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Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen

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Abstract

PIK3CA mutations occur frequently in breast cancer, predominantly in exons 9 and 20. The aim of this retrospective study is to evaluate the PIK3CA mutation status for its relationship with prognosis and first-line endocrine therapy outcome. PIK3CA exon 9 and 20 were evaluated for mutations in 1,352 primary breast cancer specimens by SnaPshot multiplex analyses. The mutation status was studied for their relationship with metastasis-free survival (MFS) in 342 untreated lymph node-negative (LNN) patients and to time to progression (TTP) in estrogen receptor (ER)-positive patients with metastatic disease treated with first-line tamoxifen (N = 447) or aromatase inhibitors (AIs; N = 84). We detected in 423 patients hotspot mutations for PIK3CA (31 %). Mutations in exon 20 were detected in 251 patients (59 %), with H1047L and H1047R mutations in 37 (15 %) and 214 (85 %) cases, respectively. Mutations in PIK3CA exon 9 were discovered in 173 patients (41 %), with E542K and E545K mutations in 57 (32 %) and 104 (60 %) cases as most prevalent ones. Evaluation of the untreated LNN patients for prognosis showed no relationship between MFS and PIK3CA mutations, neither for exon 9 [HR = 1.04 (95 % CI 0.57–1.89), P = 0.90] nor for exon 20 [HR = 0.98 (95 % CI 0.63–1.54); P = 0.94] when compared to wild-type. The PIK3CA mutation status was also not associated with treatment outcome after first-line tamoxifen. On the other hand, patients treated with first-line AIs showed a longer TTP when having a PIK3CA mutation in exon 9 [HR = 0.40 (95 % CI 0.17–0.95); P = 0.038] or exon 20 [HR = 0.50 (95 % CI 0.27–0.91); P = 0.024] compared to wild-types, both significant in uni- and multivariate analysis including traditional predictive factors. All results remained when only HER2-negative patients were evaluated for each cohort. PIK3CA mutations in ER-positive tumors were significantly associated with a favorable outcome after first-line AIs, which needs further confirmation in other datasets. Mutations were not associated with prognosis in untreated LNN patients nor predictive outcome after first-line tamoxifen therapy in advanced disease patients.

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References

  1. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501

    Article  PubMed  CAS  Google Scholar 

  2. Troxell ML (2012) PIK3CA/AKT1 mutations in breast carcinoma: a comprehensive review of experimental and clinical studies. J Clinic Experiment Pathol S1:002

    Google Scholar 

  3. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  Google Scholar 

  4. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–7681

    Article  PubMed  CAS  Google Scholar 

  5. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W et al (2009) PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15(16):5049–5059

    Article  PubMed  CAS  Google Scholar 

  6. Li SY, Rong M, Grieu F, Iacopetta B (2006) PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96(1):91–95

    Article  PubMed  CAS  Google Scholar 

  7. Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich MC, Corless CL, Troxell ML (2010) Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 120(2):409–418

    Article  PubMed  CAS  Google Scholar 

  8. Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J et al (2011) Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 29(2):166–173

    Article  PubMed  CAS  Google Scholar 

  9. Esteva FJ, Guo H, Zhang S, Santa-Maria C, Stone S, Lanchbury JS, Sahin AA, Hortobagyi GN, Yu D (2010) PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 177(4):1647–1656

    Article  PubMed  CAS  Google Scholar 

  10. Buttitta F, Felicioni L, Barassi F, Martella C, Paolizzi D, Fresu G, Salvatore S, Cuccurullo F, Mezzetti A, Campani D et al (2006) PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol 208(3):350–355

    Article  PubMed  CAS  Google Scholar 

  11. Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY (2008) PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15(4):1064–1069

    Article  PubMed  Google Scholar 

  12. Musgrove EA, Sutherland RL (2009) Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9(9):631–643

    Article  PubMed  CAS  Google Scholar 

  13. Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV, Cheng JQ (2001) Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res 61(16):5985–5991

    PubMed  CAS  Google Scholar 

  14. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68(15):6084–6091

    Article  PubMed  CAS  Google Scholar 

  15. Al Saleh S, Sharaf LH, Luqmani YA (2011) Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review). Int J Oncol 38(5):1197–1217

    PubMed  CAS  Google Scholar 

  16. Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP et al (2009) Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69(10):4192–4201

    Article  PubMed  CAS  Google Scholar 

  17. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529

    Article  PubMed  CAS  Google Scholar 

  18. Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A et al (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 107(22):10208–10213

    Article  PubMed  CAS  Google Scholar 

  19. Hayward JL, Rubens RD, Carbone PP, Heuson JC, Kumaoka S, Segaloff A (1978) Assessment of response to therapy in advanced breast cancer. A project of the programme on clinical oncology of the International Union against Cancer, Geneva, Switzerland. Eur J Cancer 14(11):1291–1292

    PubMed  CAS  Google Scholar 

  20. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of NCIEWGoCD (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235

    Article  PubMed  Google Scholar 

  21. Foekens JA, Portengen H, van Putten WL, Trapman AM, Reubi JC, Alexieva-Figusch J, Klijn JG (1989) Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer. Cancer Res 49(24 Pt 1):7002–7009

    PubMed  CAS  Google Scholar 

  22. Berns EM, Klijn JG, van Staveren IL, Portengen H, Noordegraaf E, Foekens JA (1992) Prevalence of amplification of the oncogenes c-myc, HER2/neu, and int-2 in one thousand human breast tumours: correlation with steroid receptors. Eur J Cancer 28(2–3):697–700

    Article  PubMed  CAS  Google Scholar 

  23. Roepman P, Horlings HM, Krijgsman O, Kok M, Bueno-de-Mesquita JM, Bender R, Linn SC, Glas AM, van de Vijver MJ (2009) Microarray-based determination of estrogen receptor, progesterone receptor, and HER2 receptor status in breast cancer. Clin Cancer Res 15(22):7003–7011

    Article  PubMed  CAS  Google Scholar 

  24. Nguyen B, Cusumano PG, Deck K, Kerlin D, Garcia AA, Barone JL, Rivera E, Yao K, de Snoo FA, van den Akker J et al (2012) Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients. Ann Surg Oncol 19(10):3257–3263

    Article  PubMed  Google Scholar 

  25. van Schaik RH, Kok M, Sweep FC, van Vliet M, van Fessem M, Meijer-van Gelder ME, Seynaeve C, Lindemans J, Wesseling J, Van ‘t Veer LJ et al (2011) The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics 12(8):1137–1146

    Article  PubMed  Google Scholar 

  26. Lurkin I, Stoehr R, Hurst CD, van Tilborg AA, Knowles MA, Hartmann A, Zwarthoff EC (2010) Two multiplex assays that simultaneously identify 22 possible mutation sites in the KRAS, BRAF, NRAS and PIK3CA genes. PLoS ONE 5(1):e8802

    Article  PubMed  Google Scholar 

  27. Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC (2010) FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS ONE 5(11):e13821

    Article  PubMed  Google Scholar 

  28. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13(20):6064–6069

    Article  PubMed  CAS  Google Scholar 

  29. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY et al (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16(1):21–32

    Article  PubMed  CAS  Google Scholar 

  30. Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, Fourme E, Lidereau R, Bieche I (2012) PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res 14(1):R28

    Article  PubMed  CAS  Google Scholar 

  31. Boyault S, Drouet Y, Navarro C, Bachelot T, Lasset C, Treilleux I, Tabone E, Puisieux A, Wang Q (2012) Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes. Breast Cancer Res Treat 132(1):29–39

    Article  PubMed  CAS  Google Scholar 

  32. Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Early Breast Cancer Trialists’ Collaborative G et al (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378(9793):771–784

    PubMed  CAS  Google Scholar 

  33. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Hoog J, Goiffon RJ, Goldstein TC et al (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486(7403):353–360

    PubMed  CAS  Google Scholar 

  34. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS (2005) Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65(23):10992–11000

    Article  PubMed  CAS  Google Scholar 

  35. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102(3):802–807

    Article  PubMed  CAS  Google Scholar 

  36. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103(5):1475–1479

    Article  PubMed  CAS  Google Scholar 

  37. Zhang Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J, van de Water B (2011) Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res 13(3):R52

    Article  PubMed  CAS  Google Scholar 

  38. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D et al (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30(22):2718–2724

    Article  PubMed  CAS  Google Scholar 

  39. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P et al (2013) Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 31(2):195–202

    Article  PubMed  CAS  Google Scholar 

  40. Ellis MJ, Lin L, Crowder R, Tao Y, Hoog J, Snider J, Davies S, DeSchryver K, Evans DB, Steinseifer J et al (2010) Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119(2):379–390

    Article  PubMed  CAS  Google Scholar 

  41. Dumont AG, Dumont SN, Trent JC (2012) The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chin J Cancer 31(7):327–334

    Article  PubMed  CAS  Google Scholar 

  42. Dupont Jensen J, Laenkholm AV, Knoop A, Ewertz M, Bandaru R, Liu W, Hackl W, Barrett JC, Gardner H (2011) PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 17(4):667–677

    Article  PubMed  CAS  Google Scholar 

  43. Board RE, Wardley AM, Dixon JM, Armstrong AC, Howell S, Renshaw L, Donald E, Greystoke A, Ranson M, Hughes A et al (2010) Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat 120(2):461–467

    Article  PubMed  CAS  Google Scholar 

  44. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G et al (2009) Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27(16):2630–2637

    Article  PubMed  CAS  Google Scholar 

  45. Meric-Bernstam F, Akcakanat A, Chen H, Do KA, Sangai T, Adkins F, Gonzalez-Angulo AM, Rashid A, Crosby K, Dong M et al (2012) PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res 18(6):1777–1789

    Article  PubMed  CAS  Google Scholar 

  46. Mohseni M, Park BH (2010) PIK3CA and KRAS mutations predict for response to everolimus therapy: now that’s RAD001. J Clin Invest 120(8):2655–2658

    Article  PubMed  CAS  Google Scholar 

  47. Beelen K, Zwart W, Linn SC (2012) Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy? Nat Rev Clin Oncol 9(9):529–541

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are especially grateful to Ellen Zwarthof, Anieta Sieuwerts, Anne van Galen, Marion Meijer-van Gelder, Mieke Timmermans, Vanja de Weerd, Cesar Payan for their continued contribution and technical support. DR is a recipient of the ERACOL program, which gives her the opportunity to perform this research in the Netherlands, MJ and EB are funded in part by the TI Pharma projects T3-108 and T3-502.

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The authors declare that they have no competing interests.

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Correspondence to Els M. J. J. Berns.

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Ramirez-Ardila, D.E., Helmijr, J.C., Look, M.P. et al. Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res Treat 139, 39–49 (2013). https://doi.org/10.1007/s10549-013-2529-7

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