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 woman’s 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-α)
– 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-β)
– 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 > 2 cm 5 cm
T3 > 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. 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
16. •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
17. 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)
18. 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 physician’s final judgment concerning
adjuvant therapy:
–The presence or absence of prognostic factors
–Patient’s 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
19. •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 <5 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
20. •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
21. •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
22. Combination chemotherapy regimens used in the treatment of
breast cancer
Regimen Drug Dose
CMF
Repeat every28 days
Cyclophosphamide
Methotrexate
Fluorouracil
100 mg/m2
/day PO days1-14 or 600 mg/ m2
/day IV D1
40 mg/m2
/day IV D1 and 8
600 mg/m2
/day IVD1 and 8
TAC
Repeat every21-28 days
Docetaxel
Doxorubicin
Cyclophosphamide
75 mg/m2
/day IV D1
50 mg/m2
/day IV D1
600 mg/m2
/day IVD1
AC
Repeat every21 days
Doxorubicin
Cyclophosphamide
60 mg/m2
/day IV D1
600 mg/m2
/day IVD1
FAC or CAF
Repeat every21-28 days
Fluorouracil
Doxorubicin
Cyclophosphamide
500 mg/m2
/day IVD1 and 8
50 mg/m2
/day IV D1
600 mg/m2
/day IVD1
CFM
Repeat every21 days
Cyclophosphamide
Fluorouracil
Mitoxantrone
500-600 mg/m2
/day IV D1
500-600 mg/m2
/day IV D1
10-12 mg/m2
/day IVD1
23. 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
24. •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
25. 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
26. 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
27. •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
28. •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
29. Class Drug Dose Side Effects
LHRH (GnRH)
(Premenopausal)
Goserelin
Leuprorelin
Buserelin
3.6/10.8 mg SC 4/12 weekly
3.75/11.25 mg SC 4/12 weekly
6.3 mg SC 8 weekly
Ammenorrhea, hot flushes, occasional
nausea
Antiestrogen Tamoxifen
Toremifene
Fulvestrant
20-30 mg PO daily
60 mg PO daily
250 mgIM4weekly
Disease flare, hot flushes, nausea,
vomiting edema, vaginal discharge,
Progestins Medroxypro-
gesterone
Megestrol
500-1000 mg PO daily
160 mg PO daily
Weight gain, hot flashes, vaginal
bleeding
Aromatase
inhibitors
Anastrozole
Letrozole
Exemestane
1 mgPO daily
2.5 mgPO daily
25 mg PO daily
Letheargy, dizziness, nausea, hot
fluches , skinrash, headache
Endocrine therapies used for metastatic breast cancer
30. •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
31. •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
32. •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
33. 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.
