BREAST CANCER

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BREAST CANCER
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• 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

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• 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

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• 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

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• 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

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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
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• 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.

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• 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.

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• 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)

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• 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

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• 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.

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• 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

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• 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

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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
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• 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)

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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
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• 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

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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)

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• 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

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• 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

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• 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

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• 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

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Combination chemotherapy regimens used in the
treatment of breast cancer
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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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Endocrine therapies used for metastatic breast
cancer
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• 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

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• 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

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• 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

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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.
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Toxicities of commonly used antineoplastic agents
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