35th SABCS 2012 Highlights

Loco-Regional Therapy

Patrick NevenPatrick Neven

MBC, UZ LeuvenMBC, UZ Leuven

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Re-excise if + margins (predictors residual DCIS)• Predictors relapse (subtype, gene expression profile)

– WLE for IBC • Tumor localisation, 2nd WLE

– Sentinel lymph node• Value in post-neoadjuvant setting

– Radiotherapy• START (hypofractionation)• APBI – IORT/ELIOT

– Local relapse: Secondary adjuvant chemotherapy

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– Flat epithelial atypia on core biopsy• Loyola, USA (P1-02-01) 2009-2011 726 core biopsies

– 21.4% (3/14) upgraded to DCIS or IBC

• 3 Dutch hospitals (P5-01-13) 2009-2011 104 core biopsies– R/ ranged from observation to mastectomy

– Of those excised: 20.4% had DCIS or IBC

– ADH on vacuum biopsy • Centre Oscar Lambret, Lille (P4-14-10) 2003-2010

– 52/298 WE/3159 VAB = 17.5% had DCIS or IBC

– No prognostic marker identified for upstaging

WLE if atypical lesions on core biopsy?

Wide Excision = StandardMESSAGE

A nomogram ~ clinic, imaging & histologyto predict upgrade to malignancy (WLE)

LCIS, ADH, ALH, FEA (core biopsyP4-12-01 Uzan et al.

50/205WLE-21 DCIS-20 IDA -9 ILA

Sens 77.8%, Sp 66.1%, PPV 40%, NPV 91.1%

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Residual DCIS if re-excision for + margins• Predictors for relapse (~ subtype, gene expression profile)

– Ki-67 (continuous variable) ~LRR after BCS & RT & HT?

» PD-04-07 – Pruneri et al. EIO, Milan

» 872 pts, [356 RT, 506 TAM] and 86/12 FU

» RT only of value if Ki-67 > 14%» HT only of value if lum A/B (not lum HER-2)

MESSAGE

Residual DCIS after re-excision following WLE for DCIS?

• IBC: Margin index predicts residual cancer• P3-14-06 – AS Aneja S. et al.

– 177 pts and 87 re-excision (18 rDCIS)• Index: closest margin (mm)/ extent of DCIS (mm)

– Index > margin distance

– PR most predictiveMESSAGE

Local Relapse after BCS (DCIS)• Surrogate phenotypes ~ recurrence (PD-04-06)

– 314 pts (1990 – 2010) 74 months FU

– Radiotherapy? High risk recurrence?

Luminal A 1 - -Luminal B 14.38 1.8-113.6 0.011HER-2 type 17.69 2.1-147.0 0.008Triple Negative 15.23 1.8-126.6 0.012

Predictors for IBC if relapse

Molecular predictors type LR: after BCS for DCIS PD-04-05

• Local relapse DCIS vs IBC +/- DCIS – 1991-2006, 1873 pts, 40m FU, 190 relapsed (10%), 108 blocks:

66 rDCIS & 42 rIBC qmRNA– Quantification of mRNA done by Nanostring nCounter system– 32 BC-related genes selected from literature (why these and not others?)

• HER-2;PI3K/AKT; genes involved in proliferation/recurrence

– Initial unsupervised hierarchical clustering:» 2 groups: rDCIS & rIBC enriched

– 14 genes w/ sig differential expression:» rDCIS “only” : highest levels of AKT3, EGFR, CDKN2A, MKI67,

typical of basal like tumors

Molecular predictors type LRR: after BCS for DCIS

Molecular Predictor LRR BCS for DCIS

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Re-excise if + margins (predictors residual DCIS)• Predictors relapse (subtype, gene expression profile)

– WLE for IBC • Tumor localisation• 2nd WLE

IBC: Breast conservation surgery

• Patient selection– BCS rates in SEER (PD-04-04)

• Stage I-II IBC 2006-2011: 77248 cases BCS: 64.8% & stable• Patients choice > Availability RT/Reconstr/Volume per Unit

– BCS in young women (Sydney)(PD-04-01)• N=2250 & 70/12 FU: Age <40 & BCS indep.predictors for LR

• Technique– Intraoperative ultrasound (PD-04-01)

• P4-14-08 278 not-palpable lesions USS vs wire guided = feasible

– 2ary WLE in irradiated breast (P4-15-01)

BCS: Role of intraoperative ultrasound (IOUS) palpable lesions

• PD-04-01: RCT USS (65) vs PGS (69)• 2010-2012, 6 centers, T1-2 palp IBC

Less volume excised in USS

Less margin involved 17% vs 3% USS

Less likely additional therapy

Margin definition???

Patients with IBTR: 2ary BCS?

• Second BCS-RT trial (P4-15-01) GEC-ESTRO• Patients from 8 European Institutions: • WLE + MIB (Multicatheter Interstitial Brachytherapy)

– Is 2ary BCT safe for IBTR?• 2000-2010: 217 pts repeat BCS + MIB. • Median time interval Primary – IBTR = 9.4 yrs [1.1-35.4]

• Median f/u after IBTR = 3.9 years [after 2ary BCS].• Mean T = 11mm• Median RT dose for primary was 56 Gy [30-69.6]

• 5 and 10 year actuarial – LR rates 5.6% and 7.2%– OSS 88.7% and 76.4%

• No severe complications but fibrosis.• Long term cosmesis? Clinical

PracticeChanging

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Re-excise if + margins (predictors residual DCIS)• Predictors relapse (subtype, gene expression profile)

– WLE for IBC • Tumor localisation, 2nd WLE

– Sentinel lymph node• Value in post-neoadjuvant setting

SLN Biopsy after Neoadjuvant Chemotherapy

–S2-1 (ACOSOG)

–S2-2 (SENTINA trial)

Background

SLNB ~ axillary status if cN0-pN status tailors L/R adjuvant therapy

Role of SLNB with NACT is unclear-cN0: prior to but after NACT if pN status not informative?

-cN+: downstaging to cN0 (no ALND)???-current data

-small series-retrospective data

SLN Biopsy after Neoadjuvant Chemotherapy

–S2-1 (ACOSOG)

–S2-2 (SENTINA trial)

Sentinel Node Biopsy after NAC

ACOSOG Z-0171 (2009-2011)• pT0-4N1-2M0: NAC SN and ALND (136 institutions)

– T1 (14%); T2 (55%); T3 (25%)» HR+/Her2- (45%); » Her2+ (30%); » Trip neg (24%);

• Anthracycline +/- taxane (80%), taxane based (17%)

– SN detection rate• cN1 (92.9%), cN2 (89.5%) : SLN ALND (n=643)

– SN H&E results SNALND• 40% node negative• 60% node positive

– SN negative 56 patients (14%)

756 included708 evaluable

FNR: 14.0% Clip Placement ?

172 pts FNR = 7%

- 4-arm prospective multicenter cohort study- SLN detection rate prior and after NACT- FNR if cN1 downgraded to cN0- cN1: clinic and all had US

- Negative (cN0)- Suspicious or unclear (cN1)

- FNAC/ CNB recommended but not mandatoryCortex asymmetry

- Hilum displacement or loss

SENTINA

cN+ definitionFNAC/CNB Not Mandatory

↔cN0: SLN after NACT: Accurate/ Feasible

Less Axill Clearance

Sentinel Lymph Node

Prior to NACT (~local and systemic R/)

Excellent Detection Rate (DR)After NACT

cN0ycN0: Excellent DRcN0 & SN(+)Repeat SLN = Unacceptable DR

cN1 ycN0 DR is 80.1% = LowFNR = Too High?

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Re-excise if + margins (predictors residual DCIS)• Predictors relapse (subtype, gene expression profile)

– WLE for IBC • Tumor localisation, 2nd WLE

– Sentinel lymph node• Value in post-neoadjuvant setting

– Radiotherapy• START (hypofractionation)• APBI – IORT (TARGIT- ELIOT)

Content

Hypofractionation (= less than 25 fractions)•[S4-1] The UK START (Standardisation of Breast Radiotherapy) Trials: 10-Year Follow-Up Results

APBI: Single Fraction RT•[S4-2] Targeted Intraoperative Radiotherapy for Early Breast Cancer: TARGIT-A Trial- Updated Analysis of Local Recurrence and First Analysis of Survival

•[P4-16-08] Intraoperative Electron Radiotherapy in Early Stage Breast Cancer. A Single-Institution Experience ELIOT

Local control if metastatic breast cancer •[P4-16-06] RT to Primary Tumor ~ Improved Survival in Stage IV Breast Cancer (Canadia, SEER, 768 cases EBRT vs 2761 no EBRT)

Best of SABCS 2012

Radiation Oncology

Normal a total dose 50Gy in 25 small daily fractions (5 weeks)

Hypofractionated Breast RT

Change in DOSE:

*Hypofractionatedlarger dose per fraction

*Same time vs. shorter time

versus

versus

Findings

START B: Physicians’ assessment of cosmesis

Clinical Practice

Changing

APBI• Single fraction IORT

– S 4-2 TARGIT for early stage breast cancer• TARGIT vs WB-XRT

– TARGIT “ideal” pt age ≥ 45; T preferably ≤ 3.5 cm; MRI no need

» TARGIT 20 Gy at surface, 5 Gy at 10 mm

» If “high risk” add WB-XRT to single-fraction IORT (~ 15%)

– 2000-2012: 3451 pts randomized, 1222 patients median f/u 5 yrs

ELIOT

TARGIT

APBI

TARGIT0.5% LRR/YR“EXPERIMENTAL”

• Single fraction IORT– Verona experience, phase II single fraction

IORT with IOERT (P4-16-08)

– 2006-2009, 226 pts, “low risk”, early stage IBC• Age > 50; T < 3 cm, G1-3, unifocal IDC. No DCIS,

EIC, or ILC

• 21 Gy to tumor bed with 2 cm margins laterally

• Mean f/u 51 months, 4 IBTR

IORT Following Lumpectomy for Breast Cancer Sem Br Dis Dirbas FM, Horst KC 2007

35th SABCS 2012 Loco-Regional Therapy

– Atypical lesions on core biopsyWLE?• Upgrade to malignant lesions (frequency, nomogram)

– WLE for DCIS• Re-excise if + margins (predictors residual DCIS)• Predictors relapse (subtype, gene expression profile)

– WLE for IBC • Tumor localisation, 2nd WLE

– Sentinel lymph node• Value in post-neoadjuvant setting

– Radiotherapy• TARGIT (hypofractionation)• APBI - IORT

– Local relapse: Secondary adjuvant chemotherapy Clinical Practice

Changing↓ →

Ipsilateral recurrence: Value of Secundary Adj CTPower calculation : needed to include: n= 1000…results from a RCT that stopped early: poor recruitementThe researchers closed the trial with 162 patients Followed patients for more than 5 years.Stratified by ER

Summary 35th SABCS-2012 LOCO-REGIONAL THERAPY

• Atypical breast lesions : WLE still recommended • Research efforts will continue to identify biological markers to

inform need for re-excision and adjuvant local / endocrine therapies for DCIS (and IBC)

• SNB after NACT if cN+ needs further research– high FNR requires resection of nodes with proven disease: dual tracer

and/or localization of clipped nodes. – repeat SNB alone to be avoided if cN+

• Hypofractionation is new standard after BCS (10 yrs safe)• Single fraction IORT may be equivalent to WB-XRT in select

patient subsets but higher recurrence rates in unselected patients: longer f/u required to determine if these results are sustainable and effect on CV-risk

• Secondary WLE in previously radiated breast

• Secondary adjuvant chemotherapy is important