Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer

Table 1 Neoadjuvant endocrine therapy and neoadjuvant chemo-endocrine therapy as potential approaches in the neoadjuvant settings

Clinical trial	Treatment arms (n)	Duration	Primary endpoint	ORR	BCS rate
Semiglazov et al[16], 2007	(A) NAE: EXE 25 mg/d or ANA 1 mg/d (121); (B) NAC: doxorubicin 60 mg/m2 pluspaclitaxel 200 mg/m2 (118)	3 mo	OR by clinical palpation	64% vs 64% (P > 0.5)	33% vs 24 (P = 0.58)
Alba et al[5], 2012	(A) NAE: EXE 25 mg/d (41-47); (B) NAC: Epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 then docetaxel 100 mg/ m2 (EC-T) (41-48)	24 wk	OR by MRI	48% vs 66% (P = 0.075)	56% vs 47 (P = 0.2369)
Palmieri et al[17],2014 (NEOCENT)	(A) NAE: LET 2.5 mg/d (22); (B) NAC: 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 (FE100C) (22)	18-23 wk	OR by ultrasound and mammography	59.1% vs 54.5% (P = 0.32)
Nakayama et al[18], 2018 (Neo-ACET BC)	(A) NAE: ANA 1mg/d (29); (B) NCET: ANA 1mg/d plus tegafur/uracil (UFT) 270 mg/m2 (28)	24 wk	OR by MRI and CT	39.3% vs 14.3% (P = 0.0683)
Sato et al[19], 2018	(A) NAE: EXE 25mg/d (14); (B) NCET: EXE 25 mg/d plus cyclophosphamide 50 mg/d (42)	24 wk	OR by clinical palpation	85% vs 54% (at weeks 24); 71% vs 71% (at weeks 36)	No increased rate shown
Mohammadianpanah et al [20], 2012	(A) NCT: 5-fluorouracil 600 mg/m2, doxorubicin 60 mg/m2, and cyclophosphamide 600 mg/m2 (FAC) (51); (B) NCET: letrozole 2.5 mg/d plus FAC (50)	9–13 wk	OR by clinical palpation	10.2% vs 25.5% (P = 0.049)
Yu et al[21], 2019 (CSCSG-036)	(A) NCT: EC-T or FEC-T (124); (B) NCET: letrozole 2.5 mg/d plus EC-T or FEC-T (Tleuprorelin) (125)	8-9 wk	OR by MRI	72.6% vs 84.8% (P = 0.02)

NAE: Neoadjuvant endocrine therapy; NAC: Neoadjuvant chemotherapy; NCET: Neoadjuvant chemo-endocrine therapy; EXE: Exemestane; ANA: Anastrozole; LET: Letrozole; OR: Objective response; BCS: Breast-conserving surgery.

Table 2 The optimal duration and optimal endocrine agents of neoadjuvant endocrine therapy

Clinical trial	Patient characteristics	Treatment arms (n)	Duration	Primary endpoint	ORR	BCS rate
Krainick-Strobel et al[23], 2008	ER+ and/or PR+; Postmenopausal	LET 2.5 mg/d (33)	4-8 mo	OR by clinical palpation, mammography, ultrasound, and BCS	55% vs 24% at 4 and > 4 mo	71% vs 80% at 4 and > 4 mo
Fontein et al[25], 2014	ER+; Postmenopausal	EXE (102)	3 mo vs 6 mo	OR by clinical palpation at 3 and 6 months	58.7% vs 68.3%	61.8% vs 70.6% (P = 0.012)
Carpenter et al[22], 2014	ER+ and/or PR+; Postmenopausal	LET 2.5 mg/d (146)	3–12 mo	Optimal duration to permit BCS	-	7.5 mo
Eiermann et al[7], 2001 (PO24)	ER+ and/or PR+; Postmenopausal	(A) LET 2.5 mg/d (162); (B) TAM 20 mg/d (223)	4 mo	OR by clinical palpation	55% vs 36% (P < 0.001)	45% vs 35% (P = 0.022)
Smith et al [26], 2005 (IMPACT)	ER+; Postmenopausal	(A) ANA 1 mg/d (113); (B) TAM 20 mg/d (108)	12 wk	OR by ultrasound	37% vs 36% (P < 0.087)	41% vs 31% (P = 0.23)
Catalioth et al[27], 2006 (PROACT)	ER+ and/or PR+; Postmenopausal	(A) ANA 1 mg/d (228); (B) TAM 20 mg/d (223)	3 mo	OR by ultrasound	50.0% vs 46.2% (P = 0.037)	38.1% vs 29.9% (P = 0.11)
Semiglazov et al[16], 2015	ER+ and/or PR+; Postmenopausal	(A) EXE (76); (B) TAM (75)	3 mo	OR by clinical palpation	76.3% vs 40% (P = 0.05)	36.8% vs 20% (P = 0.05)
Kuter et al[29], 2012 (NEWEST)	ER+; Postmenopausal	(A) FUL 500 mg/mo (109); (B) FUL 250 mg/mo (102)	16 wk	Expression of Ki67	17.4 vs 11.8% at week 4; 22.9 vs 20.6% at week 16	-
Quenel-Tueux et al[30], 2015	ER+; Postmenopausal	(A) ANA 1 mg/d (61); (B) FUL 500 mg/mo (59)	6 mo	OR by clinical palpation	58.9% vs 53.8%	58.9% vs 50%
Guarneri et al[31], 2014 (CARMINA 02)	ER+ and/or PR+ Her2-; Postmenopausal	(A) ANA 1 mg/d (59); (B) FUL 500 mg/mo (57)	6 mo	OR by clinical palpation	52.6% vs 36.8%	57.6% vs 50% (P = 0.5 not significant)
Ellis et al[32], 2011 (ACOSOG Z1031)	ER+ (Allred score 6-8) postmenopausal T2-T4cN0-3M0	(A) EXE 25 mg/d(124); (B) LET 2.5 mg/d (128); (C) ANA 1 mg/d(125);	16-18 wk	OR by clinical palpation	69.1% vs 62.9% vs 74.8%	45.2% vs 40% vs 48.7%
Torrisi et al[33], 2007	ER+ T2-T4N0N2; premenopausal	LET 2.5 mg/d plus GnRHa 11.25 mg/3 mo (32)	4 mo	OR by clinical palpation	50%	47%
Masuda et al [34], 2012 (STAGE)	ER+ and/or PR+ Her2-; Premenopausal	(A) ANA 1 mg/d (goseretin 3.6 mg/mo) (98); (B) TAM 20 mg/d (goseretin 3.6 mg/mo) (99)	24 wk	OR by ultrasound	70.4% vs 50.5% (P = 0.004)	85.7% vs 67.6%
Dellapasqua et al[35], 2019 (TREND)	ER+ and/or PR+ Her2-; Premenopausal	(A) Triptorelin + letrozole (26); (B) degarelix + letrozole (25)	6 mo	Time to optimal OFS	46.2% vs 44.0%	52.2% vs 42.3%

ER: Estrogen receptor; PR: Progesterone receptor; EXE: Exemestane; ANA: Anastrozole; LET: Letrozole; FUL: Fulvestrant; TAM: Tamoxifen; OR: Objective response; OFS: Ovarian function suppression; BCS: Breast-conserving surgery.

Table 3 The optimal targeted agents

Clinical trial	Treatment arms (n)	Duration	Primary endpoint	Response ( Primary endpoint)
Johnston et al[37], 2019 (PALLET)	(A) LET 14 w (103); (B) LET 2 w followed by LET + PAL 12 w (68); (C) PAL 2 w followed by LET + PAL (69); (D) LET + PAL 14 w (67); LET:2.5 mg/d PAL: 125 mg/d	14 wk	Clinical response by ultrasound and median log-fold change in Ki-67 expression	A vs B + C + D: 54.3% vs 49.5% (P = 0.2), -2.2 vs -4.1(P < 0.001)
Ma et al[38], 2017 (NeoPalAna)	ANA 1 mg/d (plus goserelin if premenopausal) followed by PAL 125 mg/d on C1D1 (50)	5 mo	CCCA (Ki67 < 2.7%) on palbociclib plus anastrozole	C1D1 vs C1D15: 26% vs 87% (P < 0.001)
Arnedos et al[40], 2018 (POP)	(A) PAL 125 mg/d (74); (B) placebo (26)	14 d	Antiproliferative response, defined as lnKi67 < 1 at day five	58% vs 12% (P < 0.001)
Curigliano et al[42], 2016 (MONALEESA-1)	(A) LET 2.5 mg/d (2); (B) LET 2.5 mg/d + RIB 400 mg/d (6); (C) LET 2.5 mg/d + RIB 600 mg/d (3)	14 d	mean decreases in the Ki67-positive cell fraction from baseline	(A) 69% (range 38%-100%); (B) 96% (range 78%-100%); (C) 92% (range 75%-100%)
Neo-MONARCH	(A) ANA 2 w; (B) abemaciclib 2 w; (C) ANA + abemaciclib 2 w followed by ANA+ abemaciclib 12 w	14 wk	Changes in Ki67 expression	Reduced Ki67 in patients 15% vs 59% vs 66%
Ma et al[46], 2017	ANA 1 mg/d (plus goserelin if premenopausal) followed by MK-2206 125 mg/w (16)	4 mo	pCR rate	0%
Baselga et al[48], 2009	(A) LET 2.5 mg/d+ placebo; (B) LET 2.5 mg/d+ everolimus 10 mg/d	4 mo	OR by clinical palpation	68.1% vs 59.1% (P = 0.062)

ER: Estrogen receptor; PR: Progesterone receptor; LET: Letrozole; ANA: Anastrozole; PAL: Palbociclib; RIB: Ribociclib; OR: Objective response; CCCA: Complete cell-cycle arrest; pCR: Pathological complete response; BCS: Breast-conserving surgery.

Table 4 Genomic assays to predict outcome in neoadjuvant endocrine therapy

Genomic assay	Gene number	Genomic information	Method	Current results in NAE	Ref.
Oncotype DX®	21 (16+5)	Proliferative-related genes: Ki67 AURKA, BIRC5, CCNB1, MYBL2	QRT-PCR	Recurrence score; low RS results imply a greater likelihood of response to NAE	[62-63]
		Invasive-related genes: MMP11, CTSL2
		Estrogen-related genes: ESR1, PGR, BCL2, SCUBE2
		HER2-related genes: ERBB2, GRB7
		Other genes: GSTM1, CD68, BAG1
		Reference genes: ACTB, GAPDH, RPLPO, GUS, TFRC
EndoPredict (EP)	12 (8+4)	Proliferative-related genes: BIRC5, UBE2C, DHCR7	QRT-PCR	Lower genomic risk related to favorable response.	[69]
		Estrogen-related genes: RBBP8, IL6ST, AZGP1, MGP, STC2
		Reference genes: CALM1, OAZ1, RPL37A, HBB
MammaPrint (and BluepPrint)	70	AA555029_RC, ALDH4A1, AP2B1, AYTL2, BBC3, C16orf61, C20orf46, C9orf30, CCNE2, CDC42BPA, CDCA7, CENPA, COL4A2, DCK, DIAPH3, DTL, EBF4, ECT2, EGLN1, ESM1, EXT1, etc.	Microarray analysis	Distinguish breast cancer subtypes; luminal-subtype patients have a promising prognosis	[73]
Four-gene predictive model	4	Proliferative-related genes: ASPM and MCM4	QRT-PCR or IHC	Associated to RFS and BCS	[75]
		Immune-related gene: IL6ST
		Apoptosis induction-related gene: NGFRAP1

NAE: Neoadjuvant endocrine therapy; QRT-PCR: Quantitative real time polymerase chain reaction; IHC: Immunohistochemistry.