Mamma Print the story of the 70 gene
- Slides: 33
Mamma. Print, the story of the 70 -gene profile René Bernards Professor of Molecular Carcinogenesis The Netherlands Cancer Institute Amsterdam Chief Scientific Officer Agendia Amsterdam
The breast cancer treatment dilemma
Of 100 women with breast cancer
Only 25% will develop distant metastases
But we treat over 75% of all patients with chemotherapy
Which means that 50% of all breast cancer patients get a toxic chemotherapy that they did not need!
Mamma. Print: improved breast cancer diagnosis Low risk High risk
Identification of the Mamma. Print 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)
Mamma. Print Discovery: Van ‘t Veer et al. (2002) Nature 415, 530 -536.
Mamma. Print prognosis Profile “the 70 gene profile” Tumor samples 70 significant prognosis genes van´t Veer et al. , Nature 415, p. 530 -536, 2002 threshold set at 10% false negatives 91 % sensitivity, 73% specificity
Mamma. Print 70 genes are involved in all aspects of tumor cell biology proliferation angiogenesis intravasation, survival, extravasation adhesion to extracellular matrix local invasion adhesion to extracellular matrix proliferation angiogenesis Genes of unknown function (25)
First validation: Van de Vijver et al. (2002) New England J. Med. 347, 1999 -2009. 295 patients
Mamma. Print: Improved Clinical Management Profiling vs St Gallen selection St Gallen metastases-free Mamma. Print: 40% in good profile 60 % in poor profile NEJM 347, p 1999 -2009, 2002 St Gallen: 15% in low risk 85% in high risk Mamma. Print improved prediction and more accurate
Mamma. Print vs St Gallen guidelines St Galle n Mamma. P rint Gene profiling: Reduction adjuvant chemotherapy selection Avoiding both over- and undertreatment Improved prognosis prediction NEJM 347, p 1999 -2009, 2002
Second validation: Buyse et al. (2006) JNCI. 98, 1183 -1192. 302 patients
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% microarray Low risk Overtreatment! Buyse et al JNCI 2006 >30% Discordant cases! 35% microarray High risk Undertreatment!
Mamma. Print predicts early metastases Time to distant metastasis Hazard Ratios highest in first 5 years JNCI 98, p 1183 -1192, 2006
Chemotherapy only reduces the early metastases No effect of Chemotherapy Courtesy: Peter Ravdin Effect of Chemotherapy
High reproducibility of microarray experiments (99%) Reproducibility; repeat of the experiment Glas et al, BMC Genomics 2007 Reproducibility; 2 samples, 7 month period
Mamma. Print: improved breast cancer diagnosis First FDA approved molecular Diagnostic test for cancer 2007 Time Magazine: Invention of the year 2007
MINDACT study design 6000 patients, <70 YRS, 1 -3 POS NODES ASSESS clinical RISK AND Mamma. Print RISK (adjuvant!online & Mamma. Print) 55% BOTH HIGH RISK 10% 35% DISCORDANT RISK BOTH LOW RISK RANDOMIZE decision-making Use clinical risk high Chemotherapy high Use Mamma. Print low No chemotherapy
Recent additional features of the Mamma. Print test: Expanded indications: all ages
Mamma. Print prognosis in postmenopausal patients KM survival curve: Breast cancer > 55 year old 1 0. 9 Good prognosis profile Metastases free probability 0. 8 Survival Probability 0. 7 0. 6 Poor prognosis profile 0. 5 0. 4 Poor Good 0. 3 0. 2 0. 1 0 150 patients Chi 2 = 15. 38 P = 8. 79 e-005(wt power = 0) 0 5 10 15 Time(year) Overall survival HR 2. 3, 0. 95 CI [ 1. 3 -4. 1], p=0. 0049
Recent additional features of the Mamma. Print test: Expanded indications: patients with 1 -3 positive lymph nodes
Validation of Mamma. Print in patients with 1 -3 positive lymph nodes Milan and NKI series 241 patients Milan EIO (B Viale): 1994 -1998 NKI series: 1984 -1995 80% treated adjuvant chemo and/or hormonal therapy Median Follow Up: Milan: 8. 97 years (0 -10. 9) NKI : 10. 4 years (1. 6 -21. 2)
Mamma. Print performance in patients with 1 -3 positive node(s) N=241 breast 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)
Breast cancer with 1 -3 positive node(s) Mamma. Print Distant metastases as first event Multivariate analysis
Target. Print: Quantification of ER, PR and HER 2
Mamma. Print: extensive regulatory approvals ÜMamma. Print is the first and only IVDMIA cleared for market by FDA ÜISO 17025 accredited and CE mark for European market ÜCLIA registered to be able to test US patients ÜCAP Accredited The College of American Pathologists
Mamma. Print is only the “tip of the iceberg” of personalized medicine Personalized medicine Who needs treatment? Which therapy will work best?
Personalized medicine: multiple answers on a single microarray chip Prognosis? Will tumor respond to Herceptin? Is there a hereditary component? Will tumor respond to DNA damaging agents?
Poor quality biomolecules: poor quality biomarkers! FFPE Fresh RNA integrity Protein integrity
Thank you!
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