Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer

Table 1 Clinical trials of targeted agents in endocrine resistant breast cancer

Agent	Class	Type of study	Study design	Patient population	Status/Results	Ref.
Targeting receptor tyrosine kinases signaling pathway
PI3K/AKT/mTOR
Everolimus	mTOR inhibitor	Phase III randomized	Exemestane +/- everolimus	ER+/HER2- LABC/MBC pts failed previous therapy with a nonsteroidal AI	PFS: 10.6 vs 4.1 mo, HR 0.36; P < 0.001, favoring combination arm	[76]
Everolimus	mTOR inhibitor	Phase II randomized	Tamoxifen +/- everolimus	ER+/HER2- MBC pts after previous therapy with AI	CBR: 61% vs 42%; TTP: 8.5 vs 4.5 mo, P = 0.008, favoring combination arm	[77]
Temsirolimus	mTOR inhibitor	Phase III randomized	Letrozole +/- temsirolimus	First line therapy for patients with ER positive MBC	No difference in CBR, terminated early	[78]
Everolimus	mTOR inhibitor	Phase II randomized	Letrozole +/- everolimus	Neoadjuvant therapy in ER + breast cancer	RR (by U/S): 58% vs 47%; P = 0.035, favoring combination arm	[75]
Sirolimus	mTOR inhibitor	Phase I/II	Tamoxifen +/- sirolimus	Pts with ER+ MBC	N = 400, TAM + SIR: 193; TAM alone: 207), ORR: TAM + SIR 40%; TAM alone 4%; Time to progression: TAM + SIR: 11 mo TAM alone: 3 mo	Bhattacharyya et al Eur.J.Cancer 47, Abstract 16LBA (2011)
Bkm120	Pan-PI3K inhibitor	Phase III randomized	Fulvestrant + BMK120	ER+/HER2- LABC/MBC Postmenopausal pts, AI Treated, Progressed on or After mtor Inhibitor		NCT01633060
Bkm120	Pan-PI3K inhibitor	Phase Ib	Fulvestrant + BMK120	Postmenopausal pts with ER+ MBC	Ongoing, to determine the maximum tolerated dose of BKM120	NCT01339442
Bez235	Dual PI3K-mTOR inhibitor	Phase Ib	Letrozole + BEZ235	Postmenopausal pts with ER+ MBC		NCT01248494
BMK120 or BEZ235	Pan-PI3K inhibitor	Phase Ib	Letrozole +BMK120 or BEZ235	Postmenopausal pts with ER+ MBC		NCT01248494
XL147 or XL765	Pan-PI3K inhibitors/dual PI3K/mTOR inhibitor	Phase I/II	Letrozole +XL147 or XL765	ER+/HER2- MBC pts refractory to a previous AI therapy		NCT01082068
GDC-0941 or GDC-0980	dual PI3K/mTOR inhibitor	Phase II randomized	Fulvestrant +GDC-0941 or GDC-0980	Part I: ER+/HER2-		NCT01437566
				postmenopausal LABC/MBC
				refractory to AI; part II: part I
				criteria pluspik3 camutation
Gdc-0032	PI3K inhibitor	Phase I/II	GDC-0032 + fulvestrant	ER+/HER2- LABC/MBC Postmenopausal pts		NCT01296555
Byl719	PI3K-α inhibitor	Phase I	BYL719 + letrozole or exemestane	ER+/HER2- LABC/MBC pts		NCT01870505
Mk2206	AKT inhibitor	Phase I	Endocrine therapy + MK2206	Postmenopausal pts with ER+ MBC		NCT01344031
Mk2206	AKT inhibitor	Phase II	MK2206 monotherapy	LABC/LRBC/MBC withpik3ca mutation or AKT mutation or PTEN loss		NCT01277757
Azd5363	AKT inhibitor	Phase I/II	Paclitaxel +/- AZD5363	Parta: all MBC, partb: ER+ MBC, stratified by PIK3CA mutation		NCT01625286
Igf-1r
Amg 479	IGF1R mAB	Phase II randomized	Addition of AMG 479 to either exemestane or fulvestrant	MBC or LABC pts who had progressed on prior endocrine therapy	No statistically significant difference in PFS (PFS: 3.9 vs 5.7 mo, favoring placebo arm, P = 0.44), OS or CBT between two arms	[87]
Bms-754807	dual IGF-1R/insulin receptor kinase inhibitor	Phase II randomized	BMS-754807 +/- letrozole	MBC or LA BC pts who had progressed on prior nonsteroidal AI		NCT01225172
Dalotuzumab (MK-0646)	IGF1R mAB	Phase I/II	MK-0646 and fulvestrant and dasatinib	ER+/HER2- MBC pts without prior therapy in metastatic setting		NCT00903006
Cixutumumab	IGF1R mAB	Phase I/II	Cixutumumab and temsirolimus	MBC or LA BC pts progressed on on one to two chemotherapy		NCT00699491
Ridaforolimus (mk-8669) with dalotuzumab (mk-0646) Fgf	mTOR inhibitor and IGF-1R mAB		Ridaforolimus and dalotuzumab vs standard care	Er + bc		NCT01234857
Dovitinib (TKI258)	TKI inhibits FGFR1–3, VEGFR and PDGFR	Phase II Phase I/II	Dovitinib monotherapy, stratified by FGF amplification	4 groups of MBC pts: (group 1: FGFR1+, HR+), (group 2: FGFR1+, HR-) (group 3: FGFR1-, HR+), (group 4: FGFR1-, HR-)	Dovitinib has activity in breast cancers with amplified FGF pathway	[94]
Dovitinib (TKI258)	TKI inhibits FGFR1–3, VEGFR and PDGFR		Dovitinib(TKI258) + AI	ER+/HER2- postmenopausal MBC resistant to AI with fgfr1 amplification status confirmed		NCT01484041
Dovitinib (TKI258)	TKI inhibits FGFR1–3, VEGFR and PDGFR	Phase II randomized	Fulvestrant +/- Dovitinib,stratified by FGF	Postmenopausal pts with HER2-/HR+ LA BC or MBC progressing within 12 mos of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting		NCT01528345
Azd4547		Phase II	amplification	HER2-MBC with fgfr1 amplification		NCT01795768
Azd4547		Phase II	Fulvestrant +/- AZD4547	ER+ postmenopausal LABC or MBC with fgfr1 polysomy or gene amplification resistant to endocrine treatment (Adjuvant or First-line Metastatic)		NCT01202591
Targeting cell cycle regulators
Pd 0332991	CDK4/6 inhibitor	Phase I/II randomized	Letrozole +/- PD 0332991	First line therapy for postmenopausal pts with ER+/HER2- MBC		[99]
Pd-0332991 (palbociclib)	CDK4/6 inhibitor	Phase III randomized	Letrozole +/- PD 0332991	First line therapy for postmenopausal pts with ER+/HER2- MBC		NCT01740427
Lee011		Phase Ib/II	LEE011 + exemestane +/-everolimus	Postmenopausal pts with ER+/HER2- LABC/MBC		NCT01857193
Epigenetic therapy
Vorinostat	HDAC inhibitor	Phase II	Vorinostat + tamoxifen	ER+ MBC progressed on previous endocrine therapy	N = 43; 34 evaluable, 7 (21%) PR; 4 (29%) SD; ORR 19%, CBR 40%	[105]
Entinostat	HDAC inhibitor	phase II randomized	Exmestane+/- entinostat	MBC or LA BC pts who had progressed on prior nonsteroidal AI	N = 130; PFS: 4.3 vs 2.3 mo ( HR 0.73, 95%CI: 0.50 to 1.07; P = 0.06); OS: 28.1 vs 19.8 mo (HR 0.59, CI, 0.36 to 0.97; P = .036), favoring combination	[106]
Panobinostat	HDAC inhibitor	Phase I/II	Panobinostat + letrozole	MBC, triple negative phase II portion		NCT01105312
Vorinostat	HDAC inhibitor	phase II	Vorinostat + AI	ER + MBC pts who previously derived benefit from AI		NCT01153672
Vorinostat		phase II	Vorinostat/placebo + nab-paclitaxel + carboplatin (n = 62)	Primary operable breast cancer, triple-negative or high grade ER-positive, HER2-negative	Ongoing	NCT00616967

MBC: Metastatic BC; LABC: Locally advanced BC; mAB: monoclonal antibody; ORR: Objective response rate; CBR: Clinical benefit rate response or stable disease >24 wk; PR: Partial response; SD: Stable disease; TKI: Tyrosine Kinase Inhibitor; PI3K/AKT/mTOR: PI3K-AKT- mammalian target of rapamycin (mTOR) pathway; IGF1R: Insulin-like growth factor-1 receptor pathway; FGF: Fibroblast growth factor. signaling.