The Management of Breast Cancer

Part II

3/22/2013

Gary M. Freedman, M.D.Associate Professor

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Outlinew Positive nodes in the breast conservation patient.w Risk factors for local-regional recurrence after mastectomy.w Regional nodal radiation therapy.w Breast conservation and radiation after neoadjuvant

chemotherapy.w Indications for radiation after neoadjuvant chemotherapy and

mastectomy.w Radiation therapy for locally advanced noninflammatory

breast cancer.w Radiation therapy for inflammatory breast cancer.

Positive nodes in the breast conservation patient

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BCS + RT: Node Positivew NSABP B04: Variations of axillary nodal treatmentw No differences in survival

Fisher et al NEJM 2002;347:567-75.

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BCS + RT: Node Positive

Fisher et al Surg Gyn Obstet 1981;152:765-72.

w NSABP B04: Variations of axillary node treatment

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BCS + RT: Node Positivew NSABP B-06 – No PMRT, and breast only without nodal RT

Fisher et al N Engl J Med 2002; 347:1233-41.

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BCS + RT: Node Positivew Vicini 1997w Regional node recurrence rare for N0-3 with breast RT alone.

Vicini et al Int J Radiat Oncol Biol Phys 1997; 39:1069-76.

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BCS + RT: Node Positivew Galper 1999w BCS + Whole Breast Radiation. w No Regional Radiation.w 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.

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BCS + RT: Node Positive

Wapnir et al J Clin Oncol 2006; 24:2028-37.

w NSABPw 2/3 1-3 + nodes, 1/3 4 or more + nodes.w BCS + Whole Breast Radiation. No Regional Radiation.

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BCS + RT: Undissected Axillaw Wong 2008w BCS + Whole Breast Radiation.w No Axillary Surgery. w No Regional Radiation.w No Local-regional Recurrences.

Wong et al Int J Radiat Oncol Biol Phys 2008; 72:866-70.

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BCS + RT: Sentinel Node Positive

Nomograms –so Y2K!

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BCS + RT: Sentinel Node Positivew ACSOG Z0011w 891 patients with positive SNBw Clinical T1/T2, Clinical N0w H&E detected metastases in 1-2 nodesw No ECEw Breast tangents only

Giuliano et al JAMA 2011;305:569-75.

•Additional nodal metastases in 27% of patients having completion node dissection.•98% Systemic Therapy (58% chemo)

•Local-regional recurrence 3.3% without completion dissection4.3% with completion dissectionP=0.28

The end of nomograms?

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NCIC CTG MA.20w 2000-2007 with median 62 months follow-up w 1832 patients with high risk node negative (T3) or node

positive breast cancer.w 1-3+ Nodes 85%

w OS 92.3% vs 90.7% (HR .76, p = .07) w LR DFS 96.8% vs 94.5% (HR.59, p.02)w DFS 89.7% vs 84 % (HR .68, p = .003) Whelan et al

ASCO 2011

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Early Breast Cancer Trialists’ Collaborative Group

Lancet 2005; 366: 2087–2106.

Risk factors for local-regional recurrence after mastectomy

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Audience Surveyw 1. Which of the following is the strongest indication for adding

postmastectomy radiation with 2 positive axillary nodes?

a) Extranodal extensionb) Premenopausalc) 7 nodes dissectedd) Multifocal breast disease

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Early Breast Cancer Trialists’ Collaborative Groupw High Risk for LRRw Node Positive Breast Cancer

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Mastectomy N+ Breast Cancer

Locoregional Relapse Survival

w British Columbia Trial

Ragaz et al J Natl Cancer Inst 2005;97:116-26.

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Mastectomy N 1-3+ Breast Cancer

Overgaard et al Radiother Oncol 2007;82:247-52.

w Danish Trial 82b+C

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Early Breast Cancer Trialists’ Collaborative Groupw Intermediate Risk for LRR

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Mastectomy N 1-3+ Breast Cancer

10-yearIsolatedLRR (%)

1-3 Nodes(# pts)

4-7 Nodes(# pts)

8 + Nodes(# pts)

T1 9 (407) 11 (180) 20 (110)

T2 7 (576) 17 (349) 20 (297)

T3 23 (35) 29 (33) 7 (29)

w ECOG

Recht et al J Clin Oncol 1999;17:1689-1700.

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Mastectomy N 1-3+ Breast Cancer

Recht et al J Clin Oncol 1999;17:1689-1700.

w ECOG

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Mastectomy N 1-3+ Breast Cancer

0 1-3 4-9 ≥10T1T2T3

61129

71229

92331

171729

≤11.1-22.1-33.1-44.1-5

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101326

Katz et al J Clin Oncol18:2817-27; 2000

w MDACC

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Mastectomy N+ Breast Cancerw MDACC

Katz et al Int J Radiat Oncol Biol Phys2001; 50:397-403.

Importance of ≥ 20% positive nodes

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Mastectomy N 1-3+ Breast Cancer

Taghian et al J Clin Oncol2004;22:4247-54.

# Isol LRR LRR+/-DF1-3 ≤ 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%

w NSABP

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Close/Positive Marginsw MGH, Harvard

Jagsi et al Int J Radiat Oncol Biol Phys2005; 62:1035-9.

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National Comprehensive Cancer Center

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Young Age

Age # Isol LRR LRR+/-DF20-39 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

w NSABPw Node Positive Breast Cancer

Taghian et al J Clin Oncol2004;22:4247-54.

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Combinations of Risk Factors

w Risk factors• Menopause status• Node neg vs. pos• 1 -3 vs. 4 + nodes positive• Tumor size• Lymphovascular invasion• Grade

w International Breast Cancer Study Group

Wallgren et al J Clin Oncol2003;21:1205-13.

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Mastectomy N 1-3+ Breast Cancer w Cleveland Clinicw 1-3 positive nodes

Tendulkar et al Int J Radiat Oncol Biol Phys 2012; 83:e577-81.

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Extranodal Extension

Gruber et al J Clin Oncol2005; 23:7089-97.

w International Breast Cancer Study Groupw ECE not significant for local-regional recurrence when

number of positive of nodes included in analysis

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Mastectomy for T3N0 Breast Cancerw NSABPw Isolated LRF 7%

Taghian J Clin Oncol 2006;24:3927-32.

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Mastectomy for T3N0 Breast Cancer

7.6%

21%

Floyd et al Int J Radiat Oncol Biol Phys2006;66:358-64.

w MGH, Harvard, MD Anderson, Yale

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Multicentric Diseasew MDACC

Katz et al Int J Radiat Oncol Biol Phys2001; 50:735-42.

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Molecular subtype

Lum A Lum B TNBC Her2

Kyndi et al J Clin Oncol2008; 26:1419-26.

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w 4 positive axillary lymph nodesw T3 node positive tumorsw T4

w 1-3 positive axillary nodesw T3 node negative tumorsw Limited / no axillary dissectionw Close / positive marginsw Lymphovascular invasionw High gradew Young Agew Gross ECEw Multicentric diseasew Triple Negativew T1 - 2w Node Negativew Margin Negative

High Risk

Definitely RT

Often RT but not always

Intermediate Risk

Sometimes RT but not always

Low Risk

No RT

Indications for PMRT

Regional nodal radiation therapy

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Classic Supraclavicular Fieldw BordersInferior: Inferior aspect of

clavicular headSuperior: Cricothyroid notchMedial: 1 cm across midline at

sternal notchLateral: Medial border of

humeral head

w Gantry angled 11-12 ° to shield spinal cord

w Block medial to sternocleidomastoid to shield larynx

w Half beam block creates nondivergent inferior edge

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Single Isocenter Match

Can’t turn collimator but can add MLC if careful about breast/CW PTV

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2 Isocenter match

Courtesy of R. Iyer

w If field size too longw If collimation desired

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w Supraclavicular field• D = 3 cm

w PAB• Calculate dose at midplane

depth at isocenter of PAB from supraclavicular field

• Prescribe PAB to raise that midplane dose.

Classic Posterior Axillary Field

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Classic IMN Electron Field

NCIC MA.20

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Classic IMN Electron Field

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IMN Partially Wide Tangents

NCIC MA.20

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Nodal Contouring

RTOG AtlasNodal Recurrence

w Supraclavicular

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Nodal Contouring

RTOG AtlasNodal Recurrence

w Axillary Level III

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Nodal Contouring

RTOG AtlasNodal Recurrence

w Axillary Levels I/II

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Nodal Contouring

RTOG Atlas

w IMN

Nodal Recurrence

Chen et al Int J Radiat Oncol Biol Phys2013;85:309-14.

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Nodal Contouringw Supraclavicular and Axillary Level III

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Nodal Contouringw Axillary Levels I-III

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Making a Supraclavicular Fieldw Louisville is not the place to try this for the first time!

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Making a Supraclavicular Field

Breast conservation and radiation after neoadjuvant chemotherapy

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Rationale for Neoadjuvant ChemotherapywHigh response rates in locally advanced

breast cancer.wUse of primary response as an in vivo

measure of tumor (presumed distant) chemosensitivity.wReduce size of primary tumor to increase

rates of breast-conserving surgery or to improve cosmetic outcome.wEarlier treatment of micrometastatic

disease to improve survival

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MetaAnalysis of Neoadjuvant Chemotherapy Randomized Trials

Mauri et al J Natl Cancer Inst2005;97:188-94.

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Importance of pCRw NSABP B-18 and B-27

w pCR is prognostic for survival.

w Increased rate of pCR by• Grade 3• Nonlobular• ER negative• High Ki-67• HER-2 positive

Rastogi et al J Clin Oncol2008;26: 778-785.

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Concerns about Neoadjuvant Chemotherapy

wClinical staging of primary and axilla.wSurgical technique for conservative

surgery.• Clip tumor prior to chemotherapy• Significance of resection margins?

wObscuring indications for regional nodal and/or postmastectomy radiation.wEffect on local control.

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MetaAnalysis of Neoadjuvant Chemotherapy Randomized Trials

Mauri et al J Natl Cancer Inst2005;97:188-94.

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NSABP B-18 Breast Conservation

IBTR (%) as site of 1st treatment failure

Postop Preop# Chemo # Chemo448 7.6 503 10.7 p=0.12

Downstaged Lump initially# to lump # proposed69 15.9 434 9.9 p=0.04

Wolmark et al J Natl Cancer Inst Monogr 2001;30:96-102.

w Modest increase in breast conservation

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Mechanism of Increased Breast-Conserving Surgery after Neoadjuvant Chemotherapy

Pre-chemo Volume

Post-chemo Volume?

w Decrease in clinical tumor size.w More favorable ratio of tumor to

breast size.

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Breast Conservation after Neoadjuvant Chemotherapy

w T3 and stage III were independent predictors of LRR.

Cebrecos et al EJSO 36:528-34; 2010

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Local Recurrence after Neoadjuvant Chemotherapy

Mamounas et al J Clin Oncol2012;30:3960-6.

w NSABP B-18 and B-27. No Regional Nodal Irradiation.

Let’s add the s’clav field atleast!

Let’s add a boost!

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Breast Conservation after Neoadjuvant Chemotherapy

w NSABP B-18 and B-27w Breast-conserving surgery and whole breast radiationw No regional nodal radiation

Mamounas et al J Clin Oncol2012;30:3960-6.

Indications for radiation after neoadjuvant chemotherapy and mastectomy

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Neoadjuvant Chemotherapy and Mastectomy

Buchholtz et al J Clin Oncol2002;20:17-23.

w MDACCw Generally cT3 or pN+ indications for PMRT

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Clinical T3N0

Nagar et al Int J Radiat Oncol Biol Phys2011;81:782-7.

0/13 complete breast and nodal pCR LRR – need more data

Nodal ypN0Nodal ypN+

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Neoadjuvant Chemotherapy and Mastectomy

Mamounas et al J Clin Oncol2012;30:3960-6.

w NSABP B-18 and B-27w No PMRT

Do clinically N+ but yp N-need radiation?

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Neoadjuvant Chemotherapy and Mastectomyw NSABP B-18 and B-27w No postmastectomy radiation

Mamounas et al J Clin Oncol2012;30:3960-6.

RT for pN+

?cN+ and ypN-need more data

Radiation Therapy for Locally Advanced Noninflammatory Breast Cancer

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Noninflammatory LABC

LABC

T4 Noninflammatory

N2 Axillary Disease

N3 Supraclavicular

Disease

N3 Internal Mammary Disease

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Noninflammatory LABC

Neoadjuvant Chemotherapy +/- Trastuzumab

Modified Radical Mastectomy

+/- Endocrine Therapy / Trastuzumab

Postmastectomy Radiation

wLocal-regional control 85 - 95%

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Noninflammatory LABC - PMRT

Huang et al J Clin Oncol2004;22:4691-9.

w MDACC

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Noninflammatory LABC - PMRT

Heuts et al The Breast2009;18:254-8.

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Noninflammatory LABC - Breast Conservation

Chen et al J Clin Oncol2004;22:2303-12.

w MDACCw Resolution of skin / chest wall involvement.w Tumor < 5 cm, no multicentric disease or diffuse calcs.

Accept T4 with caution!

Radiation therapy for inflammatory breast cancer

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Audience Surveyw 2. What is the most important prognostic factor for prognosis

in inflammatory breast cancer?

a) Dermal lymphatic invasionb) Response to chemotherapyc) Estrogen receptor positivityd) Palpable axillary adenopathy

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Inflammatory LABCw Clinical findings:

• Rapid onset• Peau D’orange > 1/3 of the breast.

w Clinical diagnosis of inflammatory BUT pathology is needed!• Core biopsy of a node• Skin punch biopsy• Breast incisional biopsy

w Dermal lymphatic invasion is not required for diagnosis.w Not to be confused with a locally advanced neglected cancer.

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Management of Inflammatory LABC

Neoadjuvant Chemotherapy

Second Line Chemotherapy if < cCR

Preop Radiation if < cCR

Modified radical mastectomy

+/- Endocrine Therapy / Trastuzumab

Postmastectomy radiation

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Inflammatory LABC – Breast Conservation

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Inflammatory LABC

Harris et al Int J Radiat Oncol Biol Phys2003;55:1200-8.

CW / Breast 50 GyBolusSupraclav in allAxilla in mostIMN in few

w PENN

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Inflammatory LABCw MSKCC

Damast et al Int J Radiat Oncol Biol Phys2010;77:1105-12.

CW 5,040 Gy Bolus Daily

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Inflammatory LABCw MDACCw Dose escalation for < partial chemotherapy response,

close/positive margins, and age < 45 years

Bristol et al Int J Radiat Oncol Biol Phys2008;72:474-84.

CW 50 Gy + 10 Gy Boost or 51 Gy BID + 15 Gy BoostComprehensive nodal RT

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Audience Surveyw 3. A 60 year old woman is treated with breast-conserving

surgery for ER+, <5cm, invasive breast cancer. In which of the following situations is it acceptable to proceed with adjuvant radiation therapy WITHOUT axillary lymph node dissection (ALND)?

a) Sentinel lymph node biopsy (SLNB) reveals 1 lymph node with micrometastasis and the patient had clinically suspicious axillary nodes on preoperative ultrasound.b) SLNB shows isolated tumor cells in 1 SLN and axilla were clinically negative.c) The patient has 1 positive SLN, clinically negative axilla and will receive partial breast irradiation.d) The patient has 2 positive SLNs, clinically negative axilla and declines chemotherapy.e) It is never acceptable to omit ALND.