Molecular Genetics and Genomics

, Volume 287, Issue 9, pp 755–764 | Cite as

Analysis of functional germline polymorphisms for prediction of response to anthracycline-based neoadjuvant chemotherapy in breast cancer

  • Joanna Szkandera
  • Gudrun Absenger
  • Nadia Dandachi
  • Peter Regitnig
  • Sigurd Lax
  • Michael Stotz
  • Hellmut Samonigg
  • Wilfried Renner
  • Armin Gerger
Original Paper

Abstract

To elucidate the role of predictive factors on individual’s drug response, based on genetic variation, we examined the association between eight germline polymorphisms in genes involved in protection against oxidative stress, apoptosis, oncogenic transformation, proliferation, immune response and DNA repair (TP53, NQO1, IL6, TLR4 and XRCC1) and the pathological response to anthracycline-based neoadjuvant chemotherapy in 70 patients with breast cancer. The DNA was genotyped for eight polymorphisms in five genes (TP53, NQO1, IL6, TLR4 and XRCC1) by 5′-exonuclease (TaqMan™) technology. Fisher’s exact test was used to evaluate the association between genotype, clinicopathological parameters and pathological response. A good pathological response, defined as a pathological complete response or residual isolated invasive tumor cells, was found significantly more frequently for estrogen (ER) and progesterone receptor (PR) negative breast carcinomas compared to ER and PR positive and ER or PR positive carcinomas, respectively (43.5 vs. 37.5 and 10.3 %, p = 0.006), and was significantly associated with high tumor grade (G3) (p = 0.002). A non-significant trend towards a good pathological response was shown in patients carrying the Arg/Arg or Arg/Pro TP53 codon 72 gene variant compared to those harboring the Pro/Pro variant (17.6 or 37.9 % vs. 0; p = 0.071). No association was found between NQO1 Pro187Ser, IL6 −174G>C, TLR4 Asp299Gly and Thr399Ile, and XRCC1 Arg194Trp, Arg399Gln and Arg280His and pathological response. The present study shows hormone receptor status and tumor grade as predictors for pathological response to neoadjuvant anthracycline-based chemotherapy. Among various functional germline polymorphisms, a potential predictive value was only found for the TP53 Arg72Pro gene variant.

Keywords

Germline polymorphisms Anthracycline Neoadjuvant chemotherapy Breast cancer 

Notes

Acknowledgments

This work was funded by the Research Department of the Cultural Office of the City of Graz.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Allegra JC, Lippman ME, Thompson EB, Simon R, Barlock A, Green L, Huff KK, Do HM, Aitken SC, Warren R (1978) Association between steroid hormone receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. Cancer Treat Rep 62:1281–1286PubMedGoogle Scholar
  2. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, André F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059. doi:10.1038/nm1622 PubMedCrossRefGoogle Scholar
  3. Archer CD, Parton M, Smith IE, Ellis PA, Salter J, Ashley S, Gui G, Sacks N, Ebbs SR, Allum W, Nasiri N, Dowsett M (2003) Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer. Br J Cancer 89:1035–1041. doi:10.1038/sj.bjc.6601173 PubMedCrossRefGoogle Scholar
  4. Bergmann C, Bachmann HS, Bankfalvi A, Lotfi R, Pütter C, Wild CA, Schuler PJ, Greve J, Hoffmann TK, Lang S, Scherag A, Lehnerdt GF (2011) Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas. J Transl Med 9:139. doi:10.1186/1479-5876-9-139 PubMedCrossRefGoogle Scholar
  5. Bewick MA, Conlon MS, Lafrenie RM (2006) Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer. J Clin Oncol 24:5645–5651. doi:10.1200/JCO.2006.05.9923 PubMedCrossRefGoogle Scholar
  6. Burcombe RJ, Makris A, Richman PI, Daley FM, Noble S, Pittam M, Wright D, Allen SA, Dove J, Wilson GD (2005) Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer 92:147–155. doi:10.1038/sj.bjc.6602256 PubMedCrossRefGoogle Scholar
  7. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334. doi:10.1158/1078-0432.CCR-06-1109 PubMedCrossRefGoogle Scholar
  8. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P (1993) Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 16:223–228PubMedCrossRefGoogle Scholar
  9. Damin AP, Frazzon AP, Damin DC, Roehe A, Hermes V, Zettler C, Alexandre CO (2006) Evidence for an association of TP53 codon 72 polymorphism with breast cancer risk. Cancer Detect Prev 30:523–529. doi:10.1016/j.cdp.2006.09.007 PubMedCrossRefGoogle Scholar
  10. DeMichele A, Gray R, Horn M, Chen J, Aplenc R, Vaughan WP, Tallman MS (2009) Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. Cancer Res 69:4184–4191. doi:10.1158/0008-5472.CAN-08-2989 PubMedCrossRefGoogle Scholar
  11. Dickson RB, Lippman ME (1988) Control of human breast cancer by estrogen, growth factors, and oncogenes. Cancer Treat Res 40:119–165PubMedCrossRefGoogle Scholar
  12. Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365. doi:10.1038/ng1093 PubMedCrossRefGoogle Scholar
  13. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) AJCC cancer staging manual, 7th edn. Springer, New York, p 439Google Scholar
  14. Ellis PA, Smith IE, McCarthy K, Detre S, Salter J, Dowsett M (1997) Preoperative chemotherapy induces apoptosis in early breast cancer. Lancet 349:849PubMedCrossRefGoogle Scholar
  15. Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjäkoski K, Kallioniemi A, Kilpivaara O, Mannermaa A, Kosma VM, Uusitupa M, Eskelinen M, Kataja V, Aittomäki K, von Smitten K, Heikkilä P, Lukas J, Holli K, Bartkova J, Blomqvist C, Bartek J, Nevanlinna H (2008) NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40:844–853. doi:10.1038/ng.155 PubMedCrossRefGoogle Scholar
  16. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685PubMedGoogle Scholar
  17. Giannitrapani L, Soresi M, Giacalone A, Campagna ME, Marasà M, Cervello M, Marasà S, Montalto G (2011) IL-6 −174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma. OMICS 15:183–186. doi:10.1089/omi.2010.0093 PubMedCrossRefGoogle Scholar
  18. Han JY, Lee GK, Jang DH, Lee SY, Lee JS (2008) Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced nonsmall cell lung cancer. Cancer 113:799–807. doi:10.1002/cncr.23668 PubMedCrossRefGoogle Scholar
  19. Huober J, von Minckwitz G, Denkert C, Tesch H, Weiss E, Zahm DM, Belau A, Khandan F, Hauschild M, Thomssen C, Högel B, Darb-Esfahani S, Mehta K, Loibl S (2010) Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 124:133–140. doi:10.1007/s10549-010-1103-9 PubMedCrossRefGoogle Scholar
  20. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. doi:10.3322/caac.20107 PubMedCrossRefGoogle Scholar
  21. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164. doi:10.1016/S0092-8674-00625-6 PubMedCrossRefGoogle Scholar
  22. Kaufmann M, Klinga K, Runnebaum B, Kubli F (1980) In vitro adriamycin sensitivity test and hormonal receptors in primary breast cancer. Eur J Cancer 16:1609–1613PubMedCrossRefGoogle Scholar
  23. Kim K, Kang SB, Chung HH, Kim JW, Park NH, Song YS (2008) XRCC1 Arginine194Tryptophan and GGH-401Cytosine/Thymine polymorphisms are associated with response to platinum-based neoadjuvant chemotherapy in cervical cancer. Gynecol Oncol 111:509–515. doi:10.1016/j.ygyno.2008.08.034 PubMedCrossRefGoogle Scholar
  24. Kim JG, Chae YS, Sohn SK, Moon JH, Ryoo HM, Bae SH, Kum Y, Jeon SW, Lim KH, Kang BM, Park IJ, Choi GS, Jun SH (2009) Prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) 8473T>C polymorphism associated with prognosis for patients with colorectal cancer treated with capecitabine and oxaliplatin. Cancer Chemother Pharmacol 64:953–960. doi:10.1007/s00280-009-0947-3 PubMedCrossRefGoogle Scholar
  25. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N, Buchholz TA, Ross MI, McNeese MD, Buzdar AU, Hortobagyi GN, Singletary SE (1999) Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460–469PubMedGoogle Scholar
  26. Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic Acids Res 36:D820–D824. doi:10.1093/nar/gkm904 PubMedCrossRefGoogle Scholar
  27. Lee PH, Shatkay H (2009) An integrative scoring system for ranking SNPs by their potential deleterious effects. Bioinformatics 25:1048–1055. doi:10.1093/bioformatics/btp103 PubMedCrossRefGoogle Scholar
  28. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefGoogle Scholar
  29. Lippman ME, Allegra JC, Thompson EB, Simon R, Barlock A, Green L, Huff KK, Do HM, Aitken SC, Warren R (1978) The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med 298:1223–1228PubMedCrossRefGoogle Scholar
  30. Loizidou MA, Michael T, Neuhausen SL, Newbold RF, Marcou Y, Kakouri E, Daniel M, Papadopoulos P, Malas S, Kyriacou K, Hadjisavvas A (2008) Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus. Breast Cancer Res Treat 112:575–579. doi:10.1007/s10549-007-9881-4 PubMedCrossRefGoogle Scholar
  31. Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV (1987) Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7:961–963. doi:10.1128/MCB.7.2.961 PubMedGoogle Scholar
  32. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12:320–327PubMedCrossRefGoogle Scholar
  33. Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, Mors R, Haegelé P, Eber M, Ghnassia JP (2004) Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 40:205–211. doi:10.1016/s0959-8049-00675-0 PubMedCrossRefGoogle Scholar
  34. Pim D, Banks L (2004) p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 108:196–199. doi:10.1002/ijc.11548 PubMedCrossRefGoogle Scholar
  35. Remmele W (1997) Pathologie, vol 4, 2nd edn. Springer, Berlin, p 259CrossRefGoogle Scholar
  36. Sakamuro D, Sabbatini P, White E, Prendergast GC (1997) The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15:887–898PubMedCrossRefGoogle Scholar
  37. Shen MR, Jones IM, Mohrenweiser H (1998) Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 58:604–608PubMedGoogle Scholar
  38. Shiraishi K, Kohno T, Tanai C, Goto Y, Kuchiba A, Yamamoto S, Tsuta K, Nokihara H, Yamamoto N, Sekine I, Ohe Y, Tamura T, Yokota J, Kunitoh H (2010) Association of DNA repair gene polymorphisms with response to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol 28:4945–4952. doi:10.1200/JCO.2010.30.5334 PubMedCrossRefGoogle Scholar
  39. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D (2001) Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol 59:263–268PubMedGoogle Scholar
  40. Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM, Matlashewski G, Banks L (1998) Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 393:229–234. doi:10.1038/30400 PubMedCrossRefGoogle Scholar
  41. Sullivan A, Syed N, Gasco M, Bergamaschi D, Trigiante G, Attard M, Hiller L, Farrell PJ, Smith P, Lu X, Crook T (2004) Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo. Oncogene 23:3328–3337. doi:10.1038/sj.onc.1207428 PubMedCrossRefGoogle Scholar
  42. Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G (1999) Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 19:1092–1100PubMedGoogle Scholar
  43. Tiezzi DG, Andrade JM, Ribeiro-Silva A, Zola FE, Marana HR, Tiezzi MG (2007) HER-2, p53, p21 and hormonal receptors proteins expression as predictive factors of response and prognosis in locally advanced breast cancer treated with neoadjuvant docetaxel plus epirubicin combination. BMC Cancer 7:36. doi:10.1186/1471-2407-7-36 PubMedCrossRefGoogle Scholar
  44. Tommiska J, Eerola H, Heinonen M, Salonen L, Kaare M, Tallila J, Ristimäki A, von Smitten K, Aittomäki K, Heikkilä P, Blomqvist C, Nevanlinna H (2005) Breast cancer patients with p53 Pro72 homozygous genotype have a poorer survival. Clin Cancer Res 11:5098–5103. doi:10.1158/1078-0432.CCR-05-0173 PubMedCrossRefGoogle Scholar
  45. Toyama T, Zhang Z, Nishio M, Hamaguchi M, Kondo N, Iwase H, Iwata H, Takahashi S, Yamashita H, Fujii Y (2007) Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients. Breast Cancer Res 9:R34. doi:10.1186/bcr1682 PubMedCrossRefGoogle Scholar
  46. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310. doi:10.1038/35042675 PubMedCrossRefGoogle Scholar
  47. Walker KK, Levine AJ (1996) Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci USA 93:15335–15340PubMedCrossRefGoogle Scholar
  48. Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS (2012) Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study. Cancer 118:1856–1867. doi:10.1002/cncr.26472 PubMedCrossRefGoogle Scholar
  49. Wolff AC, Davidson NE (2000) Primary systemic therapy in operable breast cancer. J Clin Oncol 18:1558–1569PubMedGoogle Scholar
  50. Xu Y, Yao L, Ouyang T, Li J, Wang T, Fan Z, Lin B, Lu Y, Xie Y (2005) p53 Codon 72 polymorphism predicts the pathologic response to neoadjuvant chemotherapy in patients with breast cancer. Clin Cancer Res 11:7328–7333. doi:10.1158/1078-0432.CCR-05-0507 PubMedCrossRefGoogle Scholar
  51. Yi SY, Lee WJ (2006) A p53 genetic polymorphism of gastric cancer: difference between early gastric cancer and advanced gastric cancer. World J Gastroenterol 12:6536–6539PubMedGoogle Scholar
  52. Zhang F, Yang Y, Smith T, Kau SW, McConathy JM, Esteva FJ, Kuerer HM, Symmans WF, Buzdar AU, Hortobagyi GN, Pusztai L (2003) Correlation between HER-2 expression and response to neoadjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide in patients with breast carcinoma. Cancer 97:1758–1765. doi:10.1002/cncr.11245 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Joanna Szkandera
    • 1
  • Gudrun Absenger
    • 1
  • Nadia Dandachi
    • 1
  • Peter Regitnig
    • 2
  • Sigurd Lax
    • 3
  • Michael Stotz
    • 1
  • Hellmut Samonigg
    • 1
  • Wilfried Renner
    • 4
  • Armin Gerger
    • 1
  1. 1.Research Unit: Genetic Epidemiology and Pharmacogenetics in Oncology, Division of Clinical Oncology, Department of Internal MedicineMedical University of GrazGrazAustria
  2. 2.Institute of PathologyMedical University of GrazGrazAustria
  3. 3.Department of PathologyGeneral Hospital Graz WestGrazAustria
  4. 4.Clinical Institute of Medical and Laboratory DiagnosticsMedical University of GrazGrazAustria

Personalised recommendations