ASTRO Refresher Course 2016 Breast Cancer

ASTRO Refresher Course 2016 Breast Cancer Jennifer R. Bellon, M.D. Dana-Farber Cancer Institute Associate Professor of Radiation Oncology Harvard Medical School

I have no relevant conflicts of interest

Breast Conservation for Invasive Disease Anatomy Selection for BCT and modern outcomes Substituting hormonal therapy for RT Shortening the RT course Update on hypofractionation Accelerated Partial Breast Irradiation

Outline (continued) Management of the regional nodes Axillary dissection with a positive sentinel node RT fields (SCV/IM) PMRT RT after preoperative systemic therapy Update on DCIS

Axillary nodes IM nodes

Imaging Selection of Patients for BCT U/S, spot compression for densities Magnification views for calcifications MRI (selected cases only) Tissue diagnosis Core biopsy (not FNA) Excisional biopsy if core biopsy not feasible Breast-conserving surgery Careful evaluation of margins Post-excision mammogram for residual Ca++

Use of Breast MRI at Diagnosis Not Established Fewer re-excisions Decreased LR Improved survival Established Finds multicentric dx More delays More biopsies Increased costs More mastectomies Houssami Ann Surg 2013 Turnbull Lancet 2010

Selection of Patients for BCT Contraindications: Multicentric disease Prior RT Pregnancy Positive margins (in breast tissue)? Collagen vascular disease BRCA 1/2 mutation carriers future risk Impact of biologic subtype ACOSOG Z11102 RTOG 1014 What constitutes an adequate margin?

Reduction in Local Recurrence with RT CS CS + RT Reduction NSABP B-06 36% 12% 67% Uppsala-Orebro 24% 9% 63% Ontario 35% 11% 69% Milan 24% 6% 75% Swedish 14% 4% 71%

EBCTCG: Impact of Radiation on LRR N=10801 in 17 randomized trials EBCTCG Lancet 2011 378(9804):1707-16

How Are We Doing? Local recurrence <5% at 10 years Improved imaging More detailed pathologic examination of the specimen Improved systemic therapy Both improves LR, and also makes LR more important (by controlling micrometastatic disease) Heterogeneity of outcomes by subtype

Subtype is Prognostic for LR No herceptin HER2 (No Herceptin) Triple - Lum B Lum A Lum-HER2 Arvold N et al. JCO 2011; 29(29)

Meta-Analysis of LRR by Subtype N=12,592 BCT 57% Mastectomy 43% RT in all BCT patients and 44% of mastectomy patients Chemotherapy, 48% Herceptin in HER2-positive patients, 6% Lowery et al. Breast Ca Res Treat 2012; 133: 831-41

Meta-Analysis: LRR after BCT RR 0.49 Lowery et al. Breast Ca Res Treat 2012; 133: 831-41

Meta-Analysis: LRR After Mastectomy RR 0.66 Lowery et al. Breast Ca Res Treat 2012; 133: 831-41

BCT vs. Mastectomy Retrospective series from Alberta N =768; BCT, MRM or MRM+RT Higher-risk pts had MRM or MRM+RT LRR at 5 years BCT 6% MRM 15% MRM+RT 13% MVA: MRM, LVI and nodal positivity predicted LRR; chemo protective Abdulkarim et al. JCO 2011; 29

LRR in T1/T2, N0 Subset (No RT after MRM; 35% chemotherapy) 96% 90% T1/T2, N0 unmatched P=0.022 T1/T2, N0 matched for tumor size P=0.039 Abdulkarim et al. JCO 2011; 29

Wider Margins for TNBC? Retrospective review; n=535 Margins <2 mm: 71 patients Margins >2 mm: 464 patients Median follow-up 84 months; 84% received chemotherapy Cumulative incidence of LR at 60 months 4.7% for close margins 3.7% for wide margins; p=ns Pilewskie M et al. Ann Surg Oncol 2014; 21(4)

TNBC: Is BCT Appropriate? Comfort in these results, despite selection bias BCT remains standard treatment in otherwise appropriate patients Likely biology, not extent of surgery, is the driving factor Raises question of RT for high-risk node negative TNBC after mastectomy

Margins

Goals of Margin Evaluation To identify patients more likely to have a large residual tumor burden that can t be controlled by modern systemic therapy and RT need re-excision or mastectomy

Why not just re-excise? Extent of excision most important determinant of cosmetic outcome Re-excisions associated with: - Patient anxiety - Worse cosmetic outcome - Morbidity - Cost - Patients opting for mastectomy

Margins Meta-Analysis (Basis for ASTRO-SSO Consensus) 33 studies, invasive cancer, 1979 2001 N = 28,162; 1506 LRs Follow up: 79 months (range: 48-160) Series reports used not individual patient data Does not apply to: no RT, neoadjuvant, APBI, pure DCIS Houssami N, et al. Ann Surg Oncol 2014; 21: 717-730

Margins Meta-Analysis Margins and LR (adjusted for length of FU) OR 95% CI p-value Margin status Negative 1.0 <.001 Positive/Close 1.96 1.72-2.24 Margin status Negative 1.0 Close 1.74 1.42-2.15 Positive 2.44 1.97-3.03 < 0.001 Increased local recurrence rate associated with positive margins not nullified by radiation boost, systemic therapy, or favorable biology Houssami N, et al. Ann Surg Oncol 2014; 21: 717-730

Margins Meta-Analysis Relationship Between LR and Margin Threshold Distance # studies #LRs/#subjects OR* 95% CI 1 mm 6 235/2376 1.0 2 mm 10 414/8350 0.91 0.46-1.80 5 mm 3 103/2355 0.77 0.32-1.88 * Adjusted for length of FU p (association) = 0.90 p (trend) = 0.58 Houssami N, et al. Ann Surg Oncol 2014; 21: 717-730

ASTRO-SSO Margins Consensus: Summary Negative margins (no ink on tumor) optimizes local control Positive margin associated with at least a 2-fold increased risk of LR Not nullified by the boost, systemic therapy, or favorable biology Wider margin widths do not significantly improve local control The routine practice of obtaining margins more widely clear than no ink on tumor is not indicated J Clin Oncol. 2014 May 10;32(14):1507-15

Boost

EORTC Boost Stage I/II; n=5318 Microscopic complete resection For invasive disease only Randomization: 50 Gy whole breast 50 Gy whole breast + 16 Gy boost Median follow-up 17.2 years Bartelink H, et al. Lancet Oncol. 2015 Jan;16(1):47-56

EORTC Boost: 20-Year Results Ipsilateral breast tumor recurrence as a first event 16.4% vs 12.0% HR 0.65; 99% CI 0.52 0.81, p<0 0001 No difference in distant metastasesfree survival or overall survival Severe fibrosis 5.2% vs 1.8%, p<0.0001 Any fibrosis 71.4% vs 57.2%. P<0.001 Bartelink H, et al. Lancet Oncol. 2015 Jan;16(1):47-56

Local Recurrence by Age <40 41-50 51-60 >60 Bartelink H, et al. Lancet Oncol. 2015 Jan;16(1):47-56

Omission of Radiation

NSABP B-21: BCT in Tumors < 1.0 cm N=1009, T1a,1b N0 Randomized to RT + placebo, Tam, Tam + RT Only 54-59% known to be ER+ RT 50 Gy whole breast; boost optional (20%) Fisher et al, J Clin Oncol. 2002 Oct 15;20(20):4141-9

IBTR by Treatment Arm 17% 9% 3% All comparisons p<0.05 Bernard Fisher et al. JCO 2002;20:4141-4149

Omission of Radiation: CALGB 9343 Randomized trial of tamoxifen alone or tam with radiation in women over 70 Axillary dissection discouraged 37% dissection; 63% no axillary surgery All clinically node negative RT 45 Gy whole breast + 14 Gy boost Median follow-up 12.6 years Hughes KS et al JCO 2013, 45: 2615

CALGB 9343: Results at 10 Years N LRR Free Survival (%) DM Free Survival (%) Overall Survival (%) Mastectomy Free Survival (%) TAM 319 90 95 66 96 TAM + RT 317 98* 95 67 98 * P<.001; HR 0.18 Not able to assess subtleties in risk groups (LVI, grade)) Hughes KS et al JCO 2013, 45: 2615

PRIME II: RT + Hormonal therapy vs Hormonal therapy alone RT + hormonal therapy vs hormonal therapy alone Age greater than 65 < 3.0 cm, N0 HR positive Margins >1 mm (CALGB no ink on tumor) Grade 3 or LVI permitted (not both) Kunkler I, Lancet Oncol. 2015 Mar;16(3):266-73

PRIME II: 5-year Results RT NO RT P IBTR (%) 1.3 4.1 0.001 DM (%).3 1.0 NS OS (%) 94.2 93.8 NS N=1326 Kunkler I, Lancet Oncol. 2015 Mar;16(3):266-73

Fyles, A. et al. NEJM 2004;351:963-970 Omission of Radiation Princess Margaret Hospital Phase III, randomized trial RT + TAM vs TAM alone Eligibility 50 and older T1, T2 Path node negative if younger than 65 (clinically node negative if older than 65)

Fyles, A. et al. NEJM 2004;351:963-970 PMH Stratification Tumor size (<2.0 cm, >2.0 cm) ER (positive, negative or unknown) Participating center Method of determining axillary status in women over 65 (clinical or surgical)

Patient Characteristics (n=769) Fyles, A. et al. NEJM 2004;351:963-970

Fyles, A. et al. NEJM 2004;351:963-970 Cumulative Incidence of Local Relapse PMH: Time to Local Recurrence 8 yr LR: 17.6% vs 3.5%

Disease-free Survival. Disease-Free Survival No difference in OS 93.2% vs 92.8% Fyles AW et al. N Engl J Med 2004;351:963-970

RT for Luminal A Disease? Subset of 304 patients Approximation of intrinsic molecular subtyping ER, PR, Ki-67, Her2, EGFR and CK5/6 Luminal A (+/+/-, Ki67<14%) and grade I/II; n=114) Luminal B (+/+/-, Ki67>14%; n=82) Liu et al JCO, 33 (18), 2015

Response to RT by Subtype Luminal A Luminal B "unfavorable subtypes" Liu et al JCO, 33 (18), 2015

Three Hormonal Therapy Alone Prospective Single-Arm Trials Premise: There exists a subset of patients with early-stage disease with such a low likelihood of recurrence such that radiation can be safely omitted

PRECISION (DFCI) Age 50-75 Unifocal, <2.0 cm Node negative (path); N0i+ permitted ER positive, PR positive, HER2 negative Grade I/II Luminal A by PAM50 Eligible and willing to receive endocrine therapy Accrual goal: 345 ClinicalTrials.gov NCT02653755

LUMINA (Ontario Clinical Oncology Group) T1N0 Grade I or II and Ki67 < 13.25% (luminal A) Age >55 Margins > 1 mm No lobular cancers, No EIC Accrual goal: 500 ClinicalTrials.gov NCT01791829

Individualized Decisions for Endocrine Therapy Alone (IDEA) Multicenter, led by University of Michigan T1N0 (i+ allowed) ER+/PR+/HER2 neg Age 50-69 Oncotype <18 Minimum 5 years of endocrine therapy Accrual goal: 200 ClinicalTrials.Gov NCT02400190

Hypofractionation

Ontario Clinical Oncology Group Trial 1234 patients randomized to: 50 Gy/2 Gy fx/35 days vs 42.5 Gy/16 fx/22 days T1 T2 tumors; all node negative Large breasted women excluded (separation > 25 cm) Non-inferiority with 80% power to rule out 5% increase in local recurrence Whelan et al, J Natl Cancer Inst 2002, 94(15):1143-50

Whelan et al: Results Median follow-up: 12 years Tam : 41% Chemo: 11% Whelan et al NEJM 362 (6), 2010

Long-term Toxicity Late Effects of Radiation No difference in skin/subcutaneous toxicities Whelan TJ, NEJM 2010; 362:513-20

Global Cosmetic Outcome, Assessed According to the EORTC Scale. Long Term Cosmetic Results No difference in long-term cosmetic result Whelan TJ et al. N Engl J Med 2010;362:513-520

UK Start B N=2215 Median follow-up: 9.9 years Standard Arm: 2 Gy per fraction 25 fractions/5 weeks Experimental arm: 2.66 Gy per fraction 15 fractions/3 weeks Haviland JS et al. Lancet Oncology (14), 2013

Start B: Cumulative Incidence LRR LRR 0.1 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0 0 HR.77 (0.51-1.116); p=0.21 50 Gy 40 Gy 0 1 2 3 4 5 6 7 8 9 10 Time from randomisation (years) Haviland JS et al. Lancet Oncology (14), 2013

Start B: Marked/Moderate Cosmetic Defect % of patients with no moderate / marked effect 100 90 80 70 60 50 40 30 20 10 0 HR.77 (.66-.89) 40 Gy 50 Gy 0 1 2 3 4 5 6 7 8 9 10 Time from randomisation (years) Haviland JS et al. Lancet Oncology (14), 2013

Use of Hypofractionation by Institution (October, 2011 - December, 2013) Total: 31% Fig. 1. Rates of hypofractionation use by institution for patients with T1-2, N0 tumors treated with lumpectomy and whole-breast radiation therapy (n=913). Jagsi et al, IJROBP Volume 90, Issue 5, 2014, 1010 1016

Hypofrac vs Conventional: MDACC 50 Gy/25 fx + 10-14 Gy/7 fx (n=149) Vs 42.56 Gy/16 + 10-12.5 Gy/4-5 fx (n=138) Eligibility 40 or older Stage 0-2 Breast only radiation Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Primary Objectives MD-reported acute and 6-month toxicity NCI-CTC Patient reported QOL at 6 months Functional assessment of cancer therapy for patients with breast cancer (FACT-B) Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Key Patient/Treatment Characteristics 79% C cup or larger 25% sep > 25.6 76% overweight or obese Prone or supine permitted Multiple subfields encouraged to maximize homogeneity 75% dmax < 107.7% Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Max MD-reported acute toxic effect Not significant: Wound complications Breast infection Skin ulceration Seroma UE edema Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

6-months Results Physician-reported fatigue: 0% HF vs 6% CF (p=0.01) Patient reported lack of energy: 23% HF vs 39% CF (p=<0.001) Trouble meeting family needs: 3% HF vs 9% CF (p=0.01) Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Predictors of Lack of Energy at 6 Months n OR p Randomization Conventional 140 1 Hypofrac 128 0.39 <0.001 Age 40-49 27 1 50-59 97 1.10.83 60-69 104 1.92.13 70 and older 40 2.39.08 BMI <24.5 68 1 24.5 29.1 70 0.88 0.72 29.2 33.6 66 1.60 0.25 >33.6 64 1.02 0.97 Tumor behavior Invasive 69 1 Non-invasive 70 0.56 0.07 Shaitelman et al, JAMA Oncol. 2015;1(7):931-941

Hypofractionation Hypofractionation is rapidly becoming standard of care for most women treated with breast conserving surgery and whole breast radiation Note only is long-term LR similar, but now we have convincing data that short-term toxicity and QOL is improved, and long-term toxicity isn't compromised

Unanswered Questions Is the biology the same in all subgroups? Triple negative? DCIS? What is the optimal dose/fractionation/boost? What about chest wall/nodal irradiation? Brachial plexopathy? Lymphedema???

Other Hypofractionation Trials IMPORT High (UK) 2.4 Gy x 15 fx (integrated boost) 2.67 Gy x 15 fx (sequential boost) Accrual goal 840 FAST (UK) 2 Gy x 25 fx 5.7 Gy x 5 fx 6 Gy x 5 fx All in 5 weeks

TROG Trial for DCIS Accrual goal 1600 Conventional fractionation, no boost 50 Gy, 25 fractions Conventional fractionation, boost 50 Gy, 25 fractions + 16 Gy, 8 fractions Hypofractionated, no boost 42.5 Gy, 16 fractions Hypofractionated, boost 42.5 Gy 16 fractions + 16 Gy, 8 fractions

RTOG 1005 Randomized non-inferiority trial Conventional fractionation (2 Gy x 25 fx) with sequential boost VS Hypofractionation (2.67 x 15 fx) with concomitant boost Closed 6/20/14 Over-accrued 2354 ClinicalTrials.gov NCT01349322

Accelerated Partial Breast Irradiation

Accelerated Partial Breast Irradiation Starting to see maturation of the modern randomized trials GEC-ESTRO Interstitial brachytherapy Targit A IORT photons ELIOT IORT electrons RAPID External beam photons

GEC-ESTRO Prospective, randomized non-inferiority trial 3% non-inferiority margin Primary endpoint: IBTR Primary < 3.0 cm, N0 (micromets allowed) Randomization 50 Gy/25 fx whole breast Insterstitial brachytherapy HDR: 4 Gy x 8 or 4.3 Gy x 7 PDR: 0.6 Gy-0.8 Gy to 50 Gy Strnad, et al Lancet 2015 epub ahead of print

Strnad, et al Lancet 2015 epub ahead of print Patient Characteristics APBI (n=633) WBI (n=551) P-value Age (years, median) 62 (40-92) 62 (40-85) 0.86 Menopausal status pre 108 (17%) 92 (17%) post 525 (83%) 459 (83%) 0.93 Tumor size (mm, range) 12 (9-30) 12 (9-30) 0.19 Margin (mm, range) 8 (2-40) 7 (2-25) 0.39 Grade 1 248 (39%) 217 (39%) 2 319 (50%) 288 (52%) 0.55 3 57 (9%) 42 (8%) Systemic Therapy Yes 572 (90%) 505 (92%) No 59 (9%) 46 (8%) 0.63

Strnad V, et al Lancet 2015 epub ahead of print Ipsilateral Breast Recurrence

Disease-Free Survival Strnad, et al Lancet 2015 epub ahead of print

Results still early GEC-ESTRO Late recurrences seen with luminal A disease Long-term toxicity and cosmetic outcome Are these patients that don t need treatment? Interstitial will likely not be routinely used in the majority of centers in the US Strnad, et al Lancet 2015 epub ahead of print

Targeted Intraoperative RT (TARGIT) 50 kv x-rays N= 3451 Multi-institutional Accrued 200-2012 Age >45 Unifocal External beam whole breast 40 Gy-5 Gy in 15-25 fractions +/- boost (10-16 Gy in 5-8 fractions) IORT: 20 Gy at surface *If high risk, add 45-50 Gy whole breast (lobular carcinoma, EIC, <1 mm margin) Can be at time of surgery, or delayed Vaidya JS et al, Lancet 2014 383(9917):603-13

TARGIT: Low Risk Patients Median age: 63 <2.0 cm 86% Grade I/II 84% Node negative 83% Hormonal therapy 66% Chemotherapy 12% Vaidya JS et al, Lancet 2014 383(9917):603-13

Follow-up: Median: 29 months TARGIT: Results minimum of 4 years: 2020 patients minimum of 5 years: 1222 patients 5-year IBTR: 3.3% TARGIT vs 1.3% WBRT HR 2.07 (95% CI 1.01-4.25) Within pre-specified non-inferiority margin (2.5%) Vaidya JS et al, Lancet 2013. epub ahead of print Vaidya JS et al, Lancet 2014 383(9917):603-13

TARGIT: Results Concurrent with lumpectomy: 2.1% TARGIT vs 1.1% WBRT (p=0.31) Delayed after lumpectomy 5.4% vs 1.7% (p=0.069) Overall breast cancer mortality similar 2.6% vs 1.9% (p=0.56) Decreased non-breast cancer deaths 1.4% vs 3.5% (p=0.008) Vaidya JS et al, Lancet 2013. epub ahead of print Vaidya JS et al, Lancet 2014 383(9917):603-13

Intraoperative Radiotherapy versus External Radiotherapy for Early Breast Cancer (ELIOT) EORTC randomized trial of WBRT and IORT (electrons) IORT: 21 Gy x 1 WBRT: 2 Gy x 25 WB + 2 Gy x 5 boost Primary endpoint: IBTR Equivalence trial with a 7.5% equivalence margin Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

Patient Characteristics Veronesi U, Lancet Oncology 14 (13), 2013 Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

ELIOT: Results N = 1305 Median follow-up 5.8 years IBTR WB: 0.4% IORT: 4.4 % (HR 9.3; 95% CI 3.3 to 26.3) Veronesi U, Lancet Oncol 2013 Dec;14(13):1269-77

IBTR Overall Survival Veronesi U, Lancet Oncol Veronesi 2013 Dec;14(13):1269-77 U, Lancet Oncology 14 (13), 2013

Predictors of Recurrence in IORT Group Factor IBTR P-value Path Size (cm) <1.0 1.9 1.0 to 1.5 4.2 1.5 2.0 4.7 >2.0 10.9 P=0.006 Grade 1 1.1 2 3.8 3 11.9 P=0.0003 Subtype Luminal A 1.4 Luminal B 4.9 Her2 pos 5.9 Triple negative 18.9 P=0.001 Veronesi U U, et al, Lancet Oncology 2013 14 (13), 2013 Dec;14(13):1269-77

RAPID: WB vs APBI N=2135 Median follow-up: 36 months 3d CRT APBI (38.5/10 fx BID) VS WB (42.5 in 16 fx or 50 in 25 fx +/- boost) Olivotto, IA, et al. J Clin Oncol. 2013 31(32)

Three and Five Year Toxicity and Cosmetic Assessments Olivotto, IA, et al. J Clin Oncol. 2013 31(32) Olivotto, IA, et al. J Clin Oncol. 2013 31(32)

Three and Five-year Cosmetic Results Olivotto, Olivotto, IA, et al. IA, J et Clin al. Oncol. 2013 J Clin 31(32) Oncol 2013 31(32)

Late Radiation Toxicity Olivotto, IA, Olivotto, et al. J IA, Clin et al. Oncol. 2013 J 31(32) Clin Oncol. 2013 31(32)

ASTRO Consensus Statement Suitable* Cautionary** Unadvisable*** Age >60 50-59 <50 Size <2 cm 2.1-3.0 cm >3.0 cm LVI Negative Limited Extensive Margin >2 mm Close; <2 mm Positive Histology Ductal Lobular DCIS Not pure DCIS DCIS <3 cm DCIS >3 cm Nodes N0, N0i + Node positive ER Positive Negative * Acceptable outside of a clinical trial ** Caution and concern in the use of APBI *** Not warranted outside of a study Smith BD et al. IJROBP 74(4), 2009

Modern Phase III Trials of PBI vs WBRT Institution/Trial Target (yrs of accrual) Control Arm Experimental Arm European Institute of Oncology ELIOT 1200 (2000-2007) WBI (50 Gy in 25 fx) ± 10 Gy Boost IORT (21 Gy in 1 fx, using electrons up to 9 MeV) TARGIT-A 3451 (2000-2012) WBI 40-56 Gy ± 10-16 Gy boost IORT (20 Gy in 1 fx, low energy -rays) *NSABP B 39/RTOG 0413 Closed to accrual 4/13; n=4216 50-50.4 Gy WBI ± 10-16 Gy Boost (1) MIB (34 Gy in 10 fx), or (2) MammoSite (34 Gy in 10 fx) or (3) 3D-CRT (38.5 Gy in 10 fx) French SHARE *Medical Research Council UK IMPORT LOW *Ontario Clinical Oncology Group- Canadian Trial RAPID 1170 (2004-2009) WBI (50 Gy in 25 fx) + 16 Gy Boost WBI (40 Gy in 15 fx; or 42.5 in 16 fx) 1935 (2007-2010) WB 2.67Gy X 15 2128 (2006-7/2011) WBI ± 10 Gy boost: (1) 42.5 Gy in 16 fx for small breasts or (2) 50 Gy in 25 fx for large breasts 3d-CRT (40 Gy in 10 fx, BID) (1) WB 2.4Gy X 15 (2) PB 2.67Gy X 15 (3) PB only 2.67Gy X 15 3D CRT only (38.5 Gy in 10 fx)

The Nodes

Patients Clinical T1-2 N0 1 or 2 positive SN No gross ECE Treatment: ACOSOG Z-11 Lumpectomy with whole breast irradiation Dose/precise fields not specified Adjuvant systemic therapy by choice (97%) Guiliano A et al JAMA 2011 305: 569

ACOSOG Z-11: Patients calnd SNB Alone # Patients 420 436 Age, median 56 yrs 54 yrs T size, median 1.7 cm 1.6 cm ER/PR+ 82% 82% Grade 3 29% 28% Guiliano A et al JAMA 2011 305: 569

Outcomes of Z11 (Median f/u: 6.3 years) Recurrence Type ALND (420) SLNB only (436) Locoregional (%) 4.1 2.8 Local 3.6 1.8 Axillary 0.5 0.9 DFS (%) 91.8 92.5 OS (%) 83.9 82.2 All comparisons non-significant Giuliano A et al, Ann Surg. 2010 252(3):426-32 Giuliano A et al, JAMA. 2011 305(6):569-75

Findings on calnd in Z-11 46% of positive sentinel nodes were micromets Only 106 (27.4%) of patients treated with calnd had additional positive nodes beyond the SN This is a highly select group Guiliano A et al JAMA 2011 305: 569

Radiation Fields in ACOSOG Z0011 11% did not receive RT 228 patients (28.5%) had evaluable RT records: 50% received high tangents 19% had a separate nodal field No difference between arms High vs Standard Tangent Fields Axillary Vein Standard Superior Border Axillary LN Lumpectomy Cavity Jagsi R, J Clin Oncol 32(32), 2014

IBCSG 23-01: ALND vs SN Only for Micrometastases ct1-t2, micromets in 1-2 SNs (H+E or IHC) Accrued: 934 (target 1950) between 2001-2010 Median F/U of 5 years Galimberti et al Lancet Oncol 2013;14:297

IBCSG 23-01: Characteristics ALND (n=464) SLNB (n=467) Median Age 53 yrs (23-81) 54 yrs (26-81) T <3 cm 91% 93% ER + 88% 91% Systemic Rx 95% 97% Mastectomy 9% 9% Median # SN 2 (1-9) 1 (1-8) Additional positive nodes 59 (13%) 12 (3%) RT after BCS: 70% External Beam 19% Intraop 9% combination 98% 97%

Recurrence IBCSG 23-01: Results ALND (n=464) SLNB (n=467) Local 10 (2%) 8 (2%) Regional 1 (<1%) 5 (1%) Distant 34 (7%) 25 (5%) 5Y DFS 85%* 88%* 5Y OS 96% 96% Galimberti et al Lancet Oncol 2013;14:297 *Log rank p=0.16 non-inferiority p=0.004

AMAROS: Study Design CT1-2, N0 3381 SN negative 1425 SN positive calnd (n=744) axrt (n=681) Rutgers, E. Lancet Oncology 2014; 15:303-10

Axillary RT in AMAROS Started <12 wks after SNB 25 x 2Gy or equivalent Level I, II, III and medial SCV Additional AxRT: >4 positive nodes (in dissection arm) Figure adapted from Harris, J Rutgers, E. Lancet Oncology 2014; 15:303-10

5-yr Axillary recurrence AMAROS Results (Median f/u 6.1 years) calnd n=744 0.54% (n=4) AxRT n=681 1.03% (n=7) 5Y DFS 87% 83% 5Y OS 94% 94% 5 yr Clinical Lymphedema 23% 11% P<0.0001 Rutgers, E. Lancet Oncology 2014; 15:303-10

Disease-Free and Overall Survival Rutgers, E. Lancet Oncology 2014; 15:303-10

Substituting RT for Surgery All of these trial indicate RT can substitute for calnd At least in fairly select patients But what volume to irradiate? Tangents alone? High tangents? Supraclav? IMN?

MA.20 Randomization Node positive, or high risk nodenegative, s/p breast conservation Whole breast radiation VS Whole breast and regional nodal radiation Whelan TJ et al, NEJM 2015; 373:307-316

Node positive Eligibility High risk node negative >5 cm or >2 cm and <10 nodes removed And grade 3 or LVI positive or ER negative Chemotherapy and/or endocrine therapy required Whelan TJ et al, NEJM 2015; 373:307-316

MA.20 RT Details Whole breast: 50 Gy/25 fx Cone down: 10-16 Gy (e - or brachy) IMNs treated with either partially wide tangents or anterior field (electron and photon combination) 50 Gy/25 fx SCV/axilla (AP or AP/PA) Full axilla for >3 positive nodes or <10 dissected 45 Gy (for AP/PA), 50 Gy (AP) Whelan TJ et al, NEJM 2015; 373:307-316

Baseline Characteristics WBI N=916 WBI + RNI N=916 Age (mean) 52.7 53.9 Axillary nodes removed (mean) 12.3 12.4 Node ve 89 (10) 89(10) Node +ve (1-3) 780 (85) 776 (85) Tumor size > 2 cm 416 (45) 457 (50) Grade III 387 (42) 390(43) ER ve 235 (26) 232 (25) Adj chemotherapy 829 (91) 830 (91) Adj endocrine therapy 705 (77) 700 (76) Boost irradiation 221 (24) 206 (22) in 39% Whelan TJ et al, NEJM 2015; 373:307-316

10-Year Kaplan Meier Estimates of Survival. Median follow-up 9.5 years Whelan TJ et al. N Engl J Med 2015;373:307-316

Ten-year Results (n=1832) 10-Yr No Nodal RT Nodal RT HR p- value LRR* 6.8% 4.3% 0.59.009 DFS 77.0% 82.0% 0.76.01 OS 81.8% 82.8% 0.91.38 *isolated Whelan TJ et al, NEJM 2015; 373:307-316

MA-20: Hazard Ratios for Overall Survival Whelan et al, NEJM, 2015; 373:307-316

LRR +/- RT by Subtype Approximation Danish 82 b and c ER+ HER2+ Triple Neg ER+ HER2- ER- HER2+ Kyndi et al. JCO 2008; 26: 1419-1426

Adverse Events Any lymphedema increased from 4.5% to 8.4%; p = 0.001 Radiation pneumonitis increased from.2% to 1.2%; p = 0.01 All grade 2 Major cardiac event 0.4 vs 0.9, p= 0.26 *NCI Common toxicity criteria v2 1998 Whelan TJ et al, NEJM 2015; 373:307-316

EORTC Phase III Trial 22922/10925 n= 4,004 Stage I-III, pn+ or pn- w/ central/medial ARM 1: No nodal RT ARM 2: IM and supraclav RT Poortmans PM et al. N Engl J Med 2015;373:317-327

Poortmans PM et al. N Engl J Med 2015;373:317-327

Distant Disease-free and Overall Survival P=0.02 Median follow-up: 10.9 years P=0.06 Poortmans PM et al. N Engl J Med 2015;373:317-327

Hazard Ratio for Death, According to Subgroups Poortmans PM et al. N Engl J Med 2015;373:317-327

Multicenter French Randomized Trial Randomization: CW, SCV +/- IM N=1407 Eligibility: Mastectomy, larger than 1.0 cm Any node positive Medial/central with or without positive nodes Technique: First 5 interspaces Powered for 10% difference in OS Hennequin et al IJROBP 86(5), 2013

Key Patient Characteristics No IM RT (%) IM RT (%) Location: Lateral 236 (36) 232 (35) Medial 426 (64) 440 (65) Nodal status: N0 162 (24) 169 (25) N+ 500 (76) 503 (75) Grade: I/II 349 (53) 360 (54) III 154 (23) 164 (24) Adj chemotherapy 402 (61) 410 (61) Adj hormonal therapy 348 (53) 350 (52) Hennequin et al IJROBP 86(5), 2013

Outcome Hennequin: 10 Year Results No IM RT (%) IM RT (%) OS 59.3 62.6 0.8 DFS 53.2 49.9 0.35 p LR as first event Cardiac Events 9.8 9.2 NS 2.2 1.7 NS Hennequin et al IJROBP 86(5), 2013

The Danish Experience Prospective cohort study, 2003-2007 Node positive (macroscopic), younger than age 70 All received periclavicular and chest or breast RT LT-sided: RT without IMN (n=1586) RT-sided: RT with IMN (n=1486) Thorsen LBJ et al, J Clin Oncol, epub 2015

Median age 56 Key Pt/Tx Characteristics (median follow-up 8.9 years) Mastectomy 65%; BCT 35% ER Positive 80% Positive axillary nodes: 1-3 59% 4-9 26% >10 15% High grade 28% Thorsen LBJ et al, J Clin Oncol, epub 2015

75.9% 72.2% Overall Survival, HR 0.82; p=0.005 Breast Cancer Mortality, HR 0.85; p=0.03 Distant Recurrence, HR 0.89; p=0.07 Thorsen LBJ et al, J Clin Oncol, epub 2015

More Questions (few answers) What is the relative benefit of IM vs SCV RT Does it make sense to treat SCV alone in patients with difficult anatomy Which subgroups are most likely to benefit ER negative? HER2+ One positive node? What is the long-term risk of increased lung V20 and low-dose cardiac RT?

Post-Mastectomy Radiation

Meta-analysis of PMRT Trials 22 trials with 8135 women treated with mastectomy + axillary surgery +/- PMRT Adjuvant systemic therapy was used in the majority of patients RT to chest wall, SCV +/- axilla, internal mammary nodes Lancet 2014;383(9935):2127-35

Absolute Benefits of PMRT (n=8135) 1-3+ 16.5% 11.5% 7.9% > 4+ 19.1% 8.8% 9.3% Lancet 2014;383(9935):2127-35

Impact of Number of Involved Nodes Lancet 2014;383(9935):2127-35

McBride et al, MDACC Retrospective review; n =1027 T1, T2; 1-3 nodes Early era: 1978-1997 before taxanes, AI Late era: 2000-2007 McBride et al, IJROBP Volume 89, Issue 2, 2014, 392 398

9.5% at 5 years N=505 1978-1997 3.4% at 5 years McBride et al, IJROBP Volume 89, Issue 2, 2014, 392 398

2.8% at 5 years N=522 2000-2007 4.2% at 5-years McBride et al, IJROBP Volume 89, Issue 2, 2014, 392 398

Effective Systemic Therapy Improves LRR Chemotherapy improves LRR beyond adjuvant RT alone EBCTCG Clarke et al. Lancet 2005; 365:1687 NSABP Anderson SJ et al. JCO 2005; 27 Incremental improvements in systemic therapy further lower LRR Addition of taxanes Addition of trastuzumab

TAMOXIFEN CHEMOTHERAPY EBCTCG Overview. Lancet 2005;365:1687

10-Year LR in NSABP trials for node-negative tumors Trial ER 10-Year Status LR (%) B-13 No Chemo - 13.3 B-13 Chemo - 3.5 B-14 No Tamoxifen + 11.0 B-14 Tamoxifen + 3.6 Anderson SJ et al. J Clin Oncol 2005:27;2466

Impact of Taxanes on LRR

Impact of H on LRR: First Events Patients B-31 N9831 (NCCTG) Control Trastuzumab Control Trastuzumab All patients 872 864 807 808 Alive and event-free 701 781 717 758 Any First event 171 83 90 50 Local or Reg Recurrence 35 15 22 12 Distant Recurrence 111 60 63 30 CBC 6 2 0 1 Second Primary 15 2 3 3 Death Without Disease 4 4 2 4 Romond et al NEJM 353:16, 2005

Can Systemic Therapy Select Patients who Don t Benefit from RT? NSABP Experience Preop AC arm from B-18 and the preop AC +/- T arms from B-27 N= 1,071 mastectomy patients SNB performed after chemotherapy pcr was defined as no residual invasive disease (DCIS permitted) Mamounas E et al JCO 2012 30: 3960

Predictors of LRR after Mastectomy: MVA Clinical tumor size at presentation Clinical node status at presentation Path node status after chemotherapy Path response in the breast Both the initial clinical and the final path stage must be used to determine LR risk Mamounas E et al JCO 2012 30: 3960

Mamounas et al: MVA Variable HR 95% CI P ct: > 5 vs < 5 cm 1.58 1.12 2.23.0095 cn+ vs cn- 1.53 1.08-2.18.017 pcr nodes vs Complete pcr 2.21 0.77 6.30 <.001 Node positive vs Complete pcr 4.48 1.64 12.21 <.001 Mamounas E et al JCO 2012 30: 3960

Mamounas et al: MVA Variable HR 95% CI p ct: > 5 vs < 5 cm 1.58 1.12 2.23.0095 cn+ vs cn- 1.53 1.08-2.18.017 pcr nodes vs Complete pcr 2.21 0.77 6.30 <.001 Node positive vs Complete pcr 4.48 1.64 12.21 <.001 Mamounas E et al JCO 2012 30: 3960

10-Year Risk of LRR Mastectomy, Clinical T 5 cm Mastectomy Clinical T > 5 cm Mamounas E et al JCO 2012 30: 3960

NEOADJUVANT THERAPY 1 SURGERY 2 NSABP B-51/RTOG 1304 Clinical T1 3, N1 Positive Axillary Nodes by FNA or Core Accrual goal 1636 patients over 5 years R A N D O M I Z A T I O N Mastectomy Breast Conservation PMRT No PMRT Breast alone Breast and Regional Nodes 1 Minimum 12 weeks, trastuzumab when appropriate 2 Path Documentation of Negative Axillary Nodes (by ALND or by SLNBx ± ALND)

DCIS

Randomized Trials of Excision +/- RT N FU E alone E + RT NSABP B-17 814 17 y 35% 20% invasive: 20% 11% DCIS: 15% 9% EORTC 1010 15.8 y 30% 17% invasive: 50% 56% DCIS: 50% 44% UK 1030 12.7 y 19% 7% invasive: 7% 4% DCIS: 12% 3% Swedish 1067 8 y 27% 12% invasive: 12% 7% DCIS: 15% 5%

EBCTCG Meta-Analysis: DCIS N=3729 Correa, JNCI Monogr 41:162-177, 2010

RTOG 9804: Details Randomized, RT vs No RT; 1998-2006 Low or intermediate grade Smaller than 2.5 cm; margins >3mm N = 636 (1790 planned accrual) Tam optional (62%) Median follow-up 7.1 years McCormick et al. JCO 2015;33:709-715

RTOG 9804: Results McCormick B, JCO 33(7), 2015

DCIS: Omission of RT ECOG 5194 Study design Single arm, excision without radiation Tam optional (30%) At least 3 mm margin or negative re-excision Low risk: Low or intermediate grade Smaller than 2.5 cm High risk: High grade, smaller than 1.0 cm Solin LJ, JCO epub ahead of print, 2015

ECOG 5194, Low Risk Any Ipsi Breast Event (%) Invasive Ipsi Breast Event (%) 5 years 6 (4.0-8.1) 2.7 (1.3-4.1) 7 years 9.5 (7.0-12.0) 4.8 (2.9-6.6) 10 years 12.5 (9.5-15.4) 6.4 (4.2-8.6) 12 years 14.4 (CI 11.2-17.6) 7.5 (5.1-10.0) N=561 Median follow-up 12.3 years Solin LJ, JCO epub ahead of print, 2015

ECOG 5194, High Risk (High grade, Smaller than 1.0 cm) Any Ipsi Breast Event (%) Invasive Ipsi Breast Event (%) 5 years 15 (7.7-21.7) 5.3 (0.8-9.7) 7 years 18.2 (10.6-25.8) 7.6 (2.2-13.0) 10 years 24.6 (15.7-33.4) 13.4 (5.9-20.9) 12 years 24.6 (15.7-33.4) 13.4 (5.9-20.9) N=104 Solin LJ, JCO epub ahead of print, 2015

Oncotype DX DCIS Score 12/21 genes from the Oncotype DX Recurrence Score Continues score (0-100) 3 specified risk groups Low (<39) Int (39-54) High (>54) 7 cancer-related genes 5 reference genes Solin LJ, JNCI 2013, 105

Oncotype DCIS Score: ECOG 5194 <2.5 cm, grade I or II <1.0 cm, grade III Margins > 3mm Solin LJ, et al JNCI 2013, 105

Ontario DCIS Validation N=718 0 2 4 6 8 10 Rakovitch et al Br Res Treat, 2015, 152

Conclusions Breast conservation is an appropriate option for most women with early-stage disease with outstanding long-term local control We are beginning to understand tumor biology as it relates to local control, and hopefully this will allow omission of RT in select patients Hypofractionation is the best option for most women with early-stage disease undergoing BCT Beginning to see the maturation of the APBI trials. Over the next 5 years I think we'll have a much better idea of long term toxicity and efficacy

Conclusions (continued) Axillary dissection is not warranted for many (?most) patients with 1-2 positive sentinel nodes Appropriate nodal fields still in evolution, but my bar to treat the nodes has dropped Whom to treat with PMRT is still unclear, particularly with modern systemic therapy, but overall LRR is lower than previously appreciated Clinically node positive patients who achieve pcr may not need RT (please enroll on B-51) DCIS: Hope for improved molecular characterization of disease, and ability to predict LR

Conclusions (continued) Axillary dissection is not warranted for many (?most) patients with 1-2 positive sentinel nodes Appropriate nodal fields still in evolution, but my bar to treat the nodes has dropped Whom to treat with PMRT is still unclear, particularly with modern systemic therapy, but overall LRR seems to be lower than previously appreciated Clinically node positive patients who achieve pcr may not need RT (please enroll on B-51) DCIS: Hope for improved molecular characterization of disease, and ability to predict LR