systemic treatment of triple negative breast cancer · prof sibylle loibl, md, joyce...
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Systemic Treatment ofTriple Negative Breast Cancer
Christoph Zielinski
Comprehensive Cancer CenterMedical University Vienna – General Hospital, Vienna, AustriaandCentral European Cooperative Oncology Group (CECOG, www.cecog.org)
COI Declaration
Honoraria:
BMS, MSD, AstraZeneca, Novartis, Roche
OS
DFS
Breast cancer is a heterogeneous group of diseasesAdapted from Sorlie T et al. Proc Natl Acad S 2001;98(19):10869-10874
Molecular Features of Luminal vs. Basal Epithelial Cells
Heterogeneity in the Nomenclature and Classification of TNBC
Gene Expressions in TNBC
Subtype Gene Expression Profile / High Expression of Genes
Basal-like 1 (BL-1) cell cycle progression, cell division, and DNA damage response pathways
Basal-like 2 (BL.2) cell cycle progression, cell division and growth factor signalling
Immunomodulatory immune processes and cell signaling
Mesenchymal motility and extracellular matrixMesenchymal stem-like motility, extracellular matrix, growth
factor signalling (consistent with claudin-low)
Luminal androgen hormonally regulated pathwaysreceptor
Trials for TNBC
ABC TrialsBrightness TrialCALGB 40603CREATE-XGeparSixtoNRG-BR003WSG-ADAPT TNWSG PlanB
Settings for Drug Testing in Breast Cancer
Setting Endpoints Advantage
Neoadjuvant Path. Response Shortness,Low Patient Numbers
Adjuvant DFI, OS Endpoint-Driven
Metastatic ORR, TtP, OS Risk- & Option-Driven
Pathological CR after Neoadjuvant Treatment
Surrogate for Micrometastasis (?)P. Cortazar et al., Lancet 2014: CTNeoBC pooled analysisA. Berruti et al., J. Clin. Oncol., doi: 10.1200/JCO.2014.55.2836
Klinische Abteilung für OnkologieKlinik für Innere Medizin I
Medizinische Univ. Wien – Allgemeines Krankenhaus
pCR vs. PFS by Subtype(N=4193)
von Minckwitz G et al, J Clin Oncol 2012
Luminal A Luminal B HER2-neg Luminal B HER2-pos
TNBCHER2-pos (non-lum)
Carboplatin in TN BC
• Platinum constitutes the backbone of treatment in ovarian cancer
• due to molecular similarities of TN BC with ovarian cancer, it was speculated that Platinum would be also beneficial in TN BC
GEICAM 2006-03 Study1
94 Patients with TN BCTreatment: EC x4 –> Doce100 x4 versus Doce75 + Carbo AUC6Primary Endoint: pCR (breast)
Results: pCR (breast) 35% vs. 30% (p=0.61)pCR (breast and axilla) 30%, respectively
Conclusion:No amelioration through the addition of Carboplatin(due to previous exposure to alkylating drug?)
1Alba E at al. Breast Cancer Res Treat 2012;136:487-493.
TNBC: Bevacizumab q3wHer2 pos: Trastuzumab q3w
Lapatinib 750 - 1000 mg/d
R
CarboplatinAUC 2 min/mLweekly
NPLD (Myocet)20 mg/ m²weekly
Paclitaxel80 mg/ m²weekly
blood collectioncore biopsy
GeparSixto1
cT2- 4 orcT1c if N+
N=131 / 600 pts with
Triple neg.orHER2-pos.
Sur
gery
18 weeks
Primaryendpoint:pCR
1G. von Minckwitz et al., Proc. Am. Soc. Clin. Oncol. 2013
pCR Rates by Subtypes
[TITLE]
1G. von Minckwitz et al., Proc. Am. Soc. Clin. Oncol. 2013
GeparSixto: pCR by Subtypes1
Efficacy of Carboplatin in TN BC
Post-hoc Analyses from GeparSixto
Additive effect of Carboplatin upon pCR in BRCA mutant, family (BRCA wt) and sporadic TN BC
pCR Carboplatin Group vs. ControlBRCA mut OR 2.75familiy (BRCA wt) OR 2.29sporadic TN BC OR 1.79
evidence from other phase II studies –standard despite lack of a phase III study? 2, 4
1 von Minckwitz G et al. J Clin Oncol. 2014;32(Suppl.18):#1005. 3 Tamura K et al. J Clin Oncol 2014;32(Suppl 18):#1017.2 Sikov WM et al. J Clin Oncol 2015;33:13-21. 4 Sharma P et al. J Clin Oncol. 2014;32(Suppl.18):#1022.
Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense
Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer:
CALGB 40603 (Alliance)1
Randomized Phase II Study
1W.M. Sikov et al., J Clin Oncol 2015 33:1, 13-21
CALGB 406031: Results1
1W.M. Sikov et al., J Clin Oncol 2015 33:1, 13-21
Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast
cancer (BrighTNess): a randomised, phase 3 trial
Prof Sibylle Loibl, MD, Joyce O'Shaughnessy, MD, Prof Michael Untch, MD, William M Sikov, MD, Prof Hope S Rugo, MD, Mark D McKee, MD, Prof Jens Huober, MD, Mehra Golshan, MD, Prof
Gunter von Minckwitz, MD, David Maag, PhD, Danielle Sullivan, PhD, Prof Norman Wolmark, MD, Kristi McIntyre, MD, Jose J Ponce Lorenzo, MD, Otto Metzger Filho, MD, Priya Rastogi, MD, Prof
W Fraser Symmans, MD, Xuan Liu, PhD, Prof Charles E Geyer, MD
The Lancet Oncology
DOI: 10.1016/S1470-2045(18)30111-6
Rationale for the Use of Platin plus PARP Inhibition
Figure 1
The Lancet Oncology DOI: (10.1016/S1470-2045(18)30111-6)
BrighTNess: Study Design
Figure 2
The Lancet Oncology DOI: (10.1016/S1470-2045(18)30111-6)
BrighTNess: Responses
Figure 3
The Lancet Oncology DOI: (10.1016/S1470-2045(18)30111-6)
BrighTNess: Results in Subgroups
Carboplatin in TN BC
Conclusion: there is certain evidence of a benefit of the addition of Carboplatin to chemotherapy in the neoadjuvant treatment of TN BC,
BUT: also other interventions may be efficacious....
BUT: Which Evidence for Other Chemotherapy?
ABC Trials:
4 Year invasive-Disease-Free Survival
Docetaxel plus Cyclophosphamide: 88.2%vs. Anthracycline and Cyclophosphamide plus a Taxane: 90.7%
Blum IL et al., J Clin Oncol 35: 2647-2655, 2017
Overcoming Resistance to Neoadjuvant ChemotherapyN. Masuda et al., N Engl J Med 376: 2147, 2017
Overcoming Chemotherapy Resistance: Capecitabine after Neoadjuvant Chemotherapy
N. Masuda et al., N Engl J Med 376: 2147, 2017
Which Adjuvant Chemotherapy? Conclusions
Germline BRCA-1 Mutated Disease: Platinum-BasedRegimen
BRCA-1 wildtype Disease: Combinations ContainingAnthracyclines and Taxanes
In the case of Treatment Resistance: Capecitabine
Settings for Drug Testing in Breast Cancer
Setting Endpoints Advantage
Neoadjuvant Path. Response Shortness,Low Patient
NumbersAdjuvant DFI, OS Endpoint-Driven
Metastatic ORR, TtP, OS Risk- and Option-Driven
Overall survival from MBC in dependence on molecular characteristics
• 3.726 patients• Median observation: 14.8 years
• Median OS from MBC:– Luminal A: 2.2 years– Her-2 positive: 0.7 years (remark: pre-Trastuzumab)– Basal: 0.5 years (p<0.001)
Kennecke H et al. J Clin Oncol 2010;28:3271-3277
First-Line Taxane or Carboplatin in TN MBC1
Kein Unterschied bei „core-basal-like“ und „brcaness“
1A. Tutt et al., SABCS 2014: S3-01
Doublet Chemotherapy in TN MBC
Median PFS:
nab-Paclitaxel + Carboplatin: 7.4 monthsnab-Paclitaxel + Gemcitabine: 5.4 monthsGemcitabine + Carboplatin: 6.0 months
Yardley D et al., SABCS, Abstr. 874, 2016
Multifactoral Contributions of Activated/Recruited Stromal Cells to the Hallmarks of Cancer
Douglas Hanahan, Lisa M. CoussensCancer Cell 2012, 31: 309–322
CECOG TURANDOT Study: Multicentre RandomisedPhase III Trial
51 centres, 12 countries (Europe and Israel)
• HER2-negative measurable/non-measurable LR/mBC
• ECOG PS 0‒2
• No prior chemotherapy for LR/mBC
• Prior (neo)adjuvant chemotherapy and/or radiotherapy permitted only if completed ≥6 months before randomisationa
BEV‒PAC (n=285):BEV 10 mg/kg d1 & 15
+ PAC 90 mg/m2
d1, 8 & 15 q4w
BEV‒CAP (n=279):BEV 15 mg/kg +
CAP 1000 mg/m2 bid d1‒14 q3w
Treat to PD or
toxicityR
Stratification factors:• ER/PgR status• Country• Menopausal status
• Tumour and QoL assessment q12 weeks in both arms
• Safety assessment at every cycle
C. Zielinski et al., Lancet Oncol. 2016
No. at riskBEV‒PAC 268 247 204 96 45 9 0BEV‒CAP 265 238 193 102 39 11 0
Time (months)
CECOG TURANDOT Study: OS(PP population, n=533)
BEV‒PAC(n=268)
BEV‒CAP (n=265)
Events, n (%) 89 (33) 92 (35)Median, months
(95% CI)30.5
(26.2‒NR)26.0
(22.2‒NR)
HR, stratified(97.5% repeated CI)
1.042 (–∞ to 1.686)
p-valueb 0.0593
1.0
0.8
0.6
0.4
0.2
0
Estim
ated
pro
babi
lity
0 6 12 18 24 30 36
BEV‒PACBEV‒CAP
1-year OS rate:BEV‒PAC: 81%BEV‒CAP: 79%
2-year OS rate:BEV‒PAC: 60%BEV‒CAP: 55%
18-month OS rate:BEV‒PAC: 68%BEV‒CAP: 70%
C. Zielinski et al., Lancet Oncol. 2016
CECOG TURANDOT Study: PFS (ITT population)
BEV‒PAC(n=285)
BEV‒CAP (n=279)
Events, n (%) 177 (62) 214 (77)
Median, months (95% CI)
11.0 (10.4‒12.9)
8.1 (7.1‒9.2)
HR, stratified(95% CI)
1.36(1.09‒1.68)
p-valuea 0.0052
0 6 12 18 24
a2-sided log-rank test adjusted by stratification factors
Estim
ated
pro
babi
lity
BEV‒PACBEV‒CAP
1.0
0.8
0.6
0.4
0.2
0
Time (months)
8.1 11.0
No. at riskBEV‒PAC 285 201 89 20 4BEV‒CAP 279 161 82 27 11
C. Zielinski et al., Lancet Oncol. 2016
Characteristic BEV‒PAC(n=63)
BEV‒CAP(n=67)
Median age, years (range) 54 (29–84) 56 (28–77)Premenopausal, n (%) 17 (27) 18 (27)ECOG performance status, n (%)
0 47 (75) 40 (60)1 13 (21) 24 (36)2 3 (5) 3 (4)
Disease-free interval, n (%)≤12 months 9 (14) 2 (3)>12 months 42 (67) 45 (67)None (metastatic at first diagnosis) 12 (19) 20 (30)
Metastatic sites, n (%)Visceral 41 (65) 46 (69)
Liver 17 (27) 29 (43)Lung 35 (56) 28 (42)
Bone 22 (35) 25 (37)Lymph node status, n (%)
Positive 33 (52) 44 (66)Negative 25 (40) 18 (27)Unknown 5 (8) 5 (7)
Prior (neo)adjuvant chemotherapy, n (%) 45 (71) 42 (63)Taxane 19 (30) 14 (21)Anthracycline 39 (62) 33 (49)Neither anthracycline nor taxane 4 (6) 6 (9)
TURANDOT: Baseline characteristics of the TNBC Subgroup
CECOG TURANDOT Study: PFS of the TNBC Subgroup
PFSBEV‒PAC
(n=63)BEV‒CAP
(n=67)
Events, n (%) 50 (79) 54 (81)
Median, months (95% CI)
9.0 (7.8–10.7)
5.6 (4.9–8.0)
Hazard ratioa
(95% CI)1.37
(0.93–2.02)
p-valueb 0.1078
aUnivariate Cox proportional hazards model. bTwo-sided log-rank test.
1.00
0.75
0.50
0.25
0
No. at riskBEV‒PAC 63 52 45 28 14 7 5 4 2BEV‒CAP 67 47 30 16 10 7 4 3 3
Time (months)
Estim
ated
pro
babi
lity
BEV‒PACBEV‒CAP
5.6 9.0
0 3 6 9 12 15 18 21 24
49.2
6.3
42.9
33.3
6.311.1
19.4
0
19.4
49.3
25.4
6.0
0
10
20
30
40
50
60
70
Objectiveresponse rate
Completeresponse
Partial response Stable disease Progressivedisease
Not evaluable
BEV–PAC (n=63)
BEV–CAP (n=67)p=0.0003a
Patients (%)
aPearson chi-square test.
CECOG TURANDOT Study: ORR in the TNBC Subgroup
OSBEV‒PAC
(n=63)BEV‒CAP
(n=67)
Events, n (%) 28 (44) 34 (51)
Hazard ratioa
(95% CI)1.33
(0.80–2.19)
p-valueb 0.2692
1-year OS rate, %(95% CI)
78(68–88)
63(51–75)
aUnivariate Cox proportional hazards model. bTwo-sided log-rank test.
1.00
0.75
0.50
0.25
0
No. at riskBEV‒PAC 63 59 58 52 48 32 26 17 11 4 2 1BEV‒CAP 67 63 61 47 37 30 21 15 9 5 2 0
0 6 12 18 24 30 36Time (months)
Estim
ated
pro
babi
lity
BEV‒PACBEV‒CAP
CECOG TURANDOT Study: OS of the TNBC Subgroup
Treatment Options in BC
Examples for Novel Approaches to TNBC
• Molecular interventions (PI3K, AKT, mTOR, BRCA)• Antihormal Interventions (target: AR) • Stroma-Directed
Robson M et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1706450
OlympiAD Trial in Triple-Negative, Germline BRCA-Mutated Advanced Breast Cancer
Robson M et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1706450
OlympiAD Trial in Triple-Negative, Germline BRCA-Mutated ABC
Examples for Novel Approaches to TNBC
A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapiesin Women with Advanced Breast CancerLee S. Schwartzberg, et al.: DOI: 10.1158/1078-0432.CCR-16-2339 Published January 2017
Published in: Tiffany A. Traina; Kathy Miller; Denise A. Yardley; Janice Eakle; Lee S. Schwartzberg; Joyce O’Shaughnessy; William Gradishar; Peter Schmid; Eric Winer; Catherine Kelly; Rita Nanda; Ayca Gucalp; Ahmad Awada; Laura Garcia-Estevez; Maureen E. Trudeau; Joyce Steinberg; Hirdesh Uppal; Iulia Cristina Tudor; Amy Peterson; Javier Cortes; JCO 2018, 36, 884-890.DOI: 10.1200/JCO.2016.71.3495
Enzalutamide in TN MBC: PFS in the (A) intent-to-treat (ITT) population and (B) evaluable subgroup and of
OS in the (C) ITT population and (D) evaluable subgroup.
Signalling pathways and involved entities that are unravelling experimental therapeutic targets for TNBC. Depicted molecular landscape of TNBC confers an insight of novel and investigational targeted
therapeutic strategy which are directly unlocking its heterogeneous biology.
Ji Hyun Park et al. ESMO Open 2018;3:e000357
Copyright © European Society for Medical Oncology. All rights reserved.
Future aspects of therapeutic strategies in patients with TNBC based on its chemosensitivity and immune-molecular heterogeneity.
Ji Hyun Park et al. ESMO Open 2018;3:e000357
Copyright © European Society for Medical Oncology. All rights reserved.
Systemic Treatment ofTriple Negative Breast Cancer: Conclusions
• TN BC remains a major challenge regarding ourunderstanding of its biology and consequently itstreatment.
• Platinum-based therapies seem to have certain efficacy in the neoadjuvant setting.
• In advanced disease, there might be a place forBevacizumab-based treatment if ORR is required.
• PARP inhibition seems to have various efficacy at variousstages of the disease.
• Further analyses of disease biology will certainly lead toameliorated treatment options in this diversified disease.
• Enzalutamide exerts promising activity in AR+ disease• ICPI treatment might have a certain place in selected
patients.