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35 th SABCS 2012 Highlights Loco-Regional Therapy

35 th SABCS 2012 Highlights Loco-Regional Therapy. Patrick Neven MBC, UZ Leuven. 35th SABCS 2012 Loco-Regional Therapy. Atypical lesions on core biopsy WLE? Upgrade to malignant lesions (frequency, nomogram) WLE for DCIS Re-excise if + margins (predictors residual DCIS)

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35 th SABCS 2012 Highlights Loco-Regional Therapy

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  1. 35th SABCS 2012 Highlights Loco-Regional Therapy Patrick Neven MBC, UZ Leuven

  2. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • 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

  3. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • Upgrade to malignant lesions (frequency, nomogram)

  4. WLE if atypical lesions on core biopsy? MESSAGE Wide Excision = Standard • 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

  5. A nomogram ~ clinic, imaging & histology to predict upgrade to malignancy (WLE) LCIS, ADH, ALH, FEA (corebiopsy P4-12-01 Uzan et al. 50/205WLE -21 DCIS -20 IDA -9 ILA • Sens 77.8%, Sp 66.1%, PPV40%, NPV 91.1%

  6. 35th SABCS 2012 Loco-Regional Therapy • Atypicallesions on corebiopsyWLE? • Upgrade tomalignantlesions (frequency, nomogram) • WLE for DCIS • Residual DCIS if re-excisionfor + margins • Predictorsfor 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

  7. Residual DCIS after re-excision following WLE for DCIS? MESSAGE • 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 predictive

  8. Local Relapse after BCS (DCIS) • Surrogate phenotypes ~ recurrence (PD-04-06) • 314 pts (1990 – 2010) 74 months FU • Radiotherapy? High risk recurrence?

  9. Predictors for IBC if relapse Luminal A 1 - - Luminal B 14.38 1.8-113.6 0.011 HER-2 type 17.69 2.1-147.0 0.008 Triple Negative 15.23 1.8-126.6 0.012

  10. 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

  11. Molecular predictors type LRR: after BCS for DCIS

  12. Molecular Predictor LRR BCS for DCIS

  13. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • 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

  14. 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 vswire guided = feasible • 2ary WLE in irradiated breast (P4-15-01)

  15. BCS: Role of intraoperative ultrasound (IOUS) palpable lesions Margin definition??? • 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

  16. Patients with IBTR: 2ary BCS? Clinical Practice Changing • 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?

  17. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • 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

  18. SLN Biopsy after Neoadjuvant Chemotherapy • S2-1 (ACOSOG) • S2-2 (SENTINA trial)

  19. 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

  20. SLN Biopsy after Neoadjuvant Chemotherapy • S2-1 (ACOSOG) • S2-2 (SENTINA trial)

  21. Sentinel Node Biopsy after NACACOSOG Z-0171 (2009-2011) 756 included 708 evaluable FNR: 14.0% Clip Placement ? 172 pts FNR = 7% • 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 SNALND • 40% node negative • 60% node positive • SN negative 56 patients (14%)

  22. SENTINA • 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 mandatory • Cortex asymmetry • Hilum displacement or loss

  23. cN+ definition FNAC/CNB Not Mandatory

  24. ↔ cN0: SLN after NACT: Accurate/ Feasible Less Axill Clearance

  25. Sentinel Lymph Node Prior to NACT (~local and systemic R/) Excellent Detection Rate (DR) After NACT cN0ycN0: Excellent DR cN0 & SN(+)Repeat SLN = Unacceptable DR cN1 ycN0 DR is 80.1% = Low FNR = Too High?

  26. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • 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)

  27. Best of SABCS 2012Radiation Oncology Normal a total dose 50Gy in 25 small daily fractions (5 weeks) 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)

  28. Hypofractionated Breast RT Change in DOSE: *Hypofractionatedlarger dose per fraction *Same time vs. shorter time versus versus

  29. START B: Physicians’ assessment of cosmesis Findings

  30. Clinical Practice Changing

  31. APBI ELIOT TARGIT • 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

  32. APBI TARGIT 0.5% LRR/YR “EXPERIMENTAL”

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

  34. 35th SABCS 2012 Loco-Regional Therapy • Atypical lesions on core biopsyWLE? • 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 ↓ →

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

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