Radiotherapy Management of

Breast Cancer Treated with

Neoadjuvant Chemotherapy

Julia White MD

Professor, Radiation Oncology

Agenda

• Efficacy of radiotherapy in the management

of breast cancer in the Adjuvant setting

• Neoadjuvant Chemotherapy and breast

conservation

• Neoadjuvant Chemotherapy and Post

mastectomy radiotherapy and

• Clinical trials for local regional management

post NAC:

− NSABP B51/ RTOG 1304

− Alliance 011202

What we know well….

Efficacy of Radiotherapy for

Breast Cancer Treatment in the

Adjuvant Setting

Gains from RT in Overall Recurrence (local, regional,

distant) Results in Improved Breast Cancer Survival

Updated EBCTCG Meta analyses

• Lancet 2014- Mastectomy w/ AD (n=3,131) + RT:

Local-regional

Recurrence

Overall (any)

Recurrence

Breast Cancer

Mortality

8.1% MAST + RT

26% MAST (p<0.00001)

17.9% Gain 10 year

Local Control

51.9% MAST + RT

62.5% MAST (p<0.00001)

10.6% Gain 10 year

Overall Control

58.3% MAST + RT

66.4% MAST (p<0.001)

8% Improvement 20

year Survival

Overall (any)

Recurrence

Breast Cancer

Mortality

19.3% BCS + RT

35.0% BCS (p<0.00001)

15.7% Gain 10 year

Overall Control

21.4% BCS + RT

25.2% BCS (p<0.00005)

3.8% Improvement 15 year

Survival

• Lancet 2011- BCS (n=10,801) + RT:

Regional Nodal Radiotherapy

• Breast cancer metastases to 4 or more

axillary lymph nodes has been an accepted

indication for local and regional nodal

radiotherapy post mastectomy or

lumpectomy

• More recent evidence now supports that

many women with 1-3 positive lymph

nodes will benefit from local and regional

nodal radiotherapy

Supports Local Regional Radiotherapy

in Breast Cancer Patients with 1-3

Axillary Nodal Metastases

Post Mastectomy Improve DFS/ OS

– EBCTCG Meta analysis Lancet 2014

– EORTC 22922/10925 ECCO 2013

Post Lumpectomy Improve DFS

– NCIC MA.20 ASCO 2010

– EORTC 22922/10925 ECCO 2013

Positive SNB Replace ALND

– EORTC AMOROS Lancet 2014

Radiotherapy when Surgery is First

Line for Breast Cancer Treatment

• Has a large effect on reducing local regional

recurrence after lumpectomy in nearly all patients and

after mastectomy in node positive patients

• Yields smaller but consistent effect on reducing

distant metastases and breast cancer mortality

• Indications for post mastectomy radiotherapy are

expanding to include many patients with 1-3 positive

axillary nodes

• Similarly, regional nodal radiotherapy more

frequently indicated after breast conserving surgery

when axillary nodes are positive

None of the patients included in the Phase III RCT’s analyzed in the EBCTCG meta analyses had neoadjuvant chemotherapy.

Radiation therapy clinical decision making has been based on pathologic extent of disease from surgery as first line of breast cancer treatment.

Radiation therapy indications in setting of neoadjuvant chemotherapy are evolving: is clinical stage, chemo response, or final pathologic extent of disease the key factor?

Challenge:

Efficacy of Radiotherapy for Breast

Cancer Treatment in the

Neo Adjuvant Chemotherapy Setting

What is evolving….

NeoAdjuvant Chemotherapy and

Breast Conservation

Neoadjuvant Chemotherapy: Breast Conserving Surgery and Radiation Therapy

Study N

BCT

%

F/U

(yrs.) Clinical Stage

% In-breast

recurrence

Phase III:

NSABP B-18

763

68

16

87% T-1,2

74% N-0

13

NSABP B-27 2,411 49 8.5 71% T-1,2

70% N-0 6

EORTC 10902 350 28 4.7 73% T1,2

48% N-0 10.7*

* Local regional recurrence

NSABP B18: Does Initial Surgical

Intention Pre- NAC Affect Outcome?

• 1988 – 1993

• 9 years median F/U

• n = 1533

% IBTR p

Preop Chemo 10.7 0.12

Postop Chemo 7.6

MRM pre NAC – Lumpectomy post NAC 15.9 0.04

Lumpectomy pre NAC- Same post NAC 9.9

cT1-3, N0-1

AC x4

Surgery AC x4

Surgery

R

Wolmark et al., JNCI 30:2001

MDACC Prognostic Index LRR after BCT or MRM treated with

Neoadjuvant Chemotherapy

• 815 patients 1974 - 2000

– 331 BCT

– 485 mastectomy

• Prognostic Index Score: 0-4 – Sum of each item scored 0 if absent or 1 if present for

a total score of 0-4

1. Clinical N2–N3 disease

2. Lymphovascular invasion

3. Residual pathologic primary size > 2 cm

4. Pathologically multifocal residual disease Huang EH, IJROBP 66:2006

No Difference in Local Regional Control by

MDAPI 0-1 but BCT Worse for Score > 2

Score % w/ BCT % w/ MRM

0-1 83% 58%

2 13% 28%

3-4 4% 14% Huang EH, IJROBP 66:2006

Breast Conserving Therapy after

Neoadjuvant Chemotherapy • 308 operable breast cancer patients

• Medical University Vienna 1995-2007

• Received neoadjuvant therapy on 3 ABCSG studies

AC, Taxane and Trastuzumab (ABCSG 7, 14, 24)

LRFS 5 year

All: MRM 91%

BCT 89%

Intention pre NAC:

MRM - MRM 91%

MRM - BCT 84%

BCT-BCT 97%

T1-2 ER+ G3

24% 40% 50%

54% 53% 54%

98% 70% 38%

Adverse pathologic

factors explain

variation in LRFS

Fitzal, Breast Cancer Res Treat ,2011

Local Recurrence Free Survival: Intention of Mastectomy Pre NAC Not

Associated with Worse Outcome

MX = Mastectomy

BCT= Lumpectomy + Breast XRT

Fitzal, Breast Cancer Res Treat ,2011

Impact of Multifocal or Multicentric

Disease Treated with NAC • 2002 – 2010: 6,143 breast cancer patients enrolled

on multi institution clinical trials with NAC

– Gepar trio, Gepar quattro, Gepar quinto

Unifocal Multifocal Multicentric p

N 4,733 820 588

BCT % 71.6 58.5 30

pCR % 19.4 16.5 14.4

Local Recurrence

All 7.1 4.9 9.6

BCT 8.7 4.2 8.0 0.3

Mast 11 5.9 10 0.03

Ataseven, Ann Surg Onc 2014

All All

BCT

pCR

Ataseven, Ann Surg Onc 2014

Local Recurrence Free Survival

No significant difference unifocal, multifocal,

multicentric for those treated with BCT or

who achieve pCR

MDAPI in a More Modern Treatment Era: LRR Free Survival BCT vs. MRM

Akay et al., Ann Surg Oncol 19:2012

• 551 patients neoadjuvant chemotherapy 2001-2005

• 244 BCT and 327 MRM

• Median follow– up 62 months

MDAPI 0-2: No Difference in LRR Free

Survival BCT vs. MRM

Score % w/ BCT % w/ MRM

0-1 78% 44%

2 17% 38%

3-4 6% 18% Akay Ann Surg Oncol 19:2012

Breast Radiotherapy Methods for NAC

42.56 Gy/

16 treatments

50 Gy/

25 treatments

Conventional WBI Hypofractionated WBI

Boost 10-16 Gy/

5-8 treatments

30-38 Gy/

6-10 treatments

Accelerated PBI

Regional Nodal Radiotherapy

Regional nodes:

–Axilla (what did not

get removed with

dissection,

“undissected axilla”)

–Supraclavicular

–Internal mammary (

first three intercostal

spaces)

Is Regional Nodal Irradiation Indicated

for ypN0 Breast Conservation?

• 248 patient cN0 (n=164), cN1-N2 (n=84)

• All had lumpectomy and were ypN0,

– 90 Breast RT alone

– 158 Breast + Regional RT

• Centre Rene ́Huguenin, 1990 -2004

• Median follow-up 88 months

Davieau et a IJROBP 78:2011

No Difference in LRR or OS by Use

of Nodal Radiotherapy in ypN0

Davieau et a IJROBP 78:2011

Neoadjuvant Chemotherapy and Radiotherapy: Breast Conservation

Radiation therapy following breast conserving surgery

results in acceptably low rates of in-breast recurrence.

Advanced clinical stage, T3-4, N2-3, pathologic

residual > 2 cm associated with increased rates of LRR

due to adverse pathology / poor response.

Conventional whole breast radiotherapy with boost to

surgical cavity –method of choice

Role for regional radiotherapy for clinically node

positive breast cancer that becomes node negative

(ypN0) is evolving

NeoAdjuvant Chemotherapy and

Postmastectomy Radiotherapy

6 Prospective Neoadjuvant Chemotherapy Trials MDACC 1974 - 2000

n = 636

Mastectomy

Radiation

n = 542

No Radiation

n = 134

Local Regional Recurrence and Survival: Post-mastectomy Radiation

Huang, et al., JCO, 22:2004

MDACC –Benefit PMRT after NAC

PMRT Improved 10 Year Local Regional Recurrence

Factor No RT % RT % p

Clinical: T3

T4

N2-3

22

46

40

8

15

12

0.002

< 0.001

<0.001

Pathological : Tsz 2.1-5 cm

> 5cm

> 4 pos nodes.

31

52

59

14

13

16

0.002

0.001

<0.0001

PMRT Improved 10 Year Cause Specific Survival

Factor No RT % RT % p

Clinical: > IIIb

T4

N2-3

22

24

27

44

45

49

0.002

< 0.007

<0.024

Pathological > 4 pos nodes

(ypN2)

18 44 <0.005

Huang, et al., JCO, 22:2004

Pathologic Complete Response from

Neoadjuvant Chemotherapy: Post-mastectomy Radiation Improves Outcomes

RT

n = 72

No RT

n = 34 p

% Local regional recurrence

All

Stage I-II

Stage III

5

0

7

10

0

33

ns

ns

0.04

% Cause Specific Survival 87 40 0.0014

McGuire, et al. IJROBP, 68:2007

PMRT Benefit Less Pronounced in

Clinical Stage II with

pCR or ypN0 post NAC?

Author/

treatment era n Follow

up (mo.) Path

response Clinical

Stage

LRR % OS %

PMRT NoRT PMRT NoRT

Huang

1974-2000 676

RT 73

No RT 66 RT 14%

No RT 8% II 30%

III 70 % 11* 22 54 47

McGuire

1982-2002 106 62

100%

pCR II 30%

III 70 % 5 10 -

LeScodan

1990-2004 134 91

100%

ypN0 II 63%

III 37% 4 12 88 94

Shim

1998-2009 151 57

100%

ypN0 II 60%

III 40% 2 8 93 90

Neoadjuvant Chemotherapy and Radiotherapy: Mastectomy

Radiation can improve local regional recurrence and impact survival for patients with locally advance breast cancer who receive neoadjuvant chemotherapy and mastectomy

Most Benefit – Clinical stage III-IV, pathologic

N2-3

Should be considered regardless of response to chemotherapy in Clinical Stage III

Unclear role for PMRT in down staged patients to ypN0

Association of pCR to

Event Free and Overall Survival CTNeoBC Pooled Analysis

Meta analysis of 12 neoadjuvant randomized controlled trials

Cortazar SABC 2012, Lancet 2014

Trends in Pathologic Complete

Response Rates from NAC

Trial Additional Agents Path CR

NSABP B18 AC 13%

NSABP B27 Paclitaxel 26%

NSABP B40 Bevacizumab 34.5%

NOAH* Trastuzumab 43%

NeoALTO* Trastuzumab + Lapatanib 53%

CALGB 40603† Carboplatin 60%

Tryphaena* Trastuzumab + Pertuzumab 63%

*Her2 †TNBC

Should Down Staging of the

Axilla with NeoAdjuvant

Chemotherapy affect Delivery of

Regional Nodal Radiotherapy?

2961 Patients - 318 LRR as First Events

1071 Mastectomy – NO PMRT - 137 LRR first events

NSABP B18 and B27: Patterns of LRF

Operable Breast

Cancer

AC x 4

Surgery Docetaxel x

4

AC x 4 AC x

4

Surgery

Surgery Docetaxel x

4

Surgery

AC x 4 Surgery

AC x 4

Operable Breast Cancer

R R

B-18 B-27

Mamounas et al, JCO, 2012

Mastectomy (1071 patients, 131 LRR Events)

Variable Hazard Ratio (95% CI) P

Clinical tumor size: 5 vs. 5 cm 1.58 (1.12–2.23) 0.0095

Clin. nodal status: cN(+) vs. cN(-) 1.53 (1.08–2.18) 0.017

Breast/nodal pathologic status:

ypN(-): No Breast pCR vs. Breast pCR 2.21 (0.77–6.30)

0.0002

ypNode(+) vs. ypNode(-)/Breast pCR 4.48 (1.64–12.21)

Lumpectomy Plus Breast XRT (1890 patients, 189 LRR Events)

Age: 50 vs. age 50† 0.71 (0.53–0.96) 0.025

Clin. nodal status: cN(+) vs. cN(-) 1.70 (1.26–2.31) 0.0005

Breast/nodal pathologic status:

ypN(-): No Breast pCR vs. Breast pCR 1.44 (0.90–2.33)

0.0006

ypNode(+) vs. ypNode(-)/Breast pCR† 2.25 (1.41–3.59)

Multivariate Analysis of Independent Predictors

of 10-year LRR According to Type of Surgery

10-Year Cumulative Incidence of LRR:

Lumpectomy + Breast XRT

> 50 yo < 50 yo

n=122

n=58

n=31

n=154

n=84

n=57

10-Year Cumulative Incidence of LRR:

Mastectomy

T > 5 cm T < 5 cm

n=128

n=33

n=11

n=143

n=37

n=21

Background

• With modern NAC regimens about 40% of pts with axillary nodal metastases at presentation are down-staged to pathologically negative axillary nodes at surgery (even higher proportion in TNBC or HER-2 neu + tumors)

• Several RCTs have consistently shown that achievement of pCR in the breast with negative axillary nodes predicts for excellent long-term outcomes both in terms of LRR and distant recurrence

NSABP B-51/RTOG 1304 Trial Phase III

- Clinical T1-3N1M0 breast cancer - Pathology positive axillary node (FNA/Core)

- Neoadjuvant CT + anti HER2

ypN0 at definitive Breast Surgery + AND or SNB

Randomization

Arm 1

No Regional Nodal XRT A. Lumpectomy: Breast XRT.

B. Mastectomy: Observation

Targeted accrual = 1636

Arm 2

Regional Nodal XRT A. Lump.: Breast/Nodal XRT

B. Mast: Chestwall/ Nodal XRT

Stratification: Type of Surgery (Mast v. Lump) , ER-Status (+ v. –), HER2 Status (+ v. –), pCR in Breast (yes v. no)

Thank you!