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Genomic Signaturesof Specific Sites of Metastases          Laura J. van ‘t Veer             Helen Diller Family       Comp...
Breast cancer metastasis:metastatic capacity and organ specificity?through blood or lymph vessels
Metastasis Models                I------------------primary tumor---------------I----metastasis-----I                     ...
Breast Cancer           Risk of Metastasis and Survival            Kaplan-Meier Survival Curve Stage 1/2                  ...
70 Gene Prognosis Profile MammaPrint                70 significant prognosis genesTumor samples                           ...
IGFBP5, TGFB3, FGF18, ESM1, RARRES3, PITRM1, EXT1, EXTL3, SCUBE2,        EBF4,CDC42BPA, CDCA7, CDCA7L, GMPS, MELK, RFC4, W...
Breast Cancer – node negative                        Stage 1/2 Survival by profiling                     Distinguish in: 4...
Breast Cancer – 1-3 node positive            Stage 2 Survival by profiling                                        Good pro...
Molecular portraits of breast cancer                        Capacity to metastasizePerou & Sorlie et al,Nature 2000       ...
Molecular Profiles of the Primary Tumorcan predict risk of metastasis:- MammaPrint 70-gene profile- Intrinsic subtypes (e....
Profiles hard-wired and maintained           throughout metastatic process?Nat Rev Cancer 5, p 591-602, 2005
Primary breast tumors – distant metastases  Hierarchical clustering8 primary breast tumors and distant metastases of the s...
Profiles maintained throughout                      metastatic process                      70-gene prognosis profile     ...
Profiles maintained throughout                      metastatic process               primary tumor – lymph node metastasis...
Profiles hard-wired and maintained           throughout metastatic processNat Rev Cancer 5, p 591-602, 2005
Organ-specific breast cancer metastasis                                 Prognostic profiles                               ...
Organ-specific breast cancer metastasis                                 Site of relapse                                 in...
Intrinsic Subtypes of breast cancer                             Foekens et al                                             ...
Association with site of relapse                               Foekens et al       118 patients of the 344 had a distant m...
Non-random distribution             X² statistic     42.78                                                        p   0.00...
Intrinsic Subtypes of breast cancer (IHC)                                         ERpos / Luminal                         ...
Lung metastasis profile ‘experimental model’      applied to human breast cancer                        Massague et al    ...
Lung metastasis profile ‘experimental model’      applied to human breast cancer                Massague et alEvaluated fo...
Lung metastasis profile ‘experimental model’      applied to human breast cancer                Massague et al            ...
Organ-specific breast cancer metastasis                                 Intrinsic subtypes and                            ...
Organ-specific breast cancer metastasis                                 Bone specific profile                             ...
Site of relapse                     NKI 295 breast cancer dataset       88 patients developed distant metastases as first ...
B                                                          A                         Testing                              ...
Profile for bone metastasis                     286 patients, 107 relapses (Lancet, 2005)              Training           ...
Performance of the 31-gene predictor                                Validation set of 35 patients                         ...
Organ-specific breast cancer metastasis                                 Bone metastases signatures                        ...
Breast cancer metastases Management           targeted therapies – multiple sites                                 Targeted...
Recurrent Mutations in Primary and Metastasis       one basal breast cancer example        Whole Genome Sequencing – Red h...
Progression to metastases model   prognostic hardwiring maintained,heterogeneity for (single) gene mutations
Breast cancer metastases Management           targeted therapies – multiple sites                                 Differen...
AcknowledgementsThe Netherlands Cancer InstituteAmsterdam, NL (Bas Kreike, Britta Weigelt, Marc van de Vijver, Stella Mook...
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ABC1 - L. van't Veer - Genomic signatures of specific sites of metastases

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ABC1 - L. van't Veer - Genomic signatures of specific sites of metastases

  1. 1. Genomic Signaturesof Specific Sites of Metastases Laura J. van ‘t Veer Helen Diller Family Comprehensive Cancer Center University of California San Francisco ABC1 Lisbon, Portugal, 2011
  2. 2. Breast cancer metastasis:metastatic capacity and organ specificity?through blood or lymph vessels
  3. 3. Metastasis Models I------------------primary tumor---------------I----metastasis-----I Subpopulations All cells Dynamic heterogeneity Clonal dominance GenometastasisNat Rev Cancer 5, p 591-602, 2005
  4. 4. Breast Cancer Risk of Metastasis and Survival Kaplan-Meier Survival Curve Stage 1/2 ~30% die of breast cancersurvival ~70% survive breast cancer time (years)
  5. 5. 70 Gene Prognosis Profile MammaPrint 70 significant prognosis genesTumor samples van´t Veer et al., Nature 415, p. 530-536, 2002 threshold set with 10% false negatives 91 % sensitivity, 73% specificity
  6. 6. IGFBP5, TGFB3, FGF18, ESM1, RARRES3, PITRM1, EXT1, EXTL3, SCUBE2, EBF4,CDC42BPA, CDCA7, CDCA7L, GMPS, MELK, RFC4, WISP1, HRASLS, proliferation BBC3, DTL, FBXO31, EGLN1, GNAZ, MTDH, FLT1, ECT2, DIAPH3, NUSAP1, AKAP2, NDC80, PRC1, ORC6L, CENPA, DCK, CCNE2, MCM6, QSOX2, STK32B COL4A2, FLT1, FGF18, MMP9 angiogenesis adhesion to extracellular matrix MMP9, COL4A2 FLT1, TGFB3, IGFBP5, FGF18, RARRES3, COL4A2, FLT1, MMP9, TGFB3, MTDH, DIAPH3, intravasation, survival, extravasation local invasion CDCA7L, WISP1, DIAPH3, AKAP2, CDC42BPA, PALM2, DCLK2, NMU, NMUR1, NMUR2 PALM2, DCLK2, NMU, NMUR1, NMUR2 adhesion to extracellular matrix MMP9, COL4A2 IGFBP5, TGFB3, FGF18, ESM1, RARRES3, PITRM1, EXT1, EXTL3, SCUBE2, proliferation EBF4,CDC42BPA, CDCA7, CDCA7L, GMPS, MELK, RFC4, WISP1, HRASLS, BBC3, DTL, FBXO31, EGLN1, GNAZ, MTDH, FLT1, ECT2, DIAPH3, NUSAP1, AKAP2, NDC80, PRC1, ORC6L, CENPA, DCK, CCNE2, MCM6, QSOX2, STK32B COL4A2, angiogenesis MMP9 FLT1, FGF18,Nature, 2002
  7. 7. Breast Cancer – node negative Stage 1/2 Survival by profiling Distinguish in: 40% good profile, 60% poor profile metastases-free overall survival time (years) time (years) 151 patients, <53, LN0NEJM 347, p1999-2009, 2002 10 year survival curve
  8. 8. Breast Cancer – 1-3 node positive Stage 2 Survival by profiling Good profile (n=99) Poor profile (n=142) Distant metastases as first event Overall survival 95% 95% 77% 73% HR 4.1 HR 5.4 (95%CI 1.7 – 10.0), p<0.002 (95%CI 2.1 – 13.8), p<0.001Mook et al, BCRT 2010
  9. 9. Molecular portraits of breast cancer Capacity to metastasizePerou & Sorlie et al,Nature 2000 Survival analysis was done on the 51 doxorubicin treated patients only
  10. 10. Molecular Profiles of the Primary Tumorcan predict risk of metastasis:- MammaPrint 70-gene profile- Intrinsic subtypes (e.g., basal, luminal)- Oncotype 21-gene recurrence score- etcand are clinically usefulto guide the choice of adjuvant therapy
  11. 11. Profiles hard-wired and maintained throughout metastatic process?Nat Rev Cancer 5, p 591-602, 2005
  12. 12. Primary breast tumors – distant metastases Hierarchical clustering8 primary breast tumors and distant metastases of the same patientPNAS 100, p 15901-15905, 2003
  13. 13. Profiles maintained throughout metastatic process 70-gene prognosis profile primary tumor 8goodsignature metastasis 8 primary tumor 4 primary tumor 7 metastasis 1 primary tumor 5 primary tumor 1 metastasis 5 metastasis 4 metastasis 7 primary tumor 3 primarypoor tumor 6signature metastasis 6 metastasis 3Cancer Res 65, 2005
  14. 14. Profiles maintained throughout metastatic process primary tumor – lymph node metastasis pairs primary tumor – distant metastasis pairs primary tumor – brain metastasis pair primary tumor – distant metastasis pairs autopsy Collaboration C. PerouCancer Res 65, 2005
  15. 15. Profiles hard-wired and maintained throughout metastatic processNat Rev Cancer 5, p 591-602, 2005
  16. 16. Organ-specific breast cancer metastasis Prognostic profiles for metastasis such as the 70 gene MammaPrint, 76 gene Rotterdam are maintained, but can not predict site of relapsethrough blood or lymph vessels
  17. 17. Organ-specific breast cancer metastasis Site of relapse intrinsic subtypes, model system signaturesthrough blood or lymph vessels
  18. 18. Intrinsic Subtypes of breast cancer Foekens et al HER2 ER Is there a relationship with the site of relapse? KRT5 Rotterdam data set: Affymetrix U133A chip luminal B luminal A HER2 normal basal 344 untreated lymph node-negative patientsSmid et al; Cancer Res 68, May 2008
  19. 19. Association with site of relapse Foekens et al 118 patients of the 344 had a distant metastasis: - 81 patients with metastasis to single organ - 37 patients with multiple relapse sites (30 with 2 organs) - in total 165 relapses misc: 20 bone: 71 pleura: 12 brain: 14 liver: 18 lung: 30Smid et al; Cancer Res 68, May 2008
  20. 20. Non-random distribution X² statistic 42.78 p 0.0003 Foekens et al SubtypeSmid et al; Cancer Res 68, May 2008
  21. 21. Intrinsic Subtypes of breast cancer (IHC) ERpos / Luminal Higher likelihood for Bone MetastasesHER2pos and Triple negativeHigher likelihood for Brain MetastasesKennecke, JCO 2010
  22. 22. Lung metastasis profile ‘experimental model’ applied to human breast cancer Massague et al Memorial Sloan-Kettering Netherlands Cancer Institute Erasmus Medical Center
  23. 23. Lung metastasis profile ‘experimental model’ applied to human breast cancer Massague et alEvaluated forfirst distantfailure
  24. 24. Lung metastasis profile ‘experimental model’ applied to human breast cancer Massague et al for primary tumors >3cm Netherlands Cancer Institute Erasmus Medical Center
  25. 25. Organ-specific breast cancer metastasis Intrinsic subtypes and model system signatures show differential preference Clinical useful?through blood or lymph vessels
  26. 26. Organ-specific breast cancer metastasis Bone specific profile clinically helpful to direct biphosphonate therapy?through blood or lymph vessels
  27. 27. Site of relapse NKI 295 breast cancer dataset 88 patients developed distant metastases as first site (- A: 26 bone as first event) (- B: 15 bone concurrent with other site) -C: 53 bone at any time Hierarchical clustering 84 samples by 25.000 expressed genesKreike et al, EBCC
  28. 28. B A Testing Training samples samplesKreike et al, EBCC specific genes NKI295 Gene index Classification by 223 bone site Bone-metastasis status (A) Bone-metastasis status (B) Bone-metastasis status (C) ER Status >90% bone mets
  29. 29. Profile for bone metastasis 286 patients, 107 relapses (Lancet, 2005) Training Validation 72 patients: 35 patients: - 46 x bone - 23 x bone - 26 x non-bone - 12 x non-bone SAM and PAM analysis 31 - gene setSmid et al, JCO 24, 2006
  30. 30. Performance of the 31-gene predictor Validation set of 35 patients Sensitivity: 100% (23/23) Specificity: 50% (6/12) Genes higher SAM Fold expressed in Probe-id Gene Symbol Score Change bone FDR (%) PAM Gene Title 205009_at TFF1 -4,92 3,1 * 1,9 yes trefoil factor 1 204623_at TFF3 -4,23 2,6 * 1,9 yes trefoil factor 3 (intestinal) 209173_at AGR2 -4,06 1,9 * 1,9 anterior gradient 2 homolog 214440_at NAT1 -4,04 2,5 * 1,9 yes N-acetyltransferase 1 205081_at CRIP1 -3,80 1,9 * 1,9 yes cysteine-rich protein 1 (intestinal) 214774_x_at TNRC9 -3,72 1,9 * 1,9 yes trinucleotide repeat containing 9 214858_at --- -3,60 2,0 * 1,9 yes Pp14571 219197_s_at SCUBE2 -3,59 2,1 * 1,9 signal peptide, CUB domain, EGF-like 2 215108_x_at TNRC9 -3,57 1,9 * 1,9 yes trinucleotide repeat containing 9 206754_s_at CYP2B6 -3,57 2,1 * 1,9 cytochrome P450, family 2, subfamily B, polypeptide 6 210056_at RND1 -3,48 1,7 * 1,9 yes Rho family GTPase 1Smid et al, JCO 24, 2006 205186_at DNALI1 -3,45 2,0 * 1,9 dynein, axonemal, light intermediate polypeptide 1 203130_s_at KIF5C -3,42 2,0 * 1,9 kinesin family member 5C
  31. 31. Organ-specific breast cancer metastasis Bone metastases signatures interesting, but need clinical validationthrough blood or lymph vessels
  32. 32. Breast cancer metastases Management targeted therapies – multiple sites Targeted therapies match the therapy to the biomarker status of the metastases Hardwiring of prognostic profiles seen, how about specific mutations from primary site to metastases?through blood or lymph vessels
  33. 33. Recurrent Mutations in Primary and Metastasis one basal breast cancer example Whole Genome Sequencing – Red highlighted text = mutation many more in the metastasis Primary Tumor MetastasisDing, Ellis, Mardis et al, Nature, 2010 others: new mutations occur, not all maintained
  34. 34. Progression to metastases model prognostic hardwiring maintained,heterogeneity for (single) gene mutations
  35. 35. Breast cancer metastases Management targeted therapies – multiple sites Different metastases may have different ‘mutations’ Future management: 1) assess biology of primary tumor and 2) re-assess by fine needle aspirates (multiple lesions) biomarker mutation status relevant for targeted therapies (also ER, PR, HER2)through blood or lymph vessels
  36. 36. AcknowledgementsThe Netherlands Cancer InstituteAmsterdam, NL (Bas Kreike, Britta Weigelt, Marc van de Vijver, Stella Mook, Marleen Kok,Lodewyk Wessels, Hans Peterse, Rene Bernards)University of North CarolinaChapel Hill, US (Chuck Perou, Zhiyuan Hu, Cheng Fan)Erasmus Medical CenterRotterdam, NL (Marcel Smid, John Martens, Jan Klijn, Els Berns, John Foekens)University California San FranciscoSan Francisco, US (Denise Wolf, Hope Rugo, Michelle Milesko, Pamela Munster, Joe Gray)

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