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Copyright ©The Author(s) 2019.
World J Clin Cases. Aug 6, 2019; 7(15): 1937-1953
Published online Aug 6, 2019. doi: 10.12998/wjcc.v7.i15.1937
Table 1 Neoadjuvant endocrine therapy and neoadjuvant chemo-endocrine therapy as potential approaches in the neoadjuvant settings
Clinical trialTreatment arms (n)DurationPrimary endpointORRBCS 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 moOR by clinical palpation64% 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 wkOR by MRI48% 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 wkOR by ultrasound and mammography59.1% 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 wkOR by MRI and CT39.3% 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 wkOR by clinical palpation85% 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 wkOR by clinical palpation10.2% 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 wkOR by MRI72.6% vs 84.8% (P = 0.02)
Table 2 The optimal duration and optimal endocrine agents of neoadjuvant endocrine therapy
Clinical trialPatient characteristicsTreatment arms (n)DurationPrimary endpointORRBCS rate
Krainick-Strobel et al[23], 2008ER+ and/or PR+; PostmenopausalLET 2.5 mg/d (33)4-8 moOR by clinical palpation, mammography, ultrasound, and BCS55% vs 24% at 4 and > 4 mo71% vs 80% at 4 and > 4 mo
Fontein et al[25], 2014ER+; PostmenopausalEXE (102)3 mo vs 6 moOR by clinical palpation at 3 and 6 months58.7% vs 68.3%61.8% vs 70.6% (P = 0.012)
Carpenter et al[22], 2014ER+ and/or PR+; PostmenopausalLET 2.5 mg/d (146)3–12 moOptimal 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 moOR by clinical palpation55% 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 wkOR by ultrasound37% 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 moOR by ultrasound50.0% vs 46.2% (P = 0.037)38.1% vs 29.9% (P = 0.11)
Semiglazov et al[16], 2015ER+ and/or PR+; Postmenopausal(A) EXE (76); (B) TAM (75)3 moOR by clinical palpation76.3% 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 wkExpression of Ki6717.4 vs 11.8% at week 4; 22.9 vs 20.6% at week 16-
Quenel-Tueux et al[30], 2015ER+; Postmenopausal(A) ANA 1 mg/d (61); (B) FUL 500 mg/mo (59)6 moOR by clinical palpation58.9% 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 moOR by clinical palpation52.6% 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 wkOR by clinical palpation69.1% vs 62.9% vs 74.8%45.2% vs 40% vs 48.7%
Torrisi et al[33], 2007ER+ T2-T4N0N2; premenopausalLET 2.5 mg/d plus GnRHa 11.25 mg/3 mo (32)4 moOR by clinical palpation50%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 wkOR by ultrasound70.4% 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 moTime to optimal OFS46.2% vs 44.0%52.2% vs 42.3%
Table 3 The optimal targeted agents
Clinical trialTreatment arms (n)DurationPrimary endpointResponse ( 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/d14 wkClinical response by ultrasound and median log-fold change in Ki-67 expressionA 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 moCCCA (Ki67 < 2.7%) on palbociclib plus anastrozoleC1D1 vs C1D15: 26% vs 87% (P < 0.001)
Arnedos et al[40], 2018 (POP)(A) PAL 125 mg/d (74); (B) placebo (26)14 dAntiproliferative response, defined as lnKi67 < 1 at day five58% 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 dmean 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 w14 wkChanges in Ki67 expressionReduced Ki67 in patients 15% vs 59% vs 66%
Ma et al[46], 2017ANA 1 mg/d (plus goserelin if premenopausal) followed by MK-2206 125 mg/w (16)4 mopCR rate0%
Baselga et al[48], 2009(A) LET 2.5 mg/d+ placebo; (B) LET 2.5 mg/d+ everolimus 10 mg/d4 moOR by clinical palpation68.1% vs 59.1% (P = 0.062)
Table 4 Genomic assays to predict outcome in neoadjuvant endocrine therapy
Genomic assayGene numberGenomic informationMethodCurrent results in NAERef.
Oncotype DX®21 (16+5)Proliferative-related genes: Ki67 AURKA, BIRC5, CCNB1, MYBL2QRT-PCRRecurrence 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, DHCR7QRT-PCRLower genomic risk related to favorable response.[69]
Estrogen-related genes: RBBP8, IL6ST, AZGP1, MGP, STC2
Reference genes: CALM1, OAZ1, RPL37A, HBB
MammaPrint (and BluepPrint)70AA555029_RC, ALDH4A1, AP2B1, AYTL2, BBC3, C16orf61, C20orf46, C9orf30, CCNE2, CDC42BPA, CDCA7, CENPA, COL4A2, DCK, DIAPH3, DTL, EBF4, ECT2, EGLN1, ESM1, EXT1, etc.Microarray analysisDistinguish breast cancer subtypes; luminal-subtype patients have a promising prognosis[73]
Four-gene predictive model4Proliferative-related genes: ASPM and MCM4QRT-PCR or IHCAssociated to RFS and BCS[75]
Immune-related gene: IL6ST
Apoptosis induction-related gene: NGFRAP1