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Triple Negative Breast cancer New treatment options arenowhere ?
Ofer Rotem, M.D., B.Sc. Breast Unit, Davidoff center Rabin Medical center October 2017
Case
• 6/2013 - M.D., 38 years old woman, healthy, no family Hx
Palpated mass in her right breast
• O/E & Imaging – 3cm mass in Rt breast UOQ and a 2cm mobile LN in the right axilla.
CNBx Rt breast & axilla – IDC Grade 2-3, LN-Pos
ER/PR/HER2-Neg, Ki67-40%
Systemic work-up – no evidence of Met disease
• TNBC Stage II – T2N1M0
Case
• After consulting with her surgeon, the Mrs. D refers to your clinic for Preoperative treatment.
• Mrs. D is married + 3, works as a pilot in EL-AL.
Which regimen would you prefer ?
1- DD AC Weekly Taxol
2- DD AC Taxol-Carbo
3- DD AC-Bev Taxol-Carbo-Bev
4- AC Weekly Taxol
GeparSixto: Study Design
• Randomized phase IIb study in 51 German centers
• Primary endpoint: pCR
• Secondary endpoints: RFS, DFS, OS
Pts with centrally confirmed TNBC* or HER2+ BC† with
cT2 - T4a-d or cT1 with N+
disease (N = 588)
Surgery
PMCb
Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W
Carboplatin AUC 2‡ Q1W
q.18w
(n = 295)
PM Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W
q.18w (n = 293)
*TNBC pts also received bevacizumab 15 mg/kg IV Q3W. †HER2+ BC pts also received trastuzumab 8 mg/kg IV (initial dose), then 6 mg/kg IV Q3D (subsequent doses) and lapatinib 750 mg QD. ‡Dose reduced to AUC 1.5 after 330 pts enrolled.
von Minckwitz G, et al. SABCS 2015. Abstract S2-04.
GeparSixto: pCR Outcomes
SABCS 2015
pCR, %
ypT0/is ypN0 PMCb PM
Odds
Ratio P Value
All pts (n = 588) 43.7 36.9 .107*
HER2+ BC (n = 273) 32.8 36.8 0.84 .6†
TNBC (n = 315)
gBRCA wild type (n = 241)*
gBRCA mutant (n = 50)*
53.2
55
65.4
36.9
36.4
66.7
1.94
2.14
0.94
.005†
.004
0.92
* Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer Secondary Analysis of the GeparSixto Randomized Clinical Trial Eric Hahnen. JAMA Oncology, Oct 2017. von Minckwitz G, et al. SABCS 2015. Abstract S2-04. von Minckwitz G, et al. Lancet Oncol. 2014;15:747-756. von Minckwitz G, et al. ASCO 2014. Abstract 1005.
*Level for significance = 0.2 †Test for interaction, P = .015
GeparSixto: DFS by gBRCA Status and Regimen in TNBC
Pts
Wit
h D
FS (
%)
BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb
121 120
24 26
104 107
23 25
88 95 19 20
43 40
6 7
0 0 0 0
BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb
Mos
100
80
60
40
20
0 0 12 24 36 48
BRCA1/2 Mut WT
86.3 Vs 82.5 85.3 Vs 73.5 3yDFS (%)
Non-Significant 0.53, 0.29-0.96 HR, CI
CALGB 40603
breast/axilla pCR –40603 CALGB
William M. Sikov, et al. JCO, Jan 2015
Carbo No Carbo
54% 41%
OR-1.71, p-0.0029
Bev No Bev
52% 44%
OR-1.36, p-0.057
With Bev & Carbo With Carbo With Bev Control
60% 49% 43% 39%
Carboplatin Bevacizumab
Yes No Yes No
EFS 3-year 76% 71% 75% 72%
HR 0.84 (0.58-1.22) 0.80 (0.55-1.17)
OS 3-year 81% 85% 85% 81%
HR 1.15 (0.74-1.79) 0.76 (0.49-1.19)
CALGB 40603 – EFS and OS by Factor
San Antonio Breast Cancer Symposium, December 8-12, 2015
ESMO Guidelines. 2015: Addition of carboplatin to neoadj chemotherapy in TNBC - For BRCA 1/2 or RAD mutations it is acceptable to add a platinum compound, after discussion with the patient. NCCN Guidelines version 2.2017: The NCCN panel does not recommend addition of carboplatin to neoadj standard chemotherapy for patients with TNBC outside a clinical trial setting.
ASCO 2017: I-SPY 2 Trial: Combination of Pembrolizumab Plus Standard Neoadjuvant Therapy in High-Risk Breast Cancer
ASCO 2017: I-SPY 2 Trial
• 69 pts were randomized to Pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts (25 HR+, 21 TN) have undergone surgery.
Case cont…
• Mrs. D decided she wants it all !
• 6-11.2013 - DD AC Carbo-Taxol + Bev
• 12.2013 - Rt Breast Lumpectomy + ALND
• Pathology report:
IDC Grade II, 0.5cm, LN-3/17
Next step ?
1- Adj xeloda
2- RTx and cont FU
3- NGS
4- Clinical trial – OlympiA
(In case of Germline BRCA Mut)
CREATE-X NEJM, Jun 2017
Pts 20-74 yrs of age with stage I-IIIB HER2- BC and
residual disease (non-pCR, N+) after neoadjuvant
chemotherapy* and surgery; ECOG PS 0 or 1;
no previous oral fluoropyrimidines Japan & South Korea
(N = 910)†
Capecitabine
2500 mg/m²/day PO Days 1-14
Q3W for 8 cycles‡
Hormonal therapy if ER/PgR+ (n = 455)†
Hormonal therapy if ER/PgR+
No further therapy if ER/PgR-
(n = 455)†
Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-FU, institution, node status
*Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide. †25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria. ‡IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles.[2]
1. Toi M, et al. SABCS 2015. Abstract S1-07. 2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.
Wk 24
CREATE X
• PEP – DFS • SEP – OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness
• The result of the prespecified interim analysis met the PEP, so the trial was terminated.
CREATE X - TN Pts
5yDFS 70% Vs 56% 5yOS 79% Vs 70%
Case cont…
• Mrs. D was found to be BRCA1/2 WT, and decided to get Capecitabine.
• 10.2014 - Lower back pain, fatigue.
PET scan - metastatic dis – Bones, liver.
• ECOG 1
• Blood test – Normal
WWUD ?
1- NGS
2- Chemotherapy (+/- Bev)
3- PARPi
4- Immunotherapy
Immunotherapy
0.001
0.01
0.1
1.0
10
100
1,000
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mu
tati
on
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va
len
ce
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er
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Somatic mutations in cancers
Breast Cancer and mutations: Lower median rate detected compared
to the most immune-sensitive cancers but wide range of mutations detected
Alexandrov L,B. Nature 2013
Alexandrov L,B. Nature 2013
Alexandrov L,B. Nature 2013
Alexandrov L,B. Nature 2013
Luen, The Breast, 2016
TNBC - The best of what’s left...
≥2L ≥1L
Results<br />BOR per RECIST v1.1 by line of therapy
KEYNOTE 150 - An Open-Label, Single-Arm Multicenter Phase 1b/2 Study to Evaluate the Efficacy and Safety of Eribulin
Mesylate in Combination With Pembrolizumab in Subjects With Metastatic Triple-Negative Breast Cancer (mTNBC)
SABCS 2016
Case Cont… 11.2014 – Single agent Pembrolizumab. 11.2015 – Clinical and radiographic PD. NGS: Somatic BRCA1 Mut
OlympiAD – ASCO 2017 NEJM 8.2017
OlympiAD
OlympiAD
OlympiAD
No crossover
Case Cont… 12.2015– Olaparib 9.2016 – Clinical and radiographic PD. New Liver Biopsy – TN, AR > 10%
11%
TNBC subtypes comparison with intrinsic PAM50 subtypes (Unsupervised Vs supervised clustering)
374 TNBC GE profiles were subtyped using PAM50 or TNBCtype
Anti Androgen therapy
Bicalutamide Enzalutamide
Abiraterone acetate
RR-0-8%
Triple Negative Breast cancer New treatment options arenowhere/arenowhere ?