ESMO Preceptorship Program 2017

Principles of breast radiation therapy

Boon H Chua

Professor Director of Cancer and Haematology Services

UNSW Sydney and Prince of Wales Hospital

Sydney Australia

ANZ 1601/BIG 16-02 EXPERT

Lancet 2005;366:2087-2106

Effects of RT: EBCTCG 2005

• RT after breast conserving surgery (BCS) in N- patients (n=6097)

– 16% absolute decrease in local recurrence (LR) at 5 years

– 5% absolute decrease in breast cancer mortality at 15 years

Lancet 2005;366:2087-2106

Effects of RT: EBCTCG 2005

• RT after BCS in N+ patients (n=1214)

– 30% absolute decrease in LR at 5 years

– 7% absolute decrease in breast cancer mortality at 15 years

• RT after surgery produced ≈70% proportional decrease in LR

• Four LR avoided at 5 years → one breast cancer death avoided at 15 years

Lancet 2005;366:2087-2106

Effects of RT: EBCTCG 2005

Lancet 2011;378:1707-16

Effects of RT: EBCTCG 2011

• RT after BCS (n=10801; 33% N+)

– Four recurrences avoided at 10 years: one breast cancer death avoided at 15 years

– Proportional benefits of RT vary little between risk groups

• Whole breast RT standard of care after breast conserving surgery (BCS)

– 70% decrease in local recurrence at 5 years

– 50% decrease in any first recurrence at 10 years

– 17% decrease in breast cancer mortality at 15 years

• Absolute reduction in 10-year recurrence risk <10% with RT

– 15-year breast cancer mortality benefit of RT = 0.1%

– Potential to tailor RT to recurrence risks

Lancet 2005;366:2087-2106. Lancet 2011;378:1707-16

Effects of radiation therapy

Optimising patient selection for RT after breast conserving surgery

• Clinical and public health priority to tailor RT utilisation to individual recurrence risks

– Heterogeneous tumour biology: variations in recurrence risk

– Advances in multidisciplinary care: falling recurrence rates

– Population ageing: rising breast cancer incidence underpinning importance of research to drive cost-effective health care improvements

Radiother Oncol 2009;90:14-22

Personalising RT utilisation

N Age FU LR %

RT No RT

PRIME 2 1326 ≥65 5 1.3 4.1

CALGB 9343 636 ≥70 5 1.0 4.0

12.6 2.0 10.0

BASO II 1172 <70 10.2 1.1 4.8

ABCSG 8a 869 >50 4.5 2.0 6.0

PMH 769 >50 5.6 0.6 7.7

NSABP B21 1009 >18 8 2.8 16.5

GBSG-V 347 45-75 9.9 6.0 20.0

SCTBG 585 <70 5.7 5.8 24.5

Randomised trials of RT vs no RT

• St Gallen 2009 and NCCN 2014

─ Endocrine therapy without RT may be considered in elderly patients with small ER+ N- breast cancer

• Minimal impact on changing practice

– Lack of validated clinical-pathologic markers for precise and individualised quantification of LR risk

Impact of consensus guidelines

• Systematic review of local-regional recurrence after breast conserving therapy by IHC-defined subtypes (n=7174)

• Luminal A subtype associated with lowest LR rate

Breast Cancer Res Treat 2012;133:831-41

Biomarkers of local recurrence

RR 95% CI

Luminal vs triple-negative 0.38 0.23-0.61

Luminal vs HER2+ 0.34 0.26-0.45

HER2+ vs triple-negative 1.44 1.06-1.95

• IHC analysis of archived tumour specimens of RCT of RT+Tam vs Tam (n=501)

• 10-year LR rates by luminal A subtype

─ RT+Tam vs Tam = 3.3% vs 7.3% (p=0.11)

• 10-year LR rates by clinical low-risk (age >60, T1, G1-2) luminal A subtype

─ RT+Tam vs Tam = 5.0% vs 1.3% (p=0.42)

JCO 2015;33:2035-40

Biomarkers of local recurrence

Luminal HER2, HER2-enrichedbasal-like, TN non-basal

JCO 2015;33:2035-40

Biomarkers of local recurrence

• Lack of standardised IHC assessment of biomarkers

• Multigene expression analysis for subtype identification and distant recurrence risk assessment

─ Rapid integration into systemic therapy practice

─ Modest impact on local therapy decision

Biomarkers of local recurrence

• Oncotype DX Recurrence Score (RS)

– NSABP B14 and B20 patients with HR+ N- cancer (n=1675)

JCO 2010;28:1677-83

Biomarkers of local recurrence

• EndoPredict (EP)

─ ABCSG 8 patients with HR+ HER2- cancer (n=1324)

BJC 2015;112:1405-10

Biomarkers of local recurrence

• Prosigna (PAM50) Breast Cancer Prognostic Gene Signature Assay

- ABCSG8 patients with HR+ HER2- cancer (n=1308)

- Risk of recurrence (ROR) score and LR risk, p<0.0081

ROR ≤57: 10-year LR rate 1.6%

- Intrinsic subtype and LR risk, p=0.022

Luminal A subtype: 10-year LR rate 1.9%

Fitzal F. ASCO 2014

Biomarkers of local recurrence

• Investigator-driven, randomised, non-inferiority trial of RT

vs no RT after BCS and adjuvant endocrine therapy in

patients with luminal A early breast cancer defined using

Prosigna (PAM50) Assay

• Biological research to enhance prognostic precision for LR

• Health economic research to assess cost-effectiveness of

gene expression-based, risk-adapted RT utilisation

ANZ 1601/BIG 16-02 EXPERTExamining Personalised Radiation Therapy

Optimising radiation target volume

Partial breast irradiation: rationale

• Adjuvant whole breast RT commonly involves fractionated course over 3-6 weeks

• PBI limits target volume to tumour bed where most LRs are observed

• The limited target volume permits safe acceleration of RT delivery

Partial breast irradiation: current status

• Results from RCTs (n >16,000) currently limited

• PBI endorsed by scientific bodies as acceptable option in selected low-risk patients primarily based on retrospective and single-arm prospective data

Practical Rad Oncol 2017;7:73-9

Systemic review & meta-analysis of RCTs of whole breast RT vs PBI

Radiother Oncol 2015;114:42-9

N pT1-2 pN0 PBI technique

Dodwell 174 174 (59-69%) MV photons

Livi 520 220 206 MV photons

Olivotto 2135 1752 2135 MV photons

Rodriguez 102 102 (cN0) MV photons

Ribeiro 708 708 (cN0) Electrons

Polgar 258 258 249 HDR or electrons

Veronesi 1305 1305 949 IORT (Electrons)

Vaidya 3451 3451 1764 IORT (50 kV x-rays)

Total 8653 7970 5303

Systemic review & meta-analysis of RCTs of whole breast RT vs PBI

• Meta-analysis of two trials (n=1407) with 5 years FU showed higher LR rate with PBI than whole breast RT (p=0.002)

• Overall survival: no significant difference

• Toxicity, cosmesis, quality of life: severe toxicity <3%

Radiother Oncol 2015;114:42-9

IMPORT LOW (CRUK 06/03)

• PBI using external beam (n=2018)

• Age ≥50, invasive disease ≤3 cm, pN0-1, margins ≥2 mm

Whole Reduced Partial

Lancet 2017;390:1048–60

IMPORT LOW (CRUK 06/03)

Whole (n=674)

Reduced (n=673)

Partial(n=669)

5-year LR 1.1% 0.2% 0.5%

• Median FU 72 months

Lancet 2017;390:1048–60

• Non-inferiority in terms of LR of partial-breast and reduced-dose RT vs whole-breast RT

• Equivalent or fewer late normal-tissue adverse effects

GEC-ESTRO RCT

• PBI using interstitial brachytherapy (n=1184)

• Age ≥40, invasive disease or DCIS ≤3 cm, pN0-mi, margin ≥2 mm

• Median FU 6.6 years

• 5-year LR rates: WBI 0.9% vs PBI 1.4% (p=0.42)

• No significant difference in disease free or overall survival

• No significant difference in G2-3 skin or SC tissue toxicity

Lancet 2016;387:229-38

RAPID/TROG 10.02 RCT

Adverse global cosmesis N WBRT PBI P

Nurses Baseline 2055 17% 19% 0.25

3 years 1108 17% 29% <0.001

5 years 335 13% 33% <0.001

Patients Baseline 2055 22% 24% 0.25

3 years 1100 18% 26% 0.0022

5 years 328 22% 32% 0.034

Physicians 3 years 766 17% 35% <0.001

J Clin Oncol 2013;31:4038-45

• PBI using external beam (n=2135)

• Age ≥40, invasive disease or DCIS ≤3 cm, pN0

Randomised trials of PBI

N PBI Age T cm N G3

NSABP B39 42163D CRT

Interstitial MammoSite

≥18 ≤3 N0-1 Y

RAPID 2135 3D CRT ≥40 ≤3 N0 Y

SHARE 2796 3D CRT ≥50 ≤2 N0-N0(i+) Y

IRMA 3302 3D CRT >49 ≤3 N0-N1 Y

PBI data: interpretation

• Current data support PBI use for selected patients with early breast cancer

• PBI modalities and dose-fractionations likely to yield comparable efficacy but different toxicity

• Role and therapeutic benefit of PBI uncertain

- Selected patients may not derive meaningful benefit

- Longer term data from randomised trials essential

• Current off-study application should be limited to low-risk patients defined by guidelines

Optimising regional nodal irradiation

Regional nodal irradiation after axillary dissection

RCTs of regional nodal irradiation (RNI)

CCTG MA.20 EORTC 22922

N 1832 4004

BCS 100% 76%

N0 / N1 10% / 85% 43% / 45%

Median FU 9.5 years 10.9 years

RT No RNI RNI P No RNI RNI P

DFS 77% 82% 0.01 69% 72% 0.04

Distant DFS 83% 87% 0.03 75% 78% 0.02

Overall survival 91% 92% 0.38 81% 82% 0.06

NEJM 2015;373:307-16. NEJM 2015;373:317-27

Disease Free SurvivalCCTG MA.20: exploratory analysis DFS

CCTG MA.20 and EORTC 22922: interpretation

• RNI after ALND decreased local-regional and distant recurrence rates

- Local-regional and systemic effects

• Observed benefits of RNI modest

• Challenge: patient selection for RNI after ALND

Regional nodal irradiation after positive sentinel node biopsy

ConclusionsEORTC 10981 AMAROS

®

Axillary dissection

Axillary RT

Lancet Oncol 2014;15:1303-10

• Adjuvant systemic therapy in 90% of both groups

N = 4806

cT1-2 cN0

BCS (82%) or mastectomy

SNB+

Conclusions

• Median FU 6.1 years

EORTC 10981 AMAROS

ALND Axillary RT

Axillary recurrence 0.4% 1.2%

Disease free survival 86.9% 82.7%

Overall survival 93.3% 92.5%

• Higher lymphoedema rate after ALND than axillary RT

Lancet Oncol 2014;15:1303-10

• Benefit of axillary RT likely to be modest in patients with

small volume nodal disease after SNB+

- No observation only group

- Low event rate: non-inferiority test underpowered

- Short FU

- Morbidity of axillary RT

EORTC 10981 AMAROS: interpretation

Conclusions

®

ALNDN = 891 (planned 1900)

cT1-2 cN0

BCS + SNB

1-2 SN+

Adjuvant breast RT (RNI not permitted) No ALND

JAMA 2011;305:569-75

ACOSOG Z11

Conclusions

ALND (n=420) No ALND (n=436)

Age, median (years) 56 54

T size, median (mm) 17 16

ER/PR + (%) 83.5 83.7

G 1/2 (%) 70.9 72.4

SLN micrometastasis (%) 37.5 44.8

Non-SLN metastasis (%) 27.3 -

Systemic therapy (%) 96 97

Z11 clinical-pathologic characteristics

JAMA 2011;305:569-75

Conclusions

• Median FU 6.3 years

JAMA 2011;305:569-75; Association Breast Surgical Conference UK 2016

ALND No ALND

Local recurrence 3.6% 1.8%

Axillary recurrence 0.5% 0.9%

Disease free survival 82.2% 83.9%

Overall survival 91.8% 92.5%

• Median FU 10 years

⎯ axillary recurrence: ALND 0.5% vs no ALND 1.1%

Z11 results

• Significance unclear but patients treated without ALND

may derive proportionately greater benefit from RNI,

increasing likelihood of non-inferiority finding

• Variations in RT target volumes

ALND No ALND

High tangents 50% 53.6%

Directed RNI 16.9% 21.2%

Z11 confounding variables

J Clin Oncol 2014;32:3600-6

Conclusions

• Challenge to rationalise results of Z11 vs CCTG MA.20 and

EORTC 22922

- Which patients with SNB+ should have RNI?

• Patients with SNB+ but do not fit Z11 profile

- Should be considered for ALND

- RNI may be an alternative

• Individualise RNI utilisation in patients with 1-2 SLN+

- Consider breast RT only for patients who fit Z11 profile

- Consider RNI in presence of high-risk features

- Further research to refine patient selection for RNI

RNI trials interpretation

Conclusions

®

Axillary dissection or RTN = 1900

T ≤5 cm

BCS or mastectomy

1-2 sentinel node macrometastases

No axillary dissection or RT

POSNOC

Conclusions

• To determine if avoiding RNI is not inferior to RNI in

patients with N1, ER+, biomarker low-risk breast cancer

®

RNIN = 2140

BCS or mastectomy

T ≤5 cm

1-3 N+

Endocrine therapyNo RNI

Tailor RT

Conclusions

• Remarkable progress in local-regional RT in early breast cancer

• Decision on RT based on residual disease burden estimated using conventional histopathology and nodal prognostic groups serve patients well but increasingly inadequate

• Data on new generation biomarkers for LR risk prediction promising but exploratory hence prospective evaluation

• Future in personalised local-regional RT: integration of residual disease burden with tumour biology and efficacy of systemic therapy in multidisciplinary setting