Er pos and pr neg breast cancer


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  • Microarray studies show that luminal types express high amounts of luminal cytokeratins and genetic markers of luminal epithelial cell of normal breast tissueBasal-like  no ER, PR, or ER related genes; high levels of EGFR, c-kit, and growth factors such as hepatocyte growth factor and IGF
  • 34 with distant mets at <5 yrs, 44 disease-free at >5 years, and 18 BRCA1/2 BRCA2 germline mutations; 19 to validate signatureStatistical analysis called “supervised classification,” the expression of 231 genes seemed to be significantly correlated with disease outcome (distant mets within 5 years). They were ranked on the basis of their correlation coefficient with disease outcome; the top 70 genes were shown to most accurately classify tumors in either good or poor prognosis categories.Pts with correlation coefficient >0.4 were in the good prognosis groupOdds ratio of distant mets in the poor prognosis group compared to the good prognosis group = 15
  • Er pos and pr neg breast cancer

    2. 2. Question 1• Important prognostic factors in breast cancer include: – A. Lymph node status, hormone receptor status, and TNM stage – B. Histologic subtype – C. Family History – D. Age at diagnosis
    3. 3. Question 2• Genomic Analysis: – A. Determines familial breast cancer risk – B. Oncotype DX technology is useful in ER+ and ER- breast cancers – C. Helps determine the best adjuvant chemotherapy regimen – D. Has been validated in retrospective studies
    5. 5. Outcomes of Adjuvant Chemotherapy in Breast Cancer Copyright © American Society of Clinical OncologyWalgren et al. JCO 2005;23:7342-7349
    6. 6. Changing PortraitsConcept evolution claudin low Lum A Lum B Basal Her2
    7. 7. Adjuvant Systemic Therapy forBreast Cancer: Decision Making Prognostic Factors – Estimate outcome independent of systemic treatment – Reflect tumor biology: Who should be treated? Predictive Factors – Reflect a relative resistance or sensitivity to specific therapy – What specific treatment(s) should be offered to an individual?
    8. 8. Breast Cancer Prognostic Factors Accepted – TNM Stage – Axillary Nodal Status – Tumor Size – Tumor Grade – ER Content – Oncotype DX (?) Investigational – Gene expression arrays – Proteomics – Pharmacogenetics – Novel imaging – Other
    9. 9. Breast Cancer Predictive Factors Accepted – ER status – Grade – HER 2 overexpression – Oncotype DX (?) Investigational – Gene expression arrays – Proteomics – Pharmacogenetics – Novel imaging – Other
    10. 10. Intrinsic Breast Cancer Subtypes described by Perou et al.Luminal ALuminal B HER2+Basal-like Express ↑ amountsExpress ↑ levels of EGFR, Of luminal cyto-c-kit, & growth factors like Keratins & genetichepatocyte growth factor Markers of luminaland IGF Epithelial cells of Normal tissue Sotiriou, C. et al. NEJM, 2009. 11
    11. 11. Figure 1a.Sorlie T, Tibshirani R, Parker J, et al: Repeated observation ofbreast tumor subtypes in independent gene expression datasets. Proc Natl Acad Sci U S A 100:8418-23, 2003 12
    12. 12. St. Gallen 2007 Highly Endocrine Non–endocrine Incompletely Responsive Responsive Endocrine Responsive High ER and PgR ER and PgR Low ER and PgR and both absent or No HER2 PgR absent overexpression or and Low Ki-67 HER2 overexpression or High Ki-67ER = estrogen receptor; PgR = progesterone receptor.Goldhirsch et al. Ann Oncol. 2007;18:1133. 13
    13. 13. St. Gallen – Endocrine Responsiveness“Practical” Clinical Subgroups Endocrine- responsiveness Absent Uncertain Sure ER and PR absent ER and PR low/int Both receptors and/or any of these high levels • PgR absent No • UPA/PAI-1 high No • HER-2 overexpressed No • Increased proliferation No • High grade No Chemo only options Chemo adds Chemo doesn’t work to hormonal 14
    14. 14. The Level of ER Expression IsPredictive The higher the level of expression, the greater the benefit from endocrine treatment The higher the level of expression, the lesser the added benefit of chemotherapy 15
    15. 15. Added Value of PgR Status inAssessing Endocrine Responsiveness Estrogens ER Estrogen-responsive elements Cell cycle PgR synthesis 16
    16. 16. Added Value of PgR Status Assessment Quality control of ER status assessment – ER-/PgR+ tumors do not exist (almost!) – ER 10%/PgR 90% is very unusual (and likely related to poor sensitivity of ER staining) Prognosis (among ER+ tumors) Effectiveness of endocrine therapies (and chemotherapy in premenopausal patients) Response to AI?AI = aromatase inhibitor.Viale et al. J Clin Oncol. 2007;25:3846. 17
    17. 17. STEPP for Central PgR (ER-Expressing) in the BIG 1-98 Trial 100 80 4-y DFS (%) Tamoxifen 60 Letrozole 40 20 0 0 10 30 40 50 60 75 90 99 Subpopulation by PgR%STEPP = subpopulation treatment effect pattern plot. 19
    18. 18. Is ER/PgR Status Assayed Well inClinical Practice? Inconsistent allocation to “ER/PgR-negative” – No immunoreactive cells? – Less than 10% immunoreactive cells? – Less than 20% immunoreactive cells? – A different threshold for different clinical questions/settings? Conflicting results – >15% disagreement between different laboratories (false negative) 20
    19. 19. False-Positive Assays? Local Central N % N % ER+/PgR+ 3124 71.0 3330 75.7 ER+/PgR- 965 21.9 832 18.9 ER+/PgR? 220 5.0 48 1.1 ER-/PgR+ 80 1.8 13 0.3 ER-/PgR- 5 0.1 103 2.3 ER-/PgR? 0 0 1 <0.1 ER?/PgR+ 2 <0.1 23 0.5 ER?/PgR- 0 0 7 0.2 ER?/PgR? 3 <0.1 42 1.0 21
    20. 20. Oncotype DX 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 StudiesPROLIFERATION ESTROGEN RS = + 0.47 x HER2 Group Score Ki-67 ER - 0.34 x ER Group Score STK15 PR + 1.04 x Proliferation Group Scor Survivin Bcl2 + 0.10 x Invasion Group Score Cyclin B1 SCUBE2 + 0.05 x CD68 MYBL2 - 0.08 x GSTM1 GSTM1 BAG1 - 0.07 x BAG1 INVASION Stromelysin 3 CD68 Category RS (0-100) Cathepsin L2 REFERENCE Low risk RS <18 Beta-actin Int risk RS ≥18 and <31 HER2 GAPDH GRB7 RPLPO High risk RS ≥31 HER2 GUS TFRC Paik et al. N Engl J Med. 2004;351:2817- 22
    21. 21. Standardized Quantitative Oncotype DX Assay Recurrence Score in N-, ER+ patients 40% Intermediate Low Risk Group High Risk Group Risk Group 35% Distant Recurrence at 10 Years 30% 25% 20% 15% 10% 5% 0% 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score Lower RS’s Higher RS’s •Lower likelihood of recurrence •Greater likelihood of recurrence •Greater magnitude of TAM benefit •Lower magnitude of TAM benefit •Minimal, if any, chemotherapy benefit •Clear chemotherapy benefit1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 233) Paik et al JCO 2006, 4) Gianni et al JCO 2005 23
    22. 22. Oncotype DX Extensively Studied:Study Experience in >3700 Patients Study Type No. Pts Providence Exploratory 136 Rush* Exploratory 78 NSABP B-20 Exploratory 233 NSABP B-14* Prospective 668 MD Anderson* Prospective 149 Kaiser Permanente* Prospective Case-Control 790 Cases/Controls NSABP B-14 Prospective Placebo vs Tam 645 Milan* Exploratory 89 NSABP B-20* Prospective Tam vs Tam+Chemo 651 ECOG 2197* Exploratory and Prospective 776 SWOG 8814 Prospective Tam vs Tam+Chemo 367 *Published studies24
    23. 23. Schema: TAILORx Node-Neg, ER-Pos Breast Cancer RegisterSpecimen Oncotype DX Assay banking RS 11-25 RS <10 Randomize RS >25 Hormone Hormone Rx Chemotherapy Therapy vs + Registry Chemotherapy Hormone Rx + Hormone Rx Primary study group 25
    24. 24. Mammaprint: Development of the 70-Gene Signature DNA microarray analysis of 78 breast primary tumors (untreated) – Pts were <55 years of age with T1-2/N0 disease – Pts selected based on outcome: Distant metastases within 5 years Statistical analysis, “supervised classification,” identified 231 genes correlated with disease outcome  Top 70 genes selected Genes that regulate cell cycle, invasion, metastasis, & angiogenesis Patients categorized as “good prognosis” or “poor prognosis.” Found to be a better predictor of distant metastases within 5 years than all clinical variables in this study Van ’t Veer, L. Nature, 2002. 26
    25. 25. EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative women Evaluate Clinical-Pathological risk and 70-gene signature risk N=3300 (55%) N=2100 (35%) N=600 (10%) Clinical-pathological Discordant cases Clinical-pathological and 70-gene both Clin-Path LOW Clin-Path HIGH and 70-gene both HIGH risk 70-gene HIGH 70-gene LOW LOW risk Randomize Use Clin-Path risk to Use 70-gene risk to decide decide Chemo or not Chemo or not Adjuvant Adjuvant Endocrine Chemotherapy therapy only (+ endocrine Tx if ER+) The goal of this trial is to show that MammaPrint can spare 20-30% of patients from adjuvant chemoDr Martine Piccart-Gephart JBI, Brussels 27
    26. 26. 70-gene 21-gene 2-Gene Intrinsic Signature Signature Ratio Subtypes Analysis Supervised Supervised Supervised UnsupervisedApproach Formalin-Fixed, Formalin-Fixed, Formalin-Fixed,Tissue Type Fresh or Frozen Parafin- Parafin- Parafin- embedded embedded embeddedTechnique DNA microarrays Q-RT-PCR Q-RT-PCR Q-RT-PCRPrognostic Untreated pts Untreated & TAM-treated, TAM-treated age<60, T1-2, LN- TAM-treated ER+/LN- ER+/LN- untreatedPredictive Benefit to TAM Response to TAM NO +/- CMF/MF NOValidation Retrospective Retrospective Retrospective RetrospectiveProspective Trials MINDACT TAILORX NONE NONE 28
    27. 27. Steroid Hormone Receptor SignalingReading:Handbook of cell signaling, Ed RA Bradshaw and EA Dennis, 2003.Chapter 275Cheskis, BJ, 2004. Regulation of cell signaling cascades by steroidhormonesSteroid hormones are produced by endocrine glandsEssential regulators of: reproduction, secondary sexcharacteristics Development, differentiation Glucose metabolism Response to stress and salt balance
    28. 28. Nuclear Receptor Superfamily large family of structurally related ligand-inducible transcription factors, including:  steroid receptors (SRs),  thyroid/retinoids receptors (TR, RARs and RXRs), vitamin D receptors (VDR),  estrogen receptors (ERa and ERb),  and orphan receptors for which no ligand has been yet identified. While having in common a modular structure, they are activated by distinct lipophilic small molecules such as glucocorticoids, progesterone, estrogens, retinoids, and fatty acid derivatives
    29. 29. Estrogen Receptors ER-  Uterus, testis, pituitary, ovary, epididymis, and adrenal gland. ER- (Kuiper et al. 1996)  brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis.  88% identity with rat ER-b; 47% identity with human ER-a Both ERs are localized to membrane, cytosol, and nucleus. ER and differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain. Estrogen-related orphan receptors (ERR)
    30. 30. Estrogen Receptors
    31. 31. Estrogen Receptor
    32. 32. ER effects on different cell types
    33. 33. Steroid receptor coactivators and ER-dependent gene transcription Histone P/CAF Acetylase CBP Activity SRC Family AIB1 TranscriptionEstradiol-bound ER
    34. 34. Mode of Action of Estradiol Estradiol AF2 Coactivator FULLY E + ER E E ACTIVATED E RNA E ERE TRANSCRIPTION Receptor Nuclear POLII Coactivator (tumor cell AF1dimerization localization of AF1 division) fully active ER AF1 + to ERE AF1 and AF2 AF2 recruit ACTIVE coactivatorsted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.
    35. 35. Fig.15-12
    36. 36. HREs are short cis-acting sequences located within the promoters orenhancers of target genes.HREs: inverted repeats of AGGTCA (ER and ERRs) inverted repeats of AGAACA (for GR, MR, PR, and AR)
    37. 37. Hall et al.J. Biol. Chem., Vol. 276, Issue 40, 36869-36872, October 5, 2001
    38. 38. Genomic versus Non- genomic changes in gene  changes in existing expression enzyme activity and/or protein structure delayed (hrs-days)  rapid (sec-min) requires nuclear  unknown cytosolic receptor mechanisms prevented by  not affected by transcription and transcription and translation inhibitors translation inhibitors
    39. 39. Cross-talk between signal transduction and endocrine pathways Growth factor Estrogen IGFR HER2 Trastuzumab Plasma P P membrane P P P AI P SOS PI3-K RAS RAF Cell P survival Akt MEK P ER p90RSK P MAPK P Cytoplasm Cell P P P Basal growth P transcription ER p160 CBP machinery ER Nucleus ERE ER target gene transcription Adapted from Johnston
    40. 40. Ligand E ErbB ErbB P P P Ep85 p110 Ras ER Akt MAPK P E P ER Transcription ER-Responsive Element
    42. 42. ER+/PR tumors are resistant totamoxifen (ATAC) From Cui et al. JCO 23:7721, 2005
    43. 43. Negative PR is a marker of high HER1/HER2 levels and tamoxifen resistance ER+/PR+ ER+/PR+ Arpino et al. JNCI 97:1254, 2005
    44. 44. Negative PR is a marker of high HER1/HER2 levels and tamoxifen resistance ER+/PR+ ER+/PR ER+/PR+ ER+/PR Arpino et al. JNCI 97:1254, 2005
    45. 45. The Molecular Portrait Hypothesis You can recognize the Mona Lisa by her smileand her nose and her eyes and even her hands – if you are really good, but not the sky or the trees
    46. 46. The Promise of Personalized Medicine in Breast Cancer TamoxifenPostmenopausalWomen with HR+ Aromatase breast Cancer Inhibitor Chemotherapy Biologic agents Anth, Taxane, Platimun Her2, EGFR, VEGF, Parp
    47. 47. Question 1 • Important prognostic factor in breast cancer include lymph node status, hormone receptor status, and TNM staging – Histologic subtype and family history have not been independently validated prognostically, and age at diagnosis is neither prognostic nor predictiveStearns, BCRT 1998; 52: 239-259Harris, L, J Clin Oncol 2007 Nov 20; 25 (83) 5287-312
    48. 48. Question 2 • Genomic analysis has been validated in retrospective studies – Available genomic analytic assays (Oncotype DX, Mammaprint) do not determine familial risk. Oncotype DX has been validated only in ER+ breast cancers. Neither assay determines type of adjuvant chemotherapy.Paik, S, N Eng J Med 2004 Dec 30; 351(27): 2817-26Paik, S, J Clin Oncol 2006 Aug 10; 24(23): 3726-34Albain, K, SABCS 2007 abstr #10
    49. 49. Question 3• HORMONAL THERAPY FOR ER+ PR – BREAST CANCER 1. AI - 52% lower risk for recurrence 2. EGFR INHIBITORS , m TOR INHIBITORS, PI3K INHIBITORS, IGF INHIBITORS anastrozole plus gefinitib- 49% clinical benefit.