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BREAST CANCER

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Title: BREAST CANCER


1
BREAST CANCER
2
  • Incidence and Mortality
  • Breast cancer is the most common malignancy
    diagnosed in women in the U.S.
  • The second most common cause of cancer death in
    women, surpassed only by lung cancer.
  • Approximately 213000 new cases of breast cancer
    are expected to be diagnosed in the U.S. during
    2006
  • An estimated 41,000 people are expected to die
    with breast cancer at 2006

3
  • Etiology
  • The etiology of breast cancer is unknown
  • But several predisposing factors for the disease
    have been determined.
  • These factors can be divided into three major
    categories
  • Genetic or familial factors
  • Endocrine factors
  • Environmental factors

4
  • Risk factors for breast cancer development
  • Personal history of breast cancer
  • Family history of breast cancer in first-degree
    relatives
  • Proliferative benign breast disease
  • Early menarche, late menopause
  • Nulliparity
  • First pregnancy after age 35
  • Exogenous estrogens (postmenopausal hormone
    replacement therapy, oral contraceptives)
  • Obesity (menopausal weight gain, fat
    distribution)
  • Dietary factors (alcohol, high fat diet)
  • Radiation

5
  • Pathophysiology
  • Breast anatomy
  • Human breast tissue is composed primarily of
    connective tissue and fat.
  • There is also an elaborate duct system within the
    breasts that is used during lactation.
  • Breast tissue has an abundant blood supply and an
    extensive lymphatic network.
  • Lymphatic drainage of the mammary tissues flows
    into the axillary, interpectoral, and internal
    mammary lymph nodes

6
Lymph node areas adjacent to breast area. A
pectoralis major muscle B axillary lymph nodes
levels I C axillary lymph nodes levels II D
axillary lymph nodes levels III E
supraclavicular lymph nodes F internal mammary
lymph nodes
7
  • A womans breast tissue and glands begin to
    develop around the time of puberty (limited) and
    the majority occurs during the first pregnancy.
  • The large amounts of estrogen and progesterone
    produced by the ovaries during pregnancy
    stimulate rapid growth and terminal
    differentiation of immature breast tissue.

8
  • Tumor development
  • Breast cancer occurs when breast cells lose their
    normal differentiation and proliferation controls
  • The proliferation of these abnormal cells, or
    tumor cells, is influenced by various hormones,
    oncogenes, and growth factors.
  • There is strong evidence to suggest that estrogen
    directly and indirectly stimulates the growth of
    tumor cells.
  • Also, numerous growth factors, secreted by the
    breast cancer themselves, play a role in tumor
    development.

9
  • Growth factors can be classified as either
  • Autocrine (if they stimulate their own growth),
    such as
  • Transforming Growth Factor Alpha (TGF-a)
  • Insulin-like Growth Factors I and II (IGF-I and
    IGF-II)
  • Paracrine (if they have an effect on other cells)
    such as
  • Transforming Growth Factor Beta (TGF-ß)
  • Platelet-Derived Growth Factor (PDGF)
  • Procathepsin D (52K protein)

10
  • The mechanism of action of several hormonal
    agents used for the treatment of breast cancer
    involves the alteration of the growth factors
    involved in tumor development
  • Trastuzumab is a monoclonal antibody binds
    specifically to growth factor receptors on the
    malignant cell surface

11
  • Clinical Presentation And Diagnosis
  • Sign and Symptoms
  • Breast cancer mass tend to be
  • Painless
  • Solitary
  • Unilateral
  • Hard
  • Irregular,
  • Nonmobile
  • Patients may also have
  • Skin changes
  • Nipple discharge or
  • Axillary lymphadenopathy.

12
  • Detection and Diagnosis
  • Early detection of breast cancer is critical
    because patients with early stages have a better
    prognosis.
  • Three complementary screening techniques have
    been shown to be effective for detection
  • Breast self examination (BSE)
  • Physical examination by a physician
  • Mammography
  • On presentation, any women with suspected benign
    or malignant breast disease should have a
    mammography
  • Any breast mass that is suggestive of malignancy
    by mammography or on physical examination should
    be biopsied for final diagnosis and staging

13
  • Breast Cancer Staging
  • The TNM classification system is the most
    commonly accepted staging system for breast
    cancer
  • Tumor size (T) is described on a scale of 0 to 4
    based on characteristics of the primary tumor
  • Extent of lymph node involvement (N) based on
    location and palpability
  • Involvement of ipsilateral axillary, internal
    mammary and pectoral nodes are all considered
    regional spread of the disease
  • The presence or absence of distance metastases
    (M) is also included in the system
  • Involvement of any other lymph nodes, including
    the supracalvicular, cervical, or contralateral
    internal lymph nodes, is considered distant
    metastases

14
T1 ? 2 cm T2 gt 2 cm ? 5 cm T3 gt 5 cm T4 Direct
extension to chest wall or skin N1 Metastasis
to movable ipsilateral axillary lymph nodes(s)
N2 Metastasis to ipsilateral axillary lymph
nodes(s) fixed to one another or to
other structure N3 Metastasis to ipsilateral
internal mammary lymph nodes M0 No distant
metastasis M1 Distant metastasis includes
metastasis to ipsilateral supraclavicular lymph
node(s) I T1 N0 M0 II T1
N1 M0 / T2 N0 M0 /
T2 N1 M0 / T3 N0
M0 III T0-2 N2 M0 / T3 N1-2
M0 / T4 N0-3 M0 / T1-4
N3 M0 IV T1-4 N0-3 M1
15
  • Therapeutic Plan
  • The goal of treatment in breast cancer varies by
    the stage of disease at diagnosis and
    patient-specific prognostic factors
  • Most breast cancer disease (excluding metastatic
    disease) is treated for cure
  • Some patients with isolated metastases that can
    be resected may also be treated for cure
  • When cure is not possible (such if the disease
    recurs), the goals of treatment are to prolong
    survival and palliate symptoms (palliative goal
    of treatment)

16
Noninvasive Breast Cancer Lobular
Carcinoma In Situ (LCIS) not consider a
malignancy, but may develop breast cancer in the
future
Breast profile A ducts B lobules C dilated
section of duct to hold milk D nipple E fat F
pectoralis major muscle G chest wall/rib cage
Enlargement A normal cells B lobular cancer
cells breaking through the basement membrane C
basement membrane
17
  • Standard treatment excisional biopsy and close
    observation of the patient
  • Tamoxifen has decreased the risk of developing
    breast cancer in women with LCIS and should be
    considered in the routine management of these
    women

18
Ductal Carcinoma In Situ (DCIS)
Breast profile A ducts B lobules C dilated
section of duct to hold milk D nipple E fat F
pectoralis major muscle G chest wall/rib cage
Enlargement A normal duct cells B ductal
cancer cells C basement membrane D lumen (centre
of duct)
  • Lumpectomy radiation is sufficient treatment
    for patients with DCIS (with or without
    tamoxifen)

19
  • Early-stage Breast Cancer
  • Lumpectomy radiation is appropriate therapy for
    patients with early stage breast cancer.
  • The decision to treat node-negative breast cancer
    particularly tumors less than 1 cm with adjuvant
    therapy must be made on an individual basis.
  • Factors influence the physicians final judgment
    concerning adjuvant therapy
  • The presence or absence of prognostic factors
  • Patients desire to receive treatment
  • Adjuvant therapy is chemotherapy or hormonal
    therapy that is administered in an attempt to
    treat the residual micrometastatic disease that
    remains after surgery

20
  • The CAF marginally superior to CMF
  • The addition of tamoxifen to the chemotherapy
    regimens was beneficial only in patients who were
    (ER)
  • In management of stage II breast cancer (tumor lt5
    cm with positive nodal involvement) studies
    indicate that systemic adjuvant therapy can
    prolong disease-free and overall survival
  • Combination is more effective than single-agent
    regimens
  • Clinicians should avoid chemotherapy dose
    reductions in the adjuvant settings to achieve
    the maximal benefit of therapy
  • The availability of G-CSF and other supportive
    care measures may make this more feasible
  • The optimal combination regimen has not been
    determined

21
  • The combination of cyclophosphamide,
    methotrexate, and fluorouracil has been studied
    most extensively
  • Doxorubicin (Adriamycin) has demonstrated
    significant activity as single-agent therapy
  • It has produced increased response rates when
    used in combination chemotherapy
  • CAF showed margin superiority to CMF, but the
    toxicities where also increased with CAF
  • Some clinicians choose to restrict the
    doxorubicin-containing regimens to the metastatic
    disease setting because doxorubicin-refractory
    patients are very difficult to treat
  • The approval of new agents, such as the taxanes
    and capecitabin for refractory disease setting
    change this practice

22
  • The taxanes have demonstrated the best
    single-agent activity of any drug tested to date
    in the refractory disease setting
  • Studies showed that the use of adjuvant tamoxifen
    for about 5 years produces a substantially
    greater delay in disease recurrence as compared
    with 1 or 2 years use

23
Combination chemotherapy regimens used in the
treatment of breast cancer
24
  • Locally Advanced Breast Cancer
  • Patients diagnosed with locally advanced breast
    cancer (stage III) have tumors larger than 5 cm
    or direct involvement of the skin or underlying
    chest wall
  • These patients also have extensive lymph node
    involvement.
  • Radiation, systemic chemotherapy and surgery have
    all been used in various regimens in clinical
    trials
  • Neoadjuvant therapy involves the use of
    chemotherapy before surgery to decrease the size
    of tumor and improve resectability

25
  • Other advantages of neoajuvant chemotherapy
    include
  • Earlier treatment of micrometastatic disease
  • Intact tumor vasculature resulting in improved
    drug delivery
  • The ability to determine tumor responsiveness to
    chemotherapy in vivo
  • The ability to customize postsurgical systemic
    therapy based on this response
  • After neoadjuvant chemotherapy patients will
    receive radiation therapy and surgery
  • When all three modalities are combined, more than
    90 of patients with locally advanced breast
    cancer are disease free after treatment and many
    remain disease free for 3-5 years

26
  • Metastatic Breast Cancer
  • Cure is not the primary goal of therapy at this
    point
  • The easiest, least toxic treatment that can
    provide the best possible response is generally
    preferred to palliate the patient and possibly
    prolong survival
  • Breast cancer can metastasize to any site, but
    the most common sites include bone, lung, pleura,
    liver, soft tissue, and the CNS
  • The choice of therapy for metastatic disease is
    based on the site of disease involvement and the
    presence or absence of certain patient
    characteristics

27
  • For example, patients who
  • Experience a longer disease-free survival (2
    years or longer)
  • Have disease that is primarily located on bone or
    soft tissue
  • Have responded to primary endocrine therapy
  • Are late premenopausal or postmenopausal
  • Will most likely respond to endocrine therapy
  • The most important factor predicting response to
    hormonal therapy is the presence of estrogen
    receptors (ER) and progesterone receptors (PR) on
    tumor tissues
  • In premenopausal women, LHRH analogues are to be
    used
  • In postmenopausal women, tamoxifen therapy is the
    first-line treatment of choice because of ease of
    administration and lack of serious side effects

28
  • Chemotherapeutic drugs are most commonly used as
    palliative therapy in patients who
  • -Would not be expected to respond to hormonal
    therapy (i.e. patients with rapidly progressive
    lung, liver, or bone marrow disease)
  • -Or who have failed to respond to initial
    endocrine therapy
  • Radiation therapy is primarily used in brain and
    spinal cord metastases

29
  • Progestins, aromatase inhibitors, and androgens
    are second line hormonal choices
  • Due to comparable response rates between agents,
    the choice is currently based on toxicity, cost
    and ease of administration
  • Patients with rapidly progressive disease or who
    do not fulfill the criteria or fail to respond
    for endocrine therapy should receive chemotherapy
    initially

30
Endocrine therapies used for metastatic breast
cancer
31
  • Some of the newer single agents have produced
    responses equivalent to those obtained with
    combination regimens, particularly in the
    anthracycline-refractory disease setting
  • Paclitaxel (175 mg/m2 IV 3 weekly) are used for
    the treatment of breast cancer after failure of
    combination chemotherapy for metastatic disease
    or relapse within 6 months of adjuvant therapy
  • Similarly, docetaxel (60-100 mg/m2 IV 3 weekly)
    was approved for patients with locally advanced
    or metastatic breast cancer who have progressed
    during prior chemotherapy or relapsed during
    anthracycline-based adjuvant therapy

32
  • Capecitabine is a prodrug that is converted to
    fluorouracil after oral administration
  • This drug has been approved for the treatment of
    patients with metastatic breast cancer resistant
    to both paclitaxel and anthracycline therapy or
    is not indicated
  • The recommended starting dose is 2500 mg/m2 /day
    administered twice daily with food for 2
    consecutive weeks followed by 1 week of rest
    (21-day cycles)
  • Doxorubicin has demonstrated significant activity
    in the adjuvant treatment of breast cancer and in
    the treatment of metastatic disease
  • Doxorubicin dosing is limited by the development
    of cardiomyopathy, which occurs with cumulative
    lifetime doses of greater than 400 mg/ m2

33
  • Trastuzumab, which binds to the human epidermal
    growth factor receptor 2 (HER2), was approved for
    the treatment of
  • Patients with metastatic breast cancer whose
    tumors overexpress the HER2 protein and who have
    received one or more chemotherapy regimens for
    their metastatic disease
  • Trastuzumab is also indicated in combination with
    docetaxel for the treatment of
  • Patients with metastatic breast cancer whose
    tumors overexpress HER2 and who have not received
    chemotherapy for their metastatic disease

34
Lapatinib is an oral tyrosine kinase inhibitor of
both HER2/neu and the epidermal growth factor
receptor. It has shown activity in combination
with capecitabine in patients who have
HER2-positive metastatic breast ca. that
progressed after treatment with trastuzumab.
35
Toxicities of commonly used antineoplastic agents
36
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