omitting radiation after breast- conserving surgery · 2016-07-18 · ebctcg: impact of radiation...

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


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

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


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)


Subtype is Prognostic for LR

HER2 (No Herceptin)

Triple -

Lum B

Lum A

Lum-HER2

No herceptin


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


RR 0.49

Meta-Analysis: LRR After Mastectomy


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


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


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


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


<0.001

10-Year Risk of LRR

Breast conservation

Age >50

Breast conservation

Age <50


10-Year Risk of LRR

Mastectomy,

Clinical T ≤ 5 cm

Mastectomy

Clinical T > 5 cm


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


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


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)


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)


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

omitting radiation after breast- conserving surgery · 2016-07-18 · ebctcg: impact of radiation...

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