Portal de Periódicos da CAPES

Targeted Therapy for Breast Cancer

2013; Elsevier BV; Volume: 183; Issue: 4 Linguagem: Inglês

10.1016/j.ajpath.2013.07.005

1525-2191

Ali Mohamed, Kenneth Krajewski, Burcu Çakar, X. Cynthia,

Advanced Breast Cancer Therapies

Breast cancer is a heterogeneous group of diseases that are clinically subdivided as hormone receptor–positive, human epidermal growth factor receptor 2–positive (HER2+), and triple-negative breast cancer, to guide therapeutic interventions. Agents that target estrogen receptor (ER) and HER2 are among the most successful cancer therapeutics. However, de novo or acquired resistance is common, despite the development of newer agents against these pathways. As our understanding of tumor biology improves, novel targets are being identified. Notably, inhibitors against several pathways [including, among others, the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR), cell-cycle regulation, heat shock protein, and epigenetic pathways] have demonstrated promising activity in clinical trials, and the mTOR-inhibitor everolimus has been approved for advanced or metastatic aromatase inhibitor–resistant ER+ breast cancer. At present, there are no established targeted agents for triple-negative breast cancer (negative ER, progesterone receptor, and HER2). Although poly(ADP-ribose) polymerase inhibitors have shown promising activity in BRCA-related cancers, its value in the treatment of triple-negative breast cancers remains to be demonstrated. In this Review, we present a basic understanding of the major targeted agents in current practice and under development for the treatment of breast cancer in the context of the three clinical subgroups. Breast cancer is a heterogeneous group of diseases that are clinically subdivided as hormone receptor–positive, human epidermal growth factor receptor 2–positive (HER2+), and triple-negative breast cancer, to guide therapeutic interventions. Agents that target estrogen receptor (ER) and HER2 are among the most successful cancer therapeutics. However, de novo or acquired resistance is common, despite the development of newer agents against these pathways. As our understanding of tumor biology improves, novel targets are being identified. Notably, inhibitors against several pathways [including, among others, the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR), cell-cycle regulation, heat shock protein, and epigenetic pathways] have demonstrated promising activity in clinical trials, and the mTOR-inhibitor everolimus has been approved for advanced or metastatic aromatase inhibitor–resistant ER+ breast cancer. At present, there are no established targeted agents for triple-negative breast cancer (negative ER, progesterone receptor, and HER2). Although poly(ADP-ribose) polymerase inhibitors have shown promising activity in BRCA-related cancers, its value in the treatment of triple-negative breast cancers remains to be demonstrated. In this Review, we present a basic understanding of the major targeted agents in current practice and under development for the treatment of breast cancer in the context of the three clinical subgroups. Estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are well-established therapeutic targets and have been the main focus of drug development for the treatment of breast cancer. A number of hormonal therapeutic agents have been approved for the treatment of ER+ disease, including tamoxifen, aromatase inhibitors (AIs), and fulvestrant. For HER2+ breast cancer, a growing number of HER2-targeted agents have become available, including trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. However, these agents are ineffective for triple-negative breast cancers (TNBC). In addition, de novo or acquired resistance to these agents is common, despite the presence of ER and HER2. Novel therapeutic targets are being developed as treatment strategies for TNBC and resistant ER and HER2+ diseases. In this review, we discuss major targeted therapies in current practice and under development for the treatment of hormone receptor-positive (HR+) breast cancer, HER2+ breast cancer, and TNBC. HR+ breast cancers are largely driven by the estrogen/ER pathway, and endocrine therapy targeting this pathway has been most successful. However, resistance to endocrine therapy, either de novo or acquired, is a common phenomenon and a significant clinical challenge. The mechanisms of endocrine resistance are complex and not fully understood. Experimental models indicate that endocrine resistance is accompanied by activation of estrogen-independent growth and survival signaling pathways as a result of genomic or epigenetic alterations; these pathways could be targeted for therapeutic interventions.1Roop R.P. Ma C.X. Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies.Future Oncol. 2012; 8: 273-292Crossref PubMed Scopus (35) Google Scholar A small fraction of ER+ breast cancers have amplification of the HER2 gene, ERBB2, and in these cases targeting both ER and HER2 is necessary.2Schwartzberg L.S. Franco S.X. Florance A. O'Rourke L. Maltzman J. Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.Oncologist. 2010; 15: 122-129Crossref PubMed Scopus (162) Google Scholar Letrozole in combination with lapatinib, a HER1/2 inhibitor, has been approved as a first-line therapy for metastatic ER+ HER2+ breast cancer. For ER+ HER2− breast cancer, success has been reported with combined targeting of the phosphoinositide 3-kinase (PI3K) pathway and ER.3Baselga J. Campone M. Piccart M. Burris 3rd, H.A. Rugo H.S. Sahmoud T. Noguchi S. Gnant M. Pritchard K.I. Lebrun F. Beck J.T. Ito Y. Yardley D. Deleu I. Perez A. Bachelot T. Vittori L. Xu Z. Mukhopadhyay P. Lebwohl D. Hortobagyi G.N. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2135) Google Scholar The mTOR inhibitor everolimus, in combination with exemestane, has been approved for the treatment of AI-resistant ER+ metastatic breast cancer. Promising activity has also been observed in early-phase trials of inhibitors against cyclin-dependent kinases 4 and 6 (CDK4/6) and agents that target epigenetic mechanisms. ER, which belongs to the class of steroid hormonal receptors, plays an important role in cell proliferation, survival, and invasion of ER+ breast cancer (Figure 1). Binding of estrogen to ER translocates the cytoplasmic ER to the nucleus, where estrogen-bound ER forms dimer that functions as a transcription factor via binding to the estrogen response elements of target genes and the interaction with coregulators and other transcription factors to activate downstream gene expression.4Acconcia F. Kumar R. Signaling regulation of genomic and nongenomic functions of estrogen receptors.Cancer Lett. 2006; 238: 1-14Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar In addition to this classic genomic action of ER, membrane-associated ER mediates rapid nongenomic effect through its interactions with growth factor receptor tyrosine kinases and a variety of proximal signaling molecules such as G protein, Ras, Src, and the regulatory subunit of PI3K and Shc, leading to cell growth and survival signaling activation. Endocrine therapy is the mainstay of systemic treatment for HR+ breast cancer. Various approaches are aimed at either reducing estrogen level, such as ovarian suppression or ablation in premenopausal women and AIs in postmenopausal women, or modulating the expression or function of ER, such as the selective estrogen receptor modulators, which antagonize the function of ER, and fulvestrant, which down-regulates ER. In premenopausal women with metastatic breast cancer, tamoxifen has efficacy similar to that of ovarian ablation,5Crump M. Sawka C.A. DeBoer G. Buchanan R.B. Ingle J.N. Forbes J. Meakin J.W. Shelley W. Pritchard K.I. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer.Breast Cancer Res Treat. 1997; 44: 201-210Crossref PubMed Scopus (64) Google Scholar whereas the combination of ovarian suppression plus tamoxifen demonstrates a superior disease-free survival (DFS) and overall survival (OS), compared with ovarian suppression alone.6Klijn J.G. Blamey R.W. Boccardo F. Tominaga T. Duchateau L. Sylvester R. Combined Hormone Agents Trialists' Group and the European Organization for Research and Treatment of CancerCombined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials.J Clin Oncol. 2001; 19: 343-353Crossref PubMed Scopus (394) Google Scholar In premenopausal women with early-stage disease, 5 years of adjuvant tamoxifen reduced the risk of breast cancer recurrence by 39% [relative risk (RR) for recurrence = 0.61; 95% CI = 0.57–0.65] and the risk of breast cancer mortality by 30% (RR for death = 0.70; 95% CI = 0.64–0.75), which translates into a 15-year absolute reduction of 13% in the risk of recurrence and 9% in the risk of breast cancer mortality. A recent report of results from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial indicated that 10 years of tamoxifen was associated with a 25% lower recurrence rate and a 29% lower breast cancer mortality rate, compared with 5 years of tamoxifen treatment.7Davies C. Pan H. Godwin J. Gray R. Peto R. ATLAS Collaborators WorldwideATLAS–10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: effects on outcome in the first and in the second decade after diagnosis.Cancer Res. 2012; 72 (Abstract S1-2)PubMed Google Scholar Although the risk of death from endometrial cancer was increased from 0.2% to 0.4%, the benefit outweighed this risk, which argues for the use of 10 years of tamoxifen. For patients who become postmenopausal after 5 years of tamoxifen, extended therapy with an AI is another option, based on the results of the MA17 trial.8Goss P.E. Ingle J.N. Martino S. Robert N.J. Muss H.B. Piccart M.J. Castiglione M. Tu D. Shepherd L.E. Pritchard K.I. Livingston R.B. Davidson N.E. Norton L. Perez E.A. Abrams J.S. Therasse P. Palmer M.J. Pater J.L. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.N Engl J Med. 2003; 349: 1793-1802Crossref PubMed Scopus (1641) Google Scholar As an alternative to tamoxifen, ovarian ablation or suppression could be considered as an adjuvant therapy for premenopausal women. In postmenopausal women, AIs have been shown to improve OS, compared with tamoxifen, in the metastatic setting.9Mauri D. Pavlidis N. Polyzos N.P. Ioannidis J.P. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis.J Natl Cancer Inst. 2006; 98: 1285-1291Crossref PubMed Scopus (221) Google Scholar All three AIs [letrozole and anastrozole (nonsteroidal); exemestane (steroidal)] have shown similar efficacy in the clinical setting, although non–cross-resistance exists between the nonsteroidal and the steroidal AIs. Options for second or later lines of endocrine therapy include another AI, fulvestrant, tamoxifen, testosterone, megestrol acetate (Megace), or (paradoxically) estradiol, as well as the recently approved the combination of everolimus and exemestane. In this setting, the higher dose of fulvestrant (500 mg i.m. monthly) is now the approved dose, based on the result of the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial.10Di Leo A. Jerusalem G. Petruzelka L. Torres R. Bondarenko I.N. Khasanov R. Verhoeven D. Pedrini J.L. Smirnova I. Lichinitser M.R. Pendergrass K. Garnett S. Lindemann J.P. Sapunar F. Martin M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.J Clin Oncol. 2010; 28 ([Erratum appeared in J Clin Oncol 2011, 29:229]): 4594-4600Crossref PubMed Scopus (488) Google Scholar In postmenopausal women with early-stage disease, multiple large adjuvant trials have demonstrated that monotherapy with an AI for 5 years or a switching strategy (from AI to tamoxifen or from tamoxifen to AI, with a total duration of therapy of 5 years) is superior to tamoxifen (summarized by Rao and Cobleigh11Rao R.D. Cobleigh M.A. Adjuvant endocrine therapy for breast cancer.Oncology (Williston Park). 2012; 26: 541-547PubMed Google Scholar). The BIG 1-98 trial demonstrated similar efficacy with AI monotherapy or a switching strategy with tamoxifen.12Regan M.M. Neven P. Giobbie-Hurder A. Goldhirsch A. Ejlertsen B. Mauriac L. Forbes J.F. Smith I. Láng I. Wardley A. Rabaglio M. Price K.N. Gelber R.D. Coates A.S. Thürlimann B. BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG)Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up.Lancet Oncol. 2011; 12: 1101-1108Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar Thus, AI has become a preferred approach, or at least part of the adjuvant hormonal therapy approach, in postmenopausal women with ER+ breast cancer. The four HER family members [EGFR (alias HER1), HER2, HER3, and HER4] are tyrosine kinase receptors important in promoting cell growth and survival. The HER2 gene, ERBB2, is amplified in approximately 10% of ER+ breast cancer. Compared with ER+ HER2− disease, ER+ HER2+ breast cancer is associated with a higher risk of relapse on adjuvant endocrine therapy. This is explained by the finding of incomplete cell-cycle arrest under treatment with endocrine agents alone in the neoadjuvant setting.13Ellis M.J. Tao Y. Young O. White S. Proia A.D. Murray J. Renshaw L. Faratian D. Thomas J. Dowsett M. Krause A. Evans D.B. Miller W.R. Dixon J.M. Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole.J Clin Oncol. 2006; 24: 3019-3025Crossref PubMed Scopus (140) Google Scholar The benefit of adding HER2-targeted agents in this patient population was demonstrated in studies of adjuvant trastuzumab in HER2+ breast cancer; the ER+ HER2+ subset derived a significant benefit from trastuzumab in reducing relapse. Thus, adjuvant trastuzumab, in addition to hormonal therapy, is a standard of care for these patients. In the metastatic setting, trastuzumab in combination with anastrozole was associated with a significantly longer progression-free survival (PFS) (4.8 versus 2.4 months) and a higher clinical benefit rate (CBR) (42.7% versus 20.3%), compared with anastrozole alone, in patients with metastatic breast cancer in the phase III Trastuzumab in Dual HER2 ER-Positive Metastatic Breast Cancer (TAnDEM) trial, although OS was not different.14Kaufman B. Mackey J.R. Clemens M.R. Bapsy P.P. Vaid A. Wardley A. Tjulandin S. Jahn M. Lehle M. Feyereislova A. Revil C. Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.J Clin Oncol. 2009; 27: 5529-5537Crossref PubMed Scopus (671) Google Scholar In a single-arm trial in patients with HR+ HER2+ breast cancer, trastuzumab in combination with letrozole as first- or second-line therapy was associated with an overall response rate (ORR) of 26% and a CBR of 52%, with 25% of patients experiencing durable response that lasted for more than 1 year.15Marcom P.K. Isaacs C. Harris L. Wong Z. Kommarreddy A. Novielli N. Mann G. Tao Y. Ellis M. The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers.Breast Cancer Res Treat. 2007; 102: 43-49Crossref PubMed Scopus (139) Google Scholar In a phase III trial conducted in 1298 postmenopausal women with metastatic or locally advanced ER+ breast cancer, the combination of letrozole and lapatinib, a HER1/HER2 kinase inhibitor, was compared with letrozole alone.2Schwartzberg L.S. Franco S.X. Florance A. O'Rourke L. Maltzman J. Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.Oncologist. 2010; 15: 122-129Crossref PubMed Scopus (162) Google Scholar This study demonstrated a significant difference in PFS [8.2 versus 3 months; hazard ratio (HR) = 0.53–0.96] and ORR (28% versus 15%; P = 0.021) favoring the combination therapy group to letrozole alone2Schwartzberg L.S. Franco S.X. Florance A. O'Rourke L. Maltzman J. Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.Oncologist. 2010; 15: 122-129Crossref PubMed Scopus (162) Google Scholar and leading to the approval of letrozole and lapatinib combination for the treatment of advanced ER+/HER2+ breast cancer. The PI3K-AKT-mTOR pathway is a cardinal nodal point in the transduction of extracellular and intracellular growth and survival signals (Figure 2). Deregulation of this pathway is an important mechanism of endocrine resistance.16Ma C.X. Crowder R.J. Ellis M.J. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors.Steroids. 2011; 76: 750-752Crossref PubMed Scopus (31) Google Scholar Gain-of-function mutations in the PI3 kinase α catalytic subunit gene (PIK3CA) occur at a frequency of 30% to 40% and comprise the most frequent genetic abnormality in ER+ breast cancer.17Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70Crossref PubMed Scopus (7887) Google Scholar In preclinical models, ER+ breast cancer carrying PIK3CA mutations was highly dependent on PI3Kα (alias p110α) for cell survival.18Crowder R.J. Phommaly C. Tao Y. Hoog J. Luo J. Perou C.M. Parker J.S. Miller M.A. Huntsman D.G. Lin L. Snider J. Davies S.R. Olson Jr., J.A. Watson M.A. Saporita A. Weber J.D. Ellis M.J. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.Cancer Res. 2009; 69: 3955-3962Crossref PubMed Scopus (185) Google Scholar Knockdown of PIK3CA using RNAi or inhibition of PI3K or AKT with small-molecule inhibitors induced apoptosis in the presence of estrogen deprivation in ER+ breast cancer cell lines.18Crowder R.J. Phommaly C. Tao Y. Hoog J. Luo J. Perou C.M. Parker J.S. Miller M.A. Huntsman D.G. Lin L. Snider J. Davies S.R. Olson Jr., J.A. Watson M.A. Saporita A. Weber J.D. Ellis M.J. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.Cancer Res. 2009; 69: 3955-3962Crossref PubMed Scopus (185) Google Scholar, 19Sanchez C.G. Ma C.X. Crowder R.J. Guintoli T. Phommaly C. Gao F. Lin L. Ellis M.J. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer.Breast Cancer Res. 2011; 13: R21Crossref PubMed Scopus (146) Google Scholar In addition, the development of acquired endocrine resistance was accompanied by activation of the PI3K pathway in studies of long-term estradiol-deprived breast cancer cell lines, and inhibition of PI3K pathway signaling reduced cancer cell growth and survival.19Sanchez C.G. Ma C.X. Crowder R.J. Guintoli T. Phommaly C. Gao F. Lin L. Ellis M.J. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer.Breast Cancer Res. 2011; 13: R21Crossref PubMed Scopus (146) Google Scholar, 20Miller T.W. Hennessy B.T. González-Angulo A.M. Fox E.M. Mills G.B. Chen H. Higham C. García-Echeverría C. Shyr Y. Arteaga C.L. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer.J Clin Invest. 2010; 120: 2406-2413Crossref PubMed Scopus (381) Google Scholar The rapamycin analogs, which are allosteric inhibitors of mTOR complex 1 through its interaction with FKBP12, were among the first evaluated in clinical trials. The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) trial, a randomized, double-blind, placebo-controlled phase III study of exemestane with or without the rapamycin analog everolimus (Afinitor; Novartis) in postmenopausal women with ER+ HER2− advanced breast cancer refractory to nonsteroidal AIs, demonstrated a median PFS of 10.6 months with combination therapy, compared with 4.1 months with exemestane alone (HR = 0.36; 95% CI = 0.27–0.47; P < 0.001),3Baselga J. Campone M. Piccart M. Burris 3rd, H.A. Rugo H.S. Sahmoud T. Noguchi S. Gnant M. Pritchard K.I. Lebrun F. Beck J.T. Ito Y. Yardley D. Deleu I. Perez A. Bachelot T. Vittori L. Xu Z. Mukhopadhyay P. Lebwohl D. Hortobagyi G.N. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2135) Google Scholar leading to U.S. Food and Drug Administration (FDA) approval for its application in the AI-resistant population. Similarly, the TAMRAD trial, a randomized phase II study of tamoxifen with or without everolimus in postmenopausal women with HR+ HER2−, AI-resistant metastatic breast cancer, demonstrated an improvement in CBR and time to progression (TTP).21Bachelot T. Bourgier C. Cropet C. Ray-Coquard I. Ferrero J.M. Freyer G. Abadie-Lacourtoisie S. Eymard J.C. Debled M. Spaëth D. Legouffe E. Allouache D. El Kouri C. Pujade-Lauraine E. 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: 2718-2724Crossref PubMed Scopus (581) Google Scholar Adjuvant studies of everolimus in combination with hormonal therapy in early-stage ER+ HER2− breast cancer are being planned (NCT01805271 and NCT01674140). The antitumor activity of the rapamycin analogs is likely hindered by feedback up-regulation of AKT,22O'Reilly K.E. Rojo F. She Q.B. Solit D. Mills G.B. Smith D. Lane H. Hofmann F. Hicklin D.J. Ludwig D.L. Baselga J. Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.Cancer Res. 2006; 66: 1500-1508Crossref PubMed Scopus (2121) Google Scholar and preclinical studies indicated that perhaps the upstream inhibitors that target AKT or PI3K directly would be more effective.18Crowder R.J. Phommaly C. Tao Y. Hoog J. Luo J. Perou C.M. Parker J.S. Miller M.A. Huntsman D.G. Lin L. Snider J. Davies S.R. Olson Jr., J.A. Watson M.A. Saporita A. Weber J.D. Ellis M.J. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.Cancer Res. 2009; 69: 3955-3962Crossref PubMed Scopus (185) Google Scholar, 19Sanchez C.G. Ma C.X. Crowder R.J. Guintoli T. Phommaly C. Gao F. Lin L. Ellis M.J. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer.Breast Cancer Res. 2011; 13: R21Crossref PubMed Scopus (146) Google Scholar A number of inhibitors against AKT or PI3K are in clinical trial, including the pan-PI3K isoform inhibitors, dual PI3K and mTOR inhibitors, and isoform-specific inhibitors (Table 1). The pan-PI3K inhibitor BKM120 (Novartis) is in phase III trials in combination with fulvestrant in patients with metastatic ER+ metastatic breast cancer resistant to prior AI therapy [Buparlisib Breast Cancer Clinical Evaluation 2 (BELLE 2); NCT01610284] or resistant also to an mTOR inhibitor (BELLE 3; NCT01633060). In addition, an α-specific inhibitor of PI3K has shown promising activity in PIK3CA mutant breast cancer in phase I studies.23Juric D. Argiles G. Burris H.A. Gonzalez-Angulo A.M. Saura C. Quadt C. Douglas M. Demanse D. De Buck S. Baselga J. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC).Cancer Res. 2012; 72 (Abstract P6-10-07)Google Scholar In the preliminary report of a phase I study of the α-specific inhibitor BYL719 (Novartis), 6/18 (33%) patients with heavily pretreated metastatic breast cancer with PIK3CA mutation achieved tumor shrinkage >20%, and two of these six patients achieved a partial response.23Juric D. Argiles G. Burris H.A. Gonzalez-Angulo A.M. Saura C. Quadt C. Douglas M. Demanse D. De Buck S. Baselga J. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC).Cancer Res. 2012; 72 (Abstract P6-10-07)Google Scholar Full results from these studies are eagerly awaited. A challenge in the development of these agents has been the inability to identify the predictors of response in clinical trials, and prospective studies are needed.Table 1Clinical trials of PI3K and AKT inhibitors in breast cancerTest drug (sponsor)Trial phase and design (identifier∗Details available at http://www.clinicaltrials.gov.)RegimenPopulationPanisoform inhibitor of PI3KXL147 (Sanofi)I/II (NCT01042925)XL147 + trastuzumab or XL147 + paclitaxel + trastuzumabMetastatic HER2+ breast cancer with prior progression on a trastuzumab-based regimenI/II (NCT01082068)XL147 + letrozoleNonsteroidal aromatase inhibitor–resistant ER+ HER2− metastatic breast cancerBKM120 (Novartis)II (NCT01629615 and NCT01790932)BKM120Metastatic TNBCI (NCT01623349)BKM120 + olaparibTNBCIb/II (NCT01132664)BKM120 + trastuzumabTrastuzumab-resistant metastatic HER2+ breast cancerII randomized (NCT01816594)BKM120 + trastuzumab + paclitaxel vs trastuzumab + paclitaxelNeoadjuvant HER2+ primary breast cancerIb/II (NCT01589861)BKM120 + lapatinibHER2+/PI3K-activated, trastuzumab-resistant metastatic HER2+ breast cancerIb (NCT01285466)BKM120 + paclitaxel; BKM120 + paclitaxel + trastuzumabMetastatic breast cancerII, randomized, double-blind, placebo-controlled (NCT01572727)BKM120 + paclitaxel (BELLE-4)HER2− metastatic breast cancerIb (NCT01339442)BKM120 + fulvestrantER+ metastatic breast cancerIII, randomized, double-blind, placebo-controlled (NCT01610284)BKM120 + fulvestrant (BELLE-2)Aromatase inhibitor–resistant ER+ HER2− metastatic breast cancerIII, randomized, double-blind, placebo-controlled (NCT01633060)BKM120 + fulvestrant (BELLE-3)Aromatase inhibitor–resistant ER+ HER2− metastatic breast cancer progressed on prior afinitorIb (NCT01248494)BKM120 + endocrine therapyER+ metastatic breast cancerIb (NCT01300962)BKM120 + capecitabineMetastatic breast cancerGDC-0941 (Genentech)Ib (NCT00960960)GDC-0941 + paclitaxel ± bevacizumab or trastuzumabMetastatic breast cancerIb (NCT00928330)GDC-0941 + trastuzumab or T DM1Trastuzumab-resistant metastatic HER2+ breast cancerII, randomized, single-blind, placebo-controlled (NCT01740336)GDC-0941 + paclitaxel vs paclitaxel + placeboMetastatic breast cancerII, randomized, double-blind, placebo-controlled (NCT01437566)GDC-0941 + fulvestrant vs fulvestrantAromatase inhibitor–resistant metastatic ER+ breast cancerBAY 80-6946 (Bayer)I (NCT01411410)BAY + paclitaxelExpansion cohort in breast cancerPI3Kα selective inhibitorBYL719 (Novartis)Ib (NCT01791478)BYL719 + endocrine therapyMetastatic ER+Dual PI3K/mTOR inhibitorBEZ235 (Novartis)Ib/II (NCT01471847)BEZ235 + trastuzumab vs lapatinib + capecitabineMetastatic HER2+, trastuzumab resistantIb (NCT01285466)BEZ235 + paclitaxel BEZ235 + paclitaxel + trastuzumabMetastatic ER+ breast cancerII (NCT01495247)BEZ235 + paclitaxelMetastatic HER2− breast cancerIb (NCT01300962)BEZ235 + capecitabineMetastatic breast cancerIb (NCT01248494)BEZ235 + endocrine therapyMetastatic ER+ breast cancerXL765 (Sanofi)I/II (NCT01082068)XL765 + letrozoleAromatase inhibitor–resistant ER+ metastatic breast cancerGDC-0980 (Genentech)II, randomized, double-blind, placebo-controlled (NCT01437566)GDC-0980 + fulvestrant vs fulvestrantAromatase inhibitor–resistant ER+ metastatic breast cancerIb (NCT01254526)GDC-0980 + paclitaxel ± bevacizumabMetastatic breast cancerPan-AKT inhibitorMK2206 (Merck)I (NCT01344031)MK2206 + anastrozole or fulvestrant or anastrozole/fulvestrantMetastatic ER+ breast cancerII (NCT01776008)MK2206 + anastrozoleNeoadjuvant clinical stage II or III ER+ HER2− breast cancer with PIK3CA mutationII (NCT01277757)MK2206Metastatic breast cancer with PIK3CA mutation or loss of PTENII (NCT01319539)MK2206Presurgical in operable breast cancerIb (NCT01281163)MK2206 + lapatinibMetastatic HER2+ breast cancerI (NCT00963547)MK2206 + lapatinib + trastuzumabMetastatic HER2+ breast cancerBKM120, buparlisib.∗ Details available at http://www.clinicaltrials.gov. Open table in a new tab BKM120, buparlisib. The G1-to-S phase transition is controlled by CDKs 4 and 6. These are activated on binding to D-type cyclins, leading to phosphorylation of the retinoblastoma susceptibility gene (RB1) product (Rb), which releases the E2F and DP transcription factors to drive expression from genes promoting S-phase entry (Figure 3). There is a strong link between the action of estrogen and CDK4/6 activity, through the transcriptional regulation of cyclin D1 by ER. Persistent cyclin D1 expression and Rb phosphorylation has been associated with resistance to endocrine therapy in ER+ breast cancer,24Thangavel C. Dean J.L. Ertel A. Knudsen K.E. Aldaz C.M. Witkiewicz A.K. Clarke R. Knudsen E.S. Therapeutically activating RB: reestablishing cell