The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Lauring receives support from the Susan G. Komen for the Cure Career Catalyst Grant funded by Charlotte R. Nelson, the Flight Attendant Medical Research Institute, the Avon Foundation, and the Department of Defense Breast Cancer Research Program. Dr. Park receives support from the Breast Cancer Research Foundation, the Flight Attendant Medical Research Institute, the Avon Foundation, and the National Institutes of Health. Dr. Wolff receives support from a Susan G. Komen for the Cure Scholars Grant and from the Breast Cancer Research Foundation. This work is also supported in part by the NCI Cancer Center Support Grant P30 CA006973.
Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network
Ms. Green has disclosed that she has no relevant financial relationships.
Nicole B. Harrold, BS, Manager, Continuing Education and Grants
Ms. Harrold has disclosed that she has no relevant financial relationships.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations
Ms. Gregory has disclosed that she has no relevant financial relationships.
Stephens PJ, Tarpey PS, Davies H et al.. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012;486:400-404.
Bachman KE, Argani P, Samuels Y et al.. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004;3:772-775.
Saal LH, Holm K, Maurer M et al.. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005;65:2554-2559.
Lauring J, Cosgrove DP, Fontana S et al.. Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations. Oncogene 2010;29:2337-2345.
Carpten JD, Faber AL, Horn C et al.. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-444.
Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al.. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008;68:6084-6091.
Isakoff SJ, Engelman JA, Irie HY et al.. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 2005;65:10992-11000.
Gustin JP, Karakas B, Weiss MB et al.. Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci U S A 2009;106:2835-2840.
Zhao JJ, Liu Z, Wang L et al.. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A 2005;102:18443-18448.
Liu P, Cheng H, Santiago S et al.. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med 2011;17:1116-1120.
Meyer DS, Brinkhaus H, Muller U et al.. Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res 2011;71:4344-4351.
Stoica GE, Franke TF, Moroni M et al.. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 2003;22:7998-8011.
Stoica GE, Franke TF, Wellstein A et al.. Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol 2003;17:818-830.
Simoncini T, Hafezi-Moghadam A, Brazil DP et al.. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407:538-541.
Campbell RA, Bhat-Nakshatri P, Patel NM et al.. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 2001;276:9817-9824.
Miller TW, 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 antiestrogen resistance in breast cancer. Cancer Res 2009;69:4192-4201.
Beeram M, Tan QT, Tekmal RR et al.. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 2007;18:1323-1328.
Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002;1:707-717.
Santen RJ, Song RX, Zhang Z et al.. Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity. Endocr Relat Cancer 2005;12(Suppl 1):S61-73.
Martin MB, Franke TF, Stoica GE et al.. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 2000;141:4503-4511.
Cavazzoni A, Bonelli MA, Fumarola C et al.. Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett 2012;323:77-87.
Ghayad SE, Bieche I, Vendrell JA et al.. mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci 2008;99:1992-2003.
Boulay A, Rudloff J, Ye J, Zumstein-Mecker S et al.. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005;11:5319-5328.
deGraffenried LA, Friedrichs WE, Russell DH et al.. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004;10:8059-8067.
Miller TW, Hennessy BT, Gonzalez-Angulo AM et al.. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010;120:2406-2413.
Leung E, Kim JE, Rewcastle GW et al.. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells. Cancer Biol Ther 2011;11:938-946.
Yue W, Fan P, Wang J et al.. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 2007;106:102-110.
Berns K, Horlings HM, Hennessy BT et al.. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395-402.
Lu CH, Wyszomierski SL, Tseng LM et al.. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007;13:5883-5888.
Nagata Y, Lan KH, Zhou X et al.. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-127.
Xia W, Husain I, Liu L et al.. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res 2007;67:1170-1175.
O'Brien NA, Browne BC, Chow L et al.. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 2010;9:1489-1502.
Wang L, Zhang Q, Zhang J et al.. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 2011;11:248.
Jensen JD, Knoop A, Laenkholm AV et al.. PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Ann Oncol 2012;23:2034-2042.
Dave B, Migliaccio I, Gutierrez MC et al.. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 2011;29:166-173.
- Search Google Scholar
- Export Citation
. Dave B Migliaccio I Gutierrez MC Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 2011; 29: 166- 173.
Razis E, Bobos M, Kotoula V et al.. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat 2011;128:447-456.
Morrow PK, Wulf GM, Ensor J et al.. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011;29:3126-3132.
O'Reilly KE, Rojo F, She QB et al.. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-1508.
Chakrabarty A, Sanchez V, Kuba MG et al.. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A 2012;109:2718-2723.
Chandarlapaty S, Sawai A, Scaltriti M et al.. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19:58-71.
Engelman JA, Chen L, Tan X et al.. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-1356.
Di Nicolantonio F, Arena S, Tabernero J et al.. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010;120:2858-2866.
Macaskill EJ, Bartlett JM, Sabine VS et al.. The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study. Breast Cancer Res Treat 2011;128:725-734.
Meric-Bernstam F, Akcakanat A, Chen H et al.. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res 2012;18:1777-1789.
Brachmann SM, Hofmann I, Schnell C et al.. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A 2009;106:22299-22304.
Serra V, Markman B, Scaltriti M et al.. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008;68:8022-8030.
Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 2011;30:3222-3233.
O'Brien C, Wallin JJ, Sampath D et al.. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res 2010;16:3670-3683.
Dan S, Okamura M, Seki M et al.. Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. Cancer Res 2010;70:4982-4994.
Janku F, Wheler JJ, Naing A et al.. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 2013;73:276-284.
Janku F, Wheler JJ, Westin SN et al.. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 2012;30:777-782.
Fleming GF, Ma CX, Huo D et al.. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 2012;136:355-363.
Ellard SL, Clemons M, Gelmon KA et al.. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 2009;27:4536-4541.
Chan S, Scheulen ME, Johnston S et al.. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314-5322.
Baselga J, Semiglazov V, van Dam P et al.. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009;27:2630-2637.
Baselga J, Campone M, Piccart M et al.. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529.
Wolff AC, Lazar AA, Bondarenko I et al.. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013;31:195-202.
Bachelot T, Bourgier C, Cropet C et al.. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012;30:2718-2724.
- Search Google Scholar
- Export Citation
. Bachelot T Bourgier C Cropet C Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012; 30: 2718- 2724.
Chavez-Mac Gregor M, Barlow WE, Gonzalez-Angulo AM et al.. A phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor-(HR) positive and Her2-negative breast cancer: SWOG/NSABP S1207. Cancer Res 2012;72:42s.
- Search Google Scholar
- Export Citation
. Chavez-Mac Gregor M Barlow WE Gonzalez-Angulo AM A phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor-(HR) positive and Her2-negative breast cancer: SWOG/NSABP S1207. Cancer Res 2012; 72: 42s.
Hartford CM, Desai AA, Janisch L et al.. A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin Cancer Res 2009;15:1428-1434.
Banerji U, Dean EJ, Gonzalez M et al.. First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors [abstract]. J Clin Oncol 2012;30:Abstract 3004.
Yap TA, Yan L, Patnaik A et al.. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 2011;29:4688-4695.
Hoffman K, Holmes FA, Fraschini G et al.. Phase I-II study: triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer. Cancer Chemother Pharmacol 1996;37:254-258.
Shuttleworth SJ, Silva FA, Cecil AR et al.. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Curr Med Chem 2011;18:2686-2714.
Bendell JC, Rodon J, Burris HA et al.. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012;30:282-290.
Juric D, Rodon J, Gonzalez-Angulo AM et al.. BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results for first-in-human study [abstract]. Cancer Res 2012;72(8 Suppl):Abstract CT-01.