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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  • 75% quote: http://www.breastcancer.org/symptoms/testing/types/
  • “Tentacles” from tumor pass up into fat layer of the breast causing dimpling of the skin
  • Mammograms – specialized x-ray device with specialized camera, used for 40 yrs, used to diagnose, evaluate & follow ppl., takes about 20 minutes, takes 2 pictures from 2 directionsUltrasound - – helps distinguish solid or fluid-filled lumps , often used prior to a Mammogram in women less than 30 years old
  • Mammograms – specialized x-ray device with specialized camera, used for 40 yrs, used to diagnose, evaluate & follow ppl., takes about 20 minutes, takes 2 pictures from 2 directionsUltrasound - – helps distinguish solid or fluid-filled lumps , often used prior to a Mammogram in women less than 30 years old
  • - Having the mutation doesn’t mean your cancer is more lethal -Men with Braca mutation less likely (5-10% chance) of developing breast cancer
  • Several FA proteins, including A, C, E, F and G, form a complex in the nucleus of normal human cells. In response to DNA damage, or during the S phase of the cell cycle, this complex mediates the monoubiquitylation (Ub) of FANCD2 at lysine 561 (K561). Activated FANCD2, in turn, is translocated to chromatin and DNA-repair foci. These foci contain the BRCA1 protein and the BRCA2–FANCD1 protein complex. BRCA2/FANCD1 is known to bind directly to RAD51 and to DNA, and to participate in homology-directed DNA repair. Taken together, the model indicates that the FA/BRCA pathway regulates DNA repair.More than 1600 mutations have been identified inBRCA1. While a small number of these mutations have been identified repeatedly in unrelated families, the vast majority have not been reported in more than a few families. hetranscription of BRCA1 is induced late in the G1 phase of the cell cycle and remains elevated during the S phase, indicating some role in DNA synthesis [Gudas et al 1996,Rajan et al 1996]. A variety of evidence now points to the breast cancer type 1 susceptibility protein as being directly involved in the DNA repair process.BRCA1 colocalizes with BRCA2 and RAD51 at sites of DNA damage and activates RAD51-mediated homologous recombination repair of DNA double-strand breaks 
  • Have to be retested because this can change!
  • Anthracyclines are chemically similar to an antibiotic. Anthracyclines damage the genetic material of cancer cells, which makes the cells die. Adriamycin, Ellence, and daunorubicin are anthracyclines.Taxanes interfere with the way cancer cells divide. Taxol, Taxotere, and Abraxane are taxanes.
  • 2006, Genentech
  • 2006, Genentech
  • 2006, Genentech
  • 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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