noa efrat ben baruch : neo-adjuvant treatment in breast cancer
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Neo-‐adjuvant Treatment in Breast Cancer
Past, Present and Future
Noa Efrat Ben-‐Baruch Kaplan Medical Center Rehovot, Israel
Past, Present and Future
• Inoperable breast cancer – Haagensen grave signs
• Operable Breast cancer – One size fits all – Is it beGer than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs
• 1.Skin ulceraPon • 2.FixaPon of tumor to the chest wall • 3.Axillary nodes > 2.5 cm in diameter • 4.Edema of < 1/3rd of the skin of breast • 5.Presence of fixed axillary nodes
Relation Between Clinical Presentation and Outcomes: LABC, IBC, and Non-LABC/IBC
Hance et al. JNCI 2005; 97: 966
Past, Present and Future
• Inoperable breast cancer – Haagensen grave signs
• Operable Breast cancer – One size fits all? – Is it be3er than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs
Operation
Operation
AC X4 + TAM if >50 years
AC X4
+ TAM if >50 years
NSABP Protocol B-18
Operable Breast Cancer
Stratification Age Clinical Tumor Size Clinical Nodal Status
79
36
0%
40%
20%
Tumor Response (685pts.)
100%
80%
60%
PR cCR
13
pCR *25% pCR w DCIS
NSABP B-18:Neoadjuvant Chemotherapy Increases the Likelihood of BCT for Operable Breast Cancer
40
60
32
68
0
80 60 40 20
100
Postop Preop
%
P<.01
For >5 cm tumors, 22% BCT versus 8%
Mastectomy
Lumpectomy
Fisher B, et al. J Clin Oncol. 1997;15(7): 2483-2493.
90 80 70 60 50 40 30
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Survival
N Ev HR P Post 751 311 Pre 742 308 .99 0.90
40 30
50
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
N Ev HR No pCR pCR
599 344 86 29 .47
No pCR
NSABP B-18: DFS and pCR
P<.0001
75
pCR
52
100 90
80
70
% 60
Years Wolmark N. Presented at: National Cancer Institute State of the Science Conference on Preoperative Therapy in Invasive Breast Cancer; March 26-27, 2007; Bethesda, Maryland.
B-27
OPERABLE BREAST CANCER
Age, T, cN
AC
OPERATION
AC→Txt*
OPERATION
*100mg/m² x 4; Tam for all
AC OPERATION
Txt
Past, Present and Future
• Inoperable breast cancer – Haagensen grave signs
• Operable Breast cancer – One size fits all – Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs
HER Family Signaling
Hudis C. N Engl J Med 2007
0 10 20 30 40 50 60 70 80 90 100
Christofanilli et al 2006, n=30
Bines et al 2003, n=32 Burstein et al 2003, n=40
Kelly et al 2006, n=37
Harris et al 2003, n=40
Hurley et al 2002, n=48 Griggs et al 2005, n=18
Limentani et al 2007, n=31
Gianni et al 2007, n=115 Lybaert et al 2006, n=89
Coudert et al 2005, n=33 Buzdar et al 2007, n=64 Pernas et al 2006, n=16
Response Rates with Neoadjuvant Trastuzumab
pCR (%)
T + L (IBC only)
D + H T + H (including IBC)
AC → T + H (including IBC)
V + H (including IBC)
D + cisplatin + H (including IBC) D + H
D + V + T (including IBC)
X + D + H AT → T → CMF + H
D + H T → FEC + H
T → FEC + H Study
L, lapatinib; V, vinorelbine; X, capecitabine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide
AT → T → CMF + H (IBC only) Baselga et al 2007, n=31
Trastuzumab
NOAH, IBC only Lapatinib
NOAH, all patients
Phase 3 MDACC trial
P q3w x 4 → FEC q3w x 4
Eligibility Invasive operable HER 2+ breast cancer
Stage II to IIIA
LVEF ≥ 45%
StraRficaRon
Size (T) node status ER/PR
S U R G E R Y
R
P q3w x 4 + H qw → FEC q3w x 4 + H qw
C = cyclophosphamide, E = epirubicin, F =5-‐fluorouracil,
H = HercepPn, P = paclitaxel
n=23 + 22
n=19
Primary objective: pCR rate (ypT0 and ypN0)
The planed sample size was 164 pts. A`er 34 pts had completed therapy, the trial was stopped b/c superiority of
H + chemo
J clin Oncol. 2005; 23: 3676 Clin Cancer Res. 2007; 13: 228
66%
26%
T-FEC T-FEC + Tras 0
20
50
75 %
of
patie
nts
pCR with CT ±Trastuzumab
Buzdar AU, Clin Cancer Res 2007
P=0.041
Clin Cancer Res. 2007; 13: 228
P + FEC alone (n=19)
P + FEC +H (n=45)
pCR, percentage (95%CI) 26.3 (9-‐51) 60 (44.3-‐74.3)
85.3%
CMF q4w x 3 cycles
NOAH
HER2-positive LABC (IHC 3+ or FISH+)
AT q3w x 3 cycles
T q3w x 4 cycles
H + AT q3w x 3 cycles
H + T q3w x 4 cycles
H q3w x 4 cycles + CMF q4w x 3 cycles
H continued q3w to week 52
(n=115) (n=113) AT
q3w x 3 cycles
T q3w x 4 cycles
CMF q4w x 3 cycles
HER2-negative LABC (IHC 0/1+)
Surgery followed by radiotherapya
(n=99)
Surgery followed by radiotherapya
Surgery followed by radiotherapya
19 crossed over to H
Gianni L et al. Lancet 2010; 375: 377–84
Patients (%)
39%
20%
0
10
20
30
40
50
With H Without H
HER2 positive
p=0.002
pCR rates in the NOAH trial: intent-to-treat population
Gianni L et al. Lancet 2010; 375: 377–84
EFS: HER2-positive population
L. Gianni et al., The Lancet, 2010
Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive BC
NeoALTO Study Design
Stratification: • T ≤ 5 cm vs. T > 5 cm • ER or PgR + vs. ER & PgR – • N 0-1 vs. N ≥ 2 • Conservative surgery or not
Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF ≥ 50% N=450
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
lapatinib trastuzumab
FEC X 3
S U R G E R Y
R A N D O M I Z E
lapatinib
trastuzumab
lapatinib trastuzumab
paclitaxel
paclitaxel
paclitaxel
+ 12 wks 6 wks
Efficacy – pCR and tpCR
NeoSphere: study design
THP (n=107) docetaxel + trastuzumab + pertuzumab
HP (n=107) trastuzumab + pertuzumab
TP (n=96) docetaxel + pertuzumab
S
U
R
G
E
R
Y
docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3 trastuzumab q3w cycles 5–21
Study dosing: q3w x 4
TH (n=107) docetaxel + trastuzumab
PaPents with operable or locally advanced /inflammatory* HER2-‐posiPve BC Chemo-‐naïve & primary tumors >2cm (N=417)
BC, breast cancer; FEC, 5-‐fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel
Gianni L et al. SABCS 2010
H, trastuzumab; P, pertuzumab; T, docetaxel
NeoSphere pCR rates: ITT population summary
p = 0.0141 50
40
30
20
10
0 TH THP HP TP
pCR, % ± 95%
CI
p = 0.0198
p = 0.003
29.0
45.8
16.8 24.0
6 Gianni L et al. SABCS 2010
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR pos ER and PR neg
20.0 26.0
17.4
36.8
29.1 30.0
63.2
5.9
pCR
, % ±
95%
C
I
H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L et al. SABCS 2010
NEOSPHERE: pCR and hormone receptors status
Triple NegaPve Breast Cancer
Bevacizumab?
Von Minckwitz G, SABCS 2010
Neoadjuvant Bevacizumab and Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast Cancers: Secondary Endpoint Analysis of the GEPARQUINTO Study (GBG 44)
Gerber B et al. Proc ASCO 2011;Abstract 1006.
Gerber B et al. Proc ASCO 2011;Abstract 1006. Gerber B et al. Proc ASCO 2011;Abstract 1006.
GEPARQUINTO: Benefit of Bevacizumab Added to Neoadjuvant Chemotherapy in
TNBC Subgroup
Gerber B et al. Proc ASCO 2011;Abstract 1006.
• Benefit of bev limited to TNBC subgroup
• pCRbreast (with bev vs without bev)*
• TNBC patients: 36.4 vs 27.8% (p = 0.021) • All patients: 15.0 vs 17.5% (p = NS)
* pCRbreast = no inv/non-inv in breast and nodes
Gerber B et al. Proc ASCO 2011;Abstract 1006.
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
Operable Breast Cancer R
Tissue for Biomarkers
SURGERY
Tissue for Biomarkers
+/-
+/-
X10
T docetaxel X capecitabine G gemcitabine B bevacizumab
NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable
HER2-Negative Breast Cancer
Endpoints: pCR, cCR, DFS, gene expression patterns
T - AC TX - AC* TG - AC*
pCRbreast (n = 395; 394; 391) 32.7% 29.7% 32.0%
pCRbreast + nodes (n = 393; 390; 388) 26.0% 23.3% 27.3%
* p-value not significant versus T - AC T = docetaxel; X = capecitabine; G = gemcitabine
NSABP B-40: Effect of Capecitabine or Gemcitabine Added
to Docetaxel on pCR Rates
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
NSABP B-40: Benefit of Adding Bevacizumab to Standard Chemotherapy
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
• Benefit of bev predominant in HR+ and not TNBC patient subgroup
• pCRbreast (with bev vs without bev): • HR+ patients: 23.3 vs 15.2% (p = 0.008)
• TNBC patients: 51.3 vs 47.3% (p = 0.44)
Past, Present and Future
• Inoperable breast cancer – Haagensen grave signs
• Operable Breast cancer – One size fits all – Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted
drugs
Background PI: Laura Esserman M.D. and UCSF The I-SPY TRIALS I-SPY 1àI-SPY 2
National trials to integrate imaging and tissue biomarkers to
Predict response to Rx à Tailor Rx to response
clinicaloptions.com/oncology An Update on Breast Cancer
I-SPY2: Efficacy of Neoadjuvant Veliparib/Carboplatin + Paclitaxel
Signature, % Estimated pCR Rate (95% Probability Interval)
Probability Veliparib/Carboplatin Superior to
Control
Predictive Probability of Success in Phase III Trial HR+ HR-
All HER2- 33 (22-43) 22 (10-35) 92 55
HR+/HER2- 14 (4-27) 19 (6-35) 28 9
HR-/HER2- 52 (35-69) 26 (11-40) 99 90 Rugo HS, et al. SABCS 2013. Abstract S5-02. Reproduced with permission.
Estimated pCR Rate: All HER2- Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate
Control V/C
Probability V/C is superior to control = 0.92
Estimated pCR Rate: Triple-Negative Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate
Control V/C
Probability V/C is superior to control = 0.99
Estimated pCR Rate: HER2-/HR+ Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate
Control
V/C
Probability V/C is superior to control = 0.28
clinicaloptions.com/oncology An Update on Breast Cancer
I-SPY2: Conclusions
§ Adaptive trial design found veliparib/carboplatin treatment efficacious in patients with triple-negative breast cancer
– Trial not designed to evaluate individual contributions of veliparib and carboplatin
§ Adverse events increased with veliparib/carboplatin regimen
– Toxicity may be managed with dose reductions and delay
§ I-SPY2 trial design efficiently evaluated treatment regimen in patient subsets based on biomarker analysis
– Additional response predictors currently under investigation
Rugo HS, et al. SABCS 2013. Abstract S5-02.
pCR as Regulatory Endpoint
Past, Present and Future
• Inoperable breast cancer – Haagensen grave signs
• Operable Breast cancer – One size fits all – Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs