How can we Personalize RT

as part of

Breast-Conserving Therapy?

Jay R. Harris

Dana-Farber Cancer Institute (DFCI)

Brigham and Women’s Hospital (BWH)

Harvard Medical School

Disclosures

I have no COI disclosures

Current Results with BCT

• Our results from DF/BWCC and MGH

are illustrative of the current

excellent results seen with BCT

• Our initial results* were also the first

to illustrate the importance of

biologic subtypes in BCT

* Nguyen P et al JCO 2008

Nguyen P et al JCO 2008

• Approximated biologic subtype

using standard markers was the

only variable in the final model

• No other variables, including

margins, dose, grade, stage and

age were in the final model

Our Updated Experience

• 1434 BCT patients

• T1 80%, pN0 67%

• Margins: Negative 89%, close 8%

• ST used in 91% (No Herceptin)

• Median FU = 85 months (7.1 years)

• 5-year rate of LR = 2.1%!

Ref: Arvold N et al JCO 2011 29:3885

New 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: the Main Prognostic Factor

HER2 (No Herceptin)

Triple -

Lum B

Lum A

Lum-HER2

No Trastuzumab

HER2

TN

Lum B

Age is also Prognostic (note scale)

< 47

47- 55

56 - 64

> 64

Age 23-46

Age 47-54

Conclusions

• New definition of subtype is useful

• Both subtype and to a lesser extent

age are prognostic for LR

• LR rates are much lower than in the

past

Reasons for Excellent Outcomes

• Better imaging with mammography

(not MRI); use of MRI controversial

• Better evaluation of the resected

breast specimens, especially margins

• Use of systemic therapy (ST), which

greatly improves results of RT

10-Year LR in NSABP Trials (Ref: Anderson SJ et al. JCO 2005, 27: 2466)

Trial ER

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

B-19 Chemo - 6.5

B-20 Tam +/- Chemo + 4.7

B-23 Chemo - 4.3

Adjuvant Trastuzumab reduces LR

in HER2+ Cancers

Ref: Romand, NEJM 2005;353:1673

NSABP B31 N9831

CTX

CTX + H

2.8%

1.7%

2.7%

1.5%

Is Bigger Surgery Better for

Triple Negative Breast Cancer?

• Studies from Canada, MSKCC and MD Anderson have shown that if anything LR is lower with BCT than with mastectomy

• Abdulkarim B, JCO 2011;29:2852

Ho A et al, Cancer 2012;118:4944

Adkins F et al, Ann Surg Oncol 2011;18:3164

Conventional Fractionation

• 45-50 Gy WB with boost to 60 Gy

• With long-term FU, shown to be safe

and effective

• However, there is growing interest in

hypofractionated breast RT

Rationale for Hypofractionation

• Convenience and Cost

• Major improvements in RT delivery

with higher energies, 3-D dose

calculation and beam modulation ->

much greater 3-D dose homogeneity

• More refined radiobiologic estimate

of dose equivalence

Major 1st Generation Trials

Canadian Start A UK* Start B UK

# Pts 1234 2236 2215

Med

FU

12 yrs 9.3 yrs 9.9 yrs

Arms

(Gy x

# Fx)

2 x 25 in 5

wks

2.66 x 16 in

3+ wks

2 x 25 in 5 wks

3 x 13 in 5 wks

3.2 x 13 in 5

wks

2 x 25 in 5

wks

2.66 x 15 in 3

wks

* Trial performed to determine α/β Ratio

Major 1st Generation Trials

Canadian Start B UK

# Pts 1234 2215

Arms

(Gy x # Fx)

2 x 25 in 5 wks

2.66 x 16 in 3+

wks

2 x 25 in 5 wks

2.66 x 15 in 3 wks

Use of a

Boost

Not Allowed Allowed

(Used in half)

Major 1st Generation Trials

• The Canadian Trial with 12 years of

FU was practice-changing in the US

• Updated results of the START trials

were published in Lancet Oncol in 2013

• Together, they provide justification

for increased use of hypofractionation

Refs: Whelan T et al NEJM 362:513, 2010

Haviland J et al Lancet Oncol 14: 1086, 2013

Ref: Whelan T et al, NEJM: 362; 513, 2010

0

5

10

15

20

25

30

35

1 2 3

15F 25F 0 5 10 Years since Randomization

42.5Gy/16F

Fair + poor cosmesis (%)

50Gy/25F

42.5Gy/16F

Local tumor relapse (%)

Canadian Trial Results

50Gy/25F

Time from randomization (years)

Rate of local tumor relapse

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

50 Gy

40 Gy

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

% Free of adverse effects

40Gy

50Gy

START B Results

40 vs 50GY HR = 0.77 (0.66-0.89)

40 vs 50GY HR = 0.77 (0.51-1.16)

Ref: Haviland J et al Lancet Oncol 14: 1086, 2013

START B Hazard Ratio Results

Ref: Haviland J et al Lancet Oncol 14: 1086, 2013

DM Any BC

Event

OS

200 x 25 1.00 1.00 1.00

266 x 15 0.74

p = .01

0.79

p = .02

0.80

p = .04

Concerns/Uncertainties

• Potential effects on late-responding

normal tissue (late toxicity) -> need

long-term follow up

• ? Interaction with systemic

therapies, especially chemotherapy

• Patient selection – which patients?

Patients in the Major Trials

Canadian Start B

ER- 27% 12%

Gr 3 19% 23%

Age < 50 25% 21%

Boost 0% 43%

Nodal RT 0% 7%

Chemo 11% 22%

Generalizability of these Results

• Patients in the these trials were older

with favorable cancers

• Chemotherapy and boost not routine

• However, in START B, cosmetic

results were the same with and

without chemotherapy

Case: Need for Long FU

• 1981 BK presents with T1N0 cancer

treated with BCT including nodal RT

• 2001 (20 yrs later) She develops

numbness of right hand; no evident

recurrence -> Dx brachial plexopathy

• 2001-> present Progressive loss of

motor function to ‘useless’ arm

Clinical Trials in Progress

FAST

UK

IMPORT

High UK

IMPORT

Low UK

SHARE

France

RTOG

US

# Pts 915 840 2100 2796 2150

Arms

(Gy x

# Fx)

2 x 25

5.7 x 5

6 x 5

All in 5

weeks

2.4 x 15

integrated

boost

2.67 x 15

-> boost

2.67 x 15

2.4 x 15

integrated

boost

APBI

2.67 x 15

2 x 25 +

2 x 8

2.67 x

15

APBI

4 x 10

2.0 x 25

-> boost

2.67 x 15

integrated

boost

ASTRO Guidelines (2011)

Age/Stage > 50 yrs, T1,2 N-

Surgery BCS

Chemotherapy None

Fractionation 266 cGy x 16

Heart in Field 0

Boost No Agreement

Dose Homogeneity < 7%

Ref: Smith B et al IJROBP 2011 81: 59

New DFCI/BWH Approach

Age/Stage > 50 yo, DCIS > 60,

Tangents only

Surgery BCS

Chemotherapy OK

Fractionation 266 cGy x 15-16

Heart in Field 0

Boost 250 cGy x 2-4

Dose Homogeneity < 7%

Hypofractionation

• The available RCTs, particularly the

Canadian and START B Trials, provide

increased support for hypofractionation

• This approach is clearly indicated in

many patients and will likely be

increasingly used

‘Personalized’ BCT based on

Subtype, Age (DFCI/BWH)

• Luminals > 60: 266 x 16, no boost

• Luminals 50-60: 266 x 15, 250 x 2

• HER2+ > 50: 266 x 15, 250 x 4

< 50: 200 x 22 + 200 x 8 = 60 Gy

• TN: Conventional + concurrent

platinum on protocol