This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berns, E. M. J. J. Articles by Klijn, J. G. M. Search for Related Content PubMed PubMed Citation Articles by Berns, E. M. J. J. Articles by Klijn, J. G. M.

Complete Sequencing of TP53 Predicts Poor Response to Systemic Therapy of Advanced Breast Cancer¹

Department of Medical Oncology, Division of Endocrine Oncology [E. M. J. J. B., J. A. F., S. C. H-L., M. P. L., I. L. v. S., M. E. M-v. G., C. J. C. C., H. P., J. G. M. K.] and Department of Statistics [W. L. J. v. P.], Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/University Hospital Rotterdam, 3008 AE Rotterdam, the Netherlands; Departments of Human and Clinical Genetics [R. V., P. D., B. B.] and Pathology [C. C.], Leiden University Medical Center, Leiden 2300, the Netherlands; and Amersham Pharmacia Biotech, Upsala, Sweden [M. I.]

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2–11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12–0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09–1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13–0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

This article has been cited by other articles:

				S. H. Shirley, J. E. Rundhaug, J. Tian, N. Cullinan-Ammann, I. Lambertz, C. J. Conti, and R. Fuchs-Young Transcriptional Regulation of Estrogen Receptor-{alpha} by p53 in Human Breast Cancer Cells Cancer Res., April 15, 2009; 69(8): 3405 - 3414. [Abstract] [Full Text] [PDF]

				B. J. Chae, J. S. Bae, A. Lee, W. C. Park, Y. J. Seo, B. J. Song, J. S. Kim, and S. S. Jung p53 as a Specific Prognostic Factor in Triple-negative Breast Cancer Jpn. J. Clin. Oncol., April 1, 2009; 39(4): 217 - 224. [Abstract] [Full Text] [PDF]

				F.-C. Bidard, M.-C. Matthieu, P. Chollet, I. Raoefils, C. Abrial, J. Domont, M. Spielmann, S. Delaloge, F. Andre, and F. Penault-Llorca p53 status and efficacy of primary anthracyclines/alkylating agent-based regimen according to breast cancer molecular classes Ann. Onc., July 1, 2008; 19(7): 1261 - 1265. [Abstract] [Full Text] [PDF]

				R A Walker Immunohistochemical markers as predictive tools for breast cancer J. Clin. Pathol., June 1, 2008; 61(6): 689 - 696. [Abstract] [Full Text] [PDF]

				C. Xue, M. Haber, C. Flemming, G. M. Marshall, R. B. Lock, K. L. MacKenzie, K. V. Gurova, M. D. Norris, and A. V. Gudkov p53 Determines Multidrug Sensitivity of Childhood Neuroblastoma Cancer Res., November 1, 2007; 67(21): 10351 - 10360. [Abstract] [Full Text] [PDF]

				L. G. Burdelya, E. A. Komarova, J. E. Hill, T. Browder, N. D. Tararova, L. Mavrakis, P. E. DiCorleto, J. Folkman, and A. V. Gudkov Inhibition of p53 Response in Tumor Stroma Improves Efficacy of Anticancer Treatment by Increasing Antiangiogenic Effects of Chemotherapy and Radiotherapy in Mice Cancer Res., October 1, 2006; 66(19): 9356 - 9361. [Abstract] [Full Text] [PDF]

				J. W. Watters and C. J. Roberts Developing gene expression signatures of pathway deregulation in tumors. Mol. Cancer Ther., October 1, 2006; 5(10): 2444 - 2449. [Abstract] [Full Text] [PDF]

				E. Dahl, G. Kristiansen, K. Gottlob, I. Klaman, E. Ebner, B. Hinzmann, K. Hermann, C. Pilarsky, M. Durst, M. Klinkhammer-Schalke, et al. Molecular Profiling of Laser-Microdissected Matched Tumor and Normal Breast Tissue Identifies Karyopherin {alpha}2 as a Potential Novel Prognostic Marker in Breast Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 3950 - 3960. [Abstract] [Full Text] [PDF]

				M. Lacroix, R.-A. Toillon, and G. Leclercq p53 and breast cancer, an update. Endocr. Relat. Cancer, June 1, 2006; 13(2): 293 - 325. [Abstract] [Full Text] [PDF]

				A. W. Tolcher, D. Hao, J. de Bono, A. Miller, A. Patnaik, L. A. Hammond, L. Smetzer, J. Van Wart Hood, J. Merritt, E. K. Rowinsky, et al. Phase I, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered Ad5CMV-p53, an Adenoviral Vector Containing the Wild-Type p53 Gene, in Patients With Advanced Cancer J. Clin. Oncol., May 1, 2006; 24(13): 2052 - 2058. [Abstract] [Full Text] [PDF]

				M. Olivier, A. Langerod, P. Carrieri, J. Bergh, S. Klaar, J. Eyfjord, C. Theillet, C. Rodriguez, R. Lidereau, I. Bieche, et al. The Clinical Value of Somatic TP53 Gene Mutations in 1,794 Patients with Breast Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1157 - 1167. [Abstract] [Full Text] [PDF]

				L. D. Miller, J. Smeds, J. George, V. B. Vega, L. Vergara, A. Ploner, Y. Pawitan, P. Hall, S. Klaar, E. T. Liu, et al. From The Cover: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival PNAS, September 20, 2005; 102(38): 13550 - 13555. [Abstract] [Full Text] [PDF]

				J. Andersson, L. Larsson, S. Klaar, L. Holmberg, J. Nilsson, M. Inganas, G. Carlsson, J. Ohd, C.-M. Rudenstam, B. Gustavsson, et al. Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF Ann. Onc., May 1, 2005; 16(5): 743 - 748. [Abstract] [Full Text] [PDF]

				P. Daftarian, G.-Y. Song, S. Ali, M. Faynsod, J. Longmate, D. J. Diamond, and J. D. I. Ellenhorn Two Distinct Pathways of Immuno-Modulation Improve Potency of p53 Immunization in Rejecting Established Tumors Cancer Res., August 1, 2004; 64(15): 5407 - 5414. [Abstract] [Full Text] [PDF]

				P. J. Wild, A. Reichle, R. Andreesen, G. Rockelein, W. Dietmaier, J. Ruschoff, H. Blaszyk, F. Hofstadter, and A. Hartmann Microsatellite Instability Predicts Poor Short-Term Survival in Patients with Advanced Breast Cancer after High-Dose Chemotherapy and Autologous Stem-Cell Transplantation Clin. Cancer Res., January 15, 2004; 10(2): 556 - 564. [Abstract] [Full Text] [PDF]

				S. Geisler, A.-L. Borresen-Dale, H. Johnsen, T. Aas, J. Geisler, L. A. Akslen, G. Anker, and P. E. Lonning TP53 Gene Mutations Predict the Response to Neoadjuvant Treatment with 5-Fluorouracil and Mitomycin in Locally Advanced Breast Cancer Clin. Cancer Res., November 15, 2003; 9(15): 5582 - 5588. [Abstract] [Full Text] [PDF]

				M. Phelps, M. Darley, J. N. Primrose, and J. P. Blaydes p53-independent Activation of the hdm2-P2 Promoter through Multiple Transcription Factor Response Elements Results in Elevated hdm2 Expression in Estrogen Receptor {alpha}-positive Breast Cancer Cells Cancer Res., May 15, 2003; 63(10): 2616 - 2623. [Abstract] [Full Text] [PDF]

				E. M. J. J. Berns, J. G. M. Klijn, M. P. Look, N. Grebenchtchikov, R. Vossen, H. Peters, A. Geurts-Moespot, H. Portengen, I. L. van Staveren, M. E. Meijer-van Gelder, et al. Combined Vascular Endothelial Growth Factor and TP53 Status Predicts Poor Response to Tamoxifen Therapy in Estrogen Receptor-positive Advanced Breast Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1253 - 1258. [Abstract] [Full Text] [PDF]

				H. Bonnefoi, S. Diebold-Berger, P. Therasse, A. Hamilton, M. van de Vijver, G. MacGrogan, L. Shepherd, N. Amaral, C. Duval, R. Drijkoningen, et al. Locally advanced/inflammatory breast cancers treated with intensive epirubicin-based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5-year clinical outcome? Ann. Onc., March 1, 2003; 14(3): 406 - 413. [Abstract] [Full Text] [PDF]

				P. S. Bernard and C. T. Wittwer Real-Time PCR Technology for Cancer Diagnostics Clin. Chem., August 1, 2002; 48(8): 1178 - 1185. [Abstract] [Full Text] [PDF]

				H. Millward, W. Samowitz, C. T. Wittwer, and P. S. Bernard Homogeneous Amplification and Mutation Scanning of the p53 Gene Using Fluorescent Melting Curves Clin. Chem., August 1, 2002; 48(8): 1321 - 1328. [Abstract] [Full Text] [PDF]

				K. Conway, S. N. Edmiston, L. Cui, S. S. Drouin, J. Pang, M. He, C.-K. Tse, J. Geradts, L. Dressler, E. T. Liu, et al. Prevalence and Spectrum of p53 Mutations Associated with Smoking in Breast Cancer Cancer Res., April 1, 2002; 62(7): 1987 - 1995. [Abstract] [Full Text] [PDF]

				T. Sorlie, C. M. Perou, R. Tibshirani, T. Aas, S. Geisler, H. Johnsen, T. Hastie, M. B. Eisen, M. van de Rijn, S. S. Jeffrey, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications PNAS, September 11, 2001; 98(19): 10869 - 10874. [Abstract] [Full Text] [PDF]

				N. Keshelava, J. J. Zuo, P. Chen, S. N. Waidyaratne, M. C. Luna, C. J. Gomer, T. J. Triche, and C. P. Reynolds Loss of p53 Function Confers High-Level Multidrug Resistance in Neuroblastoma Cell Lines Cancer Res., August 1, 2001; 61(16): 6185 - 6193. [Abstract] [Full Text] [PDF]

				H. Elsaleh, B. Powell, K. McCaul, F. Grieu, R. Grant, D. Joseph, and B. Iacopetta P53 Alteration and Microsatellite Instability Have Predictive Value for Survival Benefit from Chemotherapy in Stage III Colorectal Carcinoma Clin. Cancer Res., May 1, 2001; 7(5): 1343 - 1349. [Abstract] [Full Text]

				S. Geisler, P. E. Lønning, T. Aas, H. Johnsen, O. Fluge, D. F. Haugen, J. R. Lillehaug, L. A. Akslen, and A.-L. Børresen-Dale Influence of TP53 Gene Alterations and c-erbB-2 Expression on the Response to Treatment with Doxorubicin in Locally Advanced Breast Cancer Cancer Res., March 1, 2001; 61(6): 2505 - 2512. [Abstract] [Full Text]