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 …

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

Transcript

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