The Management of Breast Cancer

2015 ASTRO Spring Refresher

Gary M. Freedman, M.D.

Associate Professor
Disclosure
I have no conflicts of interest to disclose.

2
Learning Objectives
Apply knowledge of randomized prospective trials to guide the
selection process for radiation in early stage breast cancer.
Be able to predict based upon current studies whether a
patient is low, intermediate or high risk for local or regional
recurrence without radiation.
Determine through enhanced knowledge of the evidence
based indications optimal patient selection for radiation
treatment to regional lymphatics, hypofractionation or
accelerated partial breast irradiation approaches.

3
Introduction
Local Therapy and Survival in Breast Cancer
Models of Breast Cancer
Halstedian 1900 1970s
A local-regional disease
Justification for more radical
surgery / radiation
Fisher 1970 1990s
A systemic disease
Justification for less radical
surgery / radiation but more
systemic therapy
5
NSABP B-04
3 Levels of Axillary Treatment (including regional node RT)
No differences in survival

Fisher et al NEJM 347: 567-75; 2002.

6
NSABP B-06
3 Levels of Breast Treatment
RT recommended for breast conservation not survival

Fisher et al N Engl J Med 2002; 347:1233-41.

7
CS + RT: Equal Survival as Mastectomy
NCI Consensus Conference June 1990
Breast conservation treatment is an appropriate method of
primary therapy for the majority of women with stage I and II
breast cancer and is preferable because it provides survival
rates equivalent to those of total mastectomy and axillary
dissection while preserving the breast.
Final nail in the Halstedian coffin
There was an unstated assumption that mastectomy
local control is probably better.

JAMA 265: 391-5; 1991

8
In the year 1990

If local control does not affect survival

Does the patient selection for breast conservation, or the quality

of the surgery or radiation matter?
WHY GIVE PMRT? JUST LOCAL CONTROL FOR LOCALLY
ADVANCED OR INFLAMMATORY CASES?

WHY CARE ABOUT LUMPECTOMY MARGINS?

9
Spectrum Model 1990s - Present

Local-regional treatment will

have an impact on survival in
some patients

Justification for careful patient

selection and techniques for
both breast conservation and
postmastectomy radiation.

10
The Spectrum Model
Not every local recurrence prevented improves survival but some do.
T
I
M
E
Primary
Treatment

RT
RT
Local
No Local and Distant
Failure Failure Distant Failure
Prevent Failure
This!

Alive Distant Dead

Failure (Early)

Dead
(Late)

11
PMRT 1st failures are not the whole story

MRM radiation
Node positive patients after 15 years
No chemotherapy/endocrine therapy
No XRT XRT Difference
First Failure
Local Failure 37% 10% - 27%
Distant Metastases 34% 43% + 9%
Total Failure
Local Failure 56% 19%
Distant Metastases 72% 54% - 18%
Death 70% 61% - 9%

Arriagada et al. JCO 13:2869 1995

12
Early Breast Cancer Trialists Collaborative Group

Message: Survival benefit is a result of the local-regional control benefit.

1 / 4 Ratio: One death from breast cancer avoided for every four LR recurrences avoided.

Lancet 2005; 366: 20872106

13
Local Control Benefit Predicts the Late Survival Benefit

No LC
No Surv

Big LC
Big Surv

EBCTCG Lancet 383: 2127-2135; 2014

14
T1-T2 Invasive Breast Cancer
BCT absolute contraindications
Multicentric disease (tumors in more than one quadrant)
Multifocal permitted if resected by single incision
Diffuse or suspicious microcalcifications
Persistently positive margins despite multiple re-excisions
Unless an anatomic boundary
Previous breast or chest RT
Pregnancy
Collagen vascular disease
Scleroderma
Active lupus?
Not RA

16
BCT relative contraindications
Ratio of tumor size to breast unacceptable for good cosmetic
outcome
Neoadjuvant chemo may be attempted to convert the patient to a
candidate for BCT
T3
Neoadjuvant chemo may be attempted to convert the patient to a
candidate for BCT
Subareolar location
Patients may choose to sacrifice nipple
BRCA 1/2
Survival outcomes with mastectomy equal
Patients may accept high rate of new primaries

17
MRI: A Coin Flip?
Affect of MRI on clinical management
22% affected management
Examples - MRI-prompted mastectomy or additional biopsy
Almost equal chance of help or harm
Can you prove favorable effects were all really improving outcome?
How do you know an addl focus would be source of LR?

Tillman et al J Clin Oncol

20: 3413-22; 2002.

18
Meta-Analysis of MRI
9 studies Increase in mastectomy
3,112 patients No reduction in positive
margins, re-excisions

Houssami et al Ann Surg

2013;257:249-55.

19
Meta-Analysis of MRI
4 studies
3,169 patients

8-yr LR-free survival

97% vs. 95%
HR MRI vs. No MRI
0.88 (0.52-1.51)
p=0.65

Houssami et al J Clin Oncol

2014;32:392-401.

20
BCS + RT Invasive Breast Cancer
Factors associated with local recurrence

Higher Lower
Positive margin Boost
Young age Systemic Therapy
Subtype

21
Margins Meta-Analysis and Consensus
Tumor on ink = positive margin
Overall median rate of IBTR 5.3%.
Makes non-significant differences in 1, 2 and 5 mm not
clinically significant either.

Moran et al Int J Radiat Oncol Biol Phys

88: 553-64; 2014.

22
Re-excision of Margins
Invasive Breast Cancer
American College of Radiology A re-excision should be performed for an involved margin.

Wider margins may be more important in select patients (young, estrogen receptor
negative, or extensive intraductal component).

American Society of Breast Surgeons Margin 1 mm usually adequate

Consider re-excision for focally positive or < 1mm margins on a case-by-case basis.

Re-excision usually needed for a positive margin.

American Society of Clinical Oncology Endorses adoption of the SSO/ASTRO Guideline but flexibility in the application of
the guideline is needed in some areas.

Heightened emphasis needed on the importance of postlumpectomy mammography for

cases involving microcalcifications.

National Comprehensive Cancer Network A positive margin should generally undergo further surgery.

Exceptions may be made for selected cases of focally positive margin and absence of
extensive intraductal component.

Society of Surgical Oncology / American A positive margin should be defined as no tumor on ink.
Society for Radiation Oncology
Negative margins are optimal for local control in most situations.

Wider margins than no tumor on ink are not routine indications for further surgery.

23
Local Recurrence By Age - Then

Bartelink et al J Clin Oncol

25: 3259-3265; 2007.

24
Young Age Now
Today the age effect is much diminished
Selection Factors: BRCA, Imaging
Treatment Factos: Margins, Systemic Therapy, Boost

Arvold et al J Clin Oncol

29:3885-3891; 2011.
25
BCS + RT by Subtype

Hattangadi-Gluth et al Int J Radiat Oncol

Biol Phys 82: 1185-91; 2012.

26
Young Age Biology
Adjusting for biology now the age effect is much diminished
Margins not significant?

Predictor AHR 95% CI P

Age, years 0.97 0.94 to 0.99 .009
BC subtype
Luminal A 1 (reference)

Luminal B 2.14 0.95 to 4.85 .067

Luminal HER2 0.48 0.06 to 3.73 .49

HER2 5.15 1.76 to 15.05 .003
Triple negative 3.94 1.72 to 9.01 .001

No. of positive nodes 1.07 1.00 to 1.16 .059

Tumor size, cm 1.32 0.96 to 1.80 .08
WB dose, Gy 0.91 0.86 to 0.98 .007

Arvold et al J Clin Oncol

29:3885-3891; 2011.
27
Young Age Biology
Adjusting for biology now the age effect is much diminished

Demerci et al Int J Radiat Oncol Biol Phys

83: 814-820; 2012.
28
Survival is equal

But is it still the case that local control is better with

Mastectomy versus BCS + RT?
LOCAL CONTROL TODAY

29
BCS + RT: Node Positive
NSABP
BCS + Whole Breast Radiation. No Boost.

Wapnir et al J Clin Oncol 2006; 24:2028-37.

30
BCS + Hypofractionated Radiation
UK START B

Haviland et al Lancet Oncol 2014; 14:1086-94.

31
BCS + RT: Margins Meta-Analysis
Overall median rate of IBTR 5.3%.
Includes positive close margins, low systemic therapy
utilization in older studies.

Houssami et al Ann Surg

Oncol 21:717730; 2014.

32
BCS + RT vs. Mastectomy
T1-2 N0 triple negative

Abdulkarim et al J Clin Oncol

29:2852-2858; 2011.

33
BCS + RT vs. Mastectomy
T1-2 N0 triple negative

Zumsteg et al Ann Surg Oncol

20:34693476; 2013

34
Are there any subgroups of patients
with T1 for whom we can safely omit
adjuvant radiation?
Local Control Benefit Predicts the Late Survival Benefit

EBCTCG Lancet 378:771-84; 2011.

36
EBCTCG BCS +/- RT
No subgroup without
a benefit from RT

37
CALGB
10 years local recurrence 10% vs. 2%
21 of 334 deaths from breast cancer (6%).
Cause-specific survival 98-99%.

Hughes et al J Clin Oncol 31:2382-7; 2013.

38
PRIME II
Age 65 or older
Hormone-positive
Low-grade
Node negative

5-year IBTR 4.1% vs. 1.3%

San Antonio 2013

39
Are there any subgroups of patients
with T1 for whom we can safely omit
adjuvant radiation?
Older (>70) or reduced life expectancy
T1
N0 (doesnt have to be pN0 always)
ER or PR +
Margin
Willing / able to take 5 years endocrine therapy
Willing to accept modest higher local recurrence
Shortening Postlumpectomy Radiation
Modern Trials Pre 2002!

WHOLE BREAST
HYPOFRACTIONATION
RESULTS
42
 Phase III Trials of Whole Breast Hypofractionation

Years Fractionation Boost Local Time

Trial Conducted # Gy/# of fractions (%) Recurrence (%) Point
RMH/GOC 1986-1998 470 50/25 74 12.1 10 years
466 42.9/13 75 9.6
474 39/13 74 14.8
START A 1998-2002 749 50/25 60 6.7 10 Years
750 41.6/13 61 5.6
737 39/13 61 8.1
START B 1999-2001 1105 50/25 41 5.2 10 Years
1110 40/15 44 3.8
OCOG 1993-1996 612 50/25 0 6.7 10 Years
622 42.5/16 0 6.2

RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre

START: Standardization of Breast Radiotherapy
OCOG: Ontario Clinical Oncology Group

43
OCOG Randomized Trial

42.5 Gy 50 Gy
Cosmesis gd/exc 70% 71%
Whelan et al N Engl J Med
Whelan et al 362:513-20; 2010.
N Engl J Med 362:513-20; 2010
44
UK START A/B Cosmetic Outcomes

Haviland et al Lancet Oncol

2014; 14:1086-94.

45
ASTRO Consensus Conference
Hypofractionated WBI was My Guidelines
suitable outside of a clinical trial DCIS or invasive
in the following patients: Node positive or node negative
pT1-2 tumor size Any age
node negative Any chemo
Sequential boost allowed
age greater than 50 years old
patients who do not receive
chemotherapy.

42.5 in 16 fractions Avoid hypofractionation for

recommended for WBI Large dose inhomogeneity
Regional node irradiation

The task force did not reach

consensus on hypofractionated
WBI when a tumor bed boost
was thought to be indicated.
Smith et al
Int J Radiat Oncol Biol Phys 2011.

46
2D Planning 80-90s Wedged Tangent

Central axis contour.

Goal of 10% or lower
dose inhomogeneity.

Chest Wall/Lung
Off-axis inhomogeneity
even higher.
Prescription
Point

47
2000s - Simple Forward Planning

Basic
segments
over hot
spots in
beams eye
views
CTV/PTV
not needed

Vicini et al Int J Radiat Oncol Biol

Phys 2002; 54:1336-44

48
Modern Volume-Based 3D Planning
PTV and PTVeval Structures

49
Volume Based Forward Planning
3D Conformal Field in Field Forward Planning

50
Volume Based Inverse Planning
IMRT Inverse Planning Sliding Window

51
Isodose Distribution

Same DVH Goals for

3D or IMRT:

PTVeval 95% > 95%

V105 < 10%

V110 = 0%

52
RTOG 1005
A PHASE III TRIAL OF ACCELERATED WHOLE BREAST
IRRADIATION WITH HYPOFRACTIONATION PLUS
CONCURRENT BOOST
VERSUS
STANDARD WHOLE BREAST IRRADIATION PLUS
SEQUENTIAL BOOST
FOR EARLY-STAGE BREAST CANCER

Stratify
Age < 50 vs. 50 R ARM 1: Standard fractionation
Chemotherapy Yes/No A Whole Breast 50 Gy / 25 fractions / 2.0 Gy daily
N Optional fractionation of 42.7 Gy in 16 fractions permissible
ER positive/negative D Sequential Boost 12 Gy /6 fractions /2.0 Gy daily or
Histologic Grade 1, 2 vs. 3 O 14.0 Gy /7 fractions /2 Gy daily
M
I ARM 2: Hypofractionation (15 fractions total)
Z Whole Breast 40 Gy/15 fractions/2.67 Gy daily
5/24/2011 6/20/2014 E Concurrent boost 48.0 Gy/3.2 Gy daily
Targeted Accrual 2312

53
Accelerated Partial Breast Irradiation

APBI

54
Intracavitary Balloon Catheter Radiation
Simplest dosimetry.
Treats 1-2 cm around lumpectomy cavity.
Less operator skill dependent.

Watch for
tissue conformance
skin distance

Arthur and Vicini J Clin Oncol 23:1726-

35; 2005.
RTOG 04-13 / NSABP B-39
55
MammoSite Registry
1,449 cases
Local recurrence

Shah et al Ann Surg Oncol

20:32793285; 2013

56
 Complications in Catheter APBI
Device removal
Catheter leak
Catheter rupture
Infection
Seroma
Skin toxicity
Fat Necrosis
Fibrosis
Telangiectasia

57
3D Conformal External Beam
38.5 Gy in 10 fractions BID for 5 days.
Noninvasive.
Better dose homogeneity than brachytherapy.
Needs greater margin for set-up and motion.

Vicini et al Int J Radiat Oncol Biol

Phys 63: 1531-7; 2005
58
Results of 3D Conformal APBI

Vera et al Practical Rad Onc 4:147-52; 2014.

59
RAPID: Randomized Trial of Accelerated Partial Breast Irradiation

Age 40 or older Whole Breast:

DCIS, T1 or T2 < 3 cm 42.5 Gy / 16 fx
Negative Margin 50 Gy / 25 fx
Boost allowed
Non-lobular
Versus
APBI:
38.5 Gy / 10 fx BID
3D CRT only

Olivotto et al J Clin Oncol

31:4038-45; 2013.

60
Multicatheter Interstitial Brachytherapy
Importance of Operator Dependent
Technique Volume as low as
possible
Minimize hot spots
Dose uniformity must
be high
Watch skin and chest
wall dose
DHI = Dose Homogeneity Index

Wazer et al Int J Radiat Oncol Biol Phys

64: 489-495; 2006.

61
 National Institute of Oncology Budapest, Hungary
Randomized Trial
Arm I: External Beam Whole Breast RT 2 Gy x 25 fractions
Arm II: APBI
Interstitial 5.2 Gy x 7 fx
Electrons 2 Gy x 25 fx

Selection Criteria
T1
N0 N1mic
Grade 1-2
Nonlobular
No extensive in-situ

Polgr Int J Radiat Oncol Biol Phys

69:694-702; 2007.

62
ASTRO Consensus Statement APBI

Smith et al J Am Coll Surg

209:269-277; 2009

63
Results of 3D Conformal APBI
Caution needed in patient selection

Pashtan et al Int J Radiat Oncol Biol Phys

84:e271-7; 2012.

64
NSABP B-39 / RTOG 04-13

65
APBI Nonrandomized Results
SEER subsequent mastectomy risk
Local control close enough for most patients?

Smith G et al. Int J Radiat Oncol Biol Phys

88:274-84; 2014.
66
DCIS
Breast-Conserving Surgery
How do you assess the completeness of an excision?
Margins

Specimen radiograph

Post-excision pre-irradiation mammogram (PPM)

68
DCIS: Breast-Conserving Surgery + RT
Factors associated with local recurrence

Higher Lower
Younger age Radiation
Mode of detection Tamoxifen
Positive margin Boost
Large size / volume excised
Diffuse calcifications

69
DCIS: Consistent Benefit to BCT + RT
EBCTCG
Local recurrence reduced
regardless of:
Age at diagnosis
Extent of surgery
Use of tamoxifen
Method of detection
Margin status
Grade
Comedonecrosis
Architecture
Tumor size

J Natl Cancer Inst Monogr 2010;2010:162-177

70
DCIS: Young Age - CS + XRT

Solin Int J Radiat Oncol Biol Phys 50: 991; 2001

71
DCIS: Margins - CS + XRT

Solin Int J Radiat Oncol Biol Phys 50: 991; 2001

72
DCIS: Margin Meta-analysis
4,660 patients treated with BCT+RT.
Negative margins superior to positive margins (OR=0.36; 95% CI,
0.27- 0.47)
Negative margins superior to close margins (OR=0.59; 95% CI, 0.42-
0.83)
> 2 mm margins superior to <2 mm (OR 0.53, 95% CI 0.26-0.96)
No difference in > 2 mm compared to > 5mm

Dunn et al J Clin Oncol 2009

73
DCIS: Radiation +/-Tamoxifen

A. Invasive Ipsilateral Recurrence B. DCIS Ipsilateral Recurrence

Wapnir et al. J Natl Cancer Inst 2011

74
DCIS: Boost vs. No Boost vs. No XRT

Omlin et al Lancet Oncology 1-5; 2006

75
Are there any subgroups of patients
with DCIS for whom we can safely omit
adjuvant radiation?
Breast-Conserving Surgery No RT
Factors associated with local recurrence

Higher Lower
Younger age Tamoxifen
Grade
Necrosis
Mode of detection
Positive margin
Diffuse calcifications

77
Van Nuys Index

Silverstein and Lagios. J Natl Cancer Inst Monogr 2010; 41:193-196

78
Harvard Study
Prospective single arm
study from May 1995 July
2002

Eligibility:
DCIS of nuclear grade 1 or 2,
necrosis noted but not
excluded
Mammogram or clinical exam
with lesion 2.5cm
Wide excision with final
margins 1cm OR negative
re-excision
Radiologic confirmation that
all calcifications were
removed

Exclusion criteria
No Tamoxifen

Wong et al, JCO 2006 (24:1031-1036).

79
ECOG E5194
Low/Int Grade (n=565) High Grade (n=105)

18%

10.5%

DCIS nuclear grade 1 or 2, with lesion 2.5 cm

-OR-
DCIS nuclear grade 3, with lesion 1 cm
Wide excision with final margins 3 mm OR negative re-excision
Radiologic confirmation that all calcifications were removed
Hughes et al, JCO 2009 (27:5319-5324).

80
RTOG 98-04 Good Risk DCIS
Prospective randomized trial
Eligibility
Mammographically detected disease
Low or intermediate nuclear grade
<2.5 cm size
Margins 3 mm.
62% had Tam - no impact on LR
Median follow-up (F/U) time was 6.46 years.
7 years Local recurrence 1% RT vs. 6% No RT
(p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]).

McCormick et al J Clin Oncol 30, 2012

81
Are there any subgroups of patients
with DCIS for whom we can safely omit
adjuvant radiation?
Older (>60) or reduced life expectancy
Low-Int grade no or mimimal necrosis
ER or PR +
Margin (at least 3 mm 1 cm + optimal)
+/- endocrine therapy
Willing to accept modest higher local recurrence
Risk factors for local-regional
recurrence after mastectomy

Indications for Postmastectomy Radiation

Case 1
45 year old woman High Risk Features
Clinical T2N0 Left Breast For Local-Regional Recurrence
3 cm tumor size
Clinically node negative 4 positive axillary nodes
Core biopsy positive
invasive ductal carcinoma
ER/PR positive, Her-2 negative
Modified radical mastectomy
Pathologic T2N2
3 cm invasive ductal carcinoma
5 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative

84
National Comprehensive Cancer Center

85
ACR Appropriateness Criteria
High Risk for Local-Regional Recurrence

86
Early Breast Cancer Trialists Collaborative Group
High Risk for LRR
4 positive nodes

EBCTCG Lancet 383: 2127-2135; 2014

87
Case 2
45 year old woman Low Risk Features
Clinical T2N0 Left Breast For Local-Regional Recurrence
3 cm tumor size
Clinically node negative T1-2 Tumor Size
Core biopsy positive 0 positive axillary nodes
invasive ductal carcinoma
6 nodes dissected
ER/PR positive, Her-2 negative
Margins negative
Modified radical mastectomy
Pathologic T2N0
3 cm invasive ductal carcinoma
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative

88
National Comprehensive Cancer Center

89
ACR Appropriateness Criteria
Low Risk for Local-Regional Recurrence

90
Early Breast Cancer Trialists Collaborative Group
Low Risk for LRR
0 positive nodes

EBCTCG Lancet 383: 2127-2135; 2014

91
Case 3
45 year old woman Intermediate Risk Features
Clinical T2N0 Left Breast For Local-Regional Recurrence
3 cm tumor size
Clinically node negative T1-2 Tumor Size
Core biopsy positive 1-3 positive axillary nodes
invasive ductal carcinoma
6 nodes dissected
ER/PR positive, Her-2 negative
Modified radical mastectomy
Pathologic T2N1
3 cm invasive ductal carcinoma
2 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative

92
National Comprehensive Cancer Center

93
ACR Appropriateness Criteria
Intermediate Risk for Local-Regional Recurrence

94
Early Breast Cancer Trialists Collaborative Group
Intermediate Risk for LRR

EBCTCG Lancet 383: 2127-2135; 2014

95
Mastectomy N 1-3+ Breast Cancer
ECOG

10-year 1-3 Nodes 4-7 Nodes 8 + Nodes

Isolated (# pts) (# pts) (# pts)
LRR (%)
T1 9 (407) 11 (180) 20 (110)

T2 7 (576) 17 (349) 20 (297)

T3 23 (35) 29 (33) 7 (29)

Recht et al J Clin Oncol

1999;17:1689-1700.

96
Mastectomy N 1-3+ Breast Cancer
NSABP

# Isol LRR LRR+/-DF

1-3 2 1,045 6% 11%
2.1-5 1,489 10% 15%
>5 229 8% 11%

4-9 2 512 13% 20%

2.1-5 982 15% 24%
>5 220 20% 31%

10+ 2 187 14% 26%

2.1-5 500 20% 33%
>5 165 20% 34%

Taghian et al J Clin Oncol

2004;22:4247-54.

97
Mastectomy N 1-3+ Breast Cancer
MDACC

0 1-3 4-9 10
T1 6 7 9 17
T2 11 12 23 17
T3 29 29 31 29

1 3
1.1-2 7
2.1-3 10
3.1-4 13
4.1-5 26

Katz et al J Clin Oncol

18:2817-27; 2000

98
Mastectomy N+ Breast Cancer
MDACC Importance of 20%
positive nodes

Katz et al Int J Radiat Oncol Biol Phys

2001; 50:397-403.

99
Mastectomy N 1-3+ Breast Cancer low risk?
Cleveland Clinic
1-3 positive nodes

Tendulkar et al Int J Radiat Oncol Biol Phys

2012; 83:e577-81.

100
Microscopic Extranodal Extension
International Breast Cancer Study Group
ECE not significant for local-regional recurrence when
number of positive of nodes included in analysis

Gruber et al J Clin Oncol

2005; 23:7089-97.

101
Mastectomy N 1-3+ Breast Cancer low risk?
MD Anderson
T1-2, 1-3 positive nodes
Early era (1978-1997) vs. later era (2000-2007)
Early era 5-year 9.5% without PMRT and 3.4% with PMRT
Late era 5-year 2.8% without PMRT and 4.2% with PMRT

McBride et al Int J Radiat Oncol Biol Phys

89:392-8; 2014

102
Young Age
NSABP
Node Positive Breast Cancer

Age # Isol LRR LRR+/-DF

20-39 1130 15% 26%
40-49 2050 13% 21%
50-59 1600 11% 17%
60+ 978 10% 14%
p=0.13 p<0.0001

Significant on Multivariate Analysis

Taghian et al J Clin Oncol

2004;22:4247-54.

103
Lymphovascular Invasion& Positive Nodes

Matsunuma et al Int J Radiat Oncol Biol

Phys 2012;83: 845-52.

104
Case 4
45 year old woman Risk of Local-Regional Recurrence
Clinical T3N0 Left Breast Various Data
6 cm tumor size
Clinically node negative T3 Tumor Size
Core biopsy positive 0 positive axillary nodes
invasive ductal carcinoma
6 nodes dissected
ER/PR positive, Her-2 negative
No Lymphovascular Invasion
Modified radical mastectomy
Negative Margin
Pathologic T3N0
6 cm invasive ductal carcinoma No Very Young Age
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative

105
National Comprehensive Cancer Center

106
Mastectomy for T3N0 Breast Cancer
NSABP
Isolated LRF 7%

Taghian J Clin Oncol

2006;24:3927-32.

107
Mastectomy for T3N0 Breast Cancer
MGH, Harvard, MD Anderson, Yale
Importance of LVI

21%

7.6%

Floyd et al Int J Radiat Oncol Biol Phys

2006;66:358-64.

108
ACR Appropriateness Criteria
Risk for Local-Regional Recurrence?

109
Case 5
45 year old woman Intermediate Risk Features
Clinical T2N0 Left Breast For Local-Regional Recurrence
3 cm tumor size
Clinically node negative T1-2 Tumor Size
Core biopsy positive 0 positive axillary nodes
invasive ductal carcinoma
6 nodes dissected
ER/PR positive, Her-2 negative
Positive Margins
Modified radical mastectomy
Pathologic T2N0
3 cm invasive ductal carcinoma
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins positive

110
National Comprehensive Cancer Center

111
Close/Positive Margins
MGH, Harvard
Node negative women

Jagsi et al Int J Radiat Oncol Biol Phys

2005; 62:1035-9.

112
Close/Positive Margins
Brigham & Womens Hospital and Dana-Farber
Positive margin
+ LVI = 27%
+ grade 3 = 13%
+ triple - = 33%

Childs et al Int J Radiat Oncol Biol Phys

84:1133-8; 2012

113
ACR Appropriateness Criteria
Intermediate Risk for Local-Regional Recurrence

114
Indications for PMRT

4 positive axillary lymph nodes High Risk

T3 node positive tumors
Definitely RT
T4

1-3 positive axillary nodes

T3 node negative tumors
Often RT but
Limited / no axillary dissection not always
Close / positive margins Intermediate
Lymphovascular invasion Risk
High grade
Young Age Sometimes RT
Gross ECE for 2-3 factors
Triple Negative? but not always
Multicentric disease?
T1 - 2
Node Negative Low Risk
Margin Negative
No RT
115
Molecular subtype A Reason for PMRT?
T1-2 N0

Truong et al Int J Radiat Oncol Biol Phys

88: 57-64;2014.

116
Regional nodal radiation therapy
SClav and Axilla

LEVEL I/II DISSECTION

118
Supraclav and Axilla RT 1980 to 2000
Level I-II Dissection (6+ nodes)
N-
Breast Only
Chest Wall Only (T3,
Margin + cases)
N+
1-3
Breast Only (except
>20-40%+? Sclav)
CW + Sclav
4+
Breast/CW + Sclav
No Low Axilla
Consider for gross ECE
or >40-50% node ratio +
119
Classic Supraclavicular Field
Meant to cover undissected Level III (infraclav) and Sclav

Madu et al Radiology 221:333-9; 2001.

120
Mastectomy: Axillary Treatment
NSABP B04
Axillary RT not needed if 6+ nodes removed

Fisher et al Surg Gyn Obstet

1981;152:765-72.

121
Mastectomy: Sclav and Axillary Treatment

Strom et al Int J Radiat Oncol

Biol Phys 63:1508-13; 2005.

122
BCS + RT: Node Positive
NSABP
BCS + Whole Breast RT.
2/3 1-3 + nodes, 1/3 4 or more + nodes. No Regional RT.

Wapnir et al J Clin Oncol 2006; 24:2028-37.

123
BCS + RT: Node Positive
Regional node recurrence rare for N0-3 with breast RT alone.

Vicini et al Int J Radiat Oncol Biol Phys

1997; 39:1069-76.

124
BCS + RT: Node Positive
BCS + Whole Breast Radiation.
No Regional Radiation.
Isolated regional node recurrences at 8 years:
Sclav 1.3%, axilla 1.2%, infraclav 0.4% and IMN 0.3%

Galper et al Int J Radiat Oncol Biol Phys

1999; 45:1157-66.

125
BCS + RT: Node Positive
Consider axillary RT for >40-50% node ratio?
Consider sclav RT for 1-3 + and >40% node ratio?

Fortin et al Int J Radiat Oncol Biol Phys

2006; 65:33-39.

126
SClav and Axilla

NO DISSECTION

127
Supraclav and Axilla RT 1980 to 2000
No Dissection or
Incomplete Dissection ( 5)

Sclav and Full Axilla

128
Dissection or Radiation

NSABP B-04
1159 clinically node negative patients

RM TM+ XRT TM
Node Positive 40% ? ?
1st Failure
LR 10% 5% 15%
Axillary 1% 3% 1% (18%)
Distant 30% 31% 32%

129
Dissection or Radiation
All lumpectomy + Breast Radiation
Age < 70, 3 cm size or less, cN0
Level I/II axillary dissection
N + received RT to sclav, IMN
N received RT IMN if central / medial
No Dissection
RT included IMN and axilla

Louis-Sylvestre et al J Clin Oncol

22: 97-101; 2004.

130
Supraclav and Axilla RT 2000 to Present
No Dissection
Average patient should have had axillary assessment but
didnt for some reason.
Sclav and Low Axilla

Older, favorable patient

High tangents Only

131
BCS + RT: Undissected Axilla
Wong 2008
BCS + Whole Breast Radiation.
No Axillary Surgery.
No Regional Radiation.
No Local-regional Recurrences.

Wong et al Int J Radiat Oncol Biol Phys

2008; 72:866-70.

132
No Axillary Dissection Older Women
IBCSG 10-93
Women 60, cN0, ER +
Surgery + Axillary clearance + Tam vs. Surgery + Tam

J Clin Oncol 24:337-344; 2006.

133
BCS + RT: Undissected Axilla
CALGB
70
T1
Axillary node
dissection was
allowed but not
encouraged.
1/3 pN0, 2/3 cN0
RT to whole breast
and level I/II nodes

Hughes et al J Clin Oncol

31:2382-7; 2013.

134
BCS + RT: Incomplete Dissection
Regional node recurrence rare for N0-3 with breast RT alone.

Vicini et al Int J Radiat Oncol Biol Phys

1997; 39:1069-76.

135
No or Incomplete Dissection PreSentinel Node

Galper et al Int J Radiat Oncol

Biol Phys 48:125-32; 2000.

136
Sentinel Node Biopsy
Sentinel Node Biopsy pre-2000
N0 - Treat like a negative level I/II dissection
N+ - Complete the dissection OR treat like an incomplete
dissection (Treat the sclav and low axilla).

137
Sentinel Node Biopsy - Positive
Sentinel Node Biopsy 2000 2010
Resistance to completion dissection
Era of the Nomogram
If nomogram suggests low risk for additional + nodes then
may omit sclav and axilla
Number of + SN
Size of + SN / micromet
Number of SN
LVI
T size
Histology
Etc. Etc.

138
BCS + RT: Sentinel Node Positive
ACSOG Z0011
891 patients with positive SNB
Clinical T1/T2, Clinical N0
H&E detected metastases in 1-2 nodes
No ECE
Breast tangents only

Additional nodal metastases in 27% of patients

having completion node dissection.
98% Systemic Therapy (58% chemo)

Local-regional recurrence
3.3% without completion dissection
4.3% with completion dissection
P=0.28

Giuliano et al JAMA
2011;305:569-75.

139
BCS + RT: Sentinel Node Positive
Additional nodal metastases in 27% of patients
ACSOG Z0011 having completion node dissection.
Breast tangents only? 98% Systemic Therapy (58% chemo)

15% sclav RT Local-regional recurrence

50% high tangents 3.3% without completion dissection
4.3% with completion dissection
P=0.28

Jagsi et al J Clin Oncol

32: 3600-06; 2014.

140
BCS + RT: Sentinel Node Positive
IBCSG 2301
Axillary dissection versus no axillary dissection in patients
with sentinel-node micrometastases
931 patients (10% mastectomy)

Galimberti et al Lancet Oncol

2013; 14: 297305.

141
BCS + RT: Sentinel Node Positive
EORTC AMAROS trial
Radiotherapy or surgery of the axilla after a positive SN
12% mastectomy
All three levels of the axilla together with the medial part of the
supraclavicular fossa were considered clinical target volume.
The prescribed dose to the axilla was 50 Gy in 25 fractions.
Postoperative axillary irradiation in patients undergoing ALND
was allowed in patients with four or more tumor-positive
nodes (pN2 or pN3).

5-year axillary recurrence rate after a positive SNB was

0.54% (4/744) after ALND
1.03% (7/681) after ART

Rutgers et al ASCO 2013.

142
Sentinel Node Biopsy
Sentinel Node Biopsy post Z0011
N0 - Treat like a negative level I/II dissection
N+ - Patient selection / judgment needed
Option A: Complete the dissection will it affect systemic therapy?
Option B: Treat like an incomplete dissection
Treat the sclav and low axilla
AMAROS
Option C: Treat a high tangent or a normal tangent
Z0011 / IBCSG

143
IMN

144
IMN Treatment
Clinical IMN Recurrence is Exceedingly Low
Incidence of IMN positivity is Low
High in old series of advanced breast cancer
Much lower in modern series
Randomized Trials of IMN Treatment
Negative or <1-2% survival benefit
What is the added cost in toxicity of treatment?
Cardiac effects

145
Clinical IMN Recurrence - Mastectomy

Any IMN?

Recht et al J Clin Oncol

JCO 17: 1689-
17: 1689-1700;1999.
1700; 1999
146
Clinical IMN Recurrence - Lumpectomy
BCS + Whole Breast Radiation.
No Regional Radiation

Galper et al Int J Radiat Oncol Biol Phys

1999; 45:1157-66.

147
Extended Radical Mastectomy Old Data
IMN positive (%)

Axilla Negative Axilla Positive

Series # Inner Central Outer Total Inner Central Outer Total

Cceres 600 -- -- -- 7 44 33 19 29

Donegan 113 12 0 4 6 54 29 31 34

Handley 1000 12 7 4 8 50 46 22 35

Lacour et al. 703 11 8 9 37 22 28

Livingston and Arlen 583 14 10 5 8 59 43 23 32

Sugg 292 -- -- -- 5 -- -- -- 44

Urban and Marjani 725 13 6 3 8 65 48 42 52

Veronesi et al. 1085 -- -- -- 9 -- -- -- 28

< 10% 30%

148
Sentinel Node Studies
Review of 6 prospective studies of SNB and IMN
Modern incidence of + IMN is likely <5%

Hindie et al Int J Radiat Oncol Biol Phys 83:

1081-8; 2012.

149
IMN Irradiation Old Negative Studies

Radical Mastectomy Radical Mastectomy

Series # + IMN irradiation* # Alone Follow-up
DM OS DM OS
Fisher et al. 470 40% 56% 633 32% 62% 5 years
P=NS
Hst et al.
Stage I 170 -- 60% 186 -- 70% 15 years
P=0.08
Stage II 95 34% 42% 91 50% 44% 15 years
P=NS P=0.15 10 years
Palmer & Ribeiro
Node - 139 -- 16% 142 -- 26% 30 years
P=0.13
Node + 243 -- 8% 217 -- 8% 30 years
P=0.7
Arriagada 41 51% 59% 31 35% 74% 15 yr crude
P=0.22 p=0.29
Veronesi 23 -- 48% (DFS) 23 -- 68% (DFS) 10 years
P=NS
* Includes supraclavicular +/- axillary irradiation
Includes patients treated with lumpectomy and breast radiation

150
Randomized Trial IMN Radiation
DBCG-IMN study
3,000 + Node positive
Right breast IMN RT
Left breast no IMN RT
Median follow up of seven years.
OS 78% versus 75% in favor of IMN radiotherapy.
HR=0.86 (95% CI (0.75; 0.99), p=0.04.

Thorsen et al, ESTRO Vienna 2013.

151
Randomized Trial IMN Radiation
French Study
Mastectomy and N + or central/medial tumors.
All patients received postoperative irradiation of the chest wall
and supraclavicular nodes.
Randomly assigned to receive IMN irradiation or not.

Hennequin et al Int J Radiat Oncol Biol Phys

86: 860-6; 2013.
152
Randomized Trial IMN / Sclav Irradiation
NCIC CTG MA.20 2000-2007 with median 62 months follow-up
1832 patients with high risk node negative (T3) or node
positive breast cancer.
1-3+ Nodes 85%

OS 92.3% vs 90.7% (HR .76, p = .07)

LR DFS 96.8% vs 94.5% (HR .59, p=.02)
DFS 89.7% vs 84 % (HR .68, p = .003) Whelan et al
ASCO 2011

153
Randomized Trial IMN / Sclav Irradiation
EORTC trial 22922-10925
Axillary lymph node involvement and/or a centrally or medially
located tumour.
4,004 patients (76% BCT)
OS at 10 years was 82.3% with and 80.7% without radiation
therapy to the internal mammary and medial supraclavicular
lymph nodes
(HR=0.87 (95%CI: 0.76, 1.00), Logrank p=0.056).

Poortmans et al, ESTRO Vienna 2013.

154
IMN / Sclav Irradiation
Could all benefit be from the sclav/axillary treatment?

Budach et al Radiat Oncol 8: 267; 2013.

155
 Early Breast Cancer Trialists Collaborative Group
Is IMN RT benefit from underestimated incidence that never become
apparent local recurrence? Or all from the Sclav?
IMN benefit in absence of local control doesnt fit the EBCTCG model!

Lancet 2005;
366: 20872106.

156
Radiation after
neoadjuvant chemotherapy
Mechanism of Increased Breast-Conserving Surgery after
Neoadjuvant Chemotherapy

Decrease in clinical tumor size.

More favorable ratio of tumor to
breast size.

Post-chemo
Volume?

Pre-chemo Volume

158
NSABP B-18 Breast Conservation
Modest increase in breast conservation
Modest increase in local recurrence in downstaged patients

IBTR (%) as site of 1st treatment failure

Postop Preop
# Chemo # Chemo
448 7.6 503 10.7 p=0.12

Downstaged Lump initially

# to lump # proposed
69 15.9 434 9.9 p=0.04

Wolmark et al J Natl Cancer Inst Monogr

2001;30:96-102.

159
Breast Conservation after Neoadjuvant Chemotherapy
NSABP B-18 and B-27 ?Add a boost
Breast-conserving surgery and whole breast radiation
No regional nodal radiation
Add Sclav RT
for ypN+

Mamounas et al J Clin Oncol

2012;30:3960-6.

160
Neoadjuvant Chemotherapy and Mastectomy
MDACC
Generally cT3 or pN+ indications for PMRT

Buchholtz et al J Clin Oncol

2002;20:17-23.

161
Neoadjuvant Chemotherapy and Mastectomy
NSABP B-18 and B-27 RT for pN+
No postmastectomy radiation
?cN+ and ypN-
need more data

Mamounas et al J Clin Oncol

2012;30:3960-6.

162
NSABP B-51/RTOG 1304: pN1 to ypN0

163
Radiation therapy for inflammatory
breast cancer
Inflammatory LABC
Clinical findings:
Rapid onset
Edema, redness, skin changes
Peau Dorange > 1/3 of the breast.
Clinical diagnosis of inflammatory BUT pathology is needed!
Core biopsy of a node
Skin punch biopsy
Breast incisional biopsy
Dermal lymphatic invasion is not required for diagnosis.
Not the same as locally advanced neglected cancer.

165
Management of Inflammatory LABC

Neoadjuvant Chemotherapy

Second Line Chemotherapy if < cCR

Preop Radiation if < cCR

Modified radical mastectomy

Endocrine Therapy (if ER/PR+)

Postmastectomy radiation

166
Inflammatory LABC Breast Conservation

167
Inflammatory LABC
PENN CW / Breast 50 Gy
Bolus
Supraclav in all
Axilla in most
IMN in few

Harris et al Int J Radiat Oncol Biol Phys

2003;55:1200-8.

168
Inflammatory LABC CW 50 Gy + 10 Gy Boost or
51 Gy BID + 15 Gy Boost
MDACC Comprehensive nodal RT
Dose escalation for < partial chemotherapy response,
close/positive margins, and age < 45 years

Bristol et al Int J Radiat Oncol Biol Phys

2008;72:474-84.

169
Inflammatory LABC
CW 5,040 Gy Bolus Daily
MSKCC

Damast et al Int J Radiat Oncol Biol Phys

2010;77:1105-12.

170
The End!
Thank you

Gary M. Freedman, M.D.

Associate Professor