Post on 31-Jul-2020
transcript
Omitting Radiation After Breast-
Conserving Surgery
Jennifer R. Bellon, MD
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Associate Professor of Radiation Oncology
Harvard Medical School
I have no relevant conflicts of interest
Reduction in Local Recurrence
CS CS + RT Reduction
NSABP B-06 36% 12% 67%
Uppsala-Orebro 24% 9% 63%
Ontario 35% 11% 69%
Milan 24% 6% 75%
Swedish 14% 4% 71%
EBCTCG: Impact of Radiation
EBCTCG Lancet 2011, 378:1707 EBCTCG Lancet 2011 378(9804):1707-16
JCRT Wide Excision Alone Protocol
• Unicentric pT1N0 infiltrating ductal
• At least 1 cm negative margins (almost all with a negative re-excision)
• EIC- and LVI-
• Median age = 66 yrs
• Mammography only = 75%
• Median Path Size = 0.9 cm
Lim et al, IJROBP 2006 65(4):1149-54
JCRT Wide Excision Alone Protocol
• Accrual goal = 90 pts, but closed at 87
pts because of stopping rules
• Median FU = 86 months
• 19 pts (23%) with LR
• 4 pts (5%) with distant recurrence
• Average LR rate = 2.8%/year
Lim et al IJROBP 2006:1149-54
Finnish WEA Trial
• T1N0, Grade 1 or 2
– EIC-
– age > 40
– margins > 1 cm
• N=152
• Median FU = 80 months
Holli K et al. Br J Cancer 84:164; 2001
Finnish WEA: Results
• Median follow-up:
80 months
• LR: 18.1% vs 7.5%
(p=0.03)
• No difference in DM-
free survival or
cancer specific
survival
Holli K et al. Br J Cancer 84:164; 2001
NSABP B-21: BCT in Tumors < 1.0 cm
• N=1009, T1a,1b N0
• Randomized to RT + placebo, Tam,
Tam + RT
• Only 57% known to be ER+
• RT: 50 Gy whole breast; boost optional
(20%)
Fisher et al, J Clin Oncol. 2002 Oct 15;20(20):4141-9
Bernard Fisher et al. JCO 2002;20:4141-4149
IBTR by Treatment Arm, 8 years
All comparisons p<0.05
17%
9%
3%
Omission of Radiation: CALGB 9343
• Randomized trial of tamoxifen alone or
tam with radiation in women over 70
• Axillary dissection discouraged – 37% dissection; 63% no axillary surgery
– All clinically node negative
• RT 45 Gy whole breast + 14 Gy boost
• Median follow-up 12.6 years
Hughes KS et al JCO 2013, 45: 2615
CALGB 9343: Results at 10 Years
N LRR Free
Survival (%)
DM Free
Survival (%)
Overall
Survival (%)
Mastectomy Free
Survival (%)
TAM 319 90 95 66 96
TAM +
RT 317 98* 95 67 98
* P<.001; HR 0.18
Not able to assess subtleties in risk groups (LVI, grade))
Hughes KS et al JCO 2013, 45: 2615
PRIME II: RT + Hormonal therapy vs
Hormonal therapy alone
• RT + hormonal therapy vs hormonal therapy
alone
• Age greater than 65
• < 3.0 cm, N0
• HR positive
• Margins >1 mm (CALGB no ink on tumor)
• Grade 3 or LVI permitted (not both)
Kunkler I, Lancet Oncol. 2015 Mar;16(3):266-73
PRIME II: 5-year Results
RT NO RT P
IBTR (%) 1.3 4.1 0.001
DM (%) .3 1.0 NS
OS (%) 94.2 93.8 NS
Kunkler I, Lancet Oncol. 2015 Mar;16(3):266-73 N=1326
Omission of Radiation:
Princess Margaret Hospital
• Phase III, randomized trial
• RT + TAM vs TAM alone
• N=769, 50 and older
– T1, T2
– Path node negative if younger than 65
(clinically node negative if older than 65)
• Stratification: Tumor size, ER,
participating center
Fyles, A. et al. NEJM 2004;351:963-970
Patient
Characteristics
(n=769)
Fyles, A. et al. NEJM 2004;351:963-970
Patient
Characteristics
(n=769)
Fyles, A. et al. NEJM 2004;351:963-970
Patient
Characteristics
(n=769)
Fyles, A. et al. NEJM 2004;351:963-970
Cumulative Incidence of Local Relapse
Fyles, A. et al. NEJM 2004;351:963-970
8 –yr LR: 17.6% vs 3.5%
PMH: Time to Local Recurrence
No difference in OS
93.2% vs 92.8%
Heterogeneity of Breast Cancer D
M-F
ree
Su
rviv
al
Time to Distant Metastases (months)
Sorlie PNAS 2003; 100: 8418-842
Cheang et al. Clin Cancer Res. 2008; 14 (5)
LR by Subtype:
DFCI/BWH/MGH Experience
• 1434 consecutive BCT patients, 1997-2006
• T1 80%; pN0 67%
• Close/negative margins: 97.3%
• Systemic therapy in 91%
– No Herceptin
• Median FU = 85 months
Arvold N et al. JCO 2011; 29(29)
Definitions of Subtypes
• Luminal A: HR+, HER2-, Gr 1-2 (905)
• Luminal B: HR+, HER2-, Gr 3 (198)
• Luminal-HER: HR+, HER2+ (105)
• HER2: HR-, HER2+ (55)
• Triple Negative: HR-, HER2- (171)
Arvold N et al. JCO 2011; 29(29)
Subtype is Prognostic for LR
HER2 (No Herceptin)
Triple -
Lum B
Lum A
Lum-HER2
No herceptin
Arvold N et al. JCO 2011; 29(29)
Breast Cancer Subtype and Risk of LRR
• N= 2,985; British Columbia Cancer Agency
• Subtype approximation by ER, PR, Ki67, HER2, EGFR and CK 5/6
• Median follow-up = 12 years
• Surgery
– BCT 42%
– Mastectomy 58% (25% RT)
• Systemic therapy: 57%
Voduc et al. JCO 2010; 28: 1684-1691
Voduc et al. JCO 2010; 28: 1684-1691
Local Relapse-Free Survival after BCT
P=0.005
P<0.001
HER2-enriched (ER or PR neg, HER2 +)
Basal (TN and CK 5/6
or EGFR +)
Lum A
Lum A
Local Relapse-Free Survival after Mastectomy
P<0.01
P<0.01
Luminal A
Basal (TN and CK5/6 or
EGFR positive) Luminal A
Voduc et al. JCO 2010; 28: 1684-1691
NCCN Experience: LRR after
Mastectomy by Subtype
Tseng YD et al, IJROBP 93 (3), 2015
• N=5673
• F-U 50.1 months
Meta-Analysis of LRR by Subtype
• N=12,592
– BCT 57%
– Mastectomy 43%
• RT in all BCT patients and 44% of
mastectomy patients
• Chemotherapy, 48%
• Herceptin in HER2-positive patients, 6%
Lowery et al. Breast Ca Res Treat 2012; 133: 831-41
Meta-Analysis: LRR after BCT
Lowery et al. Breast Ca Res Treat 2012; 133: 831-41
RR 0.49
Meta-Analysis: LRR After Mastectomy
Lowery et al. Breast Ca Res Treat 2012; 133: 831-41
RR 0.66
Cumulative Incidence of Local Relapse
Fyles, A. et al. NEJM 2004;351:963-970
8 –yr LR: 17.6% vs 3.5%
PMH: Time to Local Recurrence
No difference in OS
93.2% vs 92.8%
RT for Luminal A Disease?
• Subset of 304 patients
• Approximation of intrinsic molecular
subtyping
ER, PR, Ki-67, Her2, EGFR and CK5/6
– Luminal A (+/+/-, Ki67<14%) and grade I/II;
n=114)
– Luminal B (+/+/-, Ki67>14%; n=82)
Liu et al JCO, 33 (18), 2015
Response to RT by Subtype
Liu et al JCO, 33 (18), 2015
Luminal A
Luminal B
"unfavorable subtypes"
Three Hormonal Therapy Alone
Prospective Single-Arm Trials
Premise:
There exists a subset of patients with early-
stage disease with such a low likelihood of
recurrence that radiation can be safely
omitted
PRECISION (DFCI)
• Age 50-75
• Unifocal, <2.0 cm
• Node negative (path); N0i+ permitted
• ER positive, PR positive, HER2 negative
– Grade I/II
– Luminal A by PAM50
• Eligible and willing to receive endocrine therapy
• Accrual goal: 345
ClinicalTrials.gov
NCT02653755
LUMINA
• Ontario Clinical Oncology Group (OCOG)
• T1N0
• Grade I or II and Ki67 < 13.25% (luminal A)
• Age >55
• Margins > 1 mm
• No lobular cancers, No EIC
• Accrual goal: 500
ClinicalTrials.Gov
NCT01791829
Individualized Decisions for
Endocrine Therapy Alone (IDEA)
• Multicenter, led by University of Michigan
• T1N0 (i+ allowed)
• ER+/PR+/HER2 neg
• Age 50-69
• Oncotype <18
• Minimum 5 years of endocrine therapy
• Accrual goal: 200 ClinicalTrials.Gov
NCT02400190
Oncotype DX and Risk of Recurrence
• 895 patients with available RS
• B-14 – Node negative and ER positive
– Tamoxifen vs placebo
• B-20 – Node negative and ER positive
– Tamoxifen alone vs Tamoxifen + CMF
• RT required after BCT, not permitted after mastectomy
• Primary endpoint: Time to LRR
Mamounas et al, J Clin Oncol. 2010, 28(10):1677-83
LRR (%) by Oncotype DX and Treatment
Recurrence
Score
Placebo
(B-14)
Tam
(B14/20)
Tam + Chemo
(B-20)
Low
(<18) 10.8 4.3 1.6
Intermediate
(19-30) 20 7.2 2.7
High
(>30) 18.4 15.3 7.8
P-value 0.02 <0.001 0.03
Mamounas et al, J Clin Oncol. 2010, 28(10):1677-83
Oncotype and LRR In Node +/ER +
• B-28 randomizaton to AC vs AC
followed by T
• Total n=3096 (n=1096 node+, ER+)
• All older than 50, and <50 and ER or PR
positive received concurrent tam
• Lumpectomy: RT to breast
• Mastectomy: No RT
Mamounas et al. SSO 2013
Cumulative Incidence LRR (BCT and
MRM combined) at 10 years
RS N (%) # Events
LRR
(%)
High 315 (30) 39 12.3
Int 364 (34) 23 7.2 p<0.001
Low 386 (36) 16 3.3
Mamounas et al. SSO 2013
MVA
Variable HR P value
RS 2.86 <.001
AC + T vs AC .83 .42
Age >50 vs <50 .83 .43
>4 nodes vs 1-3 2.08 .002
Mast vs lump .82 .38
Tumor size 1.26 .017
Mamounas et al. SSO 2013
10-Year Cumulative Incidence (%) of Local and
Regional Recurrence According to RS Groups
LUMP + Breast XRT
1-3 Positive Nodes
LUMP + Breast XRT
> 4 Positive Nodes
N=131
N=117
N=88
N=43
N=49
N=33
Mamounas et al: SSO 2013
10-Year Cumulative Incidence (%) of Local and
Regional Recurrence According to RS Groups
Mastectomy
1-3 Positive Nodes
Mastectomy
> 4 Positive Nodes
N=137 N=132 N=117
N=75
N=66
N=77
Mamounas et al: SSO 2013
• Preop AC arm from B-18 and the preop AC +/- T
arms from B-27
• N= 1,071 mastectomy patients
• SNB performed after chemotherapy
• pCR was defined as no residual invasive
disease (DCIS permitted)
Can Systemic Therapy Select
Patients who Don’t Benefit from RT? NSABP Experience
Mamounas E et al JCO 2012 30: 3960
Predictors of LRR: MVA
• Age
• Clinical tumor size at presentation
• Clinical node status at presentation
• Path node status after chemotherapy
• Path response in the breast
Both the initial clinical and the final path
stage must be used to determine LR risk
Mamounas E et al JCO 2012 30: 3960
Breast Conservation Patients,
Predictors of LRR
Variable HR 95% CI p
Age > 50 vs <50 0.71 0.53 – 0.96 0.025
cN+ vs cN- 1.70 1.26 - 2.31 <0.001
pCR nodes vs
Complete pCR 1.44 0.90 – 2.33
Node positive vs
Complete pCR 2.25 1.41 – 3.59
Mamounas E et al JCO 2012 30: 3960
<0.001
10-Year Risk of LRR
Breast conservation
Age >50
Breast conservation
Age <50
Mamounas E et al JCO 2012 30: 3960
10-Year Risk of LRR
Mastectomy,
Clinical T ≤ 5 cm
Mastectomy
Clinical T > 5 cm
Mamounas E et al JCO 2012 30: 3960
CT NeoBC Collaborative Trials in Neoadjuvant Breast Cancer Group
• 12 preoperative trials including 11955 patients
• Median follow-up 42 months
• Clinical Stage
– I 61 (1%)
– II 3625 (69%)
– III 1566 (30%)
• Surgery
– Lumpectomy 61% (99.9% received RT)
– Mastectomy 39% (approximately 1/3 received RT)
Mamounas et al, ASCO Breast 2015
MVA: Predictors of LRR
HR 95% CI P-value
AGE
<50 vs >50 1.41 1.06, 1.87 0.017
Subtype*
HR-/HER2+ 7.90 4.75, 13.14
<0.0001 HR+/HER2+ 3.57 2.21, 5.77
HR-/HER2- 5.16 3.26, 8.17
HR+/Her2-, grade 3 3.29 1.92, 5.65
Baseline TNM
Stage 3 vs 1/2 1.31 0.92, 1.85 0.13
pCR
Node + vs pcr 2.36 1.62, 3.43 <0.0001
ypT1-3N0 vs pCR 1.46 0.99, 2.17
*compared to HR+/HER2-, g1 or 2
Mamounas et al, ASCO Breast 2015
MVA: Predictors of LRR
HR 95% CI P-value
AGE
<50 vs >50 1.41 1.06, 1.87 0.017
Subtype*
HR-/HER2+ 7.90 4.75, 13.14
<0.0001 HR+/HER2+ 3.57 2.21, 5.77
HR-/HER2- 5.16 3.26, 8.17
HR+/Her2-, grade 3 3.29 1.92, 5.65
Baseline TNM
Stage 3 vs 1/2 1.31 0.92, 1.85 0.13
pCR
Node + vs pcr 2.36 1.62, 3.43 <0.0001
ypT103N0 vs pCR 1.46 0.99, 2.17
*compared to HR+/HER2-, g1 or 2
Mamounas et al, ASCO Breast 2015
Response to Chemotherapy and
LRR (HR+/HER2-)
<50 years >50 years
G1/2 (n) G3 (n) G1/2 (n) G3 (n)
pCR 2.8% (60) 0 (44) 2.9% (46) 3.5% (35)
ypT1-3, N0 4.0% (238) 7.8% (71) 3.8% (277) 2.8% (81)
N+ 1.5% (259) 20.6% (68) 1.1% (244) 12.7% (69)
Mamounas et al, ASCO Breast 2015
Response to Chemotherapy and
LRR (HR+/HER2-)
<50 years >50 years
G1/2 (n) G3 (n) G1/2 (n) G3 (n)
pCR 2.8% (60) 0 (44) 2.9% (46) 3.5% (35)
ypT1-3, N0 4.0% (238) 7.8% (71) 3.8% (277) 2.8% (81)
N+ 1.5% (259) 20.6% (68) 1.1% (244) 12.7% (69)
Mamounas et al, ASCO Breast 2015
Response to Chemotherapy and
LRR (HR+/HER2-)
<50 years >50 years
G1/2 (n) G3 (n) G1/2 (n) G3 (n)
pCR 2.8% (60) 0 (44) 2.9% (46) 3.5% (35)
ypT1-3, N0 4.0% (238) 7.8% (71) 3.8% (277) 2.8% (81)
N+ 1.5% (259) 20.6% (68) 1.1% (244) 12.7% (69)
Mamounas et al, ASCO Breast 2015
Response to Chemotherapy and
LRR (HR-/HER2-)
<50 years (n) >50 years (n)
pCR 7.5% (209) 3.6% (122)
ypT1-3, N0 10.5% (156) 5.7% (124)
N+ 25.7% (78) 17.2% (80)
Mamounas et al, ASCO Breast 2015
Importance of Subtype After
Preoperative Chemotherapy
Five Year LRR-Free Survival
pCR HR+
HER2-
HR+
HER2+
HR-
HER2+
HR-
HER2-
P-
value
No 97 95 83 84 <0.001
Yes 96 100 92 99 0.62
Caudle et al. Breast Ca Research 2012; 14
Importance of Subtype After
Preoperative Chemotherapy
Five Year LRR-Free Survival
pCR HR+
HER2-
HR+
HER2+
HR-
HER2+
HR-
HER2-
P-
value
No 97 95 83 84 <0.001
Yes 96 100 92 99 0.62
Caudle et al. Breast Ca Research 2012; 14
NSABP B-51/RTOG 1304
Clinical T1–3, N1
Positive Axillary Nodes by FNA or Core
Accrual goal – 1636 patients over 5 years
NEOADJUVANT THERAPY1 SURGERY2
1Minimum 12 weeks, trastuzumab when appropriate 2Path Documentation of Negative Axillary Nodes (by ALND or by SLNBx ± ALND)
RANDOMIZATION
Mastectomy
Breast Conservation
PMRT
No PMRT
Breast alone
Breast and Regional Nodes
Conclusions
• Improved understanding of the
heterogeneity of breast cancer as it
relates to the risk of LRR
Hopefully this will allow omission of RT in a
select subgroup
• Preoperative chemotherapy may also be
an effective tool to select patients for
omission of RT