Skip to main content

Advertisement

SpringerLink
Log in

Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline–taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53–PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44–0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47–0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07–2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. doi:10.1038/nature11412

    Article  Google Scholar 

  2. 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. doi:10.1186/bcr3113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W, Moynahan ME (2009) PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15(16):5049–5059. doi:10.1158/1078-0432.CCR-09-0632

    Article  CAS  PubMed  Google Scholar 

  4. Loi S, Michiels S, Lambrechts D, Fumagalli D, Claes B, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Piccart MJ, Joensuu H, Sotiriou C (2013) Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst 105(13):960–967. doi:10.1093/jnci/djt121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ng CK, Schultheis AM, Bidard FC, Weigelt B, Reis-Filho JS (2015) Breast cancer genomics from microarrays to massively parallel sequencing: paradigms and new insights. J Natl Cancer Inst 107(5):djv015

    Article  PubMed  Google Scholar 

  6. Sabine VS, Crozier C, Brookes CL, Drake C, Piper T, van de Velde CJ, Hasenburg A, Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Rea DW, Bartlett JM (2014) Mutational analysis of PI3 K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J Clin Oncol 32(27):2951–2958

    Article  CAS  PubMed  Google Scholar 

  7. Papaxoinis G, Kotoula V, Alexopoulou Z, Kalogeras KT, Zagouri F, Timotheadou E, Gogas H, Pentheroudakis G, Christodoulou C, Koutras A, Bafaloukos D, Aravantinos G, Papakostas P, Charalambous E, Papadopoulou K, Varthalitis I, Efstratiou I, Zaramboukas T, Patsea H, Scopa CD, Skondra M, Kosmidis P, Pectasides D, Fountzilas G (2015) Significance of pik3ca mutations in patients with early breast cancer treated with adjuvant chemotherapy: a Hellenic Cooperative Oncology Group (HECOG) study. PLoS ONE 10(10):e0140293. doi:10.1371/journal.pone.0140293

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pogue-Geile KL, Song N, Jeong JH, Gavin PG, Kim SR, Blackmon NL, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP, Swain SM, Wickerham DL, Geyer CE Jr, Costantino JP, Wolmark N, Paik S (2015) Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the nsabp b-31 trial. J Clin Oncol 33(12):1340–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, Khandan F, Eidtmann H, Dohnal K, Heinrichs C, Huober J, Pfitzner B, Fasching PA, Andre F, Lindner JL, Sotiriou C, Dykgers A, Guo S, Gade S, Nekljudova V, Loi S, Untch M, Denkert C (2014) PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol 32(29):3212–3220

    Article  CAS  PubMed  Google Scholar 

  10. Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, Sotiriou C, Fumagalli D, Jimenez J, Aura C, Prudkin L, Diaz-Delgado MC, de la Pena L, Loi S, Ellis C, Schultz N, de Azambuja E, Harbeck N, Piccart-Gebhart M, Bernards R, Baselga J (2015) PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 33(12):1334–1339. doi:10.1200/JCO.2014.55.2158

    Article  CAS  PubMed  Google Scholar 

  11. Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, Pectasides D, Kalogeras KT, Skarlos D, Fountzilas G (2011) Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat 128(2):447–456. doi:10.1007/s10549-011-1572-5

    Article  CAS  PubMed  Google Scholar 

  12. Bertheau P, Lehmann-Che J, Varna M, Dumay A, Poirot B, Porcher R, Turpin E, Plassa LF, de Roquancourt A, Bourstyn E, de Cremoux P, Janin A, Giacchetti S, Espie M, de The H (2013) p53 in breast cancer subtypes and new insights into response to chemotherapy. Breast 22(Suppl 2):S27–S29. doi:10.1016/j.breast.2013.07.005

    Article  PubMed  Google Scholar 

  13. Silwal-Pandit L, Vollan HK, Chin SF, Rueda OM, McKinney S, Osako T, Quigley DA, Kristensen VN, Aparicio S, Borresen-Dale AL, Caldas C, Langerod A (2014) TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 20(13):3569–3580

    Article  CAS  PubMed  Google Scholar 

  14. Gluck S, Ross JS, Royce M, McKenna EF Jr, Perou CM, Avisar E, Wu L (2012) TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab. Breast Cancer Res Treat 132(3):781–791. doi:10.1007/s10549-011-1412-7

    Article  PubMed  Google Scholar 

  15. Yamamoto M, Hosoda M, Nakano K, Jia S, Hatanaka KC, Takakuwa E, Hatanaka Y, Matsuno Y, Yamashita H (2014) p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors. Cancer Sci 105(1):81–88. doi:10.1111/cas.12302

    Article  CAS  PubMed  Google Scholar 

  16. Coates AS, Millar EK, O’Toole SA, Molloy TJ, Viale G, Goldhirsch A, Regan MM, Gelber RD, Sun Z, Castiglione-Gertsch M, Gusterson B, Musgrove EA, Sutherland RL (2012) Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX. Breast Cancer Res 14(6):R143. doi:10.1186/bcr3348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kummel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 33(9):983–991. doi:10.1200/JCO.2014.58.1967

    Article  CAS  PubMed  Google Scholar 

  18. Salgado R, Denkert C, Campbell C, Savas P, Nucifero P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S (2015) Tumor-infiltrating lymphocytes and associations With pathological complete response and event-free survival in HER2-positive early-stage Breast Cancer treated with Lapatinib and Trastuzumab: a secondary analysis of the Neoaltto trial. JAMA Oncol 1(4):448–454. doi:10.1001/jamaoncol.2015.0830

    Article  PubMed  Google Scholar 

  19. Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, Kim YJ, Kim JH, Park SY (2013) Tumour-infiltrating CD8 + lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer 109(10):2705–2713. doi:10.1038/bjc.2013.634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113. doi:10.1200/JCO.2009.23.7370

    Article  CAS  PubMed  Google Scholar 

  21. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase iii randomized adjuvant breast cancer trials: Ecog 2197 and Ecog 1199. J Clin Oncol. doi:10.1200/JCO.2013.55.0491

    Google Scholar 

  22. Kotoula V, Chatzopoulos K, Lakis S, Alexopoulou Z, Timotheadou E, Zagouri F, Pentheroudakis G, Gogas H, Galani E, Efstratiou I, Zaramboukas T, Koutras A, Aravantinos G, Samantas E, Psyrri A, Kourea H, Bobos M, Papakostas P, Kosmidis P, Pectasides D, Fountzilas G (2015) Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget. doi:10.18632/oncotarget.6231

    PubMed Central  Google Scholar 

  23. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25(8):1544–1550. doi:10.1093/annonc/mdu112

    Article  CAS  PubMed  Google Scholar 

  24. Perez EA, Ballman KV, Tenner KS, Thompson EA, Badve SS, Bailey H, Baehner FL (2016) Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-Positive Breast Cancer. JAMA Oncol 2(1):56–64. doi:10.1001/jamaoncol.2015.3239

    Article  PubMed  Google Scholar 

  25. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: bIG 02-98. J Clin Oncol 31(7):860–867. doi:10.1200/JCO.2011.41.0902

    Article  CAS  PubMed  Google Scholar 

  26. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69–74. doi:10.1126/science.aaa4971

    Article  CAS  PubMed  Google Scholar 

  27. Quigley D, Silwal-Pandit L, Dannenfelser R, Langerod A, Vollan HK, Vaske C, Siegel JU, Troyanskaya O, Chin SF, Caldas C, Balmain A, Borresen-Dale AL, Kristensen V (2015) Lymphocyte invasion in ic10/basal-like breast tumors is associated with wild-type TP53. Mol Cancer Res 13(3):493–501. doi:10.1158/1541-7786.MCR-14-0387

    Article  CAS  PubMed  Google Scholar 

  28. Fountzilas G, Dafni U, Bobos M, Batistatou A, Kotoula V, Trihia H, Malamou-Mitsi V, Miliaras S, Chrisafi S, Papadopoulos S, Sotiropoulou M, Filippidis T, Gogas H, Koletsa T, Bafaloukos D, Televantou D, Kalogeras KT, Pectasides D, Skarlos DV, Koutras A, Dimopoulos MA (2012) Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel. PLoS ONE 7(6):e37946. doi:10.1371/journal.pone.0037946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271. doi:10.1093/annonc/mdu450

    Article  CAS  PubMed  Google Scholar 

  30. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel m (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol 24(9):2206–2223. doi:10.1093/annonc/mdt303

    Article  Google Scholar 

  31. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750. doi:10.1093/jnci/djp082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kotoula V, Lyberopoulou A, Papadopoulou K, Charalambous E, Alexopoulou Z, Gakou C, Lakis S, Tsolaki E, Lilakos K, Fountzilas G (2015) Evaluation of two highly-multiplexed custom panels for massively parallel semiconductor sequencing on paraffin DNA. PLoS ONE 10(6):e0128818. doi:10.1371/journal.pone.0128818

    Article  PubMed  PubMed Central  Google Scholar 

  33. 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. doi:10.1007/s10549-006-9242-8

    Article  Google Scholar 

  34. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, Loi S (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol. doi:10.1038/nrclinonc.2015.215

    PubMed  Google Scholar 

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

    Article  Google Scholar 

  36. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR, Yates LR, Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Chapman MS, Teague J, Easton D, Langerod A, Oslo Breast Cancer C, Lee MT, Shen CY, Tee BT, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin SF, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van ‘t Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SA, Salomon AV, Borresen-Dale AL, Richardson AL, Campbell PJ, Futreal PA, Stratton MR (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486(7403):400–404. doi:10.1038/nature11017

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lubin R, Schlichtholz B, Bengoufa D, Zalcman G, Tredaniel J, Hirsch A, Caron de Fromentel C, Preudhomme C, Fenaux P, Fournier G, Mangin P, Laurent-Puig P, Pelletier G, Schlumberger M, Desgrandchamps F, Le Duc A, Peyrat JP, Janin N, Bressac B, Soussi T et al (1993) Analysis of p53 antibodies in patients with various cancers define B-cell epitopes of human p53: distribution on primary structure and exposure on protein surface. Cancer Res 53(24):5872–5876

    CAS  PubMed  Google Scholar 

  38. Yanuck M, Carbone DP, Pendleton CD, Tsukui T, Winter SF, Minna JD, Berzofsky JA (1993) A mutant p53 tumor suppressor protein is a target for peptide-induced CD8+ cytotoxic T-cells. Cancer Res 53(14):3257–3261

    CAS  PubMed  Google Scholar 

  39. Budczies J, Bockmayr M, Denkert C, Klauschen F, Lennerz JK, Györffy B, Dietel M, Loibl S, Weichert W, Stenzinger A (2015) Classical pathology and mutational load of breast cancer—integration of two worlds. J Pathol 1:225–238. doi:10.1002/cjp2.25

    CAS  Google Scholar 

  40. Cheang MC, Martin M, Nielsen TO, Prat A, Voduc D, Rodriguez-Lescure A, Ruiz A, Chia S, Shepherd L, Ruiz-Borrego M, Calvo L, Alba E, Carrasco E, Caballero R, Tu D, Pritchard KI, Levine MN, Bramwell VH, Parker J, Bernard PS, Ellis MJ, Perou CM, Di Leo A, Carey LA (2015) Defining breast cancer intrinsic subtypes by quantitative receptor expression. Oncologist 20(5):474–482. doi:10.1634/theoncologist.2014-0372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gubin MM, Artyomov MN, Mardis ER, Schreiber RD (2015) Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Investig 125(9):3413–3421. doi:10.1172/JCI80008

    Article  PubMed  Google Scholar 

  42. Michaut M, Chin SF, Majewski I, Severson TM, Bismeijer T, de Koning L, Peeters JK, Schouten PC, Rueda OM, Bosma AJ, Tarrant F, Fan Y, He B, Xue Z, Mittempergher L, Kluin RJ, Heijmans J, Snel M, Pereira B, Schlicker A, Provenzano E, Ali HR, Gaber A, O’Hurley G, Lehn S, Muris JJ, Wesseling J, Kay E, Sammut SJ, Bardwell HA, Barbet AS, Bard F, Lecerf C, O’Connor DP, Vis DJ, Benes CH, McDermott U, Garnett MJ, Simon IM, Jirstrom K, Dubois T, Linn SC, Gallagher WM, Wessels LF, Caldas C, Bernards R (2016) Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer. Sci Rep 6:18517. doi:10.1038/srep18517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Banerjee S, Wei Z, Tan F, Peck KN, Shih N, Feldman M, Rebbeck TR, Alwine JC, Robertson ES (2015) Distinct microbiological signatures associated with triple negative breast cancer. Sci Rep 5:15162. doi:10.1038/srep15162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mukohara T (2015) PI3 K mutations in breast cancer: prognostic and therapeutic implications. Breast cancer 7:111–123. doi:10.2147/BCTT.S60696

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Loi S (2013) Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology 2(7):e24720. doi:10.4161/onci.24720

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cescon DW, Bedard PL (2015) PIK3CA genotype and treatment decisions in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 33(12):1318–1321. doi:10.1200/JCO.2014.59.3160

    Article  CAS  PubMed  Google Scholar 

  47. Hart JR, Zhang Y, Liao L, Ueno L, Du L, Jonkers M, Yates JR 3rd, Vogt PK (2015) The butterfly effect in cancer: a single base mutation can remodel the cell. Proc Natl Acad Sci USA 112(4):1131–1136. doi:10.1073/pnas.1424012112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zardavas D, Phillips WA, Loi S (2014) PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res 16(1):201. doi:10.1186/bcr3605

    Article  PubMed  PubMed Central  Google Scholar 

  49. Fountzilas G, Giannoulatou E, Alexopoulou Z, Zagouri F, Timotheadou E, Papadopoulou K, Lakis S, Bobos M, Poulios C, Sotiropoulou M, Lyberopoulou A, Gogas H, Pentheroudakis G, Pectasides D, Koutras A, Christodoulou C, Papandreou C, Samantas E, Papakostas P, Kosmidis P, Bafaloukos D, Karanikiotis C, Dimopoulos MA, Kotoula V (2016) TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting. Oncotarget. doi:10.18632/oncotarget.9022

    Google Scholar 

  50. Yates LK, S.; Martincorena, I.;, M. Gerstung, M.; Stratton, M.; Lonning, P.E.; Campbell, P. (2015) The driver landscape of breast cancer metastasis and relapse. http://www.europeancancercongress.org/Scientific-Programme/Abstract-search?abstractid=21851

Download references

Acknowledgments

The authors wish to thank Mrs. Emily Daskalaki for excellent technical assistance with MPS and Ms. Maria Moschoni, and Mrs. Stella Dallidou for secretarial assistance.

Funding

This study was supported by an internal Hellenic Cooperative Oncology Group (HeCOG) translational research grant (HE TRANS_BR). The funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was also partly supported by the Greek General Secretary for Research and Technology (GSRT) Program, Research in Excellence II, funded by 75 % from the European Union, and the Operational Program ‘‘Education & Lifelong Learning’’ ESPA-THALIS#266 of the Ministry of Education, Lifelong Learning & Religious Affairs.

Author information

Authors and Affiliations

  1. Department of Pathology, School of Health Sciences, School of Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Vassiliki Kotoula

  2. Faculty of Medicine, Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece

    Vassiliki Kotoula, Sotiris Lakis, Mattheos Bobos, Kyriaki Papadopoulou, Eleftheria Tsolaki & George Fountzilas

  3. Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Vasilios Karavasilis & Georgios Lazaridis

  4. Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Flora Zagouri

  5. Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece

    George Kouvatseas

  6. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

    Eleni Giannoulatou

  7. The University of New South Wales, Kensington, NSW, Australia

    Eleni Giannoulatou

  8. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Helen Gogas

  9. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

    George Pentheroudakis

  10. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece

    Dimitrios Pectasides

  11. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

    Angelos Koutras

  12. Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

    Gerasimos Aravantinos

  13. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

    Christos Christodoulou

  14. Oncology Unit, Hippokration Hospital, Athens, Greece

    Pavlos Papakostas

  15. Second Department of Prop. Surgery, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    Christos Markopoulos

  16. Breast Unit, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

    George Zografos

  17. Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece

    Christos Papandreou

  18. Aristotle University of Thessaloniki, Thessaloniki, Greece

    George Fountzilas

Authors
  1. Vassiliki Kotoula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasilios Karavasilis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flora Zagouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George Kouvatseas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eleni Giannoulatou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Helen Gogas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sotiris Lakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. George Pentheroudakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mattheos Bobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kyriaki Papadopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eleftheria Tsolaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dimitrios Pectasides
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Georgios Lazaridis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Angelos Koutras
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gerasimos Aravantinos
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christos Christodoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Pavlos Papakostas
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Christos Markopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. George Zografos
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Christos Papandreou
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. George Fountzilas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vassiliki Kotoula.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 315 kb)

Supplementary material 2 (XLS 78 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kotoula, V., Karavasilis, V., Zagouri, F. et al. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes. Breast Cancer Res Treat 158, 307–321 (2016). https://doi.org/10.1007/s10549-016-3883-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-3883-z

Keywords

Search

Navigation