MammaPrint, the story of the 70-gene profile

Transcription

1 MammaPrint, the story of the 70-gene profile René Bernards Professor of Molecular Carcinogenesis The Netherlands Cancer Institute Amsterdam Chief Scientific Officer Agendia Amsterdam

2 The breast cancer treatment dilemma

3 Of 100 women with breast cancer

4 Only 25% will develop distant metastases

5 But we treat over 75% of all patients with chemotherapy

6 Which means that 50% of all breast cancer patients get a toxic chemotherapy that they did not need!

7 MammaPrint: improved breast cancer diagnosis Low risk High risk Low risk High risk

8 Identification of the MammaPrint breast cancer prognosis profile 78 breast tumors ( 83-94) patients < 55 years lymph node negative no adjuvant therapy Unbiased full genome gene expression analysis Prognosis Reporter Genes distant metastases < 5 years (n=34) no distant metastases in at least 5 years (n=44)

9 MammaPrint Discovery: Van t Veer et al. (2002) Nature 415,

10 Tumor samples MammaPrint prognosis Profile the 70 gene profile 70 significant prognosis genes van t Veer et al., Nature 415, p , 2002 threshold set at 10% false negatives 91 % sensitivity, 73% specificity

11 MammaPrint 70 genes are involved in all aspects of tumor cell biology proliferation angiogenesis adhesion to extracellular matrix intravasation, survival, extravasation local invasion adhesion to extracellular matrix proliferation Genes of unknown function (25) angiogenesis

12 First validation: Van de Vijver et al. (2002) New England J. Med. 347, patients

13 metastases-free MammaPrint:Improved Clinical Management Profiling vs St Gallen selection MammaPrint St Gallen MammaPrint improved prediction and more accurate MammaPrint: 40% in good profile 60 % in poor profile NEJM 347, p , 2002 St Gallen: 15% in low risk 85% in high risk

14 MammaPrint vs St Gallen guidelines Gene profiling: Reduction adjuvant chemotherapy selection Avoiding both over- and undertreatment Improved prognosis prediction NEJM 347, p , 2002

15 Second validation: Buyse et al. (2006) JNCI. 98, patients

16 Independent External Validation: Microarray outperforms all clinical risk assessment High clinical risk Adjuvant on line! N=222 73% Low clinical risk Adjuvant on line! N=80 27% 27% microarray Low risk Undertreatment! Overtreatment! 35% microarray High risk Buyse et al JNCI 2006 >30% Discordant cases!

17 MammaPrint predicts early metastases Time to distant metastasis 10 Cumulative proportion of events 29% % 50% % 100% 1 75% 83% 62% Adjusted hazard ratio for gene signature none Censoring time (in years) 0.1 Hazard Ratios highest in first 5 years JNCI 98, p , 2006

18 Chemotherapy only reduces the early metastases No effect of Chemotherapy Courtesy: Peter Ravdin Effect of Chemotherapy

19 High reproducibility of microarray experiments (99%) Reproducibility; repeat of the experiment Reproducibility; 2 samples, 7 month period Glas et al, BMC Genomics 2007

20 MammaPrint: improved breast cancer diagnosis First FDA approved molecular Diagnostic test for cancer 2007 Time Magazine: Invention of the year 2007

21 MINDACT study design 6000 patients, <70 YRS, 1-3 POS NODES ASSESS clinical RISK AND MammaPrint RISK (adjuvant!online & MammaPrint) 55% 35% 10% BOTH HIGH RISK DISCORDANT RISK BOTH LOW RISK RANDOMIZE decision-making Chemotherapy Use clinical risk high high Use MammaPrint low low No chemotherapy

22 Recent additional features of the MammaPrint test: Expanded indications: all ages

23 Survival Probability Metastases free probability MammaPrint prognosis in postmenopausal patients KM survival curve: Breast cancer > 55 year old Good prognosis profile Poor prognosis profile Poor Good Chi2 = P = 8.79e-005(wt power = 0) 150 patients Time(year) Overall survival HR 2.3, 0.95 CI [ ], p=0.0049

24 Recent additional features of the MammaPrint test: Expanded indications: patients with 1-3 positive lymph nodes

25 Validation of MammaPrint in patients with 1-3 positive lymph nodes Milan and NKI series 241 patients Milan EIO (B Viale): NKI series: % treated adjuvant chemo and/or hormonal therapy Median Follow Up: Milan: 8.97 years (0-10.9) NKI : 10.4 years ( )

26 MammaPrint performance in patients with 1-3 positive node(s) N=241breast cancer patients with 1-3 positive lymph node(s) - Milan & NKI Multivariate HR 6.59 (95% CI 1.71 to 25.45; p = 0.006)

27 Breast cancer with 1-3 positive node(s) MammaPrint Distant metastases as first event Multivariate analysis

28 TargetPrint: Quantification of ER, PR and HER2

29 MammaPrint: extensive regulatory approvals MammaPrint is the first and only IVDMIA cleared for market by FDA ISO accredited and CE mark for European market CLIA registered to be able to test US patients CAP Accredited The College of American Pathologists

30 MammaPrint is only the tip of the iceberg of personalized medicine Personalized medicine Who needs treatment? Which therapy will work best?

31 Personalized medicine: multiple answers on a single microarray chip Prognosis? Is there a hereditary component? Will tumor respond to Herceptin? Will tumor respond to DNA damaging agents?

32 Poor quality biomolecules: poor quality biomarkers! FFPE RNA integrity Protein integrity Fresh

33 Thank you!