@article {7085,
	title = {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},
	journal = {Oncotarget},
	volume = {7},
	year = {2016},
	note = {Cited By :3Export Date: 18 February 2017References: Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., Jemal, A., Global cancer statistics, 2012 (2015) CA., 65, pp. 87-108;Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2015 (2015) CA., 65, pp. 5-29; 
Perou, C.M., Sorlie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Rees, C.A., Pollack, J.R., Williams, C., Molecular portraits of human breast tumours (2000) Nature., 406, pp. 747-752; 
Sorlie, T., Perou, C.M., Tibshirani, R., Aas, T., Geisler, S., Johnsen, H., Hastie, T., Matese, J.C., Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications (2001) Proc Nat Acad Sci U S A., 98, pp. 10869-10874; 
Sotiriou, C., Neo, S.Y., McShane, L.M., Korn, E.L., Long, P.M., Jazaeri, A., Martiat, P., Liu, E.T., Breast cancer classification and prognosis based on gene expression profiles from a population-based study (2003) Proc Nat Acad Sci U S A., 100, pp. 10393-10398; 
Eroles, P., Bosch, A., Perez-Fidalgo, J.A., Lluch, A., Molecular biology in breast cancer: intrinsic subtypes and signaling pathways (2012) Treat Rev., 38, pp. 698-707; 
Gray, J., Druker, B., Genomics: the breast cancer landscape (2012) Nature., 486, pp. 328-329; 
Ding, L., Raphael, B.J., Chen, F., Wendl, M.C., Advances for studying clonal evolution in cancer (2013) Cancer letters., 340, pp. 212-219; 
Hansen, A.R., Bedard, P.L., Clinical application of highthroughput genomic technologies for treatment selection in breast cancer (2013) Breast Cancer Res., 15, p. R97; 
The Cancer Genome Atlas Network (2012) Nature., 490, pp. 61-70; 
Stephens, P.J., Tarpey, P.S., Davies, H., Van Loo, P., Greenman, C., Wedge, D.C., Nik-Zainal, S., Beare, D., The landscape of cancer genes and mutational processes in breast cancer (2012) Nature., 486, pp. 400-404; 
Varna, M., Bousquet, G., Plassa, L.F., Bertheau, P., Janin, A., TP53 status and response to treatment in breast cancers (2011) J Biomed Biotechnol., 2011, p. 284584; 
Olivier, M., Langerod, A., Carrieri, P., Bergh, J., Klaar, S., Eyfjord, J., Theillet, C., Uhrhammer, N., The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer (2006) Clin Cancer Res., 12, pp. 1157-1167; 
Berge, E.O., Huun, J., Lillehaug, J.R., Lonning, P.E., Knappskog, S., Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin (2013) Biochim Biophys Acta., 1830, pp. 2790-2797; 
Silwal-Pandit, L., Vollan, H.K., Chin, S.F., Rueda, O.M., McKinney, S., Osako, T., Quigley, D.A., Langerod, A., TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance (2014) Clin Cancer Res., 20, pp. 3569-3580; 
Joerger, A.C., Fersht, A.R., The tumor suppressor p53: from structures to drug discovery (2010) Cold Spring Harbor perspectives in biology., 2; 
Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S.V., Hainaut, P., Olivier, M., Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database (2007) Hum Mutat., 28, pp. 622-629; 
Petitjean, A., Achatz, M.I., Borresen-Dale, A.L., Hainaut, P., Olivier, M., TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes (2007) Oncogene., 26, pp. 2157-2165; 
Blagosklonny, M.V., p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominantnegative effect (2000) FASEB journal., 14, pp. 1901-1907; 
Oren, M., Maltzman, W., Levine, A.J., Post-translational regulation of the 54K cellular tumor antigen in normal and transformed cells (1981) Mol Cell Bio., 1, pp. 101-110; 
George, B., Datar, R.H., Wu, L., Cai, J., Patten, N., Beil, S.J., Groshen, S., Cote, R.J., p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer (2007) J Clin Oncol., 25, pp. 5352-5358; 
Kandioler, D., Zwrtek, R., Ludwig, C., Janschek, E., Ploner, M., Hofbauer, F., Kuhrer, I., Bergmann, M., TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer (2002) Ann Surg., 235, pp. 493-498; 
Allred, D.C., Clark, G.M., Elledge, R., Fuqua, S.A., Brown, R.W., Chamness, G.C., Osborne, C.K., McGuire, W.L., Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer (1993) J Nat Cancer Inst., 85, pp. 200-206; 
Yamamoto, M., Hosoda, M., Nakano, K., Jia, S., Hatanaka, K.C., Takakuwa, E., Hatanaka, Y., Yamashita, H., p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors (2014) Cancer science., 105, pp. 81-88; 
Lara, J.F., Thor, A.D., Dressler, L.G., Broadwater, G., Bleiweiss, I.J., Edgerton, S., Cowan, D., Winer, E.P., p53 Expression in node-positive breast cancer patients: results from the Cancer and Leukemia Group B 9344 Trial (159905) (2011) Clin Cancer Res., 17, pp. 5170-5178; 
Lee, J.W., Soung, Y.H., Kim, S.Y., Lee, H.W., Park, W.S., Nam, S.W., Kim, S.H., Lee, S.H., PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas (2005) Oncogene., 24, pp. 1477-1480; 
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Kinzler, K.W., High frequency of mutations of the PIK3CA gene in human cancers (2004) Science., 304, p. 554; 
Cizkova, M., Susini, A., Vacher, S., Cizeron-Clairac, G., Andrieu, C., Driouch, K., Fourme, E., Bieche, I., PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups (2012) Breast Cancer Res., 14, p. R28; 
Kalinsky, K., Jacks, L.M., Heguy, A., Patil, S., Drobnjak, M., Bhanot, U.K., Hedvat, C.V., Moynahan, M.E., PIK3CA mutation associates with improved outcome in breast cancer (2009) Clin Cancer Res., 15, pp. 5049-5059; 
Shah, S.P., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., Turashvili, G., Khattra, J., The clonal and mutational evolution spectrum of primary triple-negative breast cancers (2012) Nature., 486, pp. 395-399; 
Cheang, M.C., Martin, M., Nielsen, T.O., Prat, A., Voduc, D., Rodriguez-Lescure, A., Ruiz, A., Carrasco, E., Defining breast cancer intrinsic subtypes by quantitative receptor expression (2015) Oncologist., 20, pp. 474-482; 
Fountzilas, G., Skarlos, D., Dafni, U., Gogas, H., Briasoulis, E., Pectasides, D., Papadimitriou, C., Timotheadou, E., Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with highrisk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group (2005) Ann Oncology., 16, pp. 1762-1771; 
Gogas, H., Dafni, U., Karina, M., Papadimitriou, C., Batistatou, A., Bobos, M., Kalofonos, H.P., Briasoulis, E., Postoperative dosedense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial (2012) Breast Cancer Res Treat., 132, pp. 609-619; 
Fountzilas, G., Dafni, U., Papadimitriou, C., Timotheadou, E., Gogas, H., Eleftheraki, A.G., Xanthakis, I., Markopoulos, C., Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial (2014) BMC cancer., 14, p. 515; 
Walerych, D., Napoli, M., Collavin, L., Del Sal, G., The rebel angel: mutant p53 as the driving oncogene in breast cancer (2012) Carcinogenesis., 33, pp. 2007-2017; 
Loi, S., Michiels, S., Lambrechts, D., Fumagalli, D., Claes, B., Kellokumpu-Lehtinen, P.L., Bono, P., Sotiriou, C., Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer (2013) J Nat Cancer Inst., 105, pp. 960-967; 
Zardavas, D., Phillips, W.A., Loi, S., PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data (2014) Breast Cancer Res., 16, p. 201; 
Neilsen, P.M., Noll, J.E., Suetani, R.J., Schulz, R.B., Al-Ejeh, F., Evdokiou, A., Lane, D.P., Callen, D.F., Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome (2011) Oncotarget., 2, pp. 1203-1217; 
Berns, E.M., van Staveren, I.L., Look, M.P., Smid, M., Klijn, J.G., Foekens, J.A., Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer (1998) Br J Cancer., 77, pp. 1130-1136; 
Sato, K., Hara, T., Ohya, M., The code structure of the p53 DNA-binding domain and the prognosis of breast cancer patients (2013) Bioinformatics., 29, pp. 2822-2825; 
Hill, K.A., Sommer, S.S., p53 as a mutagen test in breast cancer (2002) Environ Mol Mutagen., 39, pp. 216-227; 
Olivier, M., Hainaut, P., TP53 mutation patterns in breast cancers: searching for clues of environmental carcinogenesis (2001) Semin Cancer Biol., 11, pp. 353-360; 
Curtis, C., Shah, S.P., Chin, S.F., Turashvili, G., Rueda, O.M., Dunning, M.J., Speed, D., Haffari, G., The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups (2012) Nature., 486, pp. 346-352; 
Bastien, R.R., Rodriguez-Lescure, A., Ebbert, M.T., Prat, A., Munarriz, B., Rowe, L., Miller, P., Wall, D., PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers (2012) BMC Med Genomics., 5, p. 44; 
Bertheau, P., Turpin, E., Rickman, D.S., Espie, M., de Reynies, A., Feugeas, J.P., Plassa, L.F., Marty, M., Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicincyclophosphamide regimen (2007) PLoS medicine., 4, p. e90; 
Varna, M., Lehmann-Che, J., Turpin, E., Marangoni, E., El-Bouchtaoui, M., Jeanne, M., Grigoriu, C., Janin, A., p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors (2009) Int J Cancer., 124, pp. 991-997; 
Aas, T., Borresen, A.L., Geisler, S., Smith-Sorensen, B., Johnsen, H., Varhaug, J.E., Akslen, L.A., Lonning, P.E., Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients (1996) Nat Med., 2, pp. 811-814; 
Borresen, A.L., Andersen, T.I., Eyfjord, J.E., Cornelis, R.S., Thorlacius, S., Borg, A., Johansson, U., Hartman, S., TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains (1995) Genes, Chromosomes Cancer., 14, pp. 71-75; 
Geisler, S., Lonning, P.E., Aas, T., Johnsen, H., Fluge, O., Haugen, D.F., Lillehaug, J.R., Borresen-Dale, A.L., Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer (2001) Cancer Resh., 61, pp. 2505-2512; 
Bayraktar, S., Royce, M., Stork-Sloots, L., de Snoo, F., Gluck, S., Molecular subtyping predicts pathologic tumor response in early-stage breast cancer treated with neoadjuvant docetaxel plus capecitabine with or without trastuzumab chemotherapy (2014) Med Oncol., 31, p. 163; 
Gluck, S., Ross, J.S., Royce, M., McKenna, E.F., Jr. Perou, C.M., Avisar, E., Wu, L., TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine +/-trastuzumab (2012) Breast Cancer Res Treat., 132, pp. 781-791; 
Hoadley, B.N., (2014), KAB WTP Mutational analysis of CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for H.E.R2-positive breast cancer. S3-06Berns, K., Horlings, H.M., Hennessy, B.T., Madiredjo, M., Hijmans, E.M., Beelen, K., Linn, S.C., van de Vijver, M.J., A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer (2007) Cancer cell., 12, pp. 395-402; 
Kataoka, Y., Mukohara, T., Shimada, H., Saijo, N., Hirai, M., Minami, H., Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines (2010) Ann Oncol., 21, pp. 255-262; 
Moasser, M.M., Two dimensions in targeting HER2 (2014) J Clin Oncol., 32, pp. 2074-2077; 
Joensuu, H., Kellokumpu-Lehtinen, P.L., Bono, P., Alanko, T., Kataja, V., Asola, R., Utriainen, T., Flander, M., Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer (2006) N Enlg J Med., 354, pp. 809-820; 
Romond, E.H., Perez, E.A., Bryant, J., Suman, V.J., Geyer, C.E., Jr., Davidson, N.E., Tan-Chiu, E., Fehrenbacher, L., Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer (2005) N Enlg J Med., 353, pp. 1673-1684; 
Pogue-Geile, K.L., Song, N., Jeong, J.H., Gavin, P.G., Kim, S.R., Blackmon, N.L., Finnigan, M., Geyer, C.E., Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial (2015) J Clin Oncol., 33, pp. 1340-1347; 
Cizkova, M., Dujaric, M.E., Lehmann-Che, J., Scott, V., Tembo, O., Asselain, B., Pierga, J.Y., Bieche, I., Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab (2013) Br J Cancer., 108, pp. 1807-1809; 
Gianni, L., Dafni, U., Gelber, R.D., Azambuja, E., Muehlbauer, S., Goldhirsch, A., Untch, M., Pedrini, J.L., Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial (2011) Lancet Oncology., 12, pp. 236-244; 
Guarneri, V., Dieci, M.V., Frassoldati, A., Maiorana, A., Ficarra, G., Bettelli, S., Tagliafico, E., Musolino, A., Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2- Positive Breast Cancer (2015) Oncologist., 20, pp. 1001-1010; 
Loibl, S., von Minckwitz, G., Schneeweiss, A., Paepke, S., Lehmann, A., Rezai, M., Zahm, D.M., Huober, J., 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 (2014) J Clin Oncol., 32, pp. 3212-3220; 
Majewski, I.J., Nuciforo, P., Mittempergher, L., Bosma, A.J., Eidtmann, H., Holmes, E., Sotiriou, C., de la Pena, L., PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer (2015) J Clin Oncol., 33, pp. 1334-1339; 
Fountzilas, G., Dafni, U., Bobos, M., Batistatou, A., Kotoula, V., Trihia, H., Malamou-Mitsi, V., Gogas, H., Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel (2012) PloS one., 7; 
Badve, S., Dabbs, D.J., Schnitt, S.J., Baehner, F.L., Decker, T., Eusebi, V., Fox, S.B., Richardson, A.L., Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists (2011) Mod Pathol., 24, pp. 157-167; 
Kotoula, V., Charalambous, E., Biesmans, B., Malousi, A., Vrettou, E., Fountzilas, G., Karkavelas, G., Targeted KRAS mutation assessment on patient tumor histologic material in real time diagnostics (2009) PloS one., 4; 
Kotoula, V., Lyberopoulou, A., Papadopoulou, K., Charalambous, E., Alexopoulou, Z., Gakou, C., Lakis, S., Fountzilas, G., Evaluation of two highly-multiplexed custom panels for massively parallel semiconductor sequencing on paraffin DNA (2015) PloS one., 10; 
Soussi, T., Wiman, K.G., TP53: an oncogene in disguise (2015) Cell Death Differ., 22, pp. 1239-1249; 
Thusberg, J., Olatubosun, A., Vihinen, M., Performance of mutation pathogenicity prediction methods on missense variants (2011) Hum Mutat., 32, pp. 358-368; 
Martelotto, L.G., Ng, C.K., De Filippo, M.R., Zhang, Y., Piscuoglio, S., Lim, R.S., Shen, R., Weigelt, B., Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations (2014) Genome Biol., 15, p. 484; 
Papaxoinis, G., Kotoula, V., Alexopoulou, Z., Kalogeras, K.T., Zagouri, F., Timotheadou, E., Gogas, H., Papakostas, P., Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study (2015) PloS one., 10; 
Thor, A.D., Berry, D.A., Budman, D.R., Muss, H.B., Kute, T., Henderson, I.C., Barcos, M., Liu, E.T., erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer (1998) J Nat Cancer Inst., 90, pp. 1346-1360; 
McShane, L.M., Hayes, D.F., Publication of tumor marker research results: the necessity for complete and transparent reporting (2012) J Clin Oncol., 30, pp. 4223-4232
},
	month = {2016},
	pages = {32731 - 32753},
	abstract = {Background: We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era. Results: TP53 and PIK3CA mutations were found in 380 (21.5\%) and 458 (25.9\%) cases, respectively, including 104 (5.9\%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5\%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009). Materials and Methods: TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10\% positivity cut-off). Conclusions: TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.},
	keywords = {Early breast cancer, P53 immunohistochemistry, PIK3CA mutations, TP53 mutations, Trastuzumab},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84973538526\&doi=10.18632\%2foncotarget.9022\&partnerID=40\&md5=f6bf9eb704ffadcba2695abb646d4ead},
	author = {Fountzilas, G. and Giannoulatou, E. and Alexopoulou, Z. and Zagouri, F. and Timotheadou, E. and Papadopoulou, K. and Lakis, S. and Bobos, M. and Poulios, C. and Sotiropoulou, M. and Lyberopoulou, A. and Gogas, H. and Pentheroudakis, G. and Pectasides, D. and Koutras, A. and Christodoulou, C. and Papandreou, C. and Samantas, E. and Papakostas, P. and Kosmidis, P. and Bafaloukos, D. and Karanikiotis, C. and Dimopoulos, M.-A. and Kotoula, V.}
}
