Neo- & A CTx for EBC. Yeesoo Chae, MD, PhD Oncology, Kyungpook National University Hospital, Daegu, Korea

Transcription

1 2015 혈액종양학연수강좌 Neo- & A CTx for EBC Yeesoo Chae, MD, PhD Oncology, Kyungpook National University Hospital, Daegu, Korea

2 Overview Adjuvant CTx (A) New international guidelines Adjuvant CTx for N- EBC Non-anthracycline regimen for N-EBC Neoadjuvant CTx (NACT) General principles Prognostic implications of pcr How to increase pcr New surrogate marker, RCB (residual cancer burden)

3 Breast cancer, A CTx

4 ACT: Who should be given Early Breast Cancer Any node - Any node + HR+ HR- T1a 0.5cm 10y DFS > 95% Gene signature? Luminal B? High Ki67 HER cm TN >1cm No adjuvant Adjuvant CT + Hormone if HR+ +H if HER2+

5 ACT: Who should be given Early Breast Cancer Any node - Any node + HR+ HR- 0.5cm 10y DFS > 95% Gene signature? Luminal B? High Ki67 HER cm >1cm TN No adjuvant Adjuvant CT + Hormone if HR+ +H if HER2+

6 ACT: Which regimens? CMF6 NSABP B-15 NSABP B-23 AC6 = CALGB40101 E2197 NSABP B-30 = AC4 = AT4 = TAC4 CMF Anthracycline FACS05 MA5 T+A CEF/FEC CAF/FAC NSABP B28 NSABP B27 Dose-dense PACS01 TACT GEICAM GEICAM9906 GEICAM9805 BCIRG001 NSABP B30 NCIC MA.21 ECOG1199 FEC T or P FAC wp TAC6 = AC4 T AC4 P ECOG1199 AC4 wp12 CALGB 9741 ddac4 ddp

7 N- breast cancer: Incidence of the world (2010) >50% of all newly diagnosed Oncologist. 2011

8 ACT for ER+/N- EBC Early Breast Cancer Any node - Any node + HR+ HR- 0.5cm 10y DFS > 95% Gene signature? Luminal B? High Ki67 HER cm >1cm TN No adjuvant Adjuvant CT + Hormone if HR+ +H if HER2+

9 Molecular assays available Prospective evidence is still missing expensive!! Mammaprint OncotypeDX EndoPredict Prosigna Provider Agendia Genomic health Sividon Nanostring Type 70-gene 21-gene 11-gene 50-gene Tissue Fresh frozen FFPE FFPE FFPE Technique DNA microarray qrt-pcr qrt-pcr qrt-pcr Indication Prognostic N0-1 Prognostic, N0-1 ER+ Prognostic, N0-1 ER+/HER2- Prognostic N0-1 Retrospective evidence (% of recruited) RASTER (73%) NSABP B14 (14%) NSABP B20 (28%) SWOG 8814 (40%) ATAC (30%) ABCSG6 (19%) ABCSG8 (36%) GEICAM9906 (64%) MA12 (49%) MA5 (66%) ABCSG8 (40%) ATAC (16%) GEICAM9906 (60%) Prospective (pending) MINDACT TAILORx, RxPONDER ADAPT Schmidt Breast care 2014

10 Subtypes: intrinsic vs. IHC St.Gallen Guideline (2013, 2011) Definition >1% >1% ER PR HER2 Ki or 2+ ISH> or 20% Luminal A + 20% - - Luminal B (HER2-) + <20% - + Luminal B (HER2+) + Any + Any HER2-enriched Any Basal Any Still debating 14% vs. 20%

11 ACT: Who should be given? International guidelines define based on Intrinsic Subtype defined by Gene signature (St. Gallen) Recurrence score by OncotypeDX TM (NCCN, St. Gallen) St Gallen 2013 Luminal A Luminal B Luminal B /HER2 - /HER2 + HER2 enrich TNBC T1a - +/- +/- +/- +/- T1b ( 5mm) - +/ T1c - +/ T Node /- > NCCN guidelines ER +/HER2 - ER +/HER2 + HER2 enrich TNBC T1a - - +/- - T1b ( 5mm) RS +/- +/- +/- T1c RS T2 RS Node

12 ACT: HER2+/TNBC Early Breast Cancer Any node - Any node + HR+ HR- 0.5cm 10y DFS > 95% Gene signature? Luminal B? High Ki67 HER cm >1cm TN T1c No adjuvant Adjuvant CT + Hormone if HR+ +H if HER2+

13 ACT for T1ab HER2/TNBC Early Breast Cancer Any node - Any node + HR+ HR- 0.5cm 10y DFS > 95% Gene signature? Luminal B? High Ki67 T1b HER cm >1cm TN No adjuvant? Adjuvant CT + Hormone if HR+ +H if HER2+

14 T1a,b 1cm: relapse is not rare Small but may recur which could be prevented by ACT. HER2 in T1a,b EBC: 10-15% Absolute risk of distant relapse Study n End point HER2 + v. -(%) P-value Curigliano et al, year DFS HR+ 99 vs Amar et al month RFS 92.6 vs Gonzalez-Angulo year RFS 77.1 vs 93.7 < Joensuu et al year RFS 67 vs Press et al year BCSS 70.5 vs NCCN cohort study Ines Vaz-Luis et al. JCO 2014 T1a T1b ER+/HER2- ER+/HER2+ ER-/HER2+ ER-/HER2- ER+/HER2- ER+/HER2+ ER-/HER2+ ER-/HER2- CT+/-H DRFS BCSS OS

15 ACT: HER2/TNBC International guidelines define based on Intrinsic Subtype defined by Gene signature (St. Gallen) Recurrence score by OncotypeDX TM (NCCN, St. Gallen) St Gallen 2013 Luminal A Luminal B Luminal B /HER2 - /HER2 + HER2 enrich TNBC T1a - +/- +/- +/- +/- T1b ( 5mm) - +/- +/- +/- +/- T1c - +/ T Node /- > NCCN guidelines ER +/HER2 - ER +/HER2 + HER2 enrich TNBC T1a - - +/- - T1b ( 5mm) RS +/- +/- +/- T1c RS T2 RS Node

16 ACT for T1abN0 tumor NCCN Prospective cohort study: 4,113 with T1a,bN0M0 among 24,931 EBC Pts during Median F/U of 5.5yr Ines Vaz-Luis et al. JCO 2014 &ASCO2014 abstract #522

17 ACT: Which regimens for N-EBC? AC6 = CALGB40101 (95%) CMF6 E2197 (66%) = AC4 = AT4 = TAC4 USO9735 (48%) TC4 CEF/FEC CAF/FAC NSABP B27 (70%) TACT (20%)* GEICAM (100%) GEICAM9805 (100%) NCIC MA.21 (22%) FEC T or P FAC wp TAC6 = AC4 T ECOG1199 (12%) AC4 P ECOG1199 (12%) AC4 wp12 ddac4 ddp

18 ACT: Which regimens for N-EBC? meta-analysis of RCTs 14 P-III RCTs : N=25,067- N0 (N=4,274) Study Node N HER2 T Non-T F/U GEICAM 9805, Martin N-/ % TAC FAC 5 ECOG 2197, Goldstein N-/+ 1893/989 No AT AC 5 USO 9735, Jones N-/+ 487/529 17% TC AC 7 UK TACT, Ellis N-/+ 835/ % FEC-T FEC or E-CMF 5 RAPP-01, Brain N-/+ 627 No AT AC 5 FinHer, Joensuu N-/ % T-FEC V-FEC 5 BCIRG001, Martin N % TAC FAC 4.5 TAXIT 216, Cognetti N+ 972 No E-T-CMF E-CMF 5 PACS01, Roché N No FEC-T FEC 5 BIG2-98, TAX315, N No A-T-CMF or AT-CMF A-CMF or AC-CMF 5 WSG/AGO, Nitz N Yes EC-T FEC 5 HORG, Polyzos N % T-EC FEC 5 PACS-04, Roché N Yes ET FEC 5 ADEBAR, Janni N Yes EC-T FEC 4 Taxane seems better Better PFS regardless of N But, no OS for N-EBC Jacquin et al. BCRT 2012

19 ACT: Which regimens for N-EBC? P-III RCTs GEICAM9805: T+A (concurrent) GEICAM/ : A T (sequential) Martin M et al, NEJM 2010 Martin M et al, JCO 2013

20 ACT: Which regimens for N-EBC? P-III RCTs GEICAM9805: T+A (concurrent) 90.1% 85.3% Δ4.8% DFS: HR=0.68 ( ); p=0.01 Δ6% 87.8% 81.8% GEICAM/ : A T (sequential) Δ2.7% DFS: HR=0.73 ( ); p=0.04 Δ2% 95.2% 93.5% Δ1.6% OS: HR=0.76 ( ); p=0.29 OS: HR=0.79 ( ); p=0.31 Martin M et al, NEJM 2010 Martin M et al, JCO 2013

21 GEICAM9805: Discussion GEICAM9805: Discussion High % of premenopause and younger aged Higher toxicity related with TAC Efficacy related with locoregional control than distant TAC FAC P G3,4 28.2% 17.0% P<0.001 SAE 22.4% 4.2% Discontinuatio n 4.7% 0.8% TRM 0 0 T+ A for N- EBC can not be for routine use in the practice Martin M et al, NEJM 2010

22 A-induced cardiotoxicity Late onset is NOT rare the 10-y follow-up of the BCIRG001 trial FAC is associated with an unexpectedly high cardiac toxicity. 17 (2.3%) CHF and four (0.5%) deaths LVEF drop > 20% in 41 (15%) Martin M et al, SabCS2010; Shulman LN et al JCO2012; Ryberg et al, JNCI 2008

23 non-trial population Observatory study by Giordano et al JCO vs. 14% Δ5% 47 vs. 33% Δ14% Giordano et al JCO 2006

24 Toxicities of Anthracyclines Risk of cardiotoxicity: 6-26% High emetogenic agent High proportion of young female in Korea Much more intolerant to Anthracyclines d/t Nausea Vesicant infertility Risk of leukemia ~0.5%

25 ACT: Which regimen for N- EBC? Usually good outcome with standard treatment 5y-DFS of 85-90% or more 5y-OS of 95% or more Taxane + Anthracycline Taxane based regimen is superior in terms of RFS 2 RCTs & meta-analysis for N- EBC showed better PFS, but NO OS benefit Minimal efficacy: Only 5 % for PFS and <3% for OS Higher toxicity rate with A+T Therefore, T+A for N-EBC can not be accepted as a routine use Need less toxic regimen for small sized node- EBC

26 non-anthracycline regimens for small-sized Node-negative EBC Taxane without A might be an option in N-subgroup 1. Jones SE et al. J Clin Oncol 2006;274: Jones SE et al. J Clin Oncol 2009;27: Slamon D et al. N Engl J Med 2011;365:

27 Non-anthracycline regimens for N-EBC in reality NCCN Prospective cohort study: stage I breast cancer 4,113 with T1a,bN0M0 among 24,931 EBC Pts during Median F/U of 5.5yr A) HER2+ B) HER2- HR+ C) HER2- HR- anthracycline TC A+T TCbH Other Ines Vaz-Luis et al. ASCO2014 abstract #522

28 ACT: non-anthracycline regimens for small-sized Node-negative EBC Taxane without A might be an option in low-risk group Efficacy could be estimated from P-III RCTs containng N- EBC TC [USO9735] TCbH [BCIRG006] P-II studies with N-EBC: Taxane only Trial Phase Regimen DFS OS Ref. CALGB40101 P-II wp12 AC4 88 (5yr) Shulman. JCO 2014 NCT P-IIa wp+trastuzumab 98.7 (3yr) Tolaney et al., NEJM 2015 ATTEMPT trial P-II T-DM1 wp+trastuzumab Pending Old but active CMF > Capecitabine

29 Summary: Adjuvant CTx A+T regimen for N+ BC TAC or AC-P A+T regimen for N-EBC Better PFS but No OS gain; higher toxicity Non-anthracycline regimen for N- or low risk breast cancer TC, TCH Considering low rate of relapse Lack of definitive evidence of toxic regimen High and long term side effects e.g. CHF, leukemia/mds Less toxic regimens for Small EBC (stage I tumor) New regimen such as weekly Pac+/herceptin, T-DM1 is under investigation.

30 Neo-adjuvant CTx (NACT)

31 Advantages of NACT Down-staging Inoperable operable Mastectomy breast conserving Eradicate micrometastasis Decrease relapse and Increase survival Direct measuring drug response and changes in tumor microenvironment Change regimen and treatment modalities to maximize the response New drug development

32 What we know about NACT NACT vs. ACT Breast conservation rate: NACT ACT Trials Phase (n) Tumors NA vs A Primary endpoint Other outcomes IBBGS III (272) T2 > 3 cm 3 EVM 3 BCT 63% vs. 0% or T3 N0-1 ETV ND in DFS or OS; Institut Curie S6 III (390) T2-3, N0-1 4 FAC BCT 82 vs. 77% (ns) ND in DFS and OS, Royal Marsden III (293) T0 4, N MT BCT 89 vs. 78% (P=.) ND in DFS, OS, NSABP B-18 III (1493) T1 3, N0-1 4 AC 5 y-os: 80 vs. 81% (ns); 5 y-dfs: 67 vs. 67% (ns) BCT 68 vs. 60% (P=.001) EORTC III (698) T1c T4b 4 FEC 4 y-os 82 vs. 84% (ns) 4 y-pfs 65 vs. 70% (P=.27); downstaging to BCT in 23% ABCSG-7 III (423) T1 3, N0-1 RFS better with A therapy (HR corr 56%, pcr 6%; HR + high 3 CMF 0.7; ); LRR 13 vs. 8% (P=.10) risk HR+ ND in OS (HR 0.8; ) Meta-analysis IV (3946) 9 randomized trials Same regimen ND in OS (RR 1.0); ND in DFS (RR 0.99) LRR higher for NA (RR 1.22; P=.015 ) pcr range 4 29%

33 NACT: eradicate micrometa survival? Survival: NACT = ACT NSABP B-18 : 16 years follow-up Meta-analysis of 9 trials (N=4,000) Mauri et al. JNCI, Vol. 97, No. 3, 2005; Rastogi et al. J Clin Oncol 26: (2008)

34 What we know about NACT Neoadjuvant vs. Adjuvant Breast conservation rate: yes Survival: No survival gain Taxane increase pcr, BCR% single concurrent sequential Trials N REGIMENS pcr BCS Ref. Aberdeen (Tax301) 104 CVAP CVAP4 T Smith et al, JCO 2002 NSABP B AC4 AC4 T4 S AC4 S T Bear et al, JCO2003 GEPARDUO 913 AT4 AC T von Minckwitz et al, JCO2001

35 What we know about NACT Neoadjuvant vs. Adjuvant Breast conservation rate: yes Survival: No survival gain Taxane increase pcr, BCR%

36 What we know about NACT Neoadjuvant vs. Adjuvant Breast conservation rate: yes Survival: No survival gain Taxane increase pcr, BCR% Adding trastuzumab increase response for HER2+

37 What we know about NACT Neoadjuvant vs. Adjuvant Breast conservation rate: yes Survival: No survival gain Taxane increase pcr, BCR% Adding trastuzumab increase response for HER2+ pcr as a prognostic factor Cortazar et al, Lancet, 2014

38 pcr as a surrogate marker pcr and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis (N=11,955 from 12RCTs) *pcr=ypt0/is, N0 Cortazar et al, Lancet, 2014

39 What we know about NACT Neoadjuvant vs. Adjuvant Breast conservation rate: yes Survival: No survival gain Taxane increase pcr, BCR% Adding trastuzumab increase response for HER2+ pcr predicts survival ypt0n0 = ypt 0/is N0 > ypcr breast Various by subtype No proven factors after achieving pcr Cortazar et al, Lancet, 2014

40 NeoA hypothesis An increase in pcr by adding a new agent in NA setting survival benefit

41 pcr in a NA setting The FDA may grant accelerated approval on the basis of a surrogate end point that is reasonably likely to predict clinical benefit After accelerated approval, demonstration of an improvement in DFS or OS would be require U.S. Department of Health and Human Services Food and Drug Administration, 2014

42 Increase pcr Dose dense, adding, or change additional agents Adding additional CTx Dose-dense Changing based on response tailored Targeted agents as precision medicine TNBC HER2+ bevacizumab Platinum PARP1 inhibitor H + lapatinib + pertuzumab

43 Adding other chemo-agents Trials N ER/HER2 Regimens pcr BCS Comments TOPIC Ann Oncol NE Infusional FU+ CDDP AC# % 63% 5YSR=82 vs. 74 Higher G3,4 toxicity TOPIC II Ann Oncol /NE EpiVinorelbine#6 AC# less G3,4 toxicity Dose reduction rate Neo-tAnGo Lancet /27 EC PGemcitabi ne EC P NA No trastuzumab for HER2+ NSABP B-40 NEJM /0 AC-D +/-avastin AC-DX AC-DG Bev increases pcr (34.5 vs. 28.2) ABCSG-24 Ann Oncol /17 ED + X# GeparQuattro JCO /30 EC-T (H) EC-TX EC-T-X H (trastuzumab) was given No definitive advantage over standard A-T

44 ddnact: still controversial Author Baldini, 2003 Treatment protocol Seems higher in achieving pcr But, no survival advantage was seen Higher toxicity rate interva l N F/U (m o) CEF3 S/RT CEF CEF3 S/RT CEF /-:22/ 8.6 T,% N,% BCS ccr% pcr % IB IC: 25 +/-:18.6/ IIIA: IIIB: 50 Minkcwitz, 2005 A DOC T1: 0.7; Pos: AC DOC T2: 84; T3: 15.2 Pos: Untch, T1 3: 86.2; N0: 37.2; E T CMF [PREPARE] T4: 8.5 Pos: EC T T1 3: 90.8 N0: 38.4; T4: 7.3 Pos: Baldini et al Ann Oncol2003; von Minckwitz et al JCO2005; Untch et al JCO2008

45 Tailoring therapy to response? Response Would more CTx be better Yes: tumor really sensitive to chemo Same vs. different No: already good Nonresponse Would more CTx be better Yes: High risk warrants therapy No: tumor resistant already Bear, H. D. et al. J Clin Oncol; 24:

46 Response-guided therapy Aberdeen GEPAR-TRIO Smith I et al, JCO 2002 Von Minckwitz et al. JCO 2013 Needs more!!

47 Increase pcr Dose dense, adding, or change additional agents No definitive evidence Targeted agents as precision medicine TNBC bevacizumab Platinum PARP1 inhibitor HER2+ H + lapatinib + pertuzumab

48 Bevacizumab for Breast cancer Anthracycline/taxane backbone? Add bevacizumab Bev showed better PFS but not OS in MBC E2100 AVADO RIBBON-1 RIBBON-1 Bev No Bev No Bev No Bev No mpfs HR P-value P< P= P= P= E5103: No survival advantage in Adjuvant Setting: LN+ (74%) or High risk LN- (26%) HER2- (N=4950) RANDOMIZE AC+ pla X 4 wp80*12 + pla X 4 AC+ Bev X 4 wp80*12 + Bev X 4 AC+ Bev X 4 wp80*12 + Bev X 4 Bev X 10

49 Bevacizumab for TNBC Anthracycline/taxane backbone + Bevacizumab for TNBC? CALGB [NACT] BEATRICE [ACT] + Bevacizumab HR, 0 90 ( ); p=0 33 Sikov et al. JCO2014 Cameron D et al, Lancet Oncol. 2013;

50 NACT for TNBC Anthracycline/taxane backbone? Add bevacizumab: NO? Add platinum? Add PARP inhibitor

51 subtype of TNBC 130 with NACT/146 TNBC Masuda et al, CCR 2014

52 pcr, RCB by subtype of TNBC 100% P= % 80% 70% 60% 50% % 30% 20% 10% 0% BL1 BL2 M IM MSL. LAR UNS pcr Non-pCR Masuda et al, CCR 2014

53 Platinum, PARP1 for mbrca TNBC Platinum causes DNA damage Repair system by PARP and BRCA Platinum + PARP inhibitor for BRCA mutation+ TNBC? Iglehart JD, Silver DP. NEJM 2009; 361 (2) ;

54 PARPi + platinum for mbrca Veliparib+Carbo+Pac in Xenograft model (mbrca BC model)

55 Platinum and PARPi for TNBC: PrECOG0105 I-IIIA (T 1cm) TNBC or BRCA1/2 (N=80) Gem+Cb D1,8 Iniparib 5.6mg/kg D1,4, 8, 11 S Primary endpoint: pcr (T0/isN0) 2 nd Endpoint: MRI response, BCS Q 3 weeks x 6 cycles BRCA1/2 wild mbrca1/2 TN+mBRCA1/ pcr RCB0,1 Telli ML et al, JCO 2015

56 P-3 NA veliparib+cb in TNBC AbbVie trial (Ongoing) M TNBC T2-4N0-2, T1N1-2 R Pac/Cb/Vel AC Pac/Cb/Placebo AC Pac/placebo AC 1º: pcr 2º: BCR 3º: EFS, OS, CRR.. NCT Stratified by BRCA, cn NCT , PARPi, Platinum for TNBC Not routinely indicated until confirmation

57 Increase pcr Tailored therapy based on response Dose dense, adding, or change additional agents Targeted agents TNBC HER2+ bevacizumab Platinum PARP1 inhibitor H + lapatinib + pertuzumab

58 HER2+ NeoA Therapy Options.. Anthracycline/taxane/H backbone Dual inhibition of HER2 Synergistic effect with Trastuzumab pertuzumab lapatinib

59 HER2+ NeoA Therapy Options.. Anthracycline/taxane/H backbone [MBC] Lapatinib, pertuzumab increase survival with trastuzumab CLEOPATRA IIIB-IV Pretreated w/ Trastuzu Taxane Anthra R Arm 1 Lapatinib 1250 mg/day p.o. Capecitabine 2000 mg/m 2 /day, Arm 2 Capecitabine 2500 mg/m 2 /day, HER2+mBC (N = 808) R Docetaxel Trastuzumab +Placebo Docetaxel Trastuzumab +pertuzumab 0.68 (0.58, 0.80) P=0.0002

60 NACT: lapatinib and pertuzumab increase pcr GeparQuinto (Her2 positive) Trials Phase (n) Inclusion regimens pcr% III (620) ct3/4; ct2 if HR or cn+; ct1 if HR or SLN+ CHER-LOB II (121) HER2+, II-IIIA NEO-ALTTO III (455) HER2+, 2 cm NSABP B-41 III (522) HER2+, 2 cm NeoSphere II (417) HER2+, 2 cm or ct4d TRYPHAENA II (225) HER2+, II-III EC Doc+H EC Doc+L wp12 FEC4 + H wp12 FEC4 + L wp12 FEC4 + L+ H wp12 + H wp12 + L wp12 + L+ H AC4 Doc 4+ H AC4 Doc 4+ L AC4 Doc 4+ L + H 4 Doc + H 4 Doc + H + P 4 H + P 4 Doc + P FEC3+H+P D3+H+P FEC3 D3 +H+P 6 Doc + Cb+ H+P 30 (P=0.04) (P=0.019) (P=0.019) (P=0.075) (P=0.014) Untch et al Lancet Oncol2012; Guarneri et al JCO2012; Baselga et al, Lancet2012; Robidoux et al ASCO2012; Gianni et al, Lancet Oncol2012; Shneeweiss et al, Ann Oncol2013

61 Lapatinib P-III, for MBC NeoALTTO ALTTO N=324 PFS N=455 pcr N=8381 PFS (4.5y) X+L X 0.49 (0.34, 0.71) wp+t wp+l wp + T+L ACT+T+L ACT+T L ACT+T 0.84 ( ) 0.96 ( ) Baselga et al., SABCS 2012; abstract S5-1

62 Pertuzumab CLEOPATRA P-III, 1 st line for MBC (n=808) NEOSPHERE NACT for EBC (n=417) APHINITY (n=4805) HER2+ MBC R A N D O M I Z E Placebo + T Docetaxel Pertuzumab + T Docetaxel 0.68 (0.58, 0.80) P= HER2+ EBC 15.3 TH (107) THP (107) HP (107) TP (96) S U R G E R Y S U R G E R Y HER2+ EBC R A N D O M I Z E AC T Placebo + T AC T Pertuzumab + T?

63 Increase pcr Tailored therapy based on response Dose dense, adding, or change additional agents Targeted agents TNBC HER2+ bevacizumab Platinum PARP1 inhibitor H + lapatinib fail to show its efficacy + pertuzumab pending

64 Little association btw pcr & survival (trial level) pcr between pooled analysis vs. trial level OR for pcr HR for survival pooled analysis trial level Homogenous population Adequate design for trials: use of targeted agents, sample size, F/u duration pcr rate is only 10-40% Other marker? Cortazar et al, Lancet, 2014

65 RCB = 1.4 (f inv d prim ) [4 ( LN ) d met ] 0.17 Symmans et al, JCO 2007 RCB as an alternative marker? 382 patients = 241 (T-FAC) (FAC) in MDACC Breast LN

66 RCB predicts survival MDACC cohort study Total HR- HR+ Symmans et al, JCO 2007

67 Multivariate analysis with/without RCB pcr and RCB 0/1 can be good markers But vary by subtype RCB provides additional information for individual pts Variable Without RCB With RCB HR 95%CI P HR 95%CI P Age ( 50 v 50) to to Stage pre (III v I or II) to to HR (+ v -) to to Hormone treatment (yes v no) to to Pac (3-weekly v weekly) to to Response (RD v pcr) to to RCB index to 3.69 <.001 *RCB = 1.4 (f inv d prim ) [4 ( LN ) d met ] 0.17 Symmans et al, JCO 2007

68 Multivariate analysis with/without RCB pcr and RCB 0/1 can be good markers But vary by subtype RCB provides additional information for individual pts Variable Without RCB With RCB HR 95%CI P HR 95%CI P Age ( 50 v 50) to to Stage pre (III v I or II) to to HR (+ v -) to to Hormone treatment (yes v no) to to Pac (3-weekly v weekly) to to Response (RD v pcr) to to RCB index to 3.69 <.001 *RCB = 1.4 (f inv d prim ) [4 ( LN ) d met ] 0.17 Symmans et al, JCO 2007

69 A treatment based on RCB pcr and RCB 0/1 can be good markers But vary by subtype RCB provides additional information for individual pts Discriminates responsive (R0/1) from non-r (RCB 2/3) Identify Primary refractory RCB 3 DFCI IU-UCSF-UNC Pilot: Feasibility of Novel Therapies After Preoperative CTx

70 Breast cancer: A and NA CT Less toxic regimens for N- or elderly patients Non-anthracycline regimens: TC, TCbH Predictive markers are needed pcr is surrogate marker for survival in NA setting Increase pcr in a neoadjuvant setting Adding or changing chemotherapeutic agents: No *Precision medicine: Increase accuracy HER2: H, pertuzumab, lapatinib TNBC: platinum, PARP1 inhibitor pcr survival at trial level Homogenous population RCB can be a substitute for pcr

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