The Management of Breast Cancer 2015 ASTRO Spring Refresher

The Management of Breast Cancer 2015 ASTRO Spring Refresher Gary M. Freedman, M.D. Associate Professor

Disclosure I have no conflicts of interest to disclose. 2

Learning Objectives Apply knowledge of randomized prospective trials to guide the selection process for radiation in early stage breast cancer. Be able to predict based upon current studies whether a patient is low, intermediate or high risk for local or regional recurrence without radiation. Determine through enhanced knowledge of the evidence based indications optimal patient selection for radiation treatment to regional lymphatics, hypofractionation or accelerated partial breast irradiation approaches. 3

Introduction Local Therapy and Survival in Breast Cancer

Models of Breast Cancer Halstedian 1900 1970 s A local-regional disease Justification for more radical surgery / radiation Fisher 1970 1990 s A systemic disease Justification for less radical surgery / radiation but more systemic therapy 5

NSABP B-04 3 Levels of Axillary Treatment (including regional node RT) No differences in survival Fisher et al NEJM 347: 567-75; 2002. 6

NSABP B-06 3 Levels of Breast Treatment RT recommended for breast conservation not survival Fisher et al N Engl J Med 2002; 347:1233-41. 7

CS + RT: Equal Survival as Mastectomy NCI Consensus Conference June 1990 Breast conservation treatment is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival rates equivalent to those of total mastectomy and axillary dissection while preserving the breast. Final nail in the Halstedian coffin There was an unstated assumption that mastectomy local control is probably better. JAMA 265: 391-5; 1991 8

In the year 1990 If local control does not affect survival Does the patient selection for breast conservation, or the quality of the surgery or radiation matter? WHY GIVE PMRT? JUST LOCAL CONTROL FOR LOCALLY ADVANCED OR INFLAMMATORY CASES? WHY CARE ABOUT LUMPECTOMY MARGINS? 9

Spectrum Model 1990 s - Present Local-regional treatment will have an impact on survival in some patients Justification for careful patient selection and techniques for both breast conservation and postmastectomy radiation. 10

The Spectrum Model T I M E Not every local recurrence prevented improves survival but some do. Primary Treatment No Failure RT Local Failure Prevent This! Local and Distant Failure RT Distant Failure Alive Distant Failure Dead (Early) Dead (Late) 11

PMRT 1 st failures are not the whole story MRM ± radiation Node positive patients after 15 years No chemotherapy/endocrine therapy No XRT XRT Difference First Failure Local Failure 37% 10% - 27% Distant Metastases 34% 43% + 9% Total Failure Local Failure 56% 19% Distant Metastases 72% 54% - 18% Death 70% 61% - 9% Arriagada et al. JCO 13:2869 1995 12

Early Breast Cancer Trialists Collaborative Group Message: Survival benefit is a result of the local-regional control benefit. 1 / 4 Ratio: One death from breast cancer avoided for every four LR recurrences avoided. Lancet 2005; 366: 2087 2106 13

Local Control Benefit Predicts the Late Survival Benefit No LC No Surv Big LC Big Surv EBCTCG Lancet 383: 2127-2135; 2014 14

T1-T2 Invasive Breast Cancer

BCT absolute contraindications Multicentric disease (tumors in more than one quadrant) Multifocal permitted if resected by single incision Diffuse or suspicious microcalcifications Persistently positive margins despite multiple re-excisions Unless an anatomic boundary Previous breast or chest RT Pregnancy Collagen vascular disease Scleroderma Active lupus? Not RA 16

BCT relative contraindications Ratio of tumor size to breast unacceptable for good cosmetic outcome T3 Neoadjuvant chemo may be attempted to convert the patient to a candidate for BCT Neoadjuvant chemo may be attempted to convert the patient to a candidate for BCT Subareolar location Patients may choose to sacrifice nipple BRCA 1/2 Survival outcomes with mastectomy equal Patients may accept high rate of new primaries 17

MRI: A Coin Flip? Affect of MRI on clinical management 22% affected management Examples - MRI-prompted mastectomy or additional biopsy Almost equal chance of help or harm Can you prove favorable effects were all really improving outcome? How do you know an add l focus would be source of LR? Tillman et al J Clin Oncol 20: 3413-22; 2002. 18

Meta-Analysis of MRI 9 studies 3,112 patients Increase in mastectomy No reduction in positive margins, re-excisions Houssami et al Ann Surg 2013;257:249-55. 19

Meta-Analysis of MRI 4 studies 3,169 patients 8-yr LR-free survival 97% vs. 95% HR MRI vs. No MRI 0.88 (0.52-1.51) p=0.65 Houssami et al J Clin Oncol 2014;32:392-401. 20

BCS + RT Invasive Breast Cancer Factors associated with local recurrence Higher Positive margin Young age Subtype Lower Boost Systemic Therapy 21

Margins Meta-Analysis and Consensus Tumor on ink = positive margin Overall median rate of IBTR 5.3%. Makes non-significant differences in 1, 2 and 5 mm not clinically significant either. Moran et al Int J Radiat Oncol Biol Phys 88: 553-64; 2014. 22

Re-excision of Margins American College of Radiology Invasive Breast Cancer A re-excision should be performed for an involved margin. Wider margins may be more important in select patients (young, estrogen receptor negative, or extensive intraductal component). American Society of Breast Surgeons Margin 1 mm usually adequate Consider re-excision for focally positive or < 1mm margins on a case-by-case basis. Re-excision usually needed for a positive margin. American Society of Clinical Oncology Endorses adoption of the SSO/ASTRO Guideline but flexibility in the application of the guideline is needed in some areas. Heightened emphasis needed on the importance of postlumpectomy mammography for cases involving microcalcifications. National Comprehensive Cancer Network A positive margin should generally undergo further surgery. Exceptions may be made for selected cases of focally positive margin and absence of extensive intraductal component. Society of Surgical Oncology / American Society for Radiation Oncology A positive margin should be defined as no tumor on ink. Negative margins are optimal for local control in most situations. Wider margins than no tumor on ink are not routine indications for further surgery. 23

Local Recurrence By Age - Then Bartelink et al J Clin Oncol 25: 3259-3265; 2007. 24

Young Age Now Today the age effect is much diminished Selection Factors: BRCA, Imaging Treatment Factos: Margins, Systemic Therapy, Boost Arvold et al J Clin Oncol 29:3885-3891; 2011. 25

BCS + RT by Subtype Hattangadi-Gluth et al Int J Radiat Oncol Biol Phys 82: 1185-91; 2012. 26

Young Age Biology Adjusting for biology now the age effect is much diminished Margins not significant? Predictor AHR 95% CI P Age, years 0.97 0.94 to 0.99.009 BC subtype Luminal A 1 (reference) Luminal B 2.14 0.95 to 4.85.067 Luminal HER2 0.48 0.06 to 3.73.49 HER2 5.15 1.76 to 15.05.003 Triple negative 3.94 1.72 to 9.01.001 No. of positive nodes 1.07 1.00 to 1.16.059 Tumor size, cm 1.32 0.96 to 1.80.08 WB dose, Gy 0.91 0.86 to 0.98.007 Arvold et al J Clin Oncol 29:3885-3891; 2011. 27

Young Age Biology Adjusting for biology now the age effect is much diminished Demerci et al Int J Radiat Oncol Biol Phys 83: 814-820; 2012. 28

Survival is equal But is it still the case that local control is better with Mastectomy versus BCS + RT? LOCAL CONTROL TODAY 29

BCS + RT: Node Positive NSABP BCS + Whole Breast Radiation. No Boost. Wapnir et al J Clin Oncol 2006; 24:2028-37. 30

BCS + Hypofractionated Radiation UK START B Haviland et al Lancet Oncol 2014; 14:1086-94. 31

BCS + RT: Margins Meta-Analysis Overall median rate of IBTR 5.3%. Includes positive close margins, low systemic therapy utilization in older studies. Houssami et al Ann Surg Oncol 21:717 730; 2014. 32

BCS + RT vs. Mastectomy T1-2 N0 triple negative Abdulkarim et al J Clin Oncol 29:2852-2858; 2011. 33

BCS + RT vs. Mastectomy T1-2 N0 triple negative Zumsteg et al Ann Surg Oncol 20:3469 3476; 2013 34

Are there any subgroups of patients with T1 for whom we can safely omit adjuvant radiation?

Local Control Benefit Predicts the Late Survival Benefit EBCTCG Lancet 378:771-84; 2011. 36

EBCTCG BCS +/- RT No subgroup without a benefit from RT 37

CALGB 10 years local recurrence 10% vs. 2% 21 of 334 deaths from breast cancer (6%). Cause-specific survival 98-99%. Hughes et al J Clin Oncol 31:2382-7; 2013. 38

PRIME II Age 65 or older Hormone-positive Low-grade Node negative 5-year IBTR 4.1% vs. 1.3% San Antonio 2013 39

Are there any subgroups of patients with T1 for whom we can safely omit adjuvant radiation? Older (>70) or reduced life expectancy T1 N0 (doesn t have to be pn0 always) ER or PR + Margin Willing / able to take 5 years endocrine therapy Willing to accept modest higher local recurrence

Shortening Postlumpectomy Radiation

Modern Trials Pre 2002! WHOLE BREAST HYPOFRACTIONATION RESULTS 42

Phase III Trials of Whole Breast Hypofractionation Years Fractionation Boost Local Time Trial Conducted # Gy/# of fractions (%) Recurrence (%) Point RMH/GOC 1986-1998 470 50/25 74 12.1 10 years 466 42.9/13 75 9.6 474 39/13 74 14.8 START A 1998-2002 749 50/25 60 6.7 10 Years 750 41.6/13 61 5.6 737 39/13 61 8.1 START B 1999-2001 1105 50/25 41 5.2 10 Years 1110 40/15 44 3.8 OCOG 1993-1996 612 50/25 0 6.7 10 Years 622 42.5/16 0 6.2 RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre START: Standardization of Breast Radiotherapy OCOG: Ontario Clinical Oncology Group 43

OCOG Randomized Trial 42.5 Gy 50 Gy Cosmesis gd/exc 70% 71% Whelan et al N Engl J Med Whelan et al 362:513-20; 2010. N Engl J Med 362:513-20; 2010 44

UK START A/B Cosmetic Outcomes Haviland et al Lancet Oncol 2014; 14:1086-94. 45

ASTRO Consensus Conference Hypofractionated WBI was suitable outside of a clinical trial in the following patients: pt1-2 tumor size node negative age greater than 50 years old patients who do not receive chemotherapy. My Guidelines DCIS or invasive Node positive or node negative Any age Any chemo Sequential boost allowed 42.5 in 16 fractions recommended for WBI Avoid hypofractionation for Large dose inhomogeneity Regional node irradiation The task force did not reach consensus on hypofractionated WBI when a tumor bed boost was thought to be indicated. Smith et al Int J Radiat Oncol Biol Phys 2011. 46

2D Planning 80-90 s Wedged Tangent Central axis contour. Goal of 10% or lower dose inhomogeneity. Off-axis inhomogeneity even higher. Chest Wall/Lung Prescription Point 47

2000 s - Simple Forward Planning Basic segments over hot spots in beams eye views CTV/PTV not needed Vicini et al Int J Radiat Oncol Biol Phys 2002; 54:1336-44 48

Modern Volume-Based 3D Planning PTV and PTVeval Structures 49

Volume Based Forward Planning 3D Conformal Field in Field Forward Planning 50

Volume Based Inverse Planning IMRT Inverse Planning Sliding Window 51

Isodose Distribution Same DVH Goals for 3D or IMRT: PTVeval 95% > 95% V105 < 10% V110 = 0% 52

RTOG 1005 A PHASE III TRIAL OF ACCELERATED WHOLE BREAST IRRADIATION WITH HYPOFRACTIONATION PLUS CONCURRENT BOOST VERSUS STANDARD WHOLE BREAST IRRADIATION PLUS SEQUENTIAL BOOST FOR EARLY-STAGE BREAST CANCER Stratify Age < 50 vs. 50 Chemotherapy Yes/No ER positive/negative Histologic Grade 1, 2 vs. 3 5/24/2011 6/20/2014 Targeted Accrual 2312 R A N D O M I Z E ARM 1: Standard fractionation Whole Breast 50 Gy / 25 fractions / 2.0 Gy daily Optional fractionation of 42.7 Gy in 16 fractions permissible Sequential Boost 12 Gy /6 fractions /2.0 Gy daily or 14.0 Gy /7 fractions /2 Gy daily ARM 2: Hypofractionation (15 fractions total) Whole Breast 40 Gy/15 fractions/2.67 Gy daily Concurrent boost 48.0 Gy/3.2 Gy daily 53

Accelerated Partial Breast Irradiation APBI 54

Intracavitary Balloon Catheter Radiation Simplest dosimetry. Treats 1-2 cm around lumpectomy cavity. Less operator skill dependent. Watch for tissue conformance skin distance Arthur and Vicini J Clin Oncol 23:1726-35; 2005. RTOG 04-13 / NSABP B-39 55

MammoSite Registry 1,449 cases Local recurrence Shah et al Ann Surg Oncol 20:3279 3285; 2013 56

Complications in Catheter APBI Device removal Catheter leak Catheter rupture Infection Seroma Skin toxicity Fat Necrosis Fibrosis Telangiectasia 57

3D Conformal External Beam 38.5 Gy in 10 fractions BID for 5 days. Noninvasive. Better dose homogeneity than brachytherapy. Needs greater margin for set-up and motion. Vicini et al Int J Radiat Oncol Biol Phys 63: 1531-7; 2005 58

Results of 3D Conformal APBI Vera et al Practical Rad Onc 4:147-52; 2014. 59

RAPID: Randomized Trial of Accelerated Partial Breast Irradiation Age 40 or older DCIS, T1 or T2 < 3 cm Negative Margin Non-lobular Whole Breast: 42.5 Gy / 16 fx 50 Gy / 25 fx Boost allowed Versus APBI: 38.5 Gy / 10 fx BID 3D CRT only Olivotto et al J Clin Oncol 31:4038-45; 2013. 60

Multicatheter Interstitial Brachytherapy Importance of Technique Operator Dependent Volume as low as possible Minimize hot spots Dose uniformity must be high Watch skin and chest wall dose DHI = Dose Homogeneity Index Wazer et al Int J Radiat Oncol Biol Phys 64: 489-495; 2006. 61

National Institute of Oncology Budapest, Hungary Randomized Trial Arm I: External Beam Whole Breast RT 2 Gy x 25 fractions Arm II: APBI Interstitial 5.2 Gy x 7 fx Electrons 2 Gy x 25 fx Selection Criteria T1 N0 N1mic Grade 1-2 Nonlobular No extensive in-situ Polgár Int J Radiat Oncol Biol Phys 69:694-702; 2007. 62

ASTRO Consensus Statement APBI Smith et al J Am Coll Surg 209:269-277; 2009 63

Results of 3D Conformal APBI Caution needed in patient selection Pashtan et al Int J Radiat Oncol Biol Phys 84:e271-7; 2012. 64

NSABP B-39 / RTOG 04-13 65

APBI Nonrandomized Results SEER subsequent mastectomy risk Local control close enough for most patients? Smith G et al. Int J Radiat Oncol Biol Phys 88:274-84; 2014. 66

DCIS

Breast-Conserving Surgery How do you assess the completeness of an excision? Margins Specimen radiograph Post-excision pre-irradiation mammogram (PPM) 68

DCIS: Breast-Conserving Surgery + RT Factors associated with local recurrence Higher Younger age Mode of detection Positive margin Large size / volume excised Diffuse calcifications Lower Radiation Tamoxifen Boost 69

DCIS: Consistent Benefit to BCT + RT EBCTCG Local recurrence reduced regardless of: Age at diagnosis Extent of surgery Use of tamoxifen Method of detection Margin status Grade Comedonecrosis Architecture Tumor size J Natl Cancer Inst Monogr 2010;2010:162-177 70

DCIS: Young Age - CS + XRT Solin Int J Radiat Oncol Biol Phys 50: 991; 2001 71

DCIS: Margins - CS + XRT Solin Int J Radiat Oncol Biol Phys 50: 991; 2001 72

DCIS: Margin Meta-analysis 4,660 patients treated with BCT+RT. Negative margins superior to positive margins (OR=0.36; 95% CI, 0.27-0.47) Negative margins superior to close margins (OR=0.59; 95% CI, 0.42-0.83) > 2 mm margins superior to <2 mm (OR 0.53, 95% CI 0.26-0.96) No difference in > 2 mm compared to > 5mm Dunn et al J Clin Oncol 2009 73

DCIS: Radiation +/-Tamoxifen A. Invasive Ipsilateral Recurrence B. DCIS Ipsilateral Recurrence Wapnir et al. J Natl Cancer Inst 2011 74

DCIS: Boost vs. No Boost vs. No XRT Omlin et al Lancet Oncology 1-5; 2006 75

Are there any subgroups of patients with DCIS for whom we can safely omit adjuvant radiation?

Breast-Conserving Surgery No RT Factors associated with local recurrence Higher Younger age Grade Necrosis Mode of detection Positive margin Diffuse calcifications Lower Tamoxifen 77

Van Nuys Index Silverstein and Lagios. J Natl Cancer Inst Monogr 2010; 41:193-196 78

Harvard Study Prospective single arm study from May 1995 July 2002 Eligibility: DCIS of nuclear grade 1 or 2, necrosis noted but not excluded Mammogram or clinical exam with lesion 2.5cm Wide excision with final margins 1cm OR negative re-excision Radiologic confirmation that all calcifications were removed Exclusion criteria No Tamoxifen Wong et al, JCO 2006 (24:1031-1036). 79

ECOG E5194 Low/Int Grade (n=565) High Grade (n=105) 18% 10.5% DCIS nuclear grade 1 or 2, with lesion 2.5 cm -OR- DCIS nuclear grade 3, with lesion 1 cm Wide excision with final margins 3 mm OR negative re-excision Radiologic confirmation that all calcifications were removed Hughes et al, JCO 2009 (27:5319-5324). 80

RTOG 98-04 Good Risk DCIS Prospective randomized trial Eligibility Mammographically detected disease Low or intermediate nuclear grade <2.5 cm size Margins 3 mm. 62% had Tam - no impact on LR Median follow-up (F/U) time was 6.46 years. 7 years Local recurrence 1% RT vs. 6% No RT (p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]). McCormick et al J Clin Oncol 30, 2012 81

Are there any subgroups of patients with DCIS for whom we can safely omit adjuvant radiation? Older (>60) or reduced life expectancy Low-Int grade no or mimimal necrosis ER or PR + Margin (at least 3 mm 1 cm + optimal) +/- endocrine therapy Willing to accept modest higher local recurrence

Risk factors for local-regional recurrence after mastectomy Indications for Postmastectomy Radiation

Case 1 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N2 3 cm invasive ductal carcinoma 5 of 15 positive lymph nodes No lymphovascular invasion Margins negative High Risk Features For Local-Regional Recurrence 4 positive axillary nodes 84

National Comprehensive Cancer Center 85

ACR Appropriateness Criteria High Risk for Local-Regional Recurrence 86

Early Breast Cancer Trialists Collaborative Group High Risk for LRR 4 positive nodes EBCTCG Lancet 383: 2127-2135; 2014 87

Case 2 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N0 3 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins negative Low Risk Features For Local-Regional Recurrence T1-2 Tumor Size 0 positive axillary nodes 6 nodes dissected Margins negative 88

National Comprehensive Cancer Center 89

ACR Appropriateness Criteria Low Risk for Local-Regional Recurrence 90

Early Breast Cancer Trialists Collaborative Group Low Risk for LRR 0 positive nodes EBCTCG Lancet 383: 2127-2135; 2014 91

Case 3 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N1 3 cm invasive ductal carcinoma 2 of 15 positive lymph nodes No lymphovascular invasion Margins negative Intermediate Risk Features For Local-Regional Recurrence T1-2 Tumor Size 1-3 positive axillary nodes 6 nodes dissected 92

National Comprehensive Cancer Center 93

ACR Appropriateness Criteria Intermediate Risk for Local-Regional Recurrence 94

Early Breast Cancer Trialists Collaborative Group Intermediate Risk for LRR EBCTCG Lancet 383: 2127-2135; 2014 95

Mastectomy N 1-3+ Breast Cancer ECOG 10-year Isolated 1-3 Nodes (# pts) 4-7 Nodes (# pts) 8 + Nodes (# pts) LRR (%) T1 9 (407) 11 (180) 20 (110) T2 7 (576) 17 (349) 20 (297) T3 23 (35) 29 (33) 7 (29) Recht et al J Clin Oncol 1999;17:1689-1700. 96

Mastectomy N 1-3+ Breast Cancer NSABP # Isol LRR LRR+/-DF 1-3 2 1,045 6% 11% 2.1-5 1,489 10% 15% > 5 229 8% 11% 4-9 2 512 13% 20% 2.1-5 982 15% 24% > 5 220 20% 31% 10+ 2 187 14% 26% 2.1-5 500 20% 33% > 5 165 20% 34% Taghian et al J Clin Oncol 2004;22:4247-54. 97

Mastectomy N 1-3+ Breast Cancer MDACC 0 1-3 4-9 10 T1 T2 T3 6 11 29 7 12 29 9 23 31 17 17 29 1 1.1-2 2.1-3 3.1-4 4.1-5 3 7 10 13 26 Katz et al J Clin Oncol 18:2817-27; 2000 98

Mastectomy N+ Breast Cancer MDACC Importance of 20% positive nodes Katz et al Int J Radiat Oncol Biol Phys 2001; 50:397-403. 99

Mastectomy N 1-3+ Breast Cancer low risk? Cleveland Clinic 1-3 positive nodes Tendulkar et al Int J Radiat Oncol Biol Phys 2012; 83:e577-81. 100

Microscopic Extranodal Extension International Breast Cancer Study Group ECE not significant for local-regional recurrence when number of positive of nodes included in analysis Gruber et al J Clin Oncol 2005; 23:7089-97. 101

Mastectomy N 1-3+ Breast Cancer low risk? MD Anderson T1-2, 1-3 positive nodes Early era (1978-1997) vs. later era (2000-2007) Early era 5-year 9.5% without PMRT and 3.4% with PMRT Late era 5-year 2.8% without PMRT and 4.2% with PMRT McBride et al Int J Radiat Oncol Biol Phys 89:392-8; 2014 102

Young Age NSABP Node Positive Breast Cancer Age # Isol LRR LRR+/-DF 20-39 1130 15% 26% 40-49 2050 13% 21% 50-59 1600 11% 17% 60+ 978 10% 14% p=0.13 p<0.0001 Significant on Multivariate Analysis Taghian et al J Clin Oncol 2004;22:4247-54. 103

Lymphovascular Invasion& Positive Nodes Matsunuma et al Int J Radiat Oncol Biol Phys 2012;83: 845-52. 104

Case 4 45 year old woman Clinical T3N0 Left Breast 6 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T3N0 6 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins negative Risk of Local-Regional Recurrence Various Data T3 Tumor Size 0 positive axillary nodes 6 nodes dissected No Lymphovascular Invasion Negative Margin No Very Young Age 105

National Comprehensive Cancer Center 106

Mastectomy for T3N0 Breast Cancer NSABP Isolated LRF 7% Taghian J Clin Oncol 2006;24:3927-32. 107

Mastectomy for T3N0 Breast Cancer MGH, Harvard, MD Anderson, Yale Importance of LVI 21% 7.6% Floyd et al Int J Radiat Oncol Biol Phys 2006;66:358-64. 108

ACR Appropriateness Criteria Risk for Local-Regional Recurrence? 109

Case 5 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N0 3 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins positive Intermediate Risk Features For Local-Regional Recurrence T1-2 Tumor Size 0 positive axillary nodes 6 nodes dissected Positive Margins 110

National Comprehensive Cancer Center 111

Close/Positive Margins MGH, Harvard Node negative women Jagsi et al Int J Radiat Oncol Biol Phys 2005; 62:1035-9. 112

Close/Positive Margins Brigham & Women s Hospital and Dana-Farber Positive margin + LVI = 27% + grade 3 = 13% + triple - = 33% Childs et al Int J Radiat Oncol Biol Phys 84:1133-8; 2012 113

ACR Appropriateness Criteria Intermediate Risk for Local-Regional Recurrence 114

Indications for PMRT 4 positive axillary lymph nodes T3 node positive tumors T4 1-3 positive axillary nodes T3 node negative tumors Limited / no axillary dissection Close / positive margins Lymphovascular invasion High grade Young Age Gross ECE Triple Negative? Multicentric disease? T1-2 Node Negative Margin Negative High Risk Definitely RT Often RT but not always Intermediate Risk Sometimes RT for 2-3 factors but not always Low Risk No RT 115

Molecular subtype A Reason for PMRT? T1-2 N0 Truong et al Int J Radiat Oncol Biol Phys 88: 57-64;2014. 116

Regional nodal radiation therapy

S Clav and Axilla LEVEL I/II DISSECTION 118

Supraclav and Axilla RT 1980 to 2000 Level I-II Dissection (6+ nodes) N- Breast Only Chest Wall Only (T3, Margin + cases) N+ 1-3 Breast Only (except >20-40%+? S clav) CW + S clav 4+ Breast/CW + S clav No Low Axilla Consider for gross ECE or >40-50% node ratio + 119

Classic Supraclavicular Field Meant to cover undissected Level III (infraclav) and S clav Madu et al Radiology 221:333-9; 2001. 120

Mastectomy: Axillary Treatment NSABP B04 Axillary RT not needed if 6+ nodes removed Fisher et al Surg Gyn Obstet 1981;152:765-72. 121

Mastectomy: S clav and Axillary Treatment Strom et al Int J Radiat Oncol Biol Phys 63:1508-13; 2005. 122

BCS + RT: Node Positive NSABP BCS + Whole Breast RT. 2/3 1-3 + nodes, 1/3 4 or more + nodes. No Regional RT. Wapnir et al J Clin Oncol 2006; 24:2028-37. 123

BCS + RT: Node Positive Regional node recurrence rare for N0-3 with breast RT alone. Vicini et al Int J Radiat Oncol Biol Phys 1997; 39:1069-76. 124

BCS + RT: Node Positive BCS + Whole Breast Radiation. No Regional Radiation. Isolated regional node recurrences at 8 years: S clav 1.3%, axilla 1.2%, infraclav 0.4% and IMN 0.3% Galper et al Int J Radiat Oncol Biol Phys 1999; 45:1157-66. 125

BCS + RT: Node Positive Consider axillary RT for >40-50% node ratio? Consider s clav RT for 1-3 + and >40% node ratio? Fortin et al Int J Radiat Oncol Biol Phys 2006; 65:33-39. 126

S Clav and Axilla NO DISSECTION 127

Supraclav and Axilla RT 1980 to 2000 No Dissection or Incomplete Dissection ( 5) S clav and Full Axilla 128

Dissection or Radiation NSABP B-04 1159 clinically node negative patients RM TM+ XRT TM Node Positive 40%?? 1st Failure LR 10% 5% 15% Axillary 1% 3% 1% (18%) Distant 30% 31% 32% 129

Dissection or Radiation All lumpectomy + Breast Radiation Age < 70, 3 cm size or less, cn0 Level I/II axillary dissection N + received RT to s clav, IMN N received RT IMN if central / medial No Dissection RT included IMN and axilla Louis-Sylvestre et al J Clin Oncol 22: 97-101; 2004. 130

Supraclav and Axilla RT 2000 to Present No Dissection Average patient should have had axillary assessment but didn t for some reason. S clav and Low Axilla Older, favorable patient High tangents Only 131

BCS + RT: Undissected Axilla Wong 2008 BCS + Whole Breast Radiation. No Axillary Surgery. No Regional Radiation. No Local-regional Recurrences. Wong et al Int J Radiat Oncol Biol Phys 2008; 72:866-70. 132

No Axillary Dissection Older Women IBCSG 10-93 Women 60, cn0, ER + Surgery + Axillary clearance + Tam vs. Surgery + Tam J Clin Oncol 24:337-344; 2006. 133

BCS + RT: Undissected Axilla CALGB 70 T1 Axillary node dissection was allowed but not encouraged. 1/3 pn0, 2/3 cn0 RT to whole breast and level I/II nodes Hughes et al J Clin Oncol 31:2382-7; 2013. 134

BCS + RT: Incomplete Dissection Regional node recurrence rare for N0-3 with breast RT alone. Vicini et al Int J Radiat Oncol Biol Phys 1997; 39:1069-76. 135

No or Incomplete Dissection PreSentinel Node Galper et al Int J Radiat Oncol Biol Phys 48:125-32; 2000. 136

Sentinel Node Biopsy Sentinel Node Biopsy pre-2000 N0 - Treat like a negative level I/II dissection N+ - Complete the dissection OR treat like an incomplete dissection (Treat the s clav and low axilla). 137

Sentinel Node Biopsy - Positive Sentinel Node Biopsy 2000 2010 Resistance to completion dissection Era of the Nomogram If nomogram suggests low risk for additional + nodes then may omit s clav and axilla Number of + SN Size of + SN / micromet Number of SN LVI T size Histology Etc. Etc. 138

BCS + RT: Sentinel Node Positive ACSOG Z0011 891 patients with positive SNB Clinical T1/T2, Clinical N0 H&E detected metastases in 1-2 nodes No ECE Breast tangents only Additional nodal metastases in 27% of patients having completion node dissection. 98% Systemic Therapy (58% chemo) Local-regional recurrence 3.3% without completion dissection 4.3% with completion dissection P=0.28 Giuliano et al JAMA 2011;305:569-75. 139

BCS + RT: Sentinel Node Positive ACSOG Z0011 Breast tangents only? 15% s clav RT 50% high tangents Additional nodal metastases in 27% of patients having completion node dissection. 98% Systemic Therapy (58% chemo) Local-regional recurrence 3.3% without completion dissection 4.3% with completion dissection P=0.28 Jagsi et al J Clin Oncol 32: 3600-06; 2014. 140

BCS + RT: Sentinel Node Positive IBCSG 23 01 Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases 931 patients (10% mastectomy) Galimberti et al Lancet Oncol 2013; 14: 297 305. 141

BCS + RT: Sentinel Node Positive EORTC AMAROS trial Radiotherapy or surgery of the axilla after a positive SN 12% mastectomy All three levels of the axilla together with the medial part of the supraclavicular fossa were considered clinical target volume. The prescribed dose to the axilla was 50 Gy in 25 fractions. Postoperative axillary irradiation in patients undergoing ALND was allowed in patients with four or more tumor-positive nodes (pn2 or pn3). 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND 1.03% (7/681) after ART Rutgers et al ASCO 2013. 142

Sentinel Node Biopsy Sentinel Node Biopsy post Z0011 N0 - Treat like a negative level I/II dissection N+ - Patient selection / judgment needed Option A: Complete the dissection will it affect systemic therapy? Option B: Treat like an incomplete dissection Treat the s clav and low axilla AMAROS Option C: Treat a high tangent or a normal tangent Z0011 / IBCSG 143

IMN 144

IMN Treatment Clinical IMN Recurrence is Exceedingly Low Incidence of IMN positivity is Low High in old series of advanced breast cancer Much lower in modern series Randomized Trials of IMN Treatment Negative or <1-2% survival benefit What is the added cost in toxicity of treatment? Cardiac effects 145

Clinical IMN Recurrence - Mastectomy Any IMN? Recht et al J Clin Oncol JCO 17: 1689-17: 1689-1700;1999. 1700; 1999 146

Clinical IMN Recurrence - Lumpectomy BCS + Whole Breast Radiation. No Regional Radiation Galper et al Int J Radiat Oncol Biol Phys 1999; 45:1157-66. 147

Extended Radical Mastectomy Old Data IMN positive (%) Axilla Negative Axilla Positive Series # Inner Central Outer Total Inner Central Outer Total Cáceres 600 -- -- -- 7 44 33 19 29 Donegan 113 12 0 4 6 54 29 31 34 Handley 1000 12 7 4 8 50 46 22 35 Lacour et al. 703 11 8 9 37 22 28 Livingston and Arlen 583 14 10 5 8 59 43 23 32 Sugg 292 -- -- -- 5 -- -- -- 44 Urban and Marjani 725 13 6 3 8 65 48 42 52 Veronesi et al. 1085 -- -- -- 9 -- -- -- 28 < 10% 30% 148

Sentinel Node Studies Review of 6 prospective studies of SNB and IMN Modern incidence of + IMN is likely <5% Hindie et al Int J Radiat Oncol Biol Phys 83: 1081-8; 2012. 149

IMN Irradiation Old Negative Studies Radical Mastectomy Radical Mastectomy Series # + IMN irradiation* # Alone Follow-up DM OS DM OS Fisher et al. 470 40% 56% 633 32% 62% 5 years P=NS Høst et al. Stage I 170 -- 60% 186 -- 70% 15 years P=0.08 Stage II 95 34% 42% 91 50% 44% 15 years P=NS P=0.15 10 years Palmer & Ribeiro Node - 139 -- 16% 142 -- 26% 30 years P=0.13 Node + 243 -- 8% 217 -- 8% 30 years P=0.7 Arriagada 41 51% 59% 31 35% 74% 15 yr crude P=0.22 p=0.29 Veronesi 23 -- 48% (DFS) 23 -- 68% (DFS) 10 years P=NS * Includes supraclavicular +/- axillary irradiation Includes patients treated with lumpectomy and breast radiation 150

Randomized Trial IMN Radiation DBCG-IMN study 3,000 + Node positive Right breast IMN RT Left breast no IMN RT Median follow up of seven years. OS 78% versus 75% in favor of IMN radiotherapy. HR=0.86 (95% CI (0.75; 0.99), p=0.04. Thorsen et al, ESTRO Vienna 2013. 151

Randomized Trial IMN Radiation French Study Mastectomy and N + or central/medial tumors. All patients received postoperative irradiation of the chest wall and supraclavicular nodes. Randomly assigned to receive IMN irradiation or not. Hennequin et al Int J Radiat Oncol Biol Phys 86: 860-6; 2013. 152

Randomized Trial IMN / Sclav Irradiation NCIC CTG MA.20 2000-2007 with median 62 months follow-up 1832 patients with high risk node negative (T3) or node positive breast cancer. 1-3+ Nodes 85% OS 92.3% vs 90.7% (HR.76, p =.07) LR DFS 96.8% vs 94.5% (HR.59, p=.02) DFS 89.7% vs 84 % (HR.68, p =.003) Whelan et al ASCO 2011 153

Randomized Trial IMN / Sclav Irradiation EORTC trial 22922-10925 Axillary lymph node involvement and/or a centrally or medially located tumour. 4,004 patients (76% BCT) OS at 10 years was 82.3% with and 80.7% without radiation therapy to the internal mammary and medial supraclavicular lymph nodes (HR=0.87 (95%CI: 0.76, 1.00), Logrank p=0.056). Poortmans et al, ESTRO Vienna 2013. 154

IMN / Sclav Irradiation Could all benefit be from the s clav/axillary treatment? Budach et al Radiat Oncol 8: 267; 2013. 155

Early Breast Cancer Trialists Collaborative Group Is IMN RT benefit from underestimated incidence that never become apparent local recurrence? Or all from the S clav? IMN benefit in absence of local control doesn t fit the EBCTCG model! Lancet 2005; 366: 2087 2106. 156

Radiation after neoadjuvant chemotherapy

Mechanism of Increased Breast-Conserving Surgery after Neoadjuvant Chemotherapy Decrease in clinical tumor size. More favorable ratio of tumor to breast size. Post-chemo Volume? Pre-chemo Volume 158

NSABP B-18 Breast Conservation Modest increase in breast conservation Modest increase in local recurrence in downstaged patients IBTR (%) as site of 1st treatment failure Postop Preop # Chemo # Chemo 448 7.6 503 10.7 p=0.12 Downstaged Lump initially # to lump # proposed 69 15.9 434 9.9 p=0.04 Wolmark et al J Natl Cancer Inst Monogr 2001;30:96-102. 159

Breast Conservation after Neoadjuvant Chemotherapy NSABP B-18 and B-27?Add a boost Breast-conserving surgery and whole breast radiation No regional nodal radiation Add Sclav RT for ypn+ Mamounas et al J Clin Oncol 2012;30:3960-6. 160

Neoadjuvant Chemotherapy and Mastectomy MDACC Generally ct3 or pn+ indications for PMRT Buchholtz et al J Clin Oncol 2002;20:17-23. 161

Neoadjuvant Chemotherapy and Mastectomy NSABP B-18 and B-27 No postmastectomy radiation RT for pn+?cn+ and ypnneed more data Mamounas et al J Clin Oncol 2012;30:3960-6. 162

NSABP B-51/RTOG 1304: pn1 to ypn0 163

Radiation therapy for inflammatory breast cancer

Inflammatory LABC Clinical findings: Rapid onset Edema, redness, skin changes Peau D orange > 1/3 of the breast. Clinical diagnosis of inflammatory BUT pathology is needed! Core biopsy of a node Skin punch biopsy Breast incisional biopsy Dermal lymphatic invasion is not required for diagnosis. Not the same as locally advanced neglected cancer. 165

Management of Inflammatory LABC Neoadjuvant Chemotherapy Second Line Chemotherapy if < ccr Preop Radiation if < ccr Modified radical mastectomy Endocrine Therapy (if ER/PR+) Postmastectomy radiation 166

Inflammatory LABC Breast Conservation 167

Inflammatory LABC PENN CW / Breast 50 Gy Bolus Supraclav in all Axilla in most IMN in few Harris et al Int J Radiat Oncol Biol Phys 2003;55:1200-8. 168

Inflammatory LABC CW 50 Gy + 10 Gy Boost or 51 Gy BID + 15 Gy Boost MDACC Comprehensive nodal RT Dose escalation for < partial chemotherapy response, close/positive margins, and age < 45 years Bristol et al Int J Radiat Oncol Biol Phys 2008;72:474-84. 169

Inflammatory LABC MSKCC CW 5,040 Gy Bolus Daily Damast et al Int J Radiat Oncol Biol Phys 2010;77:1105-12. 170

The End! Thank you Gary M. Freedman, M.D. Associate Professor