radiotherapy management of breast cancer treated with...
TRANSCRIPT
Radiotherapy Management of
Breast Cancer Treated with
Neoadjuvant Chemotherapy
Julia White MD
Professor, Radiation Oncology
Agenda
• Efficacy of radiotherapy in the management
of breast cancer in the Adjuvant setting
• Neoadjuvant Chemotherapy and breast
conservation
• Neoadjuvant Chemotherapy and Post
mastectomy radiotherapy and
• Clinical trials for local regional management
post NAC:
− NSABP B51/ RTOG 1304
− Alliance 011202
What we know well….
Efficacy of Radiotherapy for
Breast Cancer Treatment in the
Adjuvant Setting
Gains from RT in Overall Recurrence (local, regional,
distant) Results in Improved Breast Cancer Survival
Updated EBCTCG Meta analyses
• Lancet 2014- Mastectomy w/ AD (n=3,131) + RT:
Local-regional
Recurrence
Overall (any)
Recurrence
Breast Cancer
Mortality
8.1% MAST + RT
26% MAST (p<0.00001)
17.9% Gain 10 year
Local Control
51.9% MAST + RT
62.5% MAST (p<0.00001)
10.6% Gain 10 year
Overall Control
58.3% MAST + RT
66.4% MAST (p<0.001)
8% Improvement 20
year Survival
Overall (any)
Recurrence
Breast Cancer
Mortality
19.3% BCS + RT
35.0% BCS (p<0.00001)
15.7% Gain 10 year
Overall Control
21.4% BCS + RT
25.2% BCS (p<0.00005)
3.8% Improvement 15 year
Survival
• Lancet 2011- BCS (n=10,801) + RT:
Regional Nodal Radiotherapy
• Breast cancer metastases to 4 or more
axillary lymph nodes has been an accepted
indication for local and regional nodal
radiotherapy post mastectomy or
lumpectomy
• More recent evidence now supports that
many women with 1-3 positive lymph
nodes will benefit from local and regional
nodal radiotherapy
Supports Local Regional Radiotherapy
in Breast Cancer Patients with 1-3
Axillary Nodal Metastases
Post Mastectomy Improve DFS/ OS
– EBCTCG Meta analysis Lancet 2014
– EORTC 22922/10925 ECCO 2013
Post Lumpectomy Improve DFS
– NCIC MA.20 ASCO 2010
– EORTC 22922/10925 ECCO 2013
Positive SNB Replace ALND
– EORTC AMOROS Lancet 2014
Radiotherapy when Surgery is First
Line for Breast Cancer Treatment
• Has a large effect on reducing local regional
recurrence after lumpectomy in nearly all patients and
after mastectomy in node positive patients
• Yields smaller but consistent effect on reducing
distant metastases and breast cancer mortality
• Indications for post mastectomy radiotherapy are
expanding to include many patients with 1-3 positive
axillary nodes
• Similarly, regional nodal radiotherapy more
frequently indicated after breast conserving surgery
when axillary nodes are positive
None of the patients included in the Phase III RCT’s analyzed in the EBCTCG meta analyses had neoadjuvant chemotherapy.
Radiation therapy clinical decision making has been based on pathologic extent of disease from surgery as first line of breast cancer treatment.
Radiation therapy indications in setting of neoadjuvant chemotherapy are evolving: is clinical stage, chemo response, or final pathologic extent of disease the key factor?
Challenge:
Efficacy of Radiotherapy for Breast
Cancer Treatment in the
Neo Adjuvant Chemotherapy Setting
What is evolving….
NeoAdjuvant Chemotherapy and
Breast Conservation
Neoadjuvant Chemotherapy: Breast Conserving Surgery and Radiation Therapy
Study N
BCT
%
F/U
(yrs.) Clinical Stage
% In-breast
recurrence
Phase III:
NSABP B-18
763
68
16
87% T-1,2
74% N-0
13
NSABP B-27 2,411 49 8.5 71% T-1,2
70% N-0 6
EORTC 10902 350 28 4.7 73% T1,2
48% N-0 10.7*
* Local regional recurrence
NSABP B18: Does Initial Surgical
Intention Pre- NAC Affect Outcome?
• 1988 – 1993
• 9 years median F/U
• n = 1533
% IBTR p
Preop Chemo 10.7 0.12
Postop Chemo 7.6
MRM pre NAC – Lumpectomy post NAC 15.9 0.04
Lumpectomy pre NAC- Same post NAC 9.9
cT1-3, N0-1
AC x4
Surgery AC x4
Surgery
R
Wolmark et al., JNCI 30:2001
MDACC Prognostic Index LRR after BCT or MRM treated with
Neoadjuvant Chemotherapy
• 815 patients 1974 - 2000
– 331 BCT
– 485 mastectomy
• Prognostic Index Score: 0-4 – Sum of each item scored 0 if absent or 1 if present for
a total score of 0-4
1. Clinical N2–N3 disease
2. Lymphovascular invasion
3. Residual pathologic primary size > 2 cm
4. Pathologically multifocal residual disease Huang EH, IJROBP 66:2006
No Difference in Local Regional Control by
MDAPI 0-1 but BCT Worse for Score > 2
Score % w/ BCT % w/ MRM
0-1 83% 58%
2 13% 28%
3-4 4% 14% Huang EH, IJROBP 66:2006
Breast Conserving Therapy after
Neoadjuvant Chemotherapy • 308 operable breast cancer patients
• Medical University Vienna 1995-2007
• Received neoadjuvant therapy on 3 ABCSG studies
AC, Taxane and Trastuzumab (ABCSG 7, 14, 24)
LRFS 5 year
All: MRM 91%
BCT 89%
Intention pre NAC:
MRM - MRM 91%
MRM - BCT 84%
BCT-BCT 97%
T1-2 ER+ G3
24% 40% 50%
54% 53% 54%
98% 70% 38%
Adverse pathologic
factors explain
variation in LRFS
Fitzal, Breast Cancer Res Treat ,2011
Local Recurrence Free Survival: Intention of Mastectomy Pre NAC Not
Associated with Worse Outcome
MX = Mastectomy
BCT= Lumpectomy + Breast XRT
Fitzal, Breast Cancer Res Treat ,2011
Impact of Multifocal or Multicentric
Disease Treated with NAC • 2002 – 2010: 6,143 breast cancer patients enrolled
on multi institution clinical trials with NAC
– Gepar trio, Gepar quattro, Gepar quinto
Unifocal Multifocal Multicentric p
N 4,733 820 588
BCT % 71.6 58.5 30
pCR % 19.4 16.5 14.4
Local Recurrence
All 7.1 4.9 9.6
BCT 8.7 4.2 8.0 0.3
Mast 11 5.9 10 0.03
Ataseven, Ann Surg Onc 2014
All All
BCT
pCR
Ataseven, Ann Surg Onc 2014
Local Recurrence Free Survival
No significant difference unifocal, multifocal,
multicentric for those treated with BCT or
who achieve pCR
MDAPI in a More Modern Treatment Era: LRR Free Survival BCT vs. MRM
Akay et al., Ann Surg Oncol 19:2012
• 551 patients neoadjuvant chemotherapy 2001-2005
• 244 BCT and 327 MRM
• Median follow– up 62 months
MDAPI 0-2: No Difference in LRR Free
Survival BCT vs. MRM
Score % w/ BCT % w/ MRM
0-1 78% 44%
2 17% 38%
3-4 6% 18% Akay Ann Surg Oncol 19:2012
Breast Radiotherapy Methods for NAC
42.56 Gy/
16 treatments
50 Gy/
25 treatments
Conventional WBI Hypofractionated WBI
Boost 10-16 Gy/
5-8 treatments
30-38 Gy/
6-10 treatments
Accelerated PBI
Regional Nodal Radiotherapy
Regional nodes:
–Axilla (what did not
get removed with
dissection,
“undissected axilla”)
–Supraclavicular
–Internal mammary (
first three intercostal
spaces)
Is Regional Nodal Irradiation Indicated
for ypN0 Breast Conservation?
• 248 patient cN0 (n=164), cN1-N2 (n=84)
• All had lumpectomy and were ypN0,
– 90 Breast RT alone
– 158 Breast + Regional RT
• Centre Rene ́Huguenin, 1990 -2004
• Median follow-up 88 months
Davieau et a IJROBP 78:2011
No Difference in LRR or OS by Use
of Nodal Radiotherapy in ypN0
Davieau et a IJROBP 78:2011
Neoadjuvant Chemotherapy and Radiotherapy: Breast Conservation
Radiation therapy following breast conserving surgery
results in acceptably low rates of in-breast recurrence.
Advanced clinical stage, T3-4, N2-3, pathologic
residual > 2 cm associated with increased rates of LRR
due to adverse pathology / poor response.
Conventional whole breast radiotherapy with boost to
surgical cavity –method of choice
Role for regional radiotherapy for clinically node
positive breast cancer that becomes node negative
(ypN0) is evolving
NeoAdjuvant Chemotherapy and
Postmastectomy Radiotherapy
6 Prospective Neoadjuvant Chemotherapy Trials MDACC 1974 - 2000
n = 636
Mastectomy
Radiation
n = 542
No Radiation
n = 134
Local Regional Recurrence and Survival: Post-mastectomy Radiation
Huang, et al., JCO, 22:2004
MDACC –Benefit PMRT after NAC
PMRT Improved 10 Year Local Regional Recurrence
Factor No RT % RT % p
Clinical: T3
T4
N2-3
22
46
40
8
15
12
0.002
< 0.001
<0.001
Pathological : Tsz 2.1-5 cm
> 5cm
> 4 pos nodes.
31
52
59
14
13
16
0.002
0.001
<0.0001
PMRT Improved 10 Year Cause Specific Survival
Factor No RT % RT % p
Clinical: > IIIb
T4
N2-3
22
24
27
44
45
49
0.002
< 0.007
<0.024
Pathological > 4 pos nodes
(ypN2)
18 44 <0.005
Huang, et al., JCO, 22:2004
Pathologic Complete Response from
Neoadjuvant Chemotherapy: Post-mastectomy Radiation Improves Outcomes
RT
n = 72
No RT
n = 34 p
% Local regional recurrence
All
Stage I-II
Stage III
5
0
7
10
0
33
ns
ns
0.04
% Cause Specific Survival 87 40 0.0014
McGuire, et al. IJROBP, 68:2007
PMRT Benefit Less Pronounced in
Clinical Stage II with
pCR or ypN0 post NAC?
Author/
treatment era n Follow
up (mo.) Path
response Clinical
Stage
LRR % OS %
PMRT NoRT PMRT NoRT
Huang
1974-2000 676
RT 73
No RT 66 RT 14%
No RT 8% II 30%
III 70 % 11* 22 54 47
McGuire
1982-2002 106 62
100%
pCR II 30%
III 70 % 5 10 -
LeScodan
1990-2004 134 91
100%
ypN0 II 63%
III 37% 4 12 88 94
Shim
1998-2009 151 57
100%
ypN0 II 60%
III 40% 2 8 93 90
Neoadjuvant Chemotherapy and Radiotherapy: Mastectomy
Radiation can improve local regional recurrence and impact survival for patients with locally advance breast cancer who receive neoadjuvant chemotherapy and mastectomy
Most Benefit – Clinical stage III-IV, pathologic
N2-3
Should be considered regardless of response to chemotherapy in Clinical Stage III
Unclear role for PMRT in down staged patients to ypN0
Association of pCR to
Event Free and Overall Survival CTNeoBC Pooled Analysis
Meta analysis of 12 neoadjuvant randomized controlled trials
Cortazar SABC 2012, Lancet 2014
Trends in Pathologic Complete
Response Rates from NAC
Trial Additional Agents Path CR
NSABP B18 AC 13%
NSABP B27 Paclitaxel 26%
NSABP B40 Bevacizumab 34.5%
NOAH* Trastuzumab 43%
NeoALTO* Trastuzumab + Lapatanib 53%
CALGB 40603† Carboplatin 60%
Tryphaena* Trastuzumab + Pertuzumab 63%
*Her2 †TNBC
Should Down Staging of the
Axilla with NeoAdjuvant
Chemotherapy affect Delivery of
Regional Nodal Radiotherapy?
2961 Patients - 318 LRR as First Events
1071 Mastectomy – NO PMRT - 137 LRR first events
NSABP B18 and B27: Patterns of LRF
Operable Breast
Cancer
AC x 4
Surgery Docetaxel x
4
AC x 4 AC x
4
Surgery
Surgery Docetaxel x
4
Surgery
AC x 4 Surgery
AC x 4
Operable Breast Cancer
R R
B-18 B-27
Mamounas et al, JCO, 2012
Mastectomy (1071 patients, 131 LRR Events)
Variable Hazard Ratio (95% CI) P
Clinical tumor size: 5 vs. 5 cm 1.58 (1.12–2.23) 0.0095
Clin. nodal status: cN(+) vs. cN(-) 1.53 (1.08–2.18) 0.017
Breast/nodal pathologic status:
ypN(-): No Breast pCR vs. Breast pCR 2.21 (0.77–6.30)
0.0002
ypNode(+) vs. ypNode(-)/Breast pCR 4.48 (1.64–12.21)
Lumpectomy Plus Breast XRT (1890 patients, 189 LRR Events)
Age: 50 vs. age 50† 0.71 (0.53–0.96) 0.025
Clin. nodal status: cN(+) vs. cN(-) 1.70 (1.26–2.31) 0.0005
Breast/nodal pathologic status:
ypN(-): No Breast pCR vs. Breast pCR 1.44 (0.90–2.33)
0.0006
ypNode(+) vs. ypNode(-)/Breast pCR† 2.25 (1.41–3.59)
Multivariate Analysis of Independent Predictors
of 10-year LRR According to Type of Surgery
10-Year Cumulative Incidence of LRR:
Lumpectomy + Breast XRT
> 50 yo < 50 yo
n=122
n=58
n=31
n=154
n=84
n=57
10-Year Cumulative Incidence of LRR:
Mastectomy
T > 5 cm T < 5 cm
n=128
n=33
n=11
n=143
n=37
n=21
Background
• With modern NAC regimens about 40% of pts with axillary nodal metastases at presentation are down-staged to pathologically negative axillary nodes at surgery (even higher proportion in TNBC or HER-2 neu + tumors)
• Several RCTs have consistently shown that achievement of pCR in the breast with negative axillary nodes predicts for excellent long-term outcomes both in terms of LRR and distant recurrence
NSABP B-51/RTOG 1304 Trial Phase III
- Clinical T1-3N1M0 breast cancer - Pathology positive axillary node (FNA/Core)
- Neoadjuvant CT + anti HER2
ypN0 at definitive Breast Surgery + AND or SNB
Randomization
Arm 1
No Regional Nodal XRT A. Lumpectomy: Breast XRT.
B. Mastectomy: Observation
Targeted accrual = 1636
Arm 2
Regional Nodal XRT A. Lump.: Breast/Nodal XRT
B. Mast: Chestwall/ Nodal XRT
Stratification: Type of Surgery (Mast v. Lump) , ER-Status (+ v. –), HER2 Status (+ v. –), pCR in Breast (yes v. no)
Thank you!