Breast cancer is a malignancy originating from breast tissue. This chapter distinguishes between early stages, which are potentially curable, and metastatic breast cancer (MBC), which is usually incurable.

1. BREAST CANCER
PREPARED BY :- RAJEEV SAHAI
B.SC, M.PHARM. (PHARMACOLOGY)

2. DEFINITION
DEFINITION:- Breast cancer is a malignancy originating from breast tissue. This chapter
distinguishes between early stages, which are potentially curable, and metastatic breast cancer
(MBC), which is usually incurable.
EPIDEMIOLOGY:-
 The strongest risk factors for breast cancer are female gender and increasing age. Additional
risk factors include endocrine factors (e.g., early menarche, nulliparity, late age at first birth,
hormone replacement therapy), genetic factors (e.g., personal and family history, mutations of
tumor suppresser genes [BRCA1 and BRCA2]), and environmental and lifestyle factors (e.g.,
radiation exposure).
 Breast cancer cells often spread undetected by contiguity, lymph channels, and through the
blood early in the course of the disease, resulting in metastatic disease after local therapy. The
most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.

4. CLINICAL PRESENTATION:-
 The initial sign in more than 90% of women with breast cancer is a painless lump that is typically
solitary, unilateral, solid, hard, irregular, and non-mobile. Less common initial signs are pain and
nipple changes. More advanced cases present with prominent skin edema, redness, warmth, and
induration.
 Symptoms of MBC depend on the site of metastases, but may include bone pain, difficulty
breathing, abdominal pain or enlargement, jaundice, and mental status changes.
 Many women first detect some breast abnormalities themselves, but it is increasingly common for
breast cancer to be detected during routine screening mammography in asymptomatic women.
DIAGNOSIS:-
 Initial workup for a woman presenting with a localized lesion or suggestive symptoms should
include a careful history, physical examination of the breast, three-dimensional mammography, and,
possibly, other breast imag-ing techniques such as ultrasound.
 Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or a mass
that is palpable on physical examination.

6. STAGING
• Stage is based on the size of the primary tumor (T1–4), presence and extent of lymph node
involvement (N1–3), and presence or absence of distant metastases (M0–1). Simplistically stated,
these stages may be represented as follows:
✓ Early Breast Cancer
• Stage 0: Carcinoma in situ or disease that has not invaded the base- ment membrane.
• Stage I: Small primary tumor without lymph node involvement.
• Stage II: Involvement of regional lymph nodes.
✓ Locally Advanced Breast Cancer
• Stage III: Usually a large tumor with extensive nodal involvement in which node or tumor is
fixed to the chest wall; also includes inflam-matory breast cancer, which is rapidly progressive.
✓ Advanced or Metastatic Breast Cancer
• Stage IV: Metastases in organs distant from the primary tumor.

7. PATHOLOGIC EVALUATION
• The development of malignancy is a multistep process with preinvasive (or noninvasive) and
invasive phases. The goal of treatment for noninvasive carcinomas is to prevent the development of
invasive disease.
• The pathologic evaluation of breast lesions establishes the histologic diagnosis and presence or
absence of prognostic factors.
• Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular.
DESIRED OUTCOME:-
• The goal of therapy with early and locally advanced breast cancer is cure. The goals of
therapy with MBC are to improve symptoms, improve quality of life, and prolong survival.

8. PROGNOSTIC FACTORS
The ability to predict prognosis is used to design treatment recommendations to maximize quantity
and quality of life.
• Tumor size and the presence and number of involved axillary lymph nodes are primary factors in
assessing the risk for breast cancer recurrence and subsequent metastatic disease. Other disease
characteristics that provide prognostic information include histologic subtype, nuclear or histologic
grade, lymphatic and vascular invasion, and proliferation indices.
• Hormone receptors are used as indicators of prognosis and to predict response to hormone
therapy.
• HER2/neu (HER2) overexpression is associated with transmission of growth signals that control
aspects of normal cell growth and division. Overexpression of HER2 may be associated with a poor
prognosis. HER2 status should be obtained for all invasive breast cancers.
• Genetic profiling tools provide additional prognostic information to aid in treatment decisions for
subgroups of patients with otherwise favorable prognostic features.

9. TREATMENT
• The treatment of breast cancer is rapidly evolving. Treatment can cause substantial toxicity, which differs depending on
the individual agent, administration method, and combination regimen.
EARLY BREAST CANCER
1. Local-Regional Therapy
• Surgery alone can cure most patients with in situ cancers and approxi-mately one-half of those with stage II cancers.
• Breast-conserving therapy (BCT) is appropriate primary therapy for most women with stage I and II disease; it is
preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically superior results.
BCT consists of lumpectomy (i.e., excision of the primary tumor and adjacent breast tissue) followed by radiation therapy
(RT) to
prevent local recurrence.
• RT is administered to the entire breast over 4 to 6 weeks to eradicate residual disease after BCT. Reddening and
erythema of the breast tissue with subsequent shrinkage of total breast mass are minor complications associated with RT.
• Simple or total mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary
nodes. This procedure is used for carcinoma in situ where the incidence of axillary node involvement is only 1% or with
local recurrence following breast conservation therapy.
• Axillary lymph nodes should be sampled for staging and prognostic infor-mation. Lymphatic mapping with sentinel lymph
node biopsy is a new, less invasive alternative to axillary dissection; however, the procedure is contro- versial because of the
lack of long-term data.

11. TREATMENT
 EARLY BREAST CANCER
2. Systemic Adjuvant Therapy
• Systemic adjuvant therapy is the administration of systemic therapy following definitive local
therapy (surgery, radiation, or both) when there is no evidence of metastatic disease but a high
likelihood of disease recurrence. The goal of such therapy is cure.
• Chemotherapy, hormonal therapy, or both result in improved disease-free survival and/or overall
survival (OS) for all treated patients.
• The National Comprehensive Cancer Network practice guidelines reflect the trend toward the
use of chemotherapy in all women regardless of menopausal status, and the addition of hormonal
therapy in all women with receptor-positive disease regardless of age or menopausal status.
• Genetic tests are being prospectively validated as decision-support tools for adjuvant
chemotherapy in node-negative patients to identify characteris-tics of the primary tumor that may
predict for the likelihood of metastases and death.

12. TREATMENT EARLY BREAST CANCER
3. Adjuvant Chemotherapy
• Early administration of effective combination chemotherapy at a time of low tumor burden should increase
the likelihood of cure and minimize emergence of drug-resistant tumor cell clones. Combination regimens
have historically been more effective than single agent chemotherapy.
• Anthracycline-containing regimens (e.g., doxorubicin and epirubicin) significantly reduce the rate of
recurrence and improve OS 5 and 10 years after treatment as compared with regimens that contain
cyclophospha- mide, methotrexate, and fluorouracil. Both node-negative and node-positive patients benefit
from anthracycline-containing regimens.
• The addition of taxanes, docetaxel and paclitaxel, a newer class of agents, to adjuvant regimens comprised
of the drugs listed above resulted in consistently and significantly improved disease-free survival and OS in
node-positive breast cancer patients.
• Chemotherapy should be initiated within 3 weeks of surgical removal of the primary tumor. The optimal
duration of treatment is about 12 to 24 weeks.
• Dose intensity refers to the amount of drug administered per unit of time, which can be achieved by
increasing dose, decreasing time, or both. Dose density is one way of achieving dose intensity by decreasing
time between treatment cycles. Dose-dense regimens may be considered as options for adjuvant therapy for
node-positive breast cancer.
• Decreasing doses in standard regimens should be avoided unless necessitated by severe toxicity.

13. TREATMENT
EARLY BREAST CANCER
4. Adjuvant Biologic Therapy
• Trastuzumab in combination with adjuvant chemotherapy is indicated in patients with early
stage, HER2-positive breast cancer. The risk of recurrence was reduced up to 50% in clinical trials.
• Unanswered questions with the use of adjuvant trastuzumab include optimal concurrent
chemotherapy, optimal dose, schedule and duration of therapy, and use of other concurrent
therapeutic modalities.
5. Adjuvant Endocrine Therapy
• Tamoxifen has been the gold standard for adjuvant endocrine therapy. It has both estrogenic and
antiestrogenic properties, depending on the tissue and gene in question.
• Tamoxifen 20 mg daily, beginning soon after completing chemotherapy and continuing for 5
years, reduces the risk of recurrence and mortality. Tamoxifen is usually well tolerated. Symptoms
of estrogen withdrawal (hot flashes and vaginal bleeding) may occur but decrease in frequency and
intensity over time. Tamoxifen increases the risks of stroke, pulmonary embolism, deep vein
thrombosis, and endometrial cancer, particularly in women age 50 years or older.

14. TREATMENT
EARLY BREAST CANCER
5. Adjuvant Endocrine Therapy
• Premenopausal women benefit from ovarian ablation with luteinizing hormone-
releasing hormone (LHRH) agonists (e.g., goserelin) in the adjuvant setting, either
with or without concurrent tamoxifen. Trials are ongoing to further define the role
of LHRH agonists.
• Options for adjuvant hormonal therapy in postmenopausal women include
aromatase inhibitors (e.g. anastrozole, letrozole, or exemestane) either in place of
or after tamoxifen. Adverse effects with aromatase inhibitors include hot flashes,
myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea.
• The optimal drug, dose, sequence, and duration of administration of aromatase
inhibitors in the adjuvant setting are not known.

15. TREATMENT
LOCALLY ADVANCED BREAST CANCER (STAGE III)
• Neoadjuvant or primary chemotherapy is the initial treatment of choice.
Benefits include rendering inoperable tumors resectable and increasing the rate of
BCT.
• Primary chemotherapy with either an anthracycline- or taxane-containing
regimen is recommended. The use of trastuzumab with chemotherapy is
appropriate for patients with HER2-positive tumors.
• Surgery followed by chemotherapy and adjuvant RT should be administered to
minimize local recurrence.
• Cure is the primary goal of therapy for most patients with Stage III disease.

17. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
The choice of therapy for MBC is based on the site of disease involvement and presence or absence of certain
characteristics, as described below.
1. Endocrine Therapy
• Endocrine therapy is the treatment of choice for patients who have hormone receptor-positive metastases in
soft tissue, bone, pleura, or, if asymptomatic, viscera. Compared with chemotherapy, endocrine therapy has an
equal probability of response and a better safety profile.
• Patients are sequentially treated with endocrine therapy until their tumors cease to respond, at which time
chemotherapy can be given.
• Historically, the choice of an endocrine therapy was based primarily on toxicity and patient preference but
study results have led to changes in MBC treatment.
• Aromatase inhibitors reduce circulating and target organ estrogens by blocking peripheral conversion from
an androgenic precursor, the primary
source of estrogens in postmenopausal women. Newer agents are more selective and better tolerated than the
prototype, aminoglutethimide.
Anastrozole, letrozole, and exemestane are approved as second-line therapy; anastrozole and exemestane
have been shown to improve OS and time to progression compared with progestins. As first-line therapy,
anastrozole and letrozole increase time to progression and are better tolerated compared with tamoxifen.

18. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
1. Endocrine Therapy
• Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-
receptor positive, unless metastases occur within 1 year of adjuvant tamoxifen. Maximal beneficial
effects do not occur for at least 2 months. In addition to the side effects described for adjuvant
therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with MBC.
• Toremifene has similar efficacy and tolerability as tamoxifen and is an alternative to tamoxifen
in postmenopausal patients. Fulvestrant is a second-line intramuscular agent with similar efficacy
and safety when
compared to anastrozole in patients who rogressed on tamoxifen.
• Ovarian ablation (oophorectomy) is considered by some to be the endocrine therapy of choice in
premenopausal women and produces similar overall response rates as tamoxifen. Medical
castration with an LHRH analog, goserelin, leuprolide, or triptorelin, is a reversible alternative to
surgery.
• Progestins are generally reserved for third-line therapy. They cause weight gain, fluid retention,
and thromboembolic events.

19. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
1. Chemotherapy
• Chemotherapy is preferred to endocrine therapy for women with hormone receptor-
negative tumors; rapidly progressive lung, liver, or bone marrow involvement; or failure of
endocrine therapy.
• The choice of treatment depends on the individual. Agents used previously as adjuvant
therapy can be repeated unless the cancer recurred within 1 year. Single agents are
associated with lower response rates than combination therapy, but time to progression
and OS are similar. Single agents are better tolerated, an important consideration in the
palliative metastatic setting.
• Combination regimens produce objective responses in approximately 60% of patients
previously unexposed to chemotherapy, but complete response occur in less than 10% of
patients. The median duration of response is 5 to 12 months; the median survival is 14 to
33 months.

20. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
1. Chemotherapy
• Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-
line therapy for MBC. Single agent capecitabine, vinorelbine, or gemcitabine have
response rates of 20% to 25% when used after an anthracycline and a taxane
• Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in
combination with capecitabine in MBC patients who have previously received an
anthracycline and a taxane. Response rates and time to progression were increased with
combination therapy as compared with capecitabine alone. Adverse effects include
myelosuppression, peripheral neuropathy, and myalgias/arthralgias.

22. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
2. Biologic Therapy
• Trastuzumab, a monoclonal antibody that binds to HER2, produces response rates of
15% to 20% when used as a single agent and increases response rates, time to
progression, and OS when combined with chemotherapy. It has been studied in doublet
(taxane-trastuzumab; vinorelbine-trastuzumab) and triplet (trastuzumab-taxane-
platinum) combinations but the optimum regimen is unknown.
• Trastuzumab is well tolerated, but the risk of cardiotoxicity is 5% with single-agent
trastuzumab and unacceptably high in combination with an anthracycline.
• Lapatinib, a tyrosine kinase inhibitor that targets both HER2 and the epidermal growth
factor receptor, improved response rates and time to progression in combination with
capecitabine, as compared to capecita-
bine alone, in patients previously treated with an anthracycline, taxane, and
trastuzumab. The most common adverse events were rash and diarrhea.

23. TREATMENT
METASTATIC BREAST CANCER (STAGE IV)
2. Biologic Therapy
• The role of bevacizumab, a monoclonal antibody targeted against vascular endothelial
growth factor, in MBC is currently not clearly defined.
3. Radiation Therapy
Radiation is commonly used to treat painful bone metastases or other localized sites of
disease including brain and spinal cord lesions. Pain relief is seen in approximately 90%
of patients who receive RT.

24. EVALUATIONOF THERAPEUTIC OUTCOMES
1. EARLY BREAST CANCER
• The goal of adjuvant therapy in early-stage disease is cure. Because there is no
clinical evidence of disease when adjuvant therapy is administered, assessment of
this goal cannot be fully evaluated for years after initial diagnosis and treatment.
• Adjuvant chemotherapy can cause substantial toxicity. Because maintaining
dose intensity is important in cure of disease, supportive care should be optimized
with measures such as antiemetics and growth factors.
2. LOCALLY ADVANCED BREAST CANCER
•The goal of neoadjuvant chemotherapy in locally advanced breast cancer is cure.
Complete pathologic response, determined at the time of surgery, is the desired
end point.

25. EVALUATIONOF THERAPEUTIC OUTCOMES
1. METASTATIC BREAST CANCER
• Optimizing quality of life is the therapeutic endpoint in the treatment of
patients with MBC. Many valid and reliable tools are available for objective
assessment of quality of life.
• The least toxic therapies are used initially, with increasingly aggressive
therapies applied in a sequential manner that does not significantly compromise
quality of life.
• Tumor response is measured by clinical chemistry (e.g., liver enzyme elevation
in patients with hepatic metastases) or imaging techniques (e.g., bone scans or
chest x-rays).
• Assessment of the clinical status and symptom control of the patient is often
adequate to evaluate response to therapy.