title: PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer.
abstract: Phosphatase and tensin homolog (PTEN) is a key modulator of trastuzumab sensitivity in HER2-overexpressing breast cancer. Because PTEN opposes the downstream signaling of phosphoinositide 3-kinase (PI3K), we investigated the role of PTEN and other components of the PI3K pathway in trastuzumab resistance. We analyzed the status of PTEN, p-AKT-Ser473, and p-p70S6K-Thr389 using immunohistochemistry. PIK3CA mutation status was analyzed by direct sequencing. Primary tumor tissue was available from 137 patients with HER2-overexpressing metastatic breast cancer who had received trastuzumab-based chemotherapy. We observed that each of the four biomarkers alone did not significantly correlate with trastuzumab response, whereas PTEN loss alone significantly correlated with shorter survival times (P = 0.023). PI3K pathway activation, defined as PTEN loss and/or PIK3CA mutation, was associated with a poor response to trastuzumab (P = 0.047) and a shorter survival time (P = 0.015). PTEN loss was significantly associated with a poor response to trastuzumab (P = 0.028) and shorter survival time (P = 0.008) in patients who had received first-line trastuzumab and in patients with estrogen receptor- (P = 0.029) and progesterone receptor-negative tumors (P = 0.033). p-AKT-Ser473 and p-p70S6K-Thr389 each had a limited correlation with trastuzumab response. When these markers were combined with PTEN loss, an increased correlation with patient outcome was observed. In conclusion, PI3K pathway activation plays a pivotal role in trastuzumab resistance. Our findings may facilitate the evaluation of tumor response to trastuzumab-based and targeted therapies.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Cesar
authors.initials: C
authors.lastname: Santa-Maria
authors.forename: Steven
authors.initials: S
authors.lastname: Stone
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001859:Bone Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015996:Survival Rate; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000068878:Trastuzumab; C484760:PIK3CA protein, human; C494929:PTEN protein, human
references.citation: Nat Rev Clin Oncol. 2010 Feb;7(2):98-107
references.pmid: 20027191
references.citation: Cancer Res. 2002 Jul 15;62(14):4132-41
references.pmid: 12124352
references.citation: Cancer Cell. 2009 May 5;15(5):353-5
references.pmid: 19411062
references.citation: Cancer Cell. 2009 May 5;15(5):429-40
references.pmid: 19411071
references.citation: Am J Pathol. 1999 Oct;155(4):1253-60
references.pmid: 10514407
references.citation: Am J Ther. 2005 May-Jun;12(3):243-53
references.pmid: 15891269
references.citation: Breast Cancer Res Treat. 2007 Mar;101(3):249-57
references.pmid: 17006756
references.citation: Biochim Biophys Acta. 2008 Dec;1786(2):105-13
references.pmid: 18375208
references.citation: Clin Cancer Res. 2003 Jan;9(1 Pt 2):511S-5S
references.pmid: 12538508
references.citation: Biochim Biophys Acta. 2000 Feb 14;1470(1):M21-35
references.pmid: 10656987
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):177-84
references.pmid: 19208461
references.citation: Nat Med. 2000 Apr;6(4):443-6
references.pmid: 10742152
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5883-8
references.pmid: 17908983
references.citation: Nat Clin Pract Oncol. 2009 Feb;6(2):93-104
references.pmid: 19107109
references.citation: Cancer Res. 2007 Feb 1;67(3):1170-5
references.pmid: 17283152
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: J Natl Cancer Inst. 1998 Sep 2;90(17):1262-9
references.pmid: 9731732
references.citation: J Clin Oncol. 2006 Jul 10;24(20):3245-51
references.pmid: 16829648
references.citation: Ann Oncol. 2009 Apr;20(4):648-54
references.pmid: 19188134
references.citation: Med Oncol. 2009;26(3):344-9
references.pmid: 19016009
references.citation: Nat Clin Pract Oncol. 2006 May;3(5):269-80
references.pmid: 16683005
references.citation: Cancer Cell. 2009 Jul 7;16(1):21-32
references.pmid: 19573809
references.citation: Cancer Res. 2005 Dec 1;65(23):10992-1000
references.pmid: 16322248
references.citation: Cancer Res. 2006 Feb 15;66(4):2028-37
references.pmid: 16489002
references.citation: Br J Cancer. 2006 Jan 30;94(2):247-52
references.pmid: 16404430
references.citation: Cancer Biol Ther. 2004 Aug;3(8):772-5
references.pmid: 15254419
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: Cancer Cell. 2007 Oct;12(4):395-402
references.pmid: 17936563
references.citation: J Clin Oncol. 2002 Mar 15;20(6):1480-90
references.pmid: 11896095
references.citation: Cancer Res. 2001 Jun 15;61(12):4744-9
references.pmid: 11406546
references.citation: Br J Cancer. 2007 Jul 16;97(2):218-22
references.pmid: 17622239
references.citation: Expert Opin Pharmacother. 2008 Oct;9(15):2583-601
references.pmid: 18803447
references.citation: Semin Oncol. 2003 Oct;30(5 Suppl 16):93-104
references.pmid: 14613030
references.citation: Histopathology. 2008 Sep;53(3):346-7
references.pmid: 18631198
references.citation: J Clin Oncol. 2002 Apr 1;20(7):1800-8
references.pmid: 11919237
references.citation: Breast Cancer Res Treat. 2005 May;91(2):187-201
references.pmid: 15868447
references.citation: N Engl J Med. 2005 Oct 20;353(16):1659-72
references.pmid: 16236737
references.citation: Clin Cancer Res. 2007 Jun 15;13(12):3577-84
references.pmid: 17575221
references.citation: Cancer Cell. 2004 Aug;6(2):117-27
references.pmid: 15324695
references.citation: Cancer Res. 2005 Apr 1;65(7):2554-9
references.pmid: 15805248
references.citation: N Engl J Med. 2005 Oct 20;353(16):1673-84
references.pmid: 16236738
references.citation: Mod Pathol. 2001 Jul;14(7):672-6
references.pmid: 11454999