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Breast Cancer - Molecular Basis of HER2+ Disease

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This presentation was part of a graduate level advanced molecular cell biology course. It reviews Breast Cancer epidemiology, signs 7 symptoms, diagnosis, genetic testing, hormonal testing and treatment options (briefly), then discusses the specifics of HER2+ cases at the cellular level. It shows how Herceptin and Tykerb work in the cell to block signal cascades, etc.

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Breast Cancer - Molecular Basis of HER2+ Disease

  1. 1. Breast Cancer<br />Chapter 20 - Cancer<br />FarynKapala<br />
  2. 2. Outline<br />1.) Epidemiology2.) Signs & Symptoms3.) Diagnosis/Screening-Genetic Testing (BRCA1/2)-Hormonal Testing (ER/PR)-HER24.) Types of Breast Cancer5.) Treatments6.) HER2+ Pathway7.) HER2+ Drugs Available8.) Herceptin<br />
  3. 3. Epidemiology<br />Worldwide<br />Incidence rates per 100,000 people<br /> Most common cancer in women worldwide<br />http://www.time.com/time/interactive/0,31813,1668275,00.html<br />
  4. 4. Epidemiology<br />United States – FemalesIncidence by State 2007<br />DARKER BLUE = ↑ INCIDENCE<br />202,964 new cases diagnosed/yr<br />40,598 women die/yr<br />http://www.cdc.gov/cancer/breast/statistics/state.htm<br />
  5. 5. Epidemiology<br />Ethnic<br />WHITE<br />BLACK<br />HISPANIC<br />ASIAN/PACIFIC ISLANDER<br />AMER. INDIAN/ALASKA NATIVE<br />http://www.cdc.gov/cancer/breast/statistics/race.htm<br />
  6. 6. Epidemiology<br />Age<br />Age 50-59 most cases diagnosed<br />http://www.cdc.gov/cancer/breast/statistics/race.htm<br />http://columbiachronicle.com/wp-content/metro-breast-cancer.jpg<br />
  7. 7. Men & Breast Cancer<br />Not very common.<br />1 in 100 cases of breast cancer are in men.<br />Most common between 60-70 years old.<br />Signs, symptoms, treatment essentially the same for both genders.<br />
  8. 8. Signs & Symptoms<br />Lump , thickening, swelling that feels different from the surrounding tissue<br />Abnormal dischargefrom the nipple<br />Changes to the skin over the breast, such as dimpling<br />Inverted nipple<br />Peeling, scaling , flaking of the nipple or breast skin<br />Redness or pitting of the skin over the breast<br />http://www.aurorahealthcare.org/yourhealth/healthgate/images/exh38245c_105433_1.jpg<br />75% of women diagnosed had no symptoms, no family history, and felt no lumps!<br />
  9. 9. Signs & Symptoms<br />http://www.aurorahealthcare.org/yourhealth/healthgate/images/exh38245c_105433_1.jpg<br />http://www.healthyjunkie.com/blog/na/2007/8/6/tn_breast_cancer.jpg<br />http://media.jaapa.com/images/2009/04/21/breastcancerCME0907fig1_50528.jpg<br />
  10. 10. Diagnosis<br />1.) Screening Tests Physical Exams<br /> Self Exams<br /> Mammograms Ductal lavage<br />2.) Diagnostic Tests <br />-Mammogram<br />-Biopsy -Blood Marker Tests <br />(CA 15.3, TRU-QUANT, CA 27.29, CA125, CEA) -MRI<br />-Ultrasound<br />http://t3.gstatic.com/images?q=tbn:ANd9GcQN1YcpQyNSn_pUk2oPrX2bGDTphhIS0ZePKZJ0LEK9__s1QAIJ6A<br />
  11. 11. Diagnosis<br />http://www.cancer.gov/PublishedContent/Images/images/documents/f8fd346c-2b66-46db-b2c3-05bb5fd19712/show.jpg<br />
  12. 12. Genetic Testing- BRCA1 & BRCA2 <br />-Breast Cancer Susceptibility genes<br />-tumor suppressor genes<br />- Blood test  DNA analysis<br />- High-risk persons only<br />- If you have a mutation in BRCA1 or BRCA2:<br /> - 35-84% chance of developing breast cancer - 10-50% chance of developing ovarian cancer<br />- 1 in 300-500 women have BRCA mutations (one-quarter of one percent of all women)<br />http://www.cancer.gov/PublishedContent/Images/images/documents/f8fd346c-2b66-46db-b2c3-05bb5fd19712/show.jpg<br />
  13. 13. BRCA1 & BRCA2 Pathway<br />Healthy Cells<br />Diseased Cells<br />BRCA1/2 mutations:<br />-Missing protein<br />-Non-functional protein<br />Leads to defective:<br />- DNA repair<br />- Transcription<br />- G2/M cell cycle checkpoint regulation<br />- spindle checkpoint<br />Image adapted from: http://www.nature.com/nrc/journal/v3/n1/images/nrc970-f1.jpg<br />
  14. 14. Additional Testing – Hormonal Receptors<br />Estrogen & Progesterone Biomarker tests <br />Estrogen Receptor Positive (ER+)<br />-Immunohistochemistry (IHC) test from biopsied tissue sample<br />-OncotypeDx Test genomic testing, looks at groups of genes (21 genes) & how active they are.<br />-Fluorescence in situ hybridization test (FISH) – often used to help verify IHC, gene mapping technique<br />http://www.femara.com/images/how_femara_works_diaA.jpg<br />
  15. 15. Additional Testing – Hormonal Receptors<br />Estrogen & Progesterone Biomarker tests <br />ER+ or PR+ is “a good thing” <br />- indicates that these hormones help tumor cells grow<br />- numerous hormone suppression treatments available<br />-prophylactic procedures (removal of ovaries)<br />-slower growing than ER-/PR- types<br />
  16. 16. Additional Testing – HER2<br />human epidermal growth factor receptor 2<br />http://www.roche.com/med-her2-600px.jpg<br />HER2+ is “not a good thing” <br /> -targeted therapies available (Herceptin & Tykerb)<br />-tend to be more aggressive<br />-less responsive to hormone treatments<br />~25% of breast cancers are HER2+<br />
  17. 17. Types of Breast Cancer<br />http://besthealth.bmj.com/x/images/bh/en-gb/mastitis-image_default.jpg<br />
  18. 18. Types of Breast Cancer<br />
  19. 19. Types of Breast Cancer<br />Invasive<br />Non-Invasive<br />80%<br />10%<br />
  20. 20. Normal vs. Invasive Ductal Carcinoma<br />http://www.aboutcancer.com/breast_dcis_burstein1.jpg<br />Normal  Precancerous  In situ  Invasive<br />
  21. 21. Treatments<br />1.) Surgery –lumpectomy, mastectomy, lymph node removal<br />2.) Chemotherapy<br />-Doxorubicin & Docetaxel<br /> -Doxorubicin & Cyclophosphamide w/ or w/out Paclitaxel<br />-Cyclophosphamide, Methotrexate and Fluorouracil<br />3.) Radiation therapy<br />4.) Hormonal Therapy  (Hormonal Inhibitors)<br />-Aromatase Inhibitors (anastrozole, exemestane, letrozole) -Selective Estrogen Receptor Modulators (SERMs)<br /> (tamoxifen, raloxifene, toremifene)<br />-Estrogen Receptor Downregulators (ERDs)<br /> (fulvestrant)<br />
  22. 22. Normal vs. Cancerous HER2+<br />Yes, normal cells <br />have HER2<br />The difference:<br /> 1.) receptor overexpression<br />2.) dysregulation of receptor activation<br />NORMAL HER2<br />CANCER HER2+<br />http://www.herceptin.com/metastatic/what-is/how-does-it-work.jsp<br />
  23. 23. Structure of a HER family receptor<br />On the surface of cells<br /> extracellular<br />transmembrane<br />tyrosine kinase domains<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  24. 24. The HER’s are a family of structurally-related cell surface proteins<br />HER2<br />HER4<br />HER3<br />Extracellular ligand-binding domain<br />Transmembrane<br />domain<br />Intracellular tyrosine kinase domain<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  25. 25. With the exception of HER2, HER proteins undergo a conformational change upon ligand binding that is essential for dimerization and signaling<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  26. 26. HER2 is always in an open conformation making it an ideal dimerization partner <br />HER2 does not require a ligand to be primed<br />HER2<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  27. 27. Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling<br />Homodimers<br />Heterodimers<br />HER1:HER3<br />HER1:HER2<br />HER1:HER4<br />HER4:HER4<br />HER3:HER3<br />HER2:HER3<br />HER2:HER2<br />HER2:HER4<br />HER1:HER1<br />HER3:HER4<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />+<br />Signaling activity<br />Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397.<br />
  28. 28. HER2:HER3 trigger complementary oncogenic signals <br />Ligand-activated HER2:HER3 dimer<br />HER2<br />HER3<br />Phosphorylation of the tyrosine kinase domain initiates intracellular signalling<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  29. 29. AKT<br />P<br />P<br />P<br />P<br />P<br />P<br />P<br />RAS<br />Sos<br />Grb2<br />Shc<br />PI3K<br />PDK1<br />Raf<br />GSK3ß<br />NFκB<br />mTOR<br />MEK<br />BAD<br />Cyclin D1<br />MAPK<br />p27<br />HER2 signaling results in a multitude of cellular effects, including not only increased cellular proliferation, but also cell survival<br />HER2<br />HER3<br />Apoptosis<br />Survival<br />Cell cyclecontrol<br />Angiogenesis<br />Proliferation<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  30. 30. AKT<br />P<br />P<br />P<br />P<br />P<br />P<br />P<br />RAS<br />Sos<br />Grb2<br />Shc<br />PI3K<br />PDK1<br />Raf<br />GSK3ß<br />NFκB<br />mTOR<br />MEK<br />BAD<br />Cyclin D1<br />MAPK<br />p27<br />Drugs used in HER2+ Cancer Treatment<br />Herceptin attaches to HER2, blocking dimerization<br />Pertuzumab(Clinical Trials)<br />HER2<br />HER3<br />Tykerb is a tyrosine kinase inhibitor<br />Apoptosis<br />Survival<br />Cell cyclecontrol<br />Angiogenesis<br />Proliferation<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  31. 31. Herceptin blocks HER2 dimerization<br />Ligand-activated HER2:HER3 dimer<br />HER2<br />HER3<br />Blocks intracellular signalling<br />http://www.biooncology.com/research/her/multimedia/index.html<br />
  32. 32. Herceptin (trastuzumab)<br />-Monoclonal antibody <br />-Systemic treatment<br />-Intravenous infusion<br />1st dose – 90 minutes<br />Weekly or Every 3 weeks – 30 minutes<br />-Often given as part of a chemotherapy course including doxorubicin, paclitaxel or doetaxel<br />-No benefit of taking if not HER2+<br />
  33. 33. Herceptin – Cost of Tx.<br />~$10,000/dose<br />$520,000/ yr for weekly users<br />$173,000/ yr for tri-weekly users<br />-Usually taken for 1 year<br />-Patent Protection until at least 2019<br />-No generic available<br />
  34. 34. Herceptin – Side Effects<br />MOST COMMON<br />SEVERE<br />Fever<br />Nausea<br />Vomiting<br />Infusion Reactions<br />Diarrhea<br />Infections<br />Increased cough<br />Headache<br />Fatigue<br />Shortness of breath<br />Rash<br />Low white & red blood cell counts<br />Muscle pain<br />Reduced Heart Function<br />Congestive Heart Failure<br />Swelling of the Lungs<br />Severe shortness of breath<br />Fetal death<br />Worsening of blood counts<br />
  35. 35. References<br />Please see available handout, too many to list!!<br />
  36. 36. Any Questions?<br />

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