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ASTRO Refresher Course 2016

Breast Cancer

Jennifer R. Bellon, M.D.

Dana-Farber Cancer Institute

Associate Professor of Radiation Oncology

Harvard Medical School

I have no relevant conflicts of interest

Breast Conservation for Invasive Disease

• Anatomy

• Selection for BCT and modern outcomes

• Substituting hormonal therapy for RT

• Shortening the RT course

–Update on hypofractionation

–Accelerated Partial Breast Irradiation

Outline (continued)

• Management of the regional nodes

– Axillary dissection with a positive sentinel

node

– RT fields (SCV/IM)

• PMRT

• RT after preoperative systemic therapy

• Update on DCIS

IM nodes

Axillary

nodes

Selection of Patients for BCT

• Imaging

– U/S, spot compression for densities

– Magnification views for calcifications

– MRI (selected cases only)

• Tissue diagnosis

– Core biopsy (not FNA)

– Excisional biopsy if core biopsy not feasible

• Breast-conserving surgery

– Careful evaluation of margins

– Post-excision mammogram for residual Ca++

Use of Breast MRI at Diagnosis

Not Established Established

Fewer re-excisions Finds multicentric dx

Decreased LR More delays

Improved survival More biopsies

Increased costs

More mastectomies

Houssami Ann Surg 2013

Turnbull Lancet 2010

Selection of Patients for BCT

• Contraindications:

– Multicentric disease

– Prior RT

– Pregnancy

– Positive margins (in breast tissue)

– ? Collagen vascular disease

• BRCA 1/2 mutation carriers – future risk

• Impact of biologic subtype

• What constitutes an adequate margin?

ACOSOG Z11102

RTOG 1014

Reduction in Local Recurrence with RT

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 on LRR

EBCTCG Lancet 2011 378(9804):1707-16

N=10801 in 17 randomized trials

How Are We Doing?

• Local recurrence <5% at 10 years

– Improved imaging

– More detailed pathologic examination of

the specimen

– Improved systemic therapy

• Both improves LR, and also makes LR more

important (by controlling micrometastatic

disease)

• Heterogeneity of outcomes by subtype

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)

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

BCT vs. Mastectomy

• Retrospective series from Alberta

• N =768; BCT, MRM or MRM+RT

• Higher-risk pts had MRM or MRM+RT

• LRR at 5 years– BCT 6%

– MRM 15%

– MRM+RT 13%

• MVA: MRM, LVI and nodal positivity

predicted LRR; chemo protective

Abdulkarim et al. JCO 2011; 29

LRR in T1/T2, N0 Subset (No RT after MRM; 35% chemotherapy)

T1/T2, N0 unmatched

P=0.022

T1/T2, N0 matched for

tumor size

P=0.039

Abdulkarim et al. JCO 2011; 29

96%

90%

Wider Margins for TNBC?

• Retrospective review; n=535

– Margins <2 mm: 71 patients

– Margins >2 mm: 464 patients

• Median follow-up 84 months; 84% received

chemotherapy

• Cumulative incidence of LR at 60 months

– 4.7% for close margins

– 3.7% for wide margins; p=NS

Pilewskie M et al. Ann Surg Oncol 2014; 21(4)

TNBC: Is BCT Appropriate?

• Comfort in these results, despite

selection bias

– BCT remains standard treatment in

otherwise appropriate patients

• Likely biology, not extent of surgery, is

the driving factor

• Raises question of RT for high-risk node

negative TNBC after mastectomy

Margins

Goals of Margin Evaluation

• To identify patients more likely to have

a large residual tumor burden that can’t

be controlled by modern systemic

therapy and RT

– need re-excision or mastectomy

Why not just re-excise?

• Extent of excision most important determinant of cosmetic outcome

• Re-excisions associated with:

- Patient anxiety

- Worse cosmetic outcome

- Morbidity

- Cost

- Patients opting for mastectomy

Margins Meta-Analysis (Basis for ASTRO-SSO Consensus)

• 33 studies, invasive cancer, 1979 – 2001

• N = 28,162; 1506 LRs

• Follow up: 79 months (range: 48-160)

• Series reports used

– not individual patient data

• Does not apply to: no RT, neoadjuvant,

APBI, pure DCIS

Houssami N, et al. Ann Surg Oncol 2014; 21: 717-730

Margins Meta-Analysis

Margins and LR (adjusted for length of FU)

OR 95% CI p-value

Margin status

Negative 1.0 < .001

Positive/Close 1.96 1.72-2.24

Margin status

Negative 1.0

“Close” 1.74 1.42-2.15

“Positive” 2.44 1.97-3.03 < 0.001

Increased local recurrence rate associated with positive margins not nullified by

radiation boost, systemic therapy, or favorable biology


Margins Meta-AnalysisRelationship Between LR and Margin

Threshold Distance#

studies#LRs/#subjects OR* 95% CI

1 mm 6 235/2376 1.0

2 mm 10 414/8350 0.91 0.46-1.80

5 mm 3 103/2355 0.77 0.32-1.88

* Adjusted for length of FU p (association) = 0.90

p (trend) = 0.58


ASTRO-SSO Margins Consensus: Summary

• Negative margins (no ink on tumor) optimizes local

control

• Positive margin associated with at least a 2-fold

increased risk of LR

– Not nullified by the boost, systemic therapy, or favorable

biology

• Wider margin widths do not significantly improve local

control

• The routine practice of obtaining margins more widely

clear than no ink on tumor is not indicated

J Clin Oncol. 2014 May 10;32(14):1507-15

EORTC Boost

• Stage I/II; n=5318

• Microscopic complete resection

– For invasive disease only

• Randomization:

– 50 Gy whole breast

– 50 Gy whole breast + 16 Gy boost

• Median follow-up 17.2 years

Bartelink H, et al. Lancet Oncol. 2015 Jan;16(1):47-56

EORTC Boost: 20-Year Results

• Ipsilateral breast tumor recurrence as a

first event 16.4% vs 12.0%

– HR 0.65; 99% CI 0.52–0.81, p<0·0001

• No difference in distant metastases-

free survival or overall survival

• Severe fibrosis 5.2% vs 1.8%, p<0.0001

• Any fibrosis 71.4% vs 57.2%. P<0.001


Local Recurrence by Age

<40

51-60

41-50

>60


Omission of Radiation

NSABP B-21: BCT in Tumors < 1.0 cm

• N=1009, T1a,1b N0

• Randomized to RT + placebo, Tam,

Tam + RT

• Only 54-59% 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

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


Hughes KS et al JCO 2013, 45: 2615

CALGB 9343: Results at 10 Years

NLRR Free

Survival (%)

DM Free

Survival (%)

Overall

Survival (%)

Mastectomy Free

Survival (%)

TAM 319 90 95 66 96

TAM +

RT317 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):266-73N=1326

Omission of Radiation Princess Margaret Hospital

• Phase III, randomized trial

• RT + TAM vs TAM alone

• Eligibility

– 50 and older

– T1, T2

– Path node negative if younger than 65 (clinically node negative if older than 65)

Fyles, A. et al. NEJM 2004;351:963-970

PMH Stratification

• Tumor size (<2.0 cm, >2.0 cm)

• ER (positive, negative or unknown)

• Participating center

• Method of determining axillary

status in women over 65 (clinical or

surgical)

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

Fyles AW et al. N Engl J Med 2004;351:963-970

Disease-free Survival.Disease-Free Survival

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 such 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)

• T1N0

• Grade I or II and Ki67 < 13.25% (luminal A)

• Age >55

• Margins > 1 mm

• No lobular cancers, No EIC


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


ClinicalTrials.Gov

NCT02400190

Hypofractionation

Ontario Clinical Oncology Group Trial

• 1234 patients randomized to:50 Gy/2 Gy fx/35 days

vs

42.5 Gy/16 fx/22 days

• T1 – T2 tumors; all node negative

• Large breasted women excluded (separation > 25 cm)

• Non-inferiority with 80% power to rule out 5% increase in local recurrence

Whelan et al, J Natl Cancer Inst 2002, 94(15):1143-50

Whelan et al: Results

Median follow-up:

12 years

Tam : 41%

Chemo: 11%

Whelan et al NEJM 362 (6), 2010

Long-term Toxicity

Whelan TJ, NEJM 2010; 362:513-20

No difference in skin/subcutaneous toxicities

Late Effects of Radiation

Long Term Cosmetic ResultsGlobal Cosmetic Outcome, Assessed According to the EORTC Scale.

Whelan TJ et al. N Engl J Med 2010;362:513-520

No difference in long-term cosmetic result

UK Start B

• N=2215

• Median follow-up: 9.9 years

• Standard Arm:

– 2 Gy per fraction

– 25 fractions/5 weeks

• Experimental arm:

– 2.66 Gy per fraction

– 15 fractions/3 weeks

Haviland JS et al. Lancet Oncology (14), 2013

Start B: Cumulative Incidence LRR

50 Gy

40 Gy

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.1

0 1 2 3 4 5 6 7 8 9 10

Time from randomisation (years)

LRR

0

HR .77 (0.51-1.116); p=0.21


Start B: Marked/Moderate Cosmetic Defect

% of patients with no

moderate / marked

effect

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Time from randomisation (years)

40 Gy

50 Gy

HR .77 (.66-.89)


Fig. 1. Rates of hypofractionation use by institution for patients with T1-2, N0 tumors treated with lumpectomy and whole-breast

radiation therapy (n=913).

Jagsi et al, IJROBP Volume 90, Issue 5, 2014, 1010–1016

Use of Hypofractionation by Institution(October, 2011 - December, 2013)

Total:

31%

Hypofrac vs Conventional: MDACC

50 Gy/25 fx + 10-14 Gy/7 fx (n=149)

Vs

42.56 Gy/16 + 10-12.5 Gy/4-5 fx (n=138)

Eligibility

40 or older

Stage 0-2

Breast only radiation

Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Primary Objectives

• MD-reported acute and 6-month

toxicity

– NCI-CTC

• Patient reported QOL at 6 months

– Functional assessment of cancer

therapy for patients with breast cancer

(FACT-B)


Key Patient/Treatment Characteristics

• 79% C cup or larger

• 25% sep > 25.6

• 76% overweight or obese

• Prone or supine permitted

• Multiple subfields encouraged to maximize homogeneity

– 75% dmax < 107.7%


Max MD-reported

acute toxic effect

Not significant:

Wound complications

Breast infection

Skin ulceration

Seroma

UE edema


6-months Results

• Physician-reported fatigue:

– 0% HF vs 6% CF (p=0.01)

• Patient reported lack of energy:

– 23% HF vs 39% CF (p=<0.001)

• Trouble meeting family needs:

– 3% HF vs 9% CF (p=0.01)


Predictors of Lack of Energy at 6 Months

n OR p

Randomization Conventional 140 1

Hypofrac 128 0.39 <0.001

Age 40-49 27 1

50-59 97 1.10 .83

60-69 104 1.92 .13

70 and older 40 2.39 .08

BMI <24.5 68 1

24.5 – 29.1 70 0.88 0.72

29.2 – 33.6 66 1.60 0.25

>33.6 64 1.02 0.97

Tumor behavior Invasive 69 1

Non-invasive 70 0.56 0.07


Hypofractionation

Hypofractionation is rapidly becoming standard of care for most women treated with breast conserving surgery and whole breast radiation

Note only is long-term LR similar, but now we have convincing data that short-term toxicity and QOL is improved, and long-term toxicity isn't compromised

Unanswered Questions

• Is the biology the same in all subgroups?

– Triple negative?

– DCIS?

• What is the optimal

dose/fractionation/boost?

• What about chest wall/nodal irradiation?

– Brachial plexopathy? Lymphedema???

Other Hypofractionation Trials

• IMPORT High (UK)

– 2.4 Gy x 15 fx (integrated boost)

– 2.67 Gy x 15 fx (sequential boost)

– Accrual goal 840

• FAST (UK)

– 2 Gy x 25 fx

– 5.7 Gy x 5 fx

– 6 Gy x 5 fx

All in 5 weeks

TROG Trial for DCISAccrual goal 1600

• Conventional fractionation, no boost

– 50 Gy, 25 fractions

• Conventional fractionation, boost

– 50 Gy, 25 fractions + 16 Gy, 8 fractions

• Hypofractionated, no boost

– 42.5 Gy, 16 fractions

• Hypofractionated, boost

– 42.5 Gy 16 fractions + 16 Gy, 8 fractions

RTOG 1005

Randomized non-inferiority trial

Conventional fractionation (2 Gy x 25 fx) with sequential boost

VS

Hypofractionation (2.67 x 15 fx) with concomitant boost

• Closed 6/20/14

• Over-accrued 2354

ClinicalTrials.gov

NCT01349322

Accelerated Partial Breast Irradiation

Accelerated Partial Breast Irradiation

Starting to see maturation of the modern

randomized trials

GEC-ESTRO

Interstitial brachytherapy

Targit A

IORT photons

ELIOT

IORT electrons

RAPID

External beam photons

GEC-ESTRO

• Prospective, randomized non-inferiority trial

– 3% non-inferiority margin

– Primary endpoint: IBTR

• Primary < 3.0 cm, N0 (micromets allowed)

• Randomization

– 50 Gy/25 fx whole breast

– Insterstitial brachytherapy

HDR: 4 Gy x 8 or 4.3 Gy x 7

PDR: 0.6 Gy-0.8 Gy to 50 Gy

Strnad, et al Lancet 2015 epub ahead of print

Patient Characteristics

APBI (n=633) WBI (n=551) P-value

Age (years, median) 62 (40-92) 62 (40-85) 0.86

Menopausal status

pre 108 (17%) 92 (17%)0.93

post 525 (83%) 459 (83%)

Tumor size (mm, range) 12 (9-30) 12 (9-30) 0.19

Margin (mm, range) 8 (2-40) 7 (2-25) 0.39

Grade

1 248 (39%) 217 (39%)

0.552 319 (50%) 288 (52%)

3 57 (9%) 42 (8%)

Systemic Therapy

Yes 572 (90%) 505 (92%)0.63

No 59 (9%) 46 (8%)


Ipsilateral Breast Recurrence

Strnad V, et al

Lancet 2015

epub ahead of print

Disease-Free Survival


GEC-ESTRO

• Results still early

– Late recurrences seen with luminal A

disease

– Long-term toxicity and cosmetic outcome

• Are these patients that don’t need

treatment?

• Interstitial will likely not be routinely

used in the majority of centers in the US


External beam whole breast

40 Gy-5 Gy in 15-25 fractions +/-

boost (10-16 Gy in 5-8 fractions)

IORT: 20 Gy at surface

*If high risk, add 45-50 Gy whole breast

(lobular carcinoma, EIC, <1 mm margin)

Can be at time of surgery, or delayed

Targeted Intraoperative RT (TARGIT)50 kv x-rays

Vaidya JS et al, Lancet 2014 383(9917):603-13

N= 3451

Multi-institutional

Accrued 200-2012

Age >45

Unifocal

TARGIT: Low Risk Patients

• Median age: 63

• <2.0 cm 86%

• Grade I/II 84%

• Node negative 83%

• Hormonal therapy 66%

Chemotherapy 12%


TARGIT: Results

• Follow-up:

• Median: 29 months

• minimum of 4 years: 2020 patients

• minimum of 5 years: 1222 patients

• 5-year IBTR: 3.3% TARGIT vs 1.3% WBRT

• HR 2.07 (95% CI 1.01-4.25)

• Within pre-specified non-inferiority

margin (2.5%)

Vaidya JS et al, Lancet 2013. epub ahead of print


TARGIT: Results

• Concurrent with lumpectomy:

• 2.1% TARGIT vs 1.1% WBRT (p=0.31)

• Delayed after lumpectomy

• 5.4% vs 1.7% (p=0.069)

• Overall breast cancer mortality similar– 2.6% vs 1.9% (p=0.56)

• Decreased non-breast cancer deaths– 1.4% vs 3.5% (p=0.008)

Vaidya JS et al, Lancet 2013. epub ahead of printVaidya JS et al, Lancet 2014 383(9917):603-13

Intraoperative Radiotherapy versus External

Radiotherapy for Early Breast Cancer (ELIOT)

• EORTC randomized trial of WBRT and IORT

(electrons)

• IORT: 21 Gy x 1

• WBRT: 2 Gy x 25 WB + 2 Gy x 5 boost

• Primary endpoint: IBTR

• Equivalence trial with a 7.5% equivalence

margin

Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

Patient

Characteristics

Veronesi U, Lancet Oncology 14 (13), 2013Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

ELIOT: Results

• N = 1305


• IBTR

– WB: 0.4%

– IORT: 4.4 % (HR 9.3; 95% CI 3.3 to 26.3)

Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

IBTR

Overall Survival

Veronesi U, Lancet Oncology 14 (13), 2013Veronesi U, Lancet Oncol

2013 Dec;14(13):1269-77

Predictors of Recurrence in IORT Group

Factor IBTR P-value

Path Size (cm)

<1.0 1.9

1.0 to 1.5 4.2

1.5 – 2.0 4.7

>2.0 10.9 P=0.006

Grade

1 1.1

2 3.8

3 11.9 P=0.0003

Subtype

Luminal A 1.4

Luminal B 4.9

Her2 pos 5.9

Triple negative 18.9 P=0.001

Veronesi U,

Lancet Oncology

14 (13), 2013

Veronesi U et al,

Lancet Oncol

2013

Dec;14(13):1269-77

RAPID: WB vs APBI

• N=2135

• Median follow-up: 36 months

• 3d CRT APBI (38.5/10 fx BID)

VS

• WB (42.5 in 16 fx or 50 in 25 fx +/- boost)

Olivotto, IA, et al. J Clin Oncol. 2013 31(32)

Three and Five Year Toxicity and

Cosmetic Assessments

Olivotto, IA, et al. J Clin Oncol. 2013 31(32)Olivotto, IA, et al. J Clin Oncol. 2013 31(32)

Three and Five-year Cosmetic Results

Olivotto, IA, et al. J Clin

Oncol. 2013 31(32)

Olivotto, IA, et al.

J Clin Oncol

2013 31(32)

Late Radiation Toxicity

Olivotto, IA, et al. J Clin

Oncol. 2013 31(32)

Olivotto, IA, et al.

J Clin Oncol.

2013 31(32)

ASTRO Consensus Statement

Suitable* Cautionary** Unadvisable***

Age >60 50-59 <50

Size <2 cm 2.1-3.0 cm >3.0 cm

LVI Negative Limited Extensive

Margin >2 mm Close; <2 mm Positive

Histology Ductal Lobular

DCIS Not pure DCIS DCIS <3 cm DCIS >3 cm

Nodes N0, N0i+ Node positive

ER Positive Negative

Smith BD et al. IJROBP 74(4), 2009

* Acceptable outside of a clinical trial

** ”Caution and concern in the use of APBI”*** ”Not warranted outside of a study”

Modern Phase III Trials of PBI vs WBRT

Institution/Trial

Target

(yrs of

accrual)

Control

Arm

Experimental

Arm

European Institute of

Oncology

ELIOT

1200

(2000-2007)

WBI (50 Gy in 25 fx) ± 10 Gy

Boost

IORT (21 Gy in 1 fx, using electrons

up to 9 MeV)

TARGIT-A3451

(2000-2012)

WBI 40-56 Gy ± 10-16 Gy

boostIORT (20 Gy in 1 fx, low energy -rays)

*NSABP B 39/RTOG 0413

Closed to

accrual 4/13;

n=4216

50-50.4 Gy WBI

± 10-16 Gy Boost

(1) MIB (34 Gy in 10 fx), or

(2) MammoSite (34 Gy in 10 fx) or

(3) 3D-CRT (38.5 Gy in 10 fx)

French SHARE1170

(2004-2009)

WBI (50 Gy in 25 fx) + 16 Gy

Boost

WBI (40 Gy in 15 fx; or 42.5

in 16 fx)

3d-CRT (40 Gy in 10 fx, BID)

*Medical Research Council –

UK IMPORT LOW

1935

(2007-2010) WB 2.67Gy X 15

(1) WB 2.4Gy X 15

(2) PB 2.67Gy X 15

(3) PB only 2.67Gy X 15

*Ontario Clinical Oncology

Group- Canadian Trial

RAPID

2128

(2006-

7/2011)

WBI ± 10 Gy boost:

(1) 42.5 Gy in 16 fx for small

breasts or

(2) 50 Gy in 25 fx for large

breasts

3D CRT only

(38.5 Gy in 10 fx)

The Nodes

ACOSOG Z-11

• Patients– Clinical T1-2 N0

– 1 or 2 positive SN

– No gross ECE

• Treatment:

– Lumpectomy with whole breast irradiation

• Dose/precise fields not specified

– Adjuvant systemic therapy by choice (97%)

Guiliano A et al JAMA 2011 305: 569

ACOSOG Z-11: Patients

cALND SNB Alone

# Patients 420 436

Age, median 56 yrs 54 yrs

T size, median 1.7 cm 1.6 cm

ER/PR+ 82% 82%

Grade 3 29% 28%


Outcomes of Z11(Median f/u: 6.3 years)

Recurrence Type ALND (420) SLNB only (436)

Locoregional (%) 4.1 2.8

Local 3.6 1.8

Axillary 0.5 0.9

DFS (%) 91.8 92.5

OS (%) 83.9 82.2

Giuliano A et al, Ann Surg. 2010 252(3):426-32

Giuliano A et al, JAMA. 2011 305(6):569-75

All comparisons non-significant

http://www.ncbi.nlm.nih.gov/pubmed/20739842

Findings on cALND in Z-11

• 46% of positive sentinel nodes were

micromets

• Only 106 (27.4%) of patients treated

with cALND had additional positive

nodes beyond the SN

• This is a highly select group


Axillary

LN

Lumpectomy

Cavity

Axillary Vein

Standard

Superior

Border

Radiation Fields in ACOSOG Z0011

• 11% did not receive RT

• 228 patients (28.5%) had evaluable RT records:

50% received high tangents

19% had a separate nodal field

No difference between arms

High vs Standard Tangent

Fields

Jagsi R, J Clin Oncol 32(32), 2014

IBCSG 23-01: ALND vs SN Only

for Micrometastases

• cT1-T2, micromets in 1-2 SNs

(H+E or IHC)

• Accrued: 934 (target 1950) between

2001-2010

• Median F/U of 5 years

Galimberti et al Lancet Oncol 2013;14:297

IBCSG 23-01: Characteristics

ALND (n=464) SLNB (n=467)

Median Age 53 yrs (23-81) 54 yrs (26-81)

T <3 cm 91% 93%

ER + 88% 91%

Systemic Rx 95% 97%

Mastectomy 9% 9%

Median # SN 2 (1-9) 1 (1-8)

Additional positive

nodes59 (13%) 12 (3%)

RT after BCS: • 70% External Beam

• 19% Intraop

• 9% combination

98% 97%

IBCSG 23-01: Results

RecurrenceALND

(n=464)

SLNB

(n=467)

Local 10 (2%) 8 (2%)

Regional 1 (<1%) 5 (1%)

Distant 34 (7%) 25 (5%)

5Y DFS 85%* 88%*

5Y OS 96% 96%

*Log rank p=0.16

non-inferiority p=0.004Galimberti et al Lancet Oncol 2013;14:297

AMAROS: Study Design

CT1-2, N0

3381 SN negative

1425 SN positive

axRT

(n=681)

cALND

(n=744)®

Rutgers, E. Lancet Oncology 2014; 15:303-10

Axillary RT in AMAROS

• Started <12 wks after SNB

• 25 x 2Gy or equivalent

• Level I, II, III and medial

SCV

• Additional AxRT: >4

positive nodes (in

dissection arm)Figure adapted from Harris, J


cALND

n=744

AxRT

n=681

5-yr Axillary

recurrence

0.54%

(n=4)

1.03%

(n=7)

5Y DFS 87% 83%

5Y OS 94% 94%

5 yr Clinical

Lymphedema23% 11%

AMAROS Results(Median f/u 6.1 years)

P<0.0001


Disease-Free and Overall Survival


Substituting RT for Surgery

• All of these trial indicate RT can

substitute for cALND

– At least in fairly select patients

• But what volume to irradiate?

– Tangents alone?

– High tangents?

– Supraclav?

– IMN?

MA.20 Randomization

Node positive, or high risk node-

negative, s/p breast conservation

Whole breast radiationVS

Whole breast and regional nodal radiation

Whelan TJ et al, NEJM 2015; 373:307-316

Eligibility

• Node positive

• High risk node negative

– >5 cm or

– >2 cm and <10 nodes removed

And grade 3 or LVI positive or ER negative

• Chemotherapy and/or endocrine

therapy required


MA.20 RT Details

• Whole breast: 50 Gy/25 fx

– Cone down: 10-16 Gy (e- or brachy)

• IMNs treated with either partially wide tangents or anterior field (electron and photon

combination)– 50 Gy/25 fx

• SCV/axilla (AP or AP/PA)– Full axilla for >3 positive nodes or <10 dissected

– 45 Gy (for AP/PA), 50 Gy (AP)


Baseline Characteristics

WBI

N=916

WBI + RNI

N=916

Age (mean) 52.7 53.9

Axillary nodes removed (mean) 12.3 12.4

Node –ve 89 (10) 89(10)

Node +ve (1-3) 780 (85) 776 (85)

Tumor size > 2 cm 416 (45) 457 (50)

Grade III 387 (42) 390(43)

ER –ve 235 (26) 232 (25)

Adj chemotherapy 829 (91) 830 (91)

Adj endocrine therapy 705 (77) 700 (76)

Boost irradiation 221 (24) 206 (22)

in 39%


Whelan TJ et al. N Engl J Med 2015;373:307-316

10-Year Kaplan–Meier Estimates of Survival.

Median follow-up 9.5 years

Ten-year Results (n=1832)

10-YrNo Nodal

RT

Nodal

RTHR

p-

value

LRR* 6.8% 4.3% 0.59 .009

DFS 77.0% 82.0% 0.76 .01

OS 81.8% 82.8% 0.91 .38


*isolated

Whelan et al, NEJM, 2015; 373:307-316

MA-20: Hazard Ratios for Overall Survival

LRR +/- RT by Subtype Approximation

Danish 82 b and c

Kyndi et al. JCO 2008; 26: 1419-1426

ER+

HER2-

ER+HER2+

Triple Neg

ER-HER2+

Adverse Events

• Any lymphedema increased from

4.5% to 8.4%; p = 0.001

• Radiation pneumonitis increased from

.2% to 1.2%; p = 0.01

–All grade 2

• Major cardiac event 0.4 vs 0.9, p= 0.26

*NCI – Common toxicity criteria v2 1998


EORTC Phase III Trial 22922/10925n= 4,004

Stage I-III, pN+ or pN- w/ central/medial

ARM 1: No nodal RT

®

ARM 2: IM and supraclav RT

Poortmans PM et al. N Engl J Med 2015;373:317-327


Distant Disease-free and Overall Survival

Median

follow-up:

10.9 years

P=0.02

P=0.06

Poortmans PM et al.

N Engl J Med

2015;373:317-327

Hazard Ratio for Death, According to Subgroups

Multicenter French Randomized Trial

• Randomization: CW, SCV +/- IM

• N=1407

• Eligibility:

– Mastectomy, larger than 1.0 cm

– Any node positive

– Medial/central with or without positive nodes

• Technique: First 5 interspaces

• Powered for 10% difference in OS

Hennequin et al IJROBP 86(5), 2013

Key Patient Characteristics

No IM RT (%) IM RT (%)

Location: Lateral 236 (36) 232 (35)

Medial 426 (64) 440 (65)

Nodal status: N0 162 (24) 169 (25)

N+ 500 (76) 503 (75)

Grade: I/II 349 (53) 360 (54)

III 154 (23) 164 (24)

Adj chemotherapy 402 (61) 410 (61)

Adj hormonal therapy 348 (53) 350 (52)


Hennequin: 10 Year Results

OutcomeNo IM RT

(%)

IM RT

(%)p

OS 59.3 62.6 0.8

DFS 53.2 49.9 0.35

LR as first

event9.8 9.2 NS

Cardiac

Events2.2 1.7 NS


The Danish Experience

• Prospective cohort study, 2003-2007

• Node positive (macroscopic), younger

than age 70

• All received periclavicular and chest or

breast RT

• LT-sided: RT without IMN (n=1586)

• RT-sided: RT with IMN (n=1486)

Thorsen LBJ et al, J Clin Oncol, epub 2015

Key Pt/Tx Characteristics

(median follow-up 8.9 years)

• Median age 56

• Mastectomy 65%; BCT 35%

• ER Positive 80%

• Positive axillary nodes:

– 1-3 59%

– 4-9 26%

– >10 15%

• High grade 28%



Overall Survival, HR 0.82; p=0.005

Breast Cancer Mortality, HR 0.85; p=0.03

Distant Recurrence, HR 0.89; p=0.07

75.9%

72.2%

More Questions (few answers)

• What is the relative benefit of IM vs SCV RT

– Does it make sense to treat SCV alone in

patients with ‘difficult’ anatomy

• Which subgroups are most likely to benefit

– ER negative?

– HER2+

– One positive node?

• What is the long-term risk of increased lung

V20 and low-dose cardiac RT?

Post-Mastectomy Radiation

Meta-analysis of PMRT Trials

• 22 trials with 8135 women treated

with mastectomy + axillary surgery

+/- PMRT

• Adjuvant systemic therapy was

used in the majority of patients

• RT to chest wall, SCV +/- axilla,

internal mammary nodes

Lancet 2014;383(9935):2127-35

Absolute Benefits of PMRT (n=8135)

11.5%

8.8%

1-3+

> 4+

7.9%

9.3%

16.5%

19.1%

Lancet 2014;383(9935):2127-35

Impact of Number of Involved Nodes

Lancet 2014;383(9935):2127-35

McBride et al, MDACC

• Retrospective review; n =1027

• T1, T2; 1-3 nodes

• Early era: 1978-1997

– before taxanes, AI

• Late era: 2000-2007

McBride et al, IJROBP Volume 89, Issue 2, 2014, 392–398


N=505

1978-1997

9.5% at 5 years

3.4% at 5 years


N=522

2000-2007

2.8% at 5 years

4.2% at 5-years

Effective Systemic Therapy Improves LRR

• Chemotherapy improves LRR beyond

adjuvant RT alone

– EBCTCG

• Clarke et al. Lancet 2005; 365:1687

– NSABP• Anderson SJ et al. JCO 2005; 27

• Incremental improvements in systemic

therapy further lower LRR– Addition of taxanes

– Addition of trastuzumab

TA

MO

XIF

EN

CH

EM

OT

HE

RA

PY

EBCTCG Overview. Lancet 2005;365:1687

10-Year LR in NSABP trials for

node-negative tumors

TrialER

Status

10-Year

LR (%)

B-13 No Chemo - 13.3

B-13 Chemo - 3.5

B-14 No Tamoxifen + 11.0

B-14 Tamoxifen + 3.6

Anderson SJ et al. J Clin Oncol 2005:27;2466

Impact of Taxanes on LRR

Impact of H on LRR: First Events

Patients B-31 N9831 (NCCTG)

Control Trastuzumab Control Trastuzumab

All patients 872 864 807 808

Alive and event-free 701 781 717 758

Any First event 171 83 90 50

Local or Reg Recurrence

35 15 22 12

Distant Recurrence111 60 63 30

CBC 6 2 0 1

Second Primary 15 2 3 3

Death Without Disease

4 4 2 4

Romond et al NEJM 353:16, 2005

• 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 after Mastectomy: MVA

• 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 et al: MVA

Variable HR 95% CI P

cT: > 5 vs < 5 cm 1.58 1.12 – 2.23 .0095

cN+ vs cN- 1.53 1.08 - 2.18 .017

pCR nodes vs

Complete pCR2.21 0.77 – 6.30 < .001

Node positive vs

Complete pCR 4.48

1.64 –

12.21< .001


Mamounas et al: MVA

Variable HR 95% CI p

cT: > 5 vs < 5 cm 1.58 1.12 – 2.23 .0095

cN+ vs cN- 1.53 1.08 - 2.18 .017

pCR nodes vs

Complete pCR2.21 0.77 – 6.30 < .001

Node positive vs

Complete pCR 4.48

1.64 –

12.21< .001


10-Year Risk of LRR

Mastectomy,

Clinical T ≤ 5 cm

Mastectomy

Clinical T > 5 cm


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 appropriate2Path Documentation of Negative Axillary Nodes (by ALND or by SLNBx ± ALND)

RANDOMIZATION

Mastectomy

Breast Conservation

PMRT

No PMRT

Breast alone

Breast and Regional Nodes

Randomized Trials of Excision +/- RT

N FU E alone E + RT

NSABP B-17 814 17 y 35% 20%invasive: 20% 11%

DCIS: 15% 9%

EORTC 1010 15.8 y 30% 17%invasive: 50% 56%

DCIS: 50% 44%

UK 1030 12.7 y 19% 7%invasive: 7% 4%

DCIS: 12% 3%

Swedish 1067 8 y 27% 12%invasive: 12% 7%

DCIS: 15% 5%

EBCTCG Meta-Analysis: DCIS

Correa, JNCI Monogr 41:162-177, 2010

N=3729

RTOG 9804: Details

• Randomized, RT vs No RT; 1998-2006

• Low or intermediate grade

• Smaller than 2.5 cm; margins >3mm

• N = 636 (1790 planned accrual)

• Tam optional (62%)


McCormick et al. JCO 2015;33:709-715

RTOG 9804: Results

McCormick B, JCO 33(7), 2015

DCIS: Omission of RTECOG 5194

• Study design– Single arm, excision without radiation

– Tam optional (30%)

– At least 3 mm margin or negative re-excision

• Low risk: – Low or intermediate grade

– Smaller than 2.5 cm

• High risk: – High grade, smaller than 1.0 cm

Solin LJ, JCO epub ahead of print, 2015

ECOG 5194, Low Risk

Any Ipsi Breast Event (%) Invasive Ipsi Breast Event (%)

5 years 6 (4.0-8.1) 2.7 (1.3-4.1)

7 years 9.5 (7.0-12.0) 4.8 (2.9-6.6)

10 years 12.5 (9.5-15.4) 6.4 (4.2-8.6)

12 years 14.4 (CI 11.2-17.6) 7.5 (5.1-10.0)

N=561

Median follow-up 12.3 years


ECOG 5194, High Risk (High grade, Smaller than 1.0 cm)

Any Ipsi Breast Event (%) Invasive Ipsi Breast Event (%)

5 years 15 (7.7-21.7) 5.3 (0.8-9.7)

7 years 18.2 (10.6-25.8) 7.6 (2.2-13.0)

10 years 24.6 (15.7-33.4) 13.4 (5.9-20.9)

12 years 24.6 (15.7-33.4) 13.4 (5.9-20.9)


N=104

Oncotype DX DCIS Score

• 12/21 genes from the Oncotype DX Recurrence Score

• Continues score (0-100)

• 3 specified risk groups– Low (<39)

– Int (39-54)

–High (>54)

Solin LJ, JNCI 2013, 105

7 cancer-related genes 5 reference genes

Oncotype DCIS Score: ECOG 5194

<2.5 cm,

grade I or II

<1.0 cm,

grade III

Margins > 3mm

Solin LJ, et al JNCI 2013, 105

Ontario DCIS ValidationN=718

0 2 4 6 8 10

Rakovitch et al Br Res Treat, 2015, 152

Conclusions

• Breast conservation is an appropriate option for

most women with early-stage disease with

outstanding long-term local control

• We are beginning to understand tumor biology as it

relates to local control, and hopefully this will allow

omission of RT in select patients

• Hypofractionation is the best option for most women

with early-stage disease undergoing BCT

• Beginning to see the maturation of the APBI trials.

Over the next 5 years I think we'll have a much better

idea of long term toxicity and efficacy

Conclusions (continued)

• Axillary dissection is not warranted for many (?most)

patients with 1-2 positive sentinel nodes

• Appropriate nodal fields still in evolution, but my bar

to treat the nodes has dropped

• Whom to treat with PMRT is still unclear, particularly

with modern systemic therapy, but overall LRR is

lower than previously appreciated

• Clinically node positive patients who achieve pCR

may not need RT (please enroll on B-51)

• DCIS: Hope for improved molecular characterization

of disease, and ability to predict LR







with modern systemic therapy, but overall LRR

seems to be lower than previously appreciated











with modern systemic therapy, but overall LRR is

lower than previously appreciated





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