Download - Medical Oncology Training Program Resident Teaching Friday January 7th, 2011 @ PMH, 5-223
Medical Oncology Training Program Resident Teaching
Friday January 7th, 2011 @ PMH, 5-223
Locally Advanced and Inflammatory Breast Cancer
Eitan Amir
Medical Oncology
Princess Margaret Hospital
Challenges/Objectives in the Management of Locally Advanced Breast Cancer
• Surgical oncology• Who to send for
preoperative therapy?
• Role of breast conservation
• Role of SLN surgery
• Surgery on relapse
• Medical oncology• What drugs to give for
preoperative therapy?• How can we improve
response rates?• What to give on
relapse?
• Radiation oncology• Combined chemo-rads?• Role of breast
conservation• Radiotherapy for
inoperable/progressive disease despite NAT
• Radiotherapy on relapse
What is LABC?
• LABC – 10 -15% of all new Breast Cancers
• Prognosis is poor– local recurrence– systemic relapse– overall survival– 15 yr OS
• 20% IBC, 40% NIBC
Inoperable• Improve surgical options
• Deliver adequate “adjuvant” chemotherapy
• Provide in vivo anti-tumour assessment
• Assess surrogate biologic endpoints for response & survival
Goal OperableWhat are the indications for neoadjuvant therapy?
What is the current systemic treatment standard?
Challenges in the Management of LABC
Clinical response and pathologic response are currently used as a surrogate of survival and as a tool to compare chemotherapy regimens
40
50
60
70
80
90
100
0 1 2 3 4 5
% S
urv
ivin
g
Years after Surgery
•TRT N Deaths•Non pCR 1899 396•pCR 409 31 HR=0.33p<0.0001
NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)
Operable Breast CancerOperable Breast Cancer
StratificationStratification• • AgeAge• • Clinical Tumor SizeClinical Tumor Size
• • Clinical Nodal StatusClinical Nodal Status
OperationOperation
+ TAM if + TAM if >>50 50 yrsyrs
AC x AC x 44
+ TAM if + TAM if >>50 yrs.50 yrs.
AC x 4AC x 4
OperationOperation
Operable Breast Cancer: NSABP B-18
No difference in DFS and OS
Lumpectomy Rates
60% vs 68%
Preop AC
cCR pCR
36% 13%
00
20%20%
40%40%
60%60%
80%80%
100%100%
22 44 66 88YearYear
P=0.00005P=0.00005pINVpINVcPRcPRcNRcNR
pCRpCR
22 44 66 88
pINVpINVcPRcPRcNRcNR
pCRpCR
P=0.0008P=0.0008
Wolmark N: CDC, 2000Wolmark N: CDC, 2000
• Clinical response predicts overall survival Clinical response predicts overall survival
• Pathologic response predicts overall survivalPathologic response predicts overall survival
Neoadjuvant therapy - Operable Breast CancerNeoadjuvant therapy - Operable Breast Cancer
B-18 DFS by response B-18 OS by response
B-27 Schema (n=2,411)B-27 Schema (n=2,411)
Operable Breast CancerOperable Breast Cancer
RandomizationRandomization
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs
SurgerySurgery Docetaxel x 4Docetaxel x 4 SurgerySurgery
SurgerySurgery Docetaxel x 4Docetaxel x 4
B-27B-27Pathologic Response (pCR) in BreastPathologic Response (pCR) in Breast
P < 0.001P < 0.001
AC DocetaxelAC Docetaxel(718 pts)(718 pts)
ACAC(1,492 pts)(1,492 pts)
3.9%
9.8%
No TumorNo Tumor Non-InvasiveNon-Invasive
6.9%
18.7%
13.7%13.7% 25.6%25.6%
20%20%
10%10%
00
30%30%
B-27: Nodal Down-stagingB-27: Nodal Down-staging
Rastogi P, et al. J Clin Oncol 2008;26:778-85
EORTC-NCIC-SAKK Multi-centre Trial EORTC-NCIC-SAKK Multi-centre Trial in LABC:in LABC:
Patient Population(n = 448)
– 40% T4a-c
– 45% T4d
– Locoregional treatment variable
RRAANNDDOOMMIIZZAATTIIOONN
C 75 mg/m2 po q d days 1–14E 60 mg/m2 IV days 1 and 8 q 4 wk x 6 F 500 mg/m2 IV days 1 and 8
E 120 mg/m2 IV day 1 q 2 wk x 6 C 830 mg/m2 IV days 1 with G-CSF day 2-13
Therasse P et al. J Clin Oncol 2003;21:843-50
Adapted from Therasse P, et al. J Clin Oncol 2003;21:843-50
•In exploratory analysis: DFS worse in IBC (median 23.5 m) vs LABC (median 44 m)
Current “standard” neoadjuvant chemotherapy regimens:anthracycline & taxane combination – Her2 neg
• Regimen Trial pCR (%)
• Anthracycline (adriamycin / epirubicin) 15
• Anthracycline plus taxane (taxol or taxotere) 28
What is the “standard” Her2- at PMH?
AC-T (dose dense) 8 (16%)
FEC-D 38 (79%)
Endocrine 2 (4%)
In Ontario:AC-taxotere
FEC-taxotere
Dose dense AC-Taxol
Breast Cancer Biological Subtypes as Predictive Subtypes
NOAH: the largest neoadjuvant trial in HER2-positive breast cancer
aHormone receptor-positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, trastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2); CMF, cyclophosphamide, methotrexate, fluorouracil
HER2-positive LABC(IHC 3+ and / or FISH+)
n=113
H + ATq3w x 3
H + Tq3w x 4
H q3w x 4 + CMF q4w x 3
Surgery followed byradiotherapya
H continued q3wto Week 52
Tq3w x 4
CMFq4w x 3
Surgery followed byradiotherapya
n=115
ATq3w x 3
ATq3w x 3
Tq3w x 4
CMFq4w x 3
Surgery followed byradiotherapya
n=99
HER2-negative LABC(IHC 0/1+)
Patient characteristicsPatient characteristics
HER2-negative IBC, %
Total pop IBC pop(n=99) (n=14)
ER, oestrogen receptor; PgR, progesterone receptor
Characteristic
4357
5050
6436
295021
1000
Age group<50 years>50 years
Menopausal statusPrePost
Hormonal receptorsER+ and / or PgR+Both negative
Axillary nodesN0N1N2
Ipsilateral supraclavicular nodesNoYes
HER2-positive IBC, %-H
Total pop IBC pop(n=113) (n=31)
+HTotal pop IBC pop(n=115) (n=31)
4258
5050
3565
164737
964
3268
5545
1684
195526
9010
4654
5248
3565
134443
946
5545
4258
2377
265223
1000
5149
5545
6436
173844
964
Significant improvement of pCR in IBC by adding trastuzumab
+H-H0
10
20
30
40
50
60Patients(%)
HER2negative
+H HER2negative
-H
p=0.004p=0.002
HER2 positive HER2 positive
tpCRpCR
4(29%)
6(19%)
17(55%)
4(29%)
4(13%)
15(48%)p=0.49 p=0.20
eradication of invasive cancer in the breast
eradication of invasive cancer in the breast plus axillary nodes
Good cardiac safety profile
No change (LVEF >55%)
Absolute decrease >10-<20%
Absolute decrease >20%
CHF responsive to treatment
+H(n=31)
77
23
0
0
-H(n=31)
84
13
3
0
86
14
0
0
HER2-positive IBC, %
CHF, congestive heart failure;LVEF, left ventricular ejection fraction
HER2-negative IBC, %
(n=14)
LVEF worst value
Pathologic Complete Response (pCR)
Untch M et al. EBCC 2008
What is the “standard” Her2+ at PMH?
MUGA
FEC
MUGA
Taxotere + herceptin
In Ontario:AC-TaxotereH
FEC-TH
AC-TaxolH
TCH
Anything new in 2010?Anything new in 2010?
Baselga J et al, SABCS 2010
Gianni L et al, SABCS 2010
Gianni L et al, SABCS 2010
Gianni L et al, SABCS 2010
Gianni L et al, SABCS 2010
Winer EP, SABCS 2010
Winer EP, SABCS 2010
Should patients with LABC have a lumpectomy if good response to chemotherapy?
Challenges in the Management of LABC
Pre-Treatment MRI of Breast Cancer with Septal Spread
After Neo-Adjuvant ChemotherapyTumour shrunk to lesser volume along septa
Pathologic Response to Neoadjuvant Chemotherapy (TSRCC)
Study Definition pCR rate (n=117) (%)
NSABP pCR in breast only
No microinvasive disease
Can have DCIS
10.3
Aberdeen pCR in breast/axilla
No microinvasive disease
Can have DCIS
8.6
TSRCC pCR in breast and axilla
No microinvasive disease
Can have DCIS
8.6
Chevallier pCR in breast and axilla
No microinvasive disease
No DCIS
4.3
Why such low pCR rates?
1)Advanced nature of patients selected for neoadjuvant chemotherapy in a LABC dedicated program1)this is a VERY different pt population than
preoperative systemic therapy for Stage I and II pts that is becoming more common in USA
2)High incidence of ER + tumors (71%)
3)Strict definition of pCR
How effective is Neoadjuvant Chemotherapy in ER+ Breast Cancer
• Chemotherapy is less effective in ER+ disease vs ER- disease (but doesn’t mean some patients don’t benefit)
• Luminal A cohort do not benefit vs luminal B?
• Other predictive markers needed
Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+
RANDOMIZE n = 1477
tamoxifen x 5 yrs
CAF x 6, then tamoxifen
CAF x 6, with concurrent tam
Albain, et al. Breast Cancer Res Treat 2007
Superior Disease-Free Survival (DFS) and Overall Survival (OS)
over 10 Years
(n = 361)(n = 550) (n = 566)
0.0
00
.25
0.5
00
.75
1.0
0D
ise
as
e-f
ree
su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=55, 15 events)CAF-T (n=91, 26 events)
Stratified log-rank p = 0.97 at 10 years
Low risk (RS < 18)
Disease-Free Survival by TreatmentNo benefit to CAF over time if low RS (n=146)
Strong benefit if high RS
0.0
00.
25
0.5
00.
75
1.0
0
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=47, 26 events)CAF-T (n=71, 28 events)
Stratified log-rank p = 0.033 at 10 years
High risk (RS ≥31)
Disease-Free Survival by Treatment
0.0
00.
25
0.5
00.
75
1.0
0
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=46, 22 events)CAF-T (n=57, 20 events)
Stratified log-rank p = 0.48 at 10 years
Intermediate risk (RS 18-30)
Disease-Free Survival by TreatmentTest for interaction p=0.053
0.00
0.25
0.50
0.75
1.00
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=57, 20 events)
CAF-T (n=85, 30 events)
Stratified log-rank p = 0.81 at 10 years
HER2 Negative and ER Allred 7-8
0.00
0.25
0.50
0.75
1.00
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10Years since registration
Tamoxifen (n=73, 36 events)CAF-T (n=112, 39 events)
Stratified log-rank p = 0.011 at 10 years
HER2 Positive or ER Allred <7
No DFS Benefit from CAF if Central IHC is Both HER2 Negative and ER Level High* (n=142)
*Test for Interaction p=0.052
Our most successful therapies target self-sufficiency in growth signals
Growth Factor• Estrogen/ER• HER2
Therapy• SERMs, AIs,
oophorectomy, fulvestrant
• Trastuzumab– Lapatinib
Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy?
Challenges in the Management of LABC
Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy?
0
20
40
60
80
100
0 1 2 3 4 5
% S
urv
ivin
g
Years after Surgery
•Nodal Status NDeaths•Negative 884 112•1-3 Positive 587 113•4-9 Positive 308 107•10+ Positive 102 54
3-31-04NSABP B-27: Overall Survival nodal Status; Patients without pCR(Bear JCO 2003)(Bear JCO 2003)
Systemic therapy – when more is less!
• LABC patients not responding to chemotherapy – More or different chemo is not always the answer– Chemo is toxic– Importance of multidisciplinary team– Unique area for further study:
• Role of RT• Role of biologics• Understanding chemo-resistance• Response predictors• Response Assessment Tools
Our most successful therapies target self-sufficiency in growth signals
Growth Factor• Estrogen/ER• HER2
Therapy• SERMs, AIs,
oophorectomy, fulvestrant
• Trastuzumab– Lapatinib
Surely neoadjuvant chemotherapy is the best?
• Semiglazov et al. 2004– Neoadjuvant treatment in women aged >70 with ER + breast cancer
• Doxorubicin and Paclitaxel (q3 weeks, 4 cycles) (n=60)• 3 months treatment with anastrozole or exemestane (n=59)
• There was a trend towards more breast conservation in the AI arms.
chemotherapy anastrozole exemestane
pathological CRs
7.4% 3.3% 6.8%
overall clinical RRs
76% 75% 81%
SummaryPreoperative vs. Postoperative
– OS = DFS = BCS
Clinical and pathologic response predicts overall survival
Standard chemo is an anthracycline & taxane regimen
For older HR+ pts consider endocrine therapy
Currently no role for more chemo for patients with residual disease after preoperative therapy
Challenges in the Management of Locally Advanced Breast Cancer
Surgical oncology• Who to send for preoperative therapy?
– In the setting of LABC – we are hoping to make surgery feasible– This is different from using NAT as the standard for ALL patients
• Role of breast conservation– Not common for LABC population– Can be done when feasible
• Role of SLN surgery– Very high rate of nodal involvement
• Surgery on relapse– Palliation in the setting of very poor prognosis
Challenges in the Management of Locally Advanced Breast Cancer
Medical oncology• What drugs to give for preoperative therapy?
– Anthracycline and taxane (± herceptin)– Endocrine therapy
• How can we improve response rates?– More than chemo!– radiotherapy, biological agents
• What to give on relapse?– Very difficult as survival is often short