10 jaar MammaPrint. Emiel Rutgers

10 jaar MammaPrint Emiel Rutgers

De klinische vraag: Wat moeten/willen de breast specialist en de patiente weten? De prognose: is deze zo goed dat aanvullende therapie niet/nauwelijks aan levensverwachting toevoegt. Als niet: welke therapie is het meest geschikt Dus als je geen indicatie voor chemo ziet, dan hoef je verder ook niets van de tumor te weten (chemo sensitiviteit etc)

Prognose: hoe schatten we die in? - NABON richtlijnen - Adjuvant!Online - St. Gallen

NABON richtlijn Laag risico: geen AST 2004: - N-ve - >35 jaar - Graad 1 & 2 1-3 cm 2008: - N-ve - >35 yrs - Graad 1-3 < 1cm - Graad 1 <2 cm Hoog risico - N + - N -, 35 jaar behalve graad 1 en tumor 1cm - N -, > 35 jaar, graad 3 > 1cm, graad 2 > 2cm of alle tumor > 3cm - N + - N -, < 35 jaar behalve gr 1 1cm - N -, 35 jaar, graad 2 en tumor 1,1-2cm of alle tumor > 2cm

Prognose: St Gallen International Expert Consensus 2009/11

70-genen MammaPrint Is not just another prognostic factor Is designed from the beginning to tell you the metastatic potential of an individual breast cancer

Met Microarrays kan je de activiteit van alle 25,000 genen in een tumor sample meten

MammaPrint: ontworpen op gearchiveerd bevroren tumorweefsel 78 breast tumors Age < 55 years, Tumor size < 5 cm Lymph node negative & No adjuvant therapy Distant metastases within 5 years No distant metastases for at least 5 years van t Veer et al. (2002) Nature, Vol 415, 530-536

MammaPrint: : 70 genes voorspellen de recidiefkans Low Risk Signature 78 Patients High Risk Signature 70 Genes

Uitgebreide klinische Validatie. 4,879 Patienten Validation Studies Country Reference First validation study van de Vijver et al. NEJM 295 Independent European study Buyse et al J NCI 17 302 Prospective Study - Dutch patient cohort de Mesquito et al. Lancet Oncol. 8 427 Years 2002 2006 2007 2008 2009 2010 Recent Diagnosis Study de Mesquita et al Breast Cancer research tr 123 Core Needle biopsies Mayordomo et al. ESMO Meeting 35 Validation in US patients Wittner et al. Clin Cancer Res 14 100 Dutch patient cohort Bueno de Mesquita et al. Br C Res 123 Validation in 1-3 LN+ patients Mook et al. Breast Cancer Res Treat. 241 Validation in 4-9 LN+ patients Saghatchian et al. St. Gallen Conf 168 Validation in HER2+ patients Knauer et al. Br J Cancer 168 Patients treated with Tamoxifen Kok et al. (submitted) 192 Postmenopausal patients (>61) Mook et al. breast cancer research tr 148 German patient cohort Kunz et al. St. Gallen Conference 140 Japanese patient cohort Ishitobi et al. Jap Breast Cancer Symp 118 Neoadjuvant predictive study Somlo et al. ASCO meeting 68 Neoadjuvant predictive study Straver et al. Breast Cancer Res Treat 167 Predictiveness (Meta-analysis) study Knauer et al. St. Gallen Conf.erence 1,637 Validation in T1 Tumors Mook et al. Ann Oncology 427

Validatie 1: N = 151 vd Vijver et al, N Engl J Med 347: 1999-2009, 2002

Validatie 2: N = 307 Buyse M, et al.: J Natl Cancer Inst 98: 1183-92, 2006

De klinische vraag. Stap voor stap denken. Stap 1: Is de prognose zo goed dat overlevings voordeel van adjuvante chemotherapie niet opweegt tegen de nadelen ernstige late termijn bijwerkingen?

Validatie 3: N = 123 Bueno-de-Mesquita JM: Breast Cancer Res Treatm 2008 Het 70-gene Profiel is beter dan: -Adjuvant Online -St Gallen criteria -Nottingham PI -NABON richtlijn

Validatie 4: N = 100 Wittner et al., Clin Cancer Res 14: 2988, 2008 MGH series, Boston; Time to metastasis

St. Gallen Recommendations 2011 MammaPrint Accepted into St. Gallen s Oncology Guidelines for Early Stage Breast Cancer Treatment The Panel accepts the use of validated molecularly based tools if readily available as an adjunct to high-quality standard histopathologic assessment in patients with ER+ breast cancer when the doctor and patient are uncertain or ambivalent about the administration of adjunctive chemotherapy. In addition, the Panel felt intermediate results were of little clinical value. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thuerlimann B, Senn HJ; Panel members. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncology Aug. 2011

Kritische vragen bij het vroege mammacarcinoom & adjuvante chemotherapie Is goede pathologie even goed? Kleine carcinomen altijd goede prognose? Her 2 overexpressie: chemo? N +ve: altijd slechte prognose waarvoor chemo is geindiceerd? Selecteren we dan die carcinomen waarvoor chemo het meesteffectiefis?

Kritische vragen bij het vroege mammacarcinoom & adjuvante chemotherapie Is goede pathologie even goed?

MammaPrint voegt toe aan optimale gradering: 1/3 discordant 764 of 1630 patients (47%) were classified as good prognosis and 866 (53%) as poor prognosis by MammaPrint Histological grading was centrally reviewed for all patients MammaPrint high risk MammaPrint low risk

DDFS N -ve Survival Functions MammaPrint 0 1 0-censored 1-censored

DDFS N-ve Survival Functions MammaPrint 0 1 0-censored 1-censored

Kritische vragen bij het vroege mammacarcinoom & adjuvante chemotherapie Kleine carcinomen altijd goede prognose?

Patienten inclusie criteria: Alle T1 mammacarcinomen uit MammaPrint database Dus los van: Leeftijd N status ER,PgR, Her-2 => 965 patienten Mediane follow-up 7.1 jaar (0.2-25.2)

MammaPrint: Tumor T1c BCSS 11 22 mm Tumors 99% 92% Good signature (n=441) 88% 72% Poor signature (n=384) Log rank p<0.001 HR at 10 yrs: 4.42 (95% CI 2.73-7.17); p<0.001 Log rank p = 0,036 T1c tumors derived from pooled database of all MammaPrint validation studies (all, n=1696) Mook et al, Ann Surg Oncol, 2010

MammaPrint and Tumorsize T1ab BCSS 0 10 mm Tumors 100% 88% 90% 73% Good signature (n=84) Poor signature (n=55) Log rank p=0.06 HR at 10 yrs: 3.12 (95% CI 0.91-10.67); p=0.07 Log rank p = 0,036 T1ab tumors derived from pooled database of all MammaPrint validation studies (all, n=1696) Mook et al, Ann Surg Oncol 2010

En Her-2 positief Mammacarcinoom. Altijd slechte prognose?

DDFS: All patients BCSS: All patients 100 100 80 80 Survival probability 60 40 20 Log-rank (Mantel-Cox) Test Good signature (n=27) Poor signature (n=142) Survival probability 60 40 20 Log-rank (Mantel-Cox) Test Good signature (n=27) Poor signature (n=142) P value 0.0153 P value 0.0242 0 0 2 4 6 8 10 Time in years Figure 1: Distant disease-free survival (LEFT) and breast cancer-specific survival 0 0 2 4 6 8 10 Time in years (RIGHT) According to the 70-gene signature for all 169 Her2-positive breast cancer patients. Michael Knauer et al.br J Cancer 2010

DDFS: without chemotherapy/trastuzumab 100 BCSS: without chemotherapy/trastuzumab 100 Survival probability 80 60 40 20 Log-rank (Mantel-Cox) Test P value 0.0127 Good signature (n=21) Poor signature (n=69) 0 0 2 4 6 8 10 Time in years Figure 2: Distant disease-free survival (LEFT) and breast cancer-specific survival Survival probability 80 60 40 20 Log-rank (Mantel-Cox) Test P value 0.0403 Good signature (n=21) Poor signature (n=69) 0 0 2 4 6 8 10 Time in years (RIGHT) according to the 70-gene signature for 90 patients without adjuvant chemotherapy or trastuzumab. Michael Knauer et al.br J Cancer 2010

100 DDFS: highly endocrine responsive 100 BCSS: highly endocrine responsive 80 80 Survival probability 60 40 Good signature (n=11) Poor signature (n=31) Survival probability 60 40 Good signature (n=11) Poor signature (n=32) 20 Log-rank (Mantel-Cox) Test 20 Log-rank (Mantel-Cox) Test P value 0.1383 0 0 2 4 6 8 10 Time in years Figure 3: Distant disease-free survival (LEFT) and breast cancer-specific survival Michael Knauer et al.br J Cancer 2010 P value 0.1382 0 0 2 4 6 8 10 Time in years (RIGHT) according to the 70-gene signature for 42 patients with highly endocrine-responsive tumors according to the St.Gallen criteria. Out of 11 low risk patients, 7 were untreated, 4 received chemotherapy and one of those received trastuzumab.

En N +ve Mammacarcinoom? Altijd indicatie voor chemotherapie?

70-gene Profile and Prognosis in Breast Cancer with 1-3 Axillary Lymph Node Metasases S. Mook et al., Breast Cancer Res Treatm 2008. Good profile (n=99) Poor profile (n=142) Distant metastases as first event 95% Overall survival 95% HR 4.1 (95%CI 1.7 10.0) p=0.002 77% HR 5.4 (95%CI 2.1 13.8) p<0.001 73%

MammaPrint laag risico: voldoende goed? Background Objective Methods Results Conclusions

De klinische vraag: Wat moeten/willen de breast specialist en de patiente weten? Stap 2 selecteer je de goede carcinomen voor chemotherapie?

Benefit of neo-adjuvant chemotherapy for MammaPrint high risk patients Netherlands Cancer Institute Eligible patients 2 clinical trials N=167 T-stage >3 cm and/or LNplus (SNB/FNA) ultrasound guided 14 gauge biopsies MRI imaging Pathology Good prognosissignature Poor prognosissignature N=23 (14%) N=144 (86%) Antracycline-like Antracyclin-Taxane Taxane pcr(axilla+breast) n=0 P=0.015 pcr(axilla+breast) n=29 (20%) pcr: pathological complete remission Straver et al, BCRT 2009

Neo-adjuvant Standard Chemotherapy and MammaPrint Clinical Benefit 70 gene MammaPrint High Risk Signature patients show significantly higher chemosensitivity All pcr are found in the High Risk Signature group High Risk Signature Patients show Clinical Benefit of Chemotherapy Straver et al, BCRT 2009

Tot nu geen recidieven in de laag risico groep 36 Straver et al 2009, Br Cancer Res and Treatment

Chemotherapie effect MammaPrint LOW RISK patients (n=252) Percent survival 100 80 60 40 20 DDFS: MammaPrint LOW RISK (n=252) ET (n=174, 69%) ET+CT (n=78, 31%) HR 0.26 (0.03 2.02) p=0.20 99% 93% Percent survival 100 80 60 40 20 BCSS: MammaPrint LOW RISK (n=252) ET (n=174, 69%) ET+CT (n=78, 31%) HR 0.58 (0.07 4.98) p=0.62 99% 97% 0 0 1 2 3 4 5 Time in years Knauer et al, ASCO 2009, BCRT 2010 Albain et al 2009 0 0 1 2 3 4 5 Time in years

Chemotherapie effect MammaPrint HIGH RISK patients (n=289) Percent survival 100 80 60 40 20 DDFS: MammaPrint HIGH RISK (n=289) ET (n=141, 49%) ET+CT (n=148, 51%) HR 0.35 (0.17 0.71) p<0.01 88% 76% Percent survival 100 80 60 40 20 BCSS: MammaPrint HIGH RISK (n=289) ET (n=141, 49%) ET+CT (n=148, 51%) HR 0.21 (0.07 0.59) p<0.01 94% 81% 0 0 1 2 3 4 5 12% Time absolute in years benefit 50% relative benefit Knauer et al, ASCO 2009, BCRT 2010 Albain et al 2009 0 0 1 2 3 4 5 13% Time absolute in years benefit 68% relative benefit

MINDACT trial Is niet ontworpen om de prognostische waarde van MammaPrint te valideren Zal ons vertellen of chemotherapie terecht is onthouden aan patienten met een MP laag risico test die anders wel chemo gehad zouden hebben met een strake limiet van een 5 jaars breast cancer specific survival van 93-95%.

ECCO16-ESMO36 - Stockholm, 23-27 September 2011 Baseline characteristics and logistics aspects after a successful accrual Emiel Rutgers On behalf of co-pis Fatima Cardoso and Martine Piccart & the whole team

MINDACT TRIAL DESIGN N= 6600 Clinical-Pathological (C) risk (Adjuvant! Online) Genomic (G) risk (70-gene signature) C-HIGH / G-HIGH Discordant cases C-HIGH / G-LOW or C-LOW / G-HIGH C-LOW / G-LOW 1 st st randomization to treatment use Clinical vs. Genomic risk Chemotherapy HR+ 2 nd randomization Anthracycline based vs. Capecitabine-Docetaxel Endocrine therapy 3 rd randomization Tamoxifen 2y / Letrozole 5y vs. Letrozole 7y No Chemotherapy HR+

EORTC-BIG MINDACT TRIAL DESIGN The discordant cases Evaluate Clinical-Pathological risk and 70-gene signature risk Discordant cases 32% (as per protocol estimative) Clin-Path HIGH and 70-gene LOW Clin-Path LOW and 70-gene HIGH 1 st randomization treatment decision Use Clin-Path risk to decide CT Use 70-gene risk to decide CT Clin-Path HIGH and 70-gene LOW chemotherapy Clin-Path LOW and 70-gene HIGH no chemotherapy Clin-Path HIGH and 70-gene LOW no chemotherapy Clin-Path LOW and 70-gene HIGH chemotherapy Potential CT rightfully foregone

Accrual Country Enrolled pts Netherlands (NKI) 2055 France (FNCLCC) 1992 Germany (WSG) 825 Belgium (EORTC) 820 Spain (SOLTI) 523 Pilot phase 1 First 800 enrolled patients Italy (GOIRC) 186 UK (NCRIBCG ) 64 Slovenia (IOL) 37 Switzerland (EORTC) 25 Total 6527 1. Rutgers et al. Eur J Cancer 8 (3): 188, 2010 (suppl; abstr 444)

Patient characteristics Age 50: 33% > 50: 67% Tumor size < 20 mm: 72% > 20 mm: 18% Tumor grade 1: 21.7% 2: 48.9% 3: 28.8% Undefined: 0.6% Local hormone receptor status HR+: 88% (ER+ or PR+ or both) HR-: 12% Local HER2 status 86.8% negative 10.6% positive 2.5% not done/unknown Triple negative: 9.5% Nodal status 79.9% LN negative 13.7% LN +1 4.4% LN +2 2.3% LN +3

Patient risk allocation Clin-path risk and 70- gene risk at enrollment Clinical-pathological risk LOW N(%) HIGH N(%) Total 70-gene risk LOW 2586 (40) 1436 (22) 4022 (62) HIGH 678 (10) 1827 (28) 2505 (38) Total 3264 (50)* 3263 (50)* N=6527 Discordant cases (10 + 22 = 32%) match protocol hypothesis The absolute difference between C-HIGH / G-LOW and C-LOW / G-HIGH is 11.6% *The 50-50 split is coincidental

Conclusions Accrual has been successfully completed Its complex logistics, including real-time collection of frozen tumor tissue, were proven to be feasible in a multinational, multicentric setting A crucial fact to test the primary endpoint, the absolute difference between Clin-Path HIGH / 70-gene LOW and Clin-Path LOW / 70-gene HIGH cases, has been achieved (>10%) Compliance to treatment allocations is high

Met dank aan

MammaPrint: en nu? Het lijkt veilig geen chemo te geven aan patienten met een vroeg mammacarcinoom en een laag risico MammaPrint test Patienten met een MammaPrint hoog risico carcinoom profiteren het meest van adj. chemotherapie

MammaPrint: wie dan? CBO 2011: als er twijfel is. Praktijk: vooral patienten van 40-70 jaar met een carcinoom tussen de 1 en 3 cm, ER +ve.

Dank De patienten, de onderzoekers, ons Mammateam, Het Mindact team. Voor uw deelname en aandacht