Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: Current status and future directions

Clinical Breast Cancer

Volumn 10, Issue SUPPL. 3, 2010, Pages

  Bartlett, John ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

HER2; PI3KCA; PTEN; TSC1; TSC2

Indexed keywords

BIOLOGICAL MARKER; DNA; EPIDERMAL GROWTH FACTOR RECEPTOR 2; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL DEPENDENT KINASE 1; PHOSPHOTRANSFERASE; PROTEIN KINASE B; RHEB PROTEIN; TAMOXIFEN; TRASTUZUMAB; UNCLASSIFIED DRUG;

AKT 1 GENE; AKT 2 GENE; AKT 3 GENE; BREAST CANCER; DRUG TARGETING; GENE; GENE EXPRESSION; GENE FUNCTION; GENE MUTATION; GENE SILENCING; HUMAN; PATIENT SELECTION; PDK 1 GENE; PI3KCA GENE; REVIEW; RHEB 1 GENE; RHEB 2 GENE; SIGNAL TRANSDUCTION; TREATMENT RESPONSE;

EID: 78649692667     PISSN: 15268209     EISSN: None     Source Type: Journal    
DOI: 10.3816/CBC.2010.s.017     Document Type: Article

References (77)

1. Mills G, Gonzalez-Angulo AM. Deciphering the role of the PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clinical Breast Cancer 2010. In press.
2. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4:988-1004.
3. O'Regan, RM. Evolving strategies for overcoming resistance to HER2-directed therapy: Targeting the PI3K/Akt/mTOR pathway. Clinical Breast Cancer 2010. In press.
4. Johnston, SR. Targeting endocrine resistance: Is there a role for mTOR inhibition? Clinical Breast Cancer 2010. In press.
5. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PI3KCA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68:6084-91.
6. Garcia JM, Silva J, Pena C, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 2004; 41:117-24.
7. Kirkegaard T, Witton CJ, Edwards J, et al. Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH. Histopathology 2010; 56:203-11.
8. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, et al. The emerging mechanisms of isoform-specific PI3K signaling. Nat Rev Mol Cell Biol 2010; 11:329-41.
9. Wu G, Xing M, Mambo E, et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 2005; 7:R609-16.
10. Board RE, Thelwell NJ, Ravetto P F, et al. Multiplexed assays for detection of mutations in PIK3CA. Clin Chem 2008; 54:757-60.
11. Engelman JA. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9:550-62.
12. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 2010; 119:379-90.
13. Lopez-Knowles E, O'Toole SA, Mcneil CM, et al. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 2010; 126:1121-31.
14. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase Alpha catalytic subunit kinase domain mutations impart a favorable prognosis on estrogen receptor positive breast cancer through a mechanism that is independent of responsiveness to endocrine treatment. Cancer Res 2009; 69(2 suppl): (abstract 6060).
15. Whyte DB, Holbeck SL. Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Commun 2006; 340:469-75.
16. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 2000; 346:561-76.
17. Peifer C, Alessi DR. New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. Biochem J 2009; 417:e5-7.
18. Dillon RL, Marcotte R, Hennessy BT, et al. Akt1 and Akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res 2009; 69:5057-64.
19. Kirkegaard T, Witton CJ, McGlynn LM, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 2005; 207:139-46.
20. Ellis MJ, Tao Y, Lin L, et al. High nuclear p27(kip1) levels predicts sensitivity to neoadjuvant letrozole in ER plus breast cancer independent of pAKT levels, PI3KCA mutation status and cell cycle effects: a potential role for p27(kip1) in predicting enhanced autophagocytosis in response to aromatase inhibitor therapy. Breast Cancer Res Treat 2006; 100:S187.
21. Tokunaga E, Kimura Y, Oki E, et al. Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer 2006; 118:284-9.
22. Panigrahi AR, Pinder SE, Chan SY, et al. The role of PTEN and its signaling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. J Pathol 2004; 204:93-100.
23. Sabine VS, Sims AH, Macaskill EJ, et al. Transcriptional profiling of patient-matched ER-positive breast cancer tissue from post-menopausal women treated with neoadjuvant RAD001. Cancer Res 2009; 69(2 suppl): (abstract 2035).
24. Generali D, Fox SB, Brizzi M P, et al. Down-regulation of phosphatidylinositol 3 '-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. Clin Cancer Res 2008; 14:2673-80.
25. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene 2008; 27:5443-53.
26. Jones N, Bonnet F, Lafitte M, et al. Comprehensive analysis of PTEN allelic status confirms gross genomic rearrangement as the main mechanism of PTEN inactiva-tion in sporadic breast carcinomas. Cancer Res 2009; 69(24 suppl): (abstract 3151).
27. Vitolo MI, Weiss MB, Szmacinski M, et al. Deletion of PTEN promotes tumori-genic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells. Cancer Res 2009; 69:8275-83.
28. Bonnet F, Lafitte M, MacGrogan G, et al. Characterization of PTEN allelic status in a series of sporadic breast carcinomas demonstrating loss of 10q23.3 region by array-CGH. Cancer Res 2009; 69(2 suppl): (abstract 4072).
29. Alimonti A, Carracedo A, Clohessy JG, et al. Subtle variations in PTEN dose determine cancer susceptibility. Nat Genet 2010; 42:454-8.
30. Miller T W, Perez-Torres M, Narasanna A, et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-i receptor signaling to promote anti estrogen resistance in breast cancer. Cancer Res 2009; 69:4192-201.
31. Jiang BH, Liu LZ. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics 2008; 1784:150-8
32. Byun DS, Cho K, Ryu BK, et al. Frequent monoallelic deletion of PTEN and its reciprocal association with PIk3CA amplification in gastric carcinoma. Int J Cancer 2003; 104:318-27.
33. Tsutsui S, Inoue H, Yasuda K, et al. Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology 2005; 68:398-404.
34. Fabi A, Metro G, Di Benedetto A, et al. Clinical Significance of PTEN and p-Akt co-expression in HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Oncology 2010; 78:141-9.
35. Wu Y, Zhou B P. Kinases meet at TSC. Cell Res 2007; 17:971-3.
36. Ma L, Teruya-Feldstein J, Bonner P, et al. Identification of S664 TSC2 phos-phorylation as a marker for extracellular signal-regulated kinase-mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 2007; 67:7106-12.
37. Huang J, Dibble CC, Matsuzaki M, et al. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008; 28:4104-15.
38. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell 2007; 12:487-502.
39. Jiang WG, Sampson J, Martin TA, et al. Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: The role of promoter methylation of TSC genes. Eur J Cancer 2005; 41:1628-36.
40. Aspuria PJ, Tamanoi F. The Rheb family of GTP-binding proteins. Cell Signal 2004; 16:1105-12.
41. Spears M, Munro A F, Taylor KJ, et al. The use of proximity ligation assay to identify HER2:HER3 heterodimers in early breast cancers. Cancer Res 2009; 69(2 suppl): (abstract 2068).
42. Workman P, Clarke PA, Raynaud FI, et al. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res 2010; 70:2146-57.
43. Copp J, Manning G, Hunter T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 2009; 69:1821-7.
44. Fujita T, Doihara H, Kawasaki K, et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006; 94:247-52.
45. Koscielny S. Why most gene expression signatures of tumors have not been useful in the clinic. Sci Transl Med 2010; 2:14ps2.
46. Desmedt C, Sotiriou C. When should I start using a new biomarker: Focus on expression arrays (vol 5, pg 97, 2007). Eur J Cancer 2008; 44:326-8.
47. Creighton CJ, Osborne CK, van de Vijver M, et al. Gene expression profiles of ER+/PR-breast cancer are associated with genomic instability and Akt/mTOR signaling, and predict poor patient outcome better than clinically assigned PR status. Breast Cancer Res Treat 2007; 106:S10-1.
48. Sotiriou C, Loi S, Haibe-Kains B, et al. PIK3CA mutation-associated gene expression signature correlates with deactivation of the PI3K pathway and predicts benefit to endocrine therapy in high-risk ER plus (luminal B) breast cancers (BC). Proceedings of the American Association for Cancer Research Annual Meeting 2009; 50:456.
49. Loi S, Haibe-Kains B, Lallemand F, et al. Pik3Ca, Akt1 mutation and HER2 amplification gene signatures (Gs) suggest predominantly negative feedback inhibition of Pi3K/Akt pathway in human breast cancer (Bc). Ann Oncol 2009; 20:45.
50. Creighton CJ, Fu X, Hilsenbeck SG, et al. Gene expression signatures of PI3K signaling are associated with low ER levels and the luminal B subtype in breast cancer cell lines and human tumors, and in patients predicts poor outcome. Cancer Res 2009; 69(24 suppl); (abstract 31).
51. Sims AH, Ong KR, Clarke RB, et al. High-throughput genomic technology in research and clinical management of breast cancer-exploiting the potential of gene expression profiling: is it ready for the clinic? Breast Cancer Res 2006; 8:214.
52. Kitchen RR, Sabine VS, Sims AH, et al. Correcting for intra-experiment variation in Illumina BeadChip data is necessary to generate robust gene-expression profiles. BMC Genomics 2010; 24:134.
53. Sims AH. Bioinformatics and breast cancer: what can high-throughput genomic approaches actually tell us? J Clin Pathol 2009; 62:879-85.
54. Ma XJ, Salunga R, Dahiya S, et al. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res 2008; 14:2601-8.
55. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24:3726-34.
56. Ring BZ, Seitz RS, Beck R, et al. Novel prognostic immunohistochemical bio-marker panel for estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24:3039-47.
57. Hall PA, Going JJ. Predicting the future: A critical appraisal of cancer prognosis studies. Histopathology 1999; 35:489-94.
58. Taube SE, Clark GM, Dancey JE, et al. A perspective on challenges and issues in biomarker development and drug and biomarker co-development. J Natl Cancer Inst 2009; 101:1453-63.
59. Dancey JE, Dobbin KK, Groshen S, et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res 2010; 16:1745-55.
60. Simon RM, Paik S, Hayes D F. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101:1446-52.
61. Simon R. Development and validation of biomarker classifiers for treatment selection. J Statist Plann Inference 2008; 138:308-20.
62. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 2006; 100:229-35.
63. Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol 2009; 27:4027-34
64. Leyland-Jones BR, Ambrosone CB, Bartlett J, et al. Recommendations for collection and handling of specimens from group breast cancer clinical trials. J Clin Oncol 2008; 26:5638-44
65. Wolff AC, Hammond ME, Schwartz JN, et al. American society of clinical oncology/college of american pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25:118-45.
66. Press M F, Sauter G, Bernstein L, et al. Diagnostic evaluation of HER-2 as a molecular target: An assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 2005; 11:6598-607.
67. Bartlett JM, Munro A F, Dunn JA, et al. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol 2010; 11:266-74.
68. Bartlett JM, Desmedt C, Munro A, et al. Chromosome 17 polysomy: a unifying hypothesis underlying benefit from adjuvant anthracyclines? Cancer Res 2009; 69:364S.
69. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93:387-91.
70. Bartlett JM, Ellis IO, Dowsett M et al. Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J Clin Oncol 2007; 25:4423-30.
71. Viale G, Regan MM, Dell'Orto P, et al. Central review of ER, PgR and HER2 in BIG 1-98 evaluating letrozole vs. letrozole followed by tamoxifen vs. tamoxifen followed by letrozole as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. Cancer Res 2009; 69(24 suppl): (abstract 76).
72. Dowsett M, Allred C, Knox J, et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the arimidex, tamoxifen, alone or in combination trial. J Clin Oncol 2008; 26:1059-65
73. Altman DG. Suboptimal Analysis using "optimal" cutpoints. Br J Cancer 1998; 78:556-7.
74. Royston P, Altman DG. Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med 2006; 25:127-41.
75. Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall; 1999.
76. Riley RD, Sauerbrei W, Altman DG. Prognostic markers in cancer: the evolution of evidence from single studies to meta-analysis, and beyond. Br J Cancer 2009; 100:1219-29
77. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoad-juvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27:2630-7.