Gentest für DCIS? SENOLOGIE update Mai 2015 Kongress-Eventzentrum LAKE SIDE Prof. Bernhard Pestalozzi, Klinik für Onkologie, USZ

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1 Gentest für DCIS? SENOLOGIE update Mai 2015 Kongress-Eventzentrum LAKE SIDE Prof. Bernhard Pestalozzi, Klinik für Onkologie, USZ

2 Gliederung Einführung: Multigen Profile OncotypeDX (21-gene score) DCIS (12-gene score) JNCI 2013, Solin, E5194 study SABCS 2014, Rakovitch, Ontario Diskussion Pestalozzi Seite 2

3 Gen-Expression: Methodik

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5 Oncotype DX 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0-100) Low risk RS <18 Int risk RS 18 and <31 High risk RS 31 Paik et al. N Engl J Med. 2004;351:

6 DRFS Oncotype DX Clinical Validation: B-14 Results DRFS DRFS for the three distinct cohorts identified 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Low Risk (RS <18) n = 338 P < Intermediate Risk (RS 18-30) n = 149 High Risk (RS 31) n = Years Paik et al. N Engl J Med. 2004;351:

7 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast Panel of 12 genes included in the DCIS Score: Seven cancer-related genes and five reference genes

8 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast E5194 study, Hughes et al J Clin Oncol 2009, 27:5319 Non-randomized study, surgical excision without XRT Inclusion: Low/intermediate grade 25mm, high-grade 10mm E5194 Study used for validation of DCIS score N=670, final evaluable population N=327 (tissue) Ipsilateral Breast Event (IBE) in 46 pts (DCIS only in 26, invasive breast cancer in 20)

9 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast Primary Analysis Variables N HR DCIS Score ( ) DCIS Score Tam use 0.56 ( ) Recurrence Score ( ) Recurrence Score Tam use 0.56 ( )

10 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast Univariable Analysis for ipsilateral breast event (IBE) Variables HR p Age Post-menopausal (vs Pre-) 0.51 ( ) Tumor size (>10mm vs 5mm) 1.81 ( ) 0.09 Tam use (Yes vs No) 0.54 ( ) 0.09 Grade (low vs intermediate vs high) 1.0; 1.44; Van Nuys Prognostic Index

11 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast Multivariable Analysis for ipsilateral breast event (IBE) Analyses and variables HR p Premenopausal 1.00 (referent) Postmenopausal 0.49 ( ) 0.02 Tumor size (>10mm vs 5mm) 1.52 ( ) 0.01 DCIS score 2.37 ( ) 0.02

12 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast DCIS score. Low <39 Interm High 55

13 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast DCIS score. Low <39 Interm High 55

14 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast DCIS score. Low <39 Interm High 55

15 Multigene Expression Assay to Predict local Recurrence Risk for DCIS ot the Breast DCIS score. Low <39 Interm High 55

16 A Population-Based Validation Study of the DCIS Score Predicting Recurrence Risk in Individuals Treated by Breast-Conserving Surgery Rakovitch E, Nofech-Mozes S, Hanna W, Baehner FL, Saskin R, Butler SM, Tuck A, Sengupta S, Elavathil L, Jani PA, Bonin M, Chang MC, Robertson, S, Slodkowska E, Fong C, Anderson JA, Jamshidian F, Cherbavaz DB, Shak S, Paszat L 1

17 StudyObjectives Primary Objective To evaluate if the DCIS Score is associated with the risk of local recurrence (DCIS or invasive) in patients treated with BCS alone with negative margins In ER positive patients (by quantitative RT-PCR) All patients regardless of ER status Presented by Rokovitch et al. at SABCS 2014

18 San Antonio Breast Cancer Symposium December 9-13, 2014 Ontario Cohort Ontario DCIS Cohort BCS alone N=1658 Available tissue blocks N=828 Study Cohort N= 571 BCS alone With negative margins Exclusions (N= 257) No tumor (N=10) Invasive carcinoma (N=4) Insufficient RNA (n=68) Poor qpcr Sample Quality (N=28) Positive margins (N=147) Presented by Rokovitch et al. at SABCS 2014

19 Age 50 years Nuclear Grade Patient Characteristics Ontario Cohort (N=571) 459 (81%) Low 55 (10%) Intermediate 332 (58%) High 184 (32%) Comedo Necrosis 350 (61%) Solid Subtype 358 (63%) Tumor Size < 10 mm 150 (26%) > 10 mm 140 (25%) Missing 281 (49%) Multifocality * 114 (20%) ER+ by RT-PCR 541 (95%) HER2+ by RT-PCR 100 (17.5%) *Presence of at least 2 foci of DCIS in the same quadrant at least 5 mm apart Sikand et al. J Clin Path, 2005

20 Ontario Cohort Outcomes Median follow-up = 9.6 years Local recurrence = DCIS or invasive breast cancer in same breast 6 months or more after diagnosis of DCIS N=100 local recurrences N=57 invasive N=44 DCIS 10 year Kaplan Meier risk of local recurrence = 19.2%

21 Local Recurrence Risk (%) Kaplan-Meier 10-year Risk of Local Recurrence by DCIS Score Risk Group 33.0 % 27.8 % 12.7 % Years 14 This presentation is the intellectual property of the author/presenter. Contact Eileen.rakovitch@sunnybrook.ca for permission to reprint and/or distribute.

22 10-year Risk of Invasive and DCIS Local Recurrence by DCIS Score Risk Group Invasive Local Recurrence DCIS Local Recurrence 15 This presentation is the intellectual property of the author/presenter. Contact for permission to reprint and/or distribute.

23 Local Recurrence Risk (%) Local Recurrence Risk (%) Comparison of Ontario Cohort to E5194 Cohort: KM 10-year Estimates of Risk of Local Recurrence ECOG E5194 Ontario DCIS Cohort Year s 17 This presentation is the intellectual property of the author/presenter. Contact Eileen.rakovitch@sunnybrook.ca for permission to reprint and/or distribute.

24 Diskussion Take Home Messages In einer nur mit BCS-behandelten Population (DCIS 25mm) konnte der 12-Gen-DCIS Score die IBE (DCIS, invasiv) voraussagen in zwei Validations-Studien Die Rezidivraten sind niedrig. Nach 10 Jahren ist das Risiko eines invasiven Rezidivs 16-21% für high- /intermediate Risk versus 8% für Low-Risk DCIS-score Auf dieser Basis könnte die Indikation zur postoperativen Radiotherapie individualisiert werden Daten zu kombiniert (BCS + RT) behandelten DCIS werden kommen. Pestalozzi Seite 24

25 Danke für Ihre Aufmerksamkeit!