BREAST CANCER: From Traditional Treatments to New Approaches

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BREAST CANCER From Traditional Treatments to New
Approaches
Diana C. Márquez-GarbánUniversity of
California, Los AngelesDivision of
Hematology-Oncology
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Global Incidence

• 1.3 million women diagnosed worldwide
• About 555,000 will die from the disease
• 77 of cases occur in women over 50 y
• Most common cancer in women

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Risk Factors

• Age
• Personal history
• Family history (5-10)
• Benign breast disease (atypical hyperplasia
  family history)
• Endocrine factors (late menopause, early
  menarche, OCP gt 10 yrs, pm-HRT gt 15 yrs, early /
  late pregnancy)
• Environmental factors (diet, alcohol,
  carcinogens)
• No attributable risk (70-75)

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Cancer Historical Notes

• An old enemy
• Anthropologists offer evidence of tumorous
  growths in dinosaurs dating from 100-200 million
  years ago
• Mummies from Egypt 5000 years ago with tumors

Edwin Smith Papyrus (1862) Egypt 1500-3000 B.C.
describes breast tumors Treatment fire
drill- non- curable
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1860 William Halsted
Radical Mastectomy Very disfiguring, cuts
breast, muscle
1960 Bernard Fisher
Less surgery is as effective BO4 trial
modified radical mastectomy against Halsted
radical mastectomy
Fisher changes history of treatment of breast
cancer
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Anatomy of the mammary gland
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Mammary gland development
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Diagnosis of Breast Cancer

• Physical examination
• palpable mass (ductal)
• diffuse thickening (lobular)
• Mammogram (15 FN)
• microcalcifications in clusters, spiculated
  lesions
• architectural distortion
• reduced mortality on screening age group gt 50
• Biopsy -

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Mammograms for breast cancer detection
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Pathologic Evaluation Breast Histology
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Immunohistochemistry in Breast Cancer Diagnosis
Prognosis
ER-positive Tumor
HER-2-Overexpressing Tumor
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Breast Cancer Staging and Tumor Size
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Breast Cancer Stages
Stage 0 carcinoma in situ Stage I tumor lt 2
centimeters no spread outside breast. Stage IIA
cancer in axillary lymph nodes or tult 2 cm
with spread to axillary nodes or tumor is 2 -
5 cm and no axillary nodes. Stage IIB 2 - 5
cm tumor, spread to axillary nodes or gt 5 cm, no
spread to nodes. Stage IIIA cancer in
axillary nodes attached each other Stage IIIB
spread to tissues near the breast Stage IIIC
spread to lymph nodes under collarbone and near
neck and may have spread to lymph nodes within
breast or under arm and tissues near
breast. Stage IIIC breast cancer divided into
operable and inoperable stage IIIC. Stage IV
spread to other organs of body, most often bones,
lungs, liver, or brain.
Stressful time for patients -uncertainty- Treatmen
t decisions made- feeling of relieve
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Prognostic Factors
lymph node status negative tumor
size lt1cm grade nuclear grade I flow
cytometry diploid, low S histology tubular,
papillary ER/PR positive HER-2/neu negat
ive Ki67 lt10-15 slower
Investigation angiogenesis, p53 mutation, bone
marrow
micrometastasis
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Treatment
Systemic
Local-Regional
Surgery
/- Radiation
Tamoxifen for ER
Chemoteraphy
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Risks of primary surgery radiation therapy
Post-mastectomy pain syndrome Axillary
LND versus Sentinel LND Lymphedema Skin
changes Psychosexual effects
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Adjuvant chemotherapy
Benefits Decreased risk recurrence 35-50
Decreased risk mortality 20-40 Risks Acute,
reversible nausea, vomiting, fatigue, anemia,
neutrocitopenia, hair loss, etc. Long-term
Acute leukemia (lt1), cardiac toxicity (1
anthracyclines), cognitive deficits chemo
brain, psychological effects.
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Antiestrogen therapy TAMOXIFEN

• Estrogen Receptor first target identified 100 y
  ago
• Used in Estrogen Receptor breast cancer
• Approx. 80 of postmenopausal women ER
• Tamoxifen used for the past 40 years
• Standard therapy given for 5 years
• Reduces chance of late recurrence by 40
• Reduces risk of death

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Antiestrogen therapy TAMOXIFEN
Side Effects Common hot flashes, menstrual
changes, vaginal discharge, uterine
bleeds Occasional thromboembolism, retinopathy,
cataracts leukopenia, anemia, nausea, increased
risk endometrial cancer
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Antihormonal therapy AROMATASE INHIBITORS

• Decrease estrogen production
• New standard of care for ER cancer early and
  metastatic
• Arimidex (anastrozole), Aromasin (exemestane)
  Femara (letrozole)
• Taken as a pill once a day for 5 years.
  Continuously for metastatic disease
• Only given to postmenopausal women

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Antihormonal therapy AROMATASE INHIBITORS

• Benefits
• Reduce risk of cancer coming back or spreading
• Reduce risk of a new cancer starting in the
  other breast
• Shrink a medium-to-large breast cancer before
  surgery
• Side Effects
• Hot flashes, vaginal dryness, decrease libido,
  artralgias, reduced bone mass, blood cloths

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Antiestrogen therapy Faslodex (fulvestrant)

• Estrogen Receptor down regulator
• Approved for metastatic breast cancer after
  hormonal treatments failed
• No risk of endometrial cancer
• Works as well or better than AI
• Given as an injection once a month
• Similar side effects as AI and tamoxifen

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Molecular alterations in breast cancer progression



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Estrogen signaling interacts with EGFR/HER
pathways
EGFR/HER
estrogen
shc
ER
MNAR
ER
ARO
cytoplasm
MAPK/AKT
ER
ER
Ligand-independent
Ligand-dependent
P
ER
SRC-3
Growth Survival Angiogenesis
TF
ER
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nucleus
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Targeted Therapies

• Monoclonal antibodies- Herceptin
• Protein kinase inhibitors (Lapatinib, Gleevec,
  Iressa,Tarceva)
• Anti-angiogenic agents ( Squalamine, Avastin,
  SU5418, Thalidomide)
• Retinoids
• Antihormone agents- Endocrine Therapy

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Herceptin (Trastuzumab)

• Humanized antibody to HER-2 receptor
• For use in treatment of HER-2-expressing
  breast cancer
• Approved for metastatic disease and early as
  adjuvant therapy
• Increases survival and time to progression
• Infusion-related symptom complex
• Risk of cardiomyopathy

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Targeted Therapies
Monoclonal antibodies (Rituximab, Herceptin)
Protein kinase inhibitors (Lapatinib, Gleevec,
Iressa,Tarceva) Anti-angiogenic agents (
Squalamine, Avastin, SU5418, Thalidomide)
Retinoids
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Lapatinib

• TKI-targets EGFR and HER-2
• Oral drug
• Useful fro patients resistant to trastuzumab
• May be effective for brain metastasis
• Used with Capecitabine for advanced disease
• Increases survival and time to progression
• Used in inflammatory breast cancer

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Targeted Therapies
Monoclonal antibodies (Rituximab, Herceptin)
Protein kinase inhibitors (Lapatinib, Gleevec,
Iressa,Tarceva) Anti-angiogenic agents (
Squalamine, Avastin, SU5418, Thalidomide)
Retinoids
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Tumor-Associated Angiogenesis
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Bevacizumab- Avastin

• Humanized antibody to VEGF
• Approved for metastatic disease in combination
  with Taxol (HER-2 neg)
• High blood pressure, nose bleeds, protein in
  urine
• Trials combined with Paclitaxel produce overall
  response of 50

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Treatment
Systemic
Local-Regional
Tamoxifen for ER
Surgery
Chemoteraphy
/- Radiation
No-antracyclins
Aromatase Inhibitors Fulvestrant
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Life Style Changes First

• Body Weight
• Diet
• Exercise
• Stess managemenet
• Complementary therapy
• Supplements

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Body Weight and Diet

• Healthy weight reduces first time breast cancer
  and recurrence
• Low fat diet
• Plenty of vegetables and fruits (5 servings)
• Avoid trans fats, red meats and smoked foods
• Extra protein
• Non-fat dairy
• Fish, beans, tofu
• Nuts

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The 3 As
Antinflamatories Omega 3 Fatty Acids fish,
flaxseed

• Anticarcinogens
• Black raspberries
• Curry
• Citrus fruits
• Green Tea
• Pomegranate
• Nuts
• Tomatoes
• Saffron

• Antioxidants
• Pomegranate
• Red grapes and red wine
• Berries
• Beans
• Green and black tea
• Onions, chives, garlic
• Cabbage family

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Life Style Changes First

• Body Weight
• Diet
• Exercise weights and resistance exercise- bone
  health and muscle preservation
• Stress management yoga, tai chi, meditation,
  journalism, joyful activities, NO INTERNET
• Complementary therapy
• Supplements
• Spirituality

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Complementary and Alternative Therapies

• 50-70 of breast cancer patients use some form
  of complementary therapy
• Diet megavitamins, supplements
• Acupuncture, massages
• Spiritual healing
• Most patients do not tell their doctor about
  alternative therapies they are using

Evidence-based methods meditation to reduce
stress acupuncture for relief of pain and
nausea
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After cancer renewal, rebirth, recovery,
reasonable goals
Quality of Life

• Focus on wellness
• Nutrition
• Exercise
• Alternative therapies
• Stress management
• Spirituality-Journalism
• Peer support, art

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Acknowledgments
National Program Excellent University EU/Slovakia
UCLA Richard J. Pietras Hermes J.
Garbán Hsiao-Wang Chen Olga Weinberg Edward
Garon Eugene Tsai Jeison Recinos

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Angel's Fall or Churun Meru (Canaima-Venezuela)
The highest waterfall on earth with 3,212 feet
(979 m) of free fall. Photo by Fernando Santos