival in patients with HER2-positive breast cancer.


The present study included 161 consecutive white patients with HER2-positive breast cancer. Event-free survival was calculated as the time from cancer diagnosis to either relapse or death from any cause. Genomic DNA was extracted from archived formalin-fixed paraffin-embedded tumor tissue samples; five IGF-1 polymorphisms (rs2946834, rs6220, rs1520220, rs5742694, and rs5742678), all associated with IGF-1 levels, were genotyped by SNaPshot assays.


Kaplan–Meier analysis showed a poorer clinical outcome for carriers of the rare allele of SNP rs2946834 (log-rank test, p = 0.020). Concordantly, in univariate Cox regression analyses, the rare allele of SNP rs2946834 was significantly associated with a decreased event-free survival (HR = 3.06 [1.14–8.22]; p = 0.027). Multivariate analysis adjusted for age and tumor stage confirmed this result (HR = 4.02 [1.36–11.90]; p = 0.012). Other investigated polymorphisms of the IGF1 gene were not significantly associated with event-free survival (all p values >0.05).


This study provides first evidence that IGF1 rs2946834 polymorphism is associated with clinical outcome of HER2-positive breast cancer patients. Further studies are warranted to validate these findings.

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  1. Al Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P, Pharoah PD, Wareham NJ, Easton DF, Ponder BA, Dunning AM (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15:1–10

  2. Beech DJ, Parekh N, Pang Y (2001) Insulin-like growth factor-I receptor antagonism results in increased cytotoxicity of breast cancer cells to doxorubicin and taxol. Oncol Rep 8:325–329

  3. Bertrand FE, Steelman LS, Chappell WH, Abrams SL, Shelton JG, White ER, Ludwig DL, McCubrey JA (2006) Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3 K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. Leukemia 20:1254–1260

  4. Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de la Longrais IA, Mayne S, Risch H, Yu H (2007) IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors 25:346–354

  5. Chen W, Wang S, Tian T, Bai J, Hu Z, Xu Y, Dong J, Chen F, Wang X, Shen H (2009) Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies. Eur J Hum Genet 17(12):1668–1675

  6. Deming SL, Ren Z, Wen W, Shu XO, Cai Q, Gao YT, Zheng W (2007) Genetic variation in IGF1, IGF-1R, IGFALS, and IGFBP3 in breast cancer survival among Chinese women: a report from the Shanghai Breast Cancer Study. Breast Cancer Res Treat 104:309–319

  7. Dong X, Javle M, Hess KR, Shroff R, Abbruzzese JL, Li D (2010) Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer. Gastroenterology 139:464–473

  8. Dupont WD, Plummer WD Jr (1990) Power and sample size calculations. A review and computer program. Control Clin Trials 11:116–128

  9. Eckstein N, Servan K, Hildebrandt B, Politz A, von Jonquieres G, Wolf-Kummeth S, Napierski I, Hamacher A, Kassack MU, Budczies J, Beier M, Dietel M, Royer-Pokora B, Denkert C, Royer HD (2009) Hyperactivation of the insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. Cancer Res 69:2996–3003

  10. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

  11. Gerger A, El Khoueiry A, Zhang W, Yang D, Singh H, Bohanes P, Ning Y, Winder T, Labonte MJ, Wilson PM, Benhaim L, Paez D, El Khoueiry R, Absenger G, Lenz HJ (2011) Pharmacogenetic angiogenesis profiling for first-line bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res 17:5783–5792

  12. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ (2011) Panel members. Ann Oncol 22:1736–1747

  13. Grimberg A (2003) Mechanisms by which IGF-I may promote cancer. Cancer Biol Ther 2:630–635

  14. Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson J, Toivanen L, Koskenvuo M, Leinonen P, Koistinen R, Seppala M (1996) Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, IGFBP-3. J Clin Invest 98:2612–2615

  15. Helzlsouer KJ, Alberg AJ, Rollison DE, Overvad K, Kaaks R, Trichopoulos D, Clavel-Chapelon F et al (2010) Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 11:530–542

  16. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

  17. Kahán Z, Gardi J, Nyári T, Földesi I, Hajnal-Papp R, Ormándi K, Lázár G, Thurzó L, Schally AV (2006) Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case–control study. Int J Oncol 29:193–200

  18. Key TJ, Appleby PN, Reeves GK, Roddam AW (2010) Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 11:530–542

  19. Lang AH, Geller-Rhomberg S, Winder T, Stark N, Gasser K, Hartmann B, Kohler B, Grizelj I, Drexel H, Muendlein A (2012) A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients. BMC Cancer 12:20

  20. Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic Acids Res 36:D820–D824

  21. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857

  22. Mamay CL, Mingo-Sion AM, Wolf DM, Molina MD, Van Den Berg CL (2003) An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. Oncogene 22:602–614

  23. Matuoka K, Yu CK (1999) Nuclear factor Y (NF-Y) and cellular senescence. Exp Cell Res 253:365–371

  24. Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, Buring J et al (2008) IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One 3:e2578

  25. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

  26. Raile K, Berthold A, Banning U, Horn F, Pfeiffer G, Kiess W (2003a) IGFs, basic FGF, and glucose modulate proliferation and apoptosis induced by IFNgamma but not by IL-1beta in rat INS-1E beta-cells. Horm Metab Res 35:407–414

  27. Raile K, Hille R, Laue S, Schulz A, Pfeifer G, Horn F, Kiess W (2003b) Insulin-like growth factor I (IGF-I) stimulates proliferation but also increases caspase-3 activity, Annexin-V binding, and DNA-fragmentation in human MG63 osteosarcoma cells: co-activation of pro- and anti-apoptotic pathways by IGF-I. Horm Metab Res 35:786–793

  28. Rowlands MA, Holly JM, Hamdy F, Phillips J, Goodwin L, Marsden G, Gunnell D, Donovan J, Neal DE, Martin RM (2012) Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer. Cancer Causes Control 23:347–354

  29. Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J (1993) The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 260:1953–1955

  30. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

  31. Stattin P, Rinaldi S, Biessy C, Stenman UH, Hallmans G, Kaaks R (2004) High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort. J Clin Oncol 22:3104–3112

  32. Thissen JP, Ketelslegers JM, Underwood LE (1994) Nutritional regulation of the insulin-like growth factors. Endocr Rev 15:80–101

  33. Tsuchiya N, Wang L, Suzuki H, Segawa T, Fukuda H, Narita S, Shimbo M, Kamoto T, Mitsumori K, Ichikawa T, Ogawa O, Nakamura A, Habuchi T (2006) Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer. J Clin Oncol 24:1982–1989

  34. Valenciano A, Henriquez-Hernandez LA, Moreno M, Lloret M, Lara PC (2012) Role of IGF-1 receptor in radiation response. Transl Oncol 5:1–9

  35. Vlachostergios PJ, Gioulbasanis I, Kamposioras K, Georgoulias P, Baracos VE, Ghosh S, Maragouli E, Georgoulias V, Papandreou CN (2011) Baseline insulin-like growth factor-I plasma levels, systemic inflammation, weight loss and clinical outcome in metastatic non-small cell lung cancer patients. Oncology 81:113–118

  36. Winder T, Zhang W, Yang D, Ning Y, Bohanes P, Gerger A, Wilson PM, Pohl A, Mauro DJ, Langer C, Rowinsky EK, Lenz HJ (2010) Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients. Clin Cancer Res 16:5591–5602

  37. Wong AL, Lee SC (2012) Mechanisms of resistance to Trastuzumab and Novel therapeutic strategies in HER2-positive breast cancer. Int J Breast Cancer 2012:415170

  38. Zhang M, Hu Z, Huang J, Shu Y, Dai J, Jin G, Tang R, Dong J, Chen Y, Xu L, Huang X, Shen H (2010) A 3′-untranslated region polymorphism in IGF1 predicts survival of non-small cell lung cancer in a Chinese population. Clin Cancer Res 16:1236–1244

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We are grateful to Wera Hofmann (GATC Biotech, Konstanz, Germany), Bernd Hartmann (Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Austria), and Hans-Christian Fricke (Department of Obstetrics and Gynecology, Klinikum Konstanz, Germany) for their helpful and constructive comments on this manuscript. The present study was part financed by the European Union’s European Regional Development Fund through the INTERREG IV Program “Alpenrhein-Bodensee-Hochrhein”; Project Number: 179.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Correspondence to Axel Muendlein.

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Axel Muendlein and Alois H. Lang contributed equally to this work.

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Muendlein, A., Lang, A.H., Geller-Rhomberg, S. et al. Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer. J Cancer Res Clin Oncol 139, 491–498 (2013).

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  • Breast cancer
  • HER2
  • Single nucleotide polymorphisms
  • Insulin-like growth factor 1
  • Biomarker