Treatment of breast

cancer
Dr.Syed Alam Zeb
Classification
Carcinoma, NOS (not otherwise
specified).


Ductal.
Intraductal (in situ).
Invasive with predominant intraductal
component.
Invasive, NOS.
Comedo.
Inflammatory.
Medullary with lymphocytic infiltrate.
Mucinous (colloid).
Papillary.
Scirrhous.
Tubular.
Other.

Lobular.
In situ.
Invasive with predominant in situ
component.
Invasive.


Nipple.
Pagets disease, NOS.
Pagets disease with intraductal
carcinoma.
Pagets disease with invasive ductal
carcinoma.


Other.
Undifferentiated carcinoma.

Staging
TX: Primary tumor cannot be assessed


T0: No evidence of primary tumor


Tis: Intraductal carcinoma, lobular
carcinoma in situ, or Pagets disease of
the nipple with no associated invasion
of normal breast tissue
Tis (DCIS): Ductal carcinoma in situ
Tis (LCIS): Lobular carcinoma in situ
Tis (Paget's): Paget's disease of the
nipple with no tumor. [Note: Paget's
disease associated with a tumor is
classified according to the size of the
tumor.]

T1: Tumor 2.0 cm in greatest
dimension
T1mic: Microinvasion 0.1 cm in
greatest dimension
T1a: Tumor >0.1 cm but 0.5 cm in
greatest dimension
T1b: Tumor >0.5 cm but 1.0 cm in
greatest dimension
T1c: Tumor >1.0 cm but 2.0 cm in
greatest dimension


T2: Tumor >2.0 cm but 5.0 cm in
greatest dimension


T3: Tumor >5.0 cm in greatest
dimension


Staging (cont)
T4: Tumor of any size with direct extension to (a)
chest wall or (b) skin, only as described below
T4a: Extension to chest wall, not including
pectoralis muscle


T4b: Edema (including peau dorange) or ulceration
of the skin of the breast, or satellite skin nodules
confined to the same breast


T4c: Both T4a and T4b


T4d: Inflammatory carcinoma


Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
(e.g., previously removed)


N0: No regional lymph node metastasis


N1: Metastasis to movable ipsilateral axillary lymph
node(s)


N2: Metastasis to ipsilateral axillary lymph node(s)
fixed or matted, or in clinically apparent ipsilateral
internal mammary nodes in the absence of clinically
evident lymph node metastasis
N2a: Metastasis in ipsilateral axillary lymph nodes fixed
to one another (matted) or to other structures


N2b: Metastasis only in clinically apparent* ipsilateral
internal mammary nodes and in the absence of
clinically evident axillary lymph node metastasis


Staging (cont)
N3: Metastasis in ipsilateral
infraclavicular lymph node(s) with
or without axillary lymph node
involvement, or in clinically
apparent* ipsilateral internal
mammary lymph node(s) and in
the presence of clinically evident
axillary lymph node metastasis;
or, metastasis in ipsilateral
supraclavicular lymph node(s)
with or without axillary or internal
mammary lymph node
involvement


N3a: Metastasis in ipsilateral
infraclavicular lymph node(s)

N3b: Metastasis in ipsilateral
internal mammary lymph node(s)
and axillary lymph node(s)


N3c: Metastasis in ipsilateral
supraclavicular lymph node(s)

Distant metastasis (M)
MX: Presence of distant
metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

Staging (cont)
Stage 0
Tis, N0, M0
Stage I
T1*, N0, M0
Stage IIA
T0, N1, M0
T1, N1, M0
T2, N0, M0
Stage IIB
T2, N1, M0
T3, N0, M0

Stage IIIA
T0, N2, M0
T1*, N2, M0
T2, N2, M0
T3, N1, M0
T3, N2, M0
Stage IIIB
T4, N0, M0
T4, N1, M0
T4, N2, M0
Stage IIIC
Any T, N3, M0
Stage IV
Any T, Any N, M1

Breast cancer is commonly treated
by various combinations of:
Surgery
radiation therapy
chemotherapy, and
hormone therapy.

Prognosis and selection of therapy
may be influenced by:
the age and menopausal status
stage,
histologic and nuclear grade of the
primary tumor,
estrogen-receptor (ER) and progesterone-
receptor (PR) status,
measures of proliferative capacity, and
HER2/neu gene amplification.

Since criteria for
menopausal status vary
widely, some studies have
substituted age older than
50 years as a surrogate for
the postmenopausal state.
Patient management following
initial suspicion of breast cancer
generally includes:
Confirmation of the diagnosis,
Evaluation of stage of disease,
Establishment of unilateral or bilateral
disease
Selection of therapy.

Ductal Carcinoma In Situ


Ductal carcinoma in situ (DCIS) is a noninvasive,
precancerous condition.
DCIS can progress to become invasive cancer,
but estimates of the likelihood of this vary
widely.
DCIS accounts for about 18% of all newly
diagnosed invasive plus noninvasive breast
tumors in the United States.
Very few cases of DCIS present as a palpable
mass; 80% are diagnosed by mammography
alone
Treatment options for DCIS
Total mastectomy with or without tamoxifen.

Breast-conserving surgery and radiation therapy,
with or without tamoxifen.


Breast-conserving surgery without radiation
therapy. A large national clinical trial comparing
breast-conserving surgery and tamoxifen with or
without radiation therapy is currently under way
Lobular Carcinoma In Situ


Strictly speaking, it is not known to be a
premalignant lesion, but rather a marker that
identifies women at an increased risk for
subsequent development of invasive breast
cancer. This risk remains elevated even beyond
2 decades, and most of the subsequent cancers
are ductal rather than lobular.
LCIS is usually multicentric and is frequently
bilateral.
Treatment of Lobular
Carcinoma In Situ


Most women with LCIS can be managed without
additional local therapy after biopsy.
No evidence is available that re-excision to obtain clear
margins is required.
Tamoxifen has decreased the risk of developing breast
cancer in women with LCIS and should be considered in
the routine management of these women
Bilateral prophylactic mastectomy is sometimes
considered an alternative approach for women at high
risk for breast cancer.
Axillary lymph node dissection is not necessary.
Treatment options for patients
with LCIS
Observation after diagnostic biopsy.


Tamoxifen to decrease the incidence of
subsequent breast cancers.


Ongoing breast cancer prevention trials.

Bilateral prophylactic total mastectomy, without
axillary node dissection.

Management of Stage I, II,
IIIA, and Operable IIIC Breast
Cancer
Locoregional therapy
Surgery
Radiation therapy

Adjuvant therapy
Hormonal therapy
Chemotherapy
Locoregional therapy

After the presence of a malignancy is confirmed and
histology is determined, treatment options should be
discussed with the patient before a therapeutic
procedure is selected.
The surgeon may proceed with a definitive procedure

Estrogen-receptor (ER) and progesterone-receptor (PR)
status should be determined for the primary
tumor.Additional pathologic characteristics, including
grade, proliferative activity, and human epidermal
growth factor receptor 2 (HER2/neu) status, may also be
of value.
Options for surgical management
of the primary tumor include:
breast-conserving surgery plus radiation
therapy,
mastectomy plus reconstruction, and
mastectomy alone.
Selection of a local therapeutic
approach depends on:
the location of the lesion
size of the lesion
analysis of the mammogram
breast size, and
the patients attitude toward preserving
the breast.
relative contraindications to breast-
conserving therapy
The presence of multifocal disease in the breast
history of collagen vascular disease.

A patients age should not be a determining
factor in the selection of breast-conserving
treatment versus mastectomy
Whether young women with germ-line
mutations or strong family histories are good
candidates for breast-conserving therapy is not
certain.


surgical techniques used include:
Lumpectomy
Quadrantectomy
segmental mastectomy
Which option?
Patients whose tumors have these characteristics
may benefit from a more generous initial excision
to avoid the need for a re-excision:

1. large tumors (T2 lesions),
2. positive axillary nodes,
3. extensive intraductal component,
4. palpable tumors, and
5. lobular histology
Dealing with axillary lymph nodes
Axillary node dissection even in the presence of
clinically negative nodes is a necessary staging
procedure.
Controversy exists as to the extent of the
procedure because of long-term morbidity

The standard evaluation usually involves only a
level I and II dissection, thereby removing a
satisfactory number of nodes for evaluation (i.e.,
6-10 at a minimum), while reducing morbidity
from the procedure.
Sentinel lymph node biopsy
The SLN is defined as the first node in the lymphatic basin that
receives primary lymphatic flow.
Studies have shown that the injection of technetium-labeled sulfur
colloid, vital blue dye, or both around the tumor or biopsy cavity, or
in the subareolar area, and subsequent drainage of these
compounds to the axilla results in the identification of the SLN in
92% to 98% of patients
These reports demonstrate a 97.5% to 100% concordance between
SLN biopsy and complete axillary lymph node dissection
The results of a randomized trial of 532 patients with T1 carcinomas
undergoing either SLN biopsy plus complete axillary dissection or
SLN biopsy alone showed no axillary recurrences in either group and
no difference in the 3-year disease-free survival
The reported false-negative rates (i.e., the number of patients with
negative SLN biopsy divided by the number of patients with positive
axillary nodes at the time of axillary node dissection) of SLN biopsy
range from 0% to 10%.
Radiation therapy
Following Breast conservation
Following mastectomy
Radiation therapy following Breast
conservation
Postoperative external-beam radiation therapy to the
entire breast with doses of 45 Gy to 50 Gy, in 1.8 Gy to
2.0 Gy daily fractions over a 5-week period.
Shorter hypofractionation schemes achieve comparable
results.
A further radiation boost is commonly given to the tumor
bed. Two randomized trials conducted in Europe have
shown that using boosts of 10 Gy to 16 Gy reduces the
risk of local recurrence from 4.6% to 3.6% at 3 years (P
= .044),[and from 7.3% to 4.3% at 5 years (P < .0001),
respectively
If a boost is used, it can be delivered either by external-
beam radiation therapy,or by using an interstitial
radioactive implant.
Radiation therapy following
mastectomy
Postoperative chest wall and regional lymph node adjuvant
irradiation is given to selected patients considered at high risk for
local-regional failure following mastectomy:
1. Those with 4 or more positive axillary nodes
2. Grossly evident extracapsular nodal extension
3. Large primary tumors, and
4. Very close or positive deep margins of resection of the primary
tumor.

Patients with 1 to 3 involved nodes without any of the previously
noted risk factors are at low risk of local recurrence, and the value
of routine use of adjuvant radiation therapy is unclear.
Adjuvant systemic therapy
Hormone therapy
Chemotherapy
Monoclonal antibodies
Hormone therapy
Tamoxifen
Aromatase inhibitors: anastrozole,
exemestane, letrozole
Ovarian ablation
Tamoxifen

The benefit of tamoxifen was found to be restricted to women with
ER-positive or ER-unknown breast tumors. In these women, the 15-
year absolute reductions in recurrence and mortality associated with
5 years of use are 12% and 9%, respectively.
Women younger than 50 years obtained a degree of benefit from 5
years of tamoxifen similar to that obtained by older women.
In addition, the proportional reductions in both recurrence and
mortality associated with tamoxifen use were similar in women with
either node-negative or node-positive breast cancer, but the
absolute improvement in survival at 10 years was greater in the
latter group (5.3% vs. 12.5% with 5 years of use)
The current recommendation is that adjuvant tamoxifen be
discontinued after 5 years in all patients as current standard
therapy.
Tamoxifen toxic effects
Endometrial cancer
Increased incidence of deep venous
thrombosis and pulmonary emboli.
Benign ovarian cysts
Visual problems
Aromatase inhibitors:
anastrozole
Patients on anastrozole have a
significantly longer disease-free survival
than those on tamoxifen.
Aromatase inhibitors:
exemestane
Better disease free survival
Women on exemestane had significantly more
visual disturbances, arthralgia, diarrhea, and
osteoporosis, but women on tamoxifen had
significantly more gynecologic symptoms,
muscle cramps, vaginal bleeding,
thromboembolic disease, and second
malignancies other than breast cancer.
No difference was observed in overall survival
Aromatase inhibitors: letrozole
Better disease free survival
Significantly more hot flashes, arthritis,
arthralgia and myalgia, but less vaginal
bleeding. New diagnoses of osteoporosis
were more frequent on letrozole
Improvement in overall survival
Ovarian Ablation
Surgery, radiation therapy or ovarian
suppression with LHRH agonists
Ovarian suppression or ablation reduced
the absolute risk of recurrence at 15 years
by 4.3% and the risk of death from breast
cancer by 3.2.
Chemotherapy
CMF based
Anthracycline based
Duration of CMF-based
chemotherapy
No survival benefit was demonstrated for
durations greater than 6 months.
Anthracycline based
chemotharapy
Slight advantage for the anthracycline regimens in both
premenopausal and postmenopausal patients.
Uncertainty remains, however, about whether there is an
advantage to combining both regimens.
Evidence suggests that particular tumor characteristics
may predict anthracycline-responsiveness. Data from
retrospective analyses of randomized clinical trials
suggest that, in patients with node-positive breast
cancer, the benefit is restricted to those patients whose
tumors overexpress HER2/neu. The routine use of
HER2/neu to select those patients that should or should
not receive anthracycline-containing regimens should
await further confirmation
Role of Preoperative adjuvant
chemotherapy
Preoperative chemotherapy may be
beneficial in women who desire breast
conservation surgery but who would
otherwise not be considered candidates
because of the size of their tumor.
Monoclonal antibodies
Three clinical trials addressing the role of
the anti-HER2/neu antibody, trastuzumab,
as adjuvant therapy for patients with
HER2 overexpressing cancers released the
results of interim analyses.
Highly significant improvement in disease-
free survival and overall survival
Risk Categories for Women With
Node-Negative Breast Cancer
Low risk
(has all
listed
factors)
Intermediat
e risk
High risk
(has at
least 1
listed
factor)
Tumor size
1cm 1-2 cm >2 cm

ER or PR Status
positive positive negative
Tumor grade
Grade 1 grade 1-2 grade 2-3

Adjuvant systemic treatment for
node negative premenopausal
women
Patient
group
Low risk Intermediat
e risk
High risk


ER-positive or
PR-positive
None or
tamoxifen
1.T C 2.Ov Ab
3.GnRH analog
1. C & T
2. C & Ov Ab/
GnRH
analog
3. C & T & Ov
Ab/ GnRH
analog
4.Ov ab T
5.GnRH T
ER-negative or
PR-negative

Chemotherapy
Adjuvant systemic treatment for
node negative postmenopausal
women
Patient
group
Low risk Intermediat
e risk
High risk


ER-positive or
PR-positive
None or
tamoxifen
T C T C
ER-negative or
PR-negative

Chemotherapy
Older than 70
years
None or
tamoxifen

T C

T. Consider
chemotherapy if
ER-negative or
PR-negative
Adjuvant systemic treatment for
node positive premenopausal
women
Patient group Treatments
ER or PR-positive 1. C & T
2. C & Ov Ab/ GnRH analog
3. C & T & Ov Ab/ GnRH analog
4. Ov ab T
5. GnRH T

ER-negative or PR-negative Chemotherapy
Adjuvant systemic treatment for
node positive postmenopausal
women
Patient group Treatments
ER or PR-positive T C


ER-negative or PR-negative Chemotherapy
Older than 70 years Tamoxifen alone; consider
chemotherapy if receptor-negative
Candidates for whom adjuvant
therapy may not be necessary
Individuals with small primary tumors (<1 cm) and
negative axillary nodes who have an excellent prognosis,
with nearly 90% of patients alive and free of disease at
20 years in one series.
Proposals have been made to treat elderly patients with
tamoxifen alone and without surgery. This approach has
unacceptably high local failure rates and, outside of a
clinical trial setting, should be used only for patients who
are not candidates for mastectomy or breast-conserving
surgery plus radiation therapy, or for those who refuse
these options.
Inoperable stage IIIB or IIIC or
inflammatory breast cancer
Multimodality therapy delivered with curative intent is the standard of care
for patients with clinical stage IIIB disease.
32% of patients with ipsilateral supraclavicular node involvement and no
evidence of distant metastases (pN3c) can have prolonged disease-free
survival at 10 years with combined modality therapy.This result suggests
such patients should be treated with the same intent.
Initial surgery is generally limited to biopsy to permit the determination of
histology, ER and PR levels, and HER2/neu overexpression.
Initial treatment with anthracycline-based chemotherapy and/or taxane-
based therapy is standard.
For patients who respond to neoadjuvant chemotherapy, local therapy may
consist of total mastectomy with axillary lymph node dissection followed by
postoperative radiation therapy to the chest wall and regional lymphatics.
Breast-conserving therapy can be considered in patients with a good partial
or complete response to neoadjuvant chemotherapy. Subsequent systemic
therapy may consist of further chemotherapy.
Hormone therapy should be administered to patients whose tumors are ER-
positive or unknown.
Stage IV breast cancer
Treatment of metastatic breast cancer will
usually involve hormone therapy and/or
chemotherapy with or without trastuzumab
(Herceptin). Radiation therapy and/or surgery
may be indicated for patients with limited
symptomatic metastases. Fungating tumours
Bisphosphonates to reduce skeletal morbidity in
patients with bone metastases
Stage IV breast cancer (cont)
Hormone therapy as initial treatment for a postmenopausal patient
with newly diagnosed metastatic disease if the patients tumor is
ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is
especially indicated if the patients disease involves only bone and
soft tissue and the patient has either not received adjuvant
antiestrogen therapy or has been off such therapy for more than 1
year.
Women whose tumors are ER-positive or unknown, with bone or
soft tissue metastases only, who have received an antiestrogen
within the past year should be given second-line hormone therapy.
Examples of second-line hormone therapy in postmenopausal
women include selective aromatase inhibitors, such as anastrozole,
letrozole, or exemestane; megestrol acetate; estrogens; androgens;
and the ER down-regulator, fulvestrant.[
Stage IV breast cancer (cont)
Premenopausal women should undergo oophorectomy (surgically,
with external-beam radiation therapy or with an LHRH agonist).
Patients with lymphangitic pulmonary metastases, major liver
involvement, and/or central nervous system involvement should not
receive hormone therapy as a single modality. Patients with
structural compromise of weight-bearing bones should be
considered for surgical intervention and/or radiation in addition to
systemic therapy. Patients with vertebral body involvement should
be evaluated for impending cord compression even in the absence
of neurologic symptoms. Increasing bone pain and increasing
alkaline phosphatase within the first several weeks of hormone
therapy does not necessarily imply disease
Patients whose tumors have progressed on hormone therapy are
candidates for cytotoxic chemotherapy. Patients with hormone
receptor-negative tumors and those with visceral metastases are
also candidates for cytotoxic agents.
Follow-up
Evidence from randomized trials that periodic follow-up
with bone scans, liver sonography, chest x-rays, and
blood tests of liver function does not improve survival or
quality of life when compared to routine physical
examinations.Even when these tests permit earlier
detection of recurrent disease, patient survival is
unaffected.

Based on these data, some investigators recommend
that acceptable follow-up be limited to physical
examination and annual mammography for
asymptomatic patients who complete treatment for
stage I to stage III breast cancer.