ANZ 1601/BIG 16-02 EXPERT 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
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 Lancet 2005;366:2087-2106
Effects of RT: EBCTCG 2005 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 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 Lancet 2011;378:1707-16
Effects of radiation therapy 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
Optimising patient selection for RT after breast conserving surgery
Personalising RT utilisation 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
Randomised trials of RT vs no RT 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
Impact of consensus guidelines 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
Biomarkers of local recurrence Systematic review of local-regional recurrence after breast conserving therapy by IHC-defined subtypes (n=7174) Luminal A subtype associated with lowest LR rate 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 Breast Cancer Res Treat 2012;133:831-41
Biomarkers of local recurrence 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-enriched basal-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
ANZ 1601/BIG 16-02 EXPERT Examining Personalised Radiation Therapy 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
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 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 Radiother Oncol 2015;114:42-9
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) Median FU 72 months Whole (n=674) Reduced (n=673) Partial (n=669) 5-year LR 1.1% 0.2% 0.5% Non-inferiority in terms of LR of partial-breast and reduceddose RT vs whole-breast RT Equivalent or fewer late normal-tissue adverse effects Lancet 2017;390:1048 60
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 PBI using external beam (n=2135) Age 40, invasive disease or DCIS 3 cm, pn0 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
Randomised trials of PBI N PBI Age T cm N G3 NSABP B39 4216 3D 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 Survival CCTG 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
Conclusions EORTC 10981 AMAROS N = 4806 ct1-2 cn0 BCS (82%) or mastectomy SNB+ Axillary dissection Axillary RT Adjuvant systemic therapy in 90% of both groups Lancet Oncol 2014;15:1303-10
EORTC 10981 AMAROS Conclusions Median FU 6.1 years 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
EORTC 10981 AMAROS: interpretation 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
ACOSOG Z11 Conclusions N = 891 (planned 1900) ct1-2 cn0 BCS + SNB 1-2 SN+ Adjuvant breast RT (RNI not permitted) ALND No ALND JAMA 2011;305:569-75
Conclusions Z11 clinical-pathologic characteristics 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 JAMA 2011;305:569-75
Z11 results Conclusions Median FU 6.3 years 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% JAMA 2011;305:569-75; Association Breast Surgical Conference UK 2016
Z11 confounding variables Variations in RT target volumes ALND No ALND High tangents 50% 53.6% Directed RNI 16.9% 21.2% Significance unclear but patients treated without ALND may derive proportionately greater benefit from RNI, increasing likelihood of non-inferiority finding J Clin Oncol 2014;32:3600-6
RNI trials interpretation 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
POSNOC Conclusions N = 1900 T 5 cm BCS or mastectomy 1-2 sentinel node macrometastases Axillary dissection or RT No axillary dissection or RT
Tailor RT Conclusions To determine if avoiding RNI is not inferior to RNI in patients with N1, ER+, biomarker low-risk breast cancer N = 2140 BCS or mastectomy T 5 cm 1-3 N+ Endocrine therapy RNI No RNI
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