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01-08-2008 | Original Article

Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas

Authors: Enrique Lerma, Lluis Catasus, Alberto Gallardo, Gloria Peiro, Carmen Alonso, Ignacio Aranda, Agusti Barnadas, Jaime Prat

Published in: Virchows Archiv | Issue 2/2008

Abstract

PIK3CA mutations at 9 and 20 exons were studied in a series of 56 selected aggressive breast carcinomas (BC): 27 with Her-2 over-expression and negativity for estrogen receptors (ER) and progesterone receptors (PR), and 29 “triple negative” BC (negative for ER, PR and Her-2). Also, immunohistochemical studies of p53, ki-67, Her-1 (EGFR), pIGF-1R, PTEN, p110α, and pAkt were performed. Six mutations in exon 20 PIK3CA were identified among the 27 Her-2 positive BC, whereas only one exon 9 PIK3CA mutation was detected in a triple negative tumor (p = 0.035). Furthermore, PIK3CA mutations were associated with p110α over-expression (p = 0.001). Overall survival was shorter in cases with PIK3CA mutations (p = 0.015 in all series; and p = 0.041 for Her-2+ tumors), although multivariate analyses did not show statistical differences. No statistical significance was related with disease-free survival. Exon 20 PIK3CA mutations are relatively frequent in Her-2+ tumors and shorten survival, whereas neither exons 9 and 20 mutations seem related with “triple negative” breast carcinomas.

Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775PubMedCrossRef

Bader AG, Kang S, Zhao L, Vogt PK (2005) Oncogenic PIK3 deregulates transcription and translation. Nat Rev Cancer 5:921–929PubMedCrossRef

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 carcinoma. Clin Cancer Res 13:6064–6069PubMedCrossRef

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

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 64:7678–7681PubMedCrossRef

Ferlay P, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592PubMedCrossRef

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

Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459PubMedCrossRef

Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, Barlett JM (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–146PubMedCrossRef

10.

Hollestelle A, Elstrodt F, Nagel JH, Kallemeijn WW, Schutte M (2007) Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res 5:195–201PubMedCrossRef

11.

Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY (2008) PIK3CA exon 20 mutation is independently associated with poor prognosis in breast cancer patients. Ann Surg Oncol Jan 9 PMID:18183466

12.

Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24:1477–1480PubMedCrossRef

13.

Lerma E, Peiro G, Ramon y Cajal T, Fernandez S, Martinez D, Pons C, Muñoz F, Sabate JM, Alonso C, Ojeda B, Prat J, Barnadas A (2007) Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal like breast carcinomas). Modern Pathology 20:1200–1207PubMedCrossRef

14.

Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, Boyd J (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11:2875–2878PubMedCrossRef

15.

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

16.

Liang K, Lu Y, Li X, Glazer RI, Mills GB, Fan Z (2006) Differential roles of phosphoinositide-dependent protein kinase-1 and Akt1 expression and phosphorylation in breast cancer cell resistance to paclitaxel, doxorubicin, and gemcitabine. Mol Pharmacol 70:1045–1052PubMedCrossRef

17.

Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S (2007) Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 3:408–414CrossRef

18.

Massion PP, Taflan PM, Shyr Y, Rahman SM, Yildiz P, Shakthour B, Edgerton ME, Ninan M, Andersen JJ, Gonzalez AL (2004) Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med 170:1088–1094PubMedCrossRef

19.

Pérez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjöld B, Rutqvist LE, Skoog L, Stål O (2007) PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13:3577–3584PubMedCrossRef

20.

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumors. Nature 406:747–752PubMedCrossRef

21.

Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmström P, Memeo L, Isola J, Bendahl PO, Rosen N, Hibshoosh H, Ringnér M, Borg A, Parsons R (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A 104:7564–7569PubMedCrossRef

22.

Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559PubMedCrossRef

23.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554PubMedCrossRef

24.

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRef

25.

Stephens L, Williams R, Hawkins P (2003) Phosphoinositide 3-kinases as drug targets in cancer. Curr Opinion in Pharmacology 5:357–365CrossRef

26.

van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene expression signature as a predictor of survival in breast cancer. N Eng J Med 347:1999–2009CrossRef

27.

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

28.

Weinberg OK, Marquez-Garban DC, Pietras RJ (2005) New approaches to reverse resistance to hormonal therapy in human breast cancer. Drug Resist Updates 8:219–233CrossRef

29.

Whyte DB, Holbeck SL (2006) Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Comunn 340:469–475CrossRef

30.

Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S, Trink B, Sidransky D (2005) Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7:R609–R616PubMedCrossRef

Title: Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas
Authors: Enrique Lerma
Lluis Catasus
Alberto Gallardo
Gloria Peiro
Carmen Alonso
Ignacio Aranda
Agusti Barnadas
Jaime Prat
Publication date: 01-08-2008
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 2/2008
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-008-0643-4

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Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas

Abstract

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Springer Medicine

Abstract

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