Breast Cancer
Definition
• Breast cancer is a malignancy originating from breast tissue.
• Disease confined to a localized breast lesion is referred to as early,
primary, localized, or curable.
• Disease detected clinically or radiologically in sites distant from the
breast is referred to as advanced or metastatic breast cancer (MBC),
which is usually incurable.
EPIDEMIOLOGY
• Two variables most strongly associated with the occurrence of breast
cancer are gender and age.
• Additional risk factors include endocrine factors (eg, early menarche,
nulliparity, late age at first birth, and hormone replacement therapy),
genetic factors (eg, personal and family history, mutations of tumor
suppressor genes [BRCA1 and BRCA2]), and environmental and lifestyle
factors (eg, radiation exposure, weight, height, and alcohol use).
Mutations of tumor suppressor genes
• 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.
Breast cancer cells spread
PREVENTION OF BREAST CANCER
• Risk reduction strategies include prophylactic mastectomy, oophorectomy, and
pharmacologic agents.
• Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs)
are being studied for pharmacologic risk reduction of breast cancer.
• The most clinical information is available for the SERMs, tamoxifen, and raloxifene,
which reduce the rates of invasive breast cancer in women at high risk for
developing the disease.
• Tamoxifen increased the incidence of endometrial cancer and both agents
increased thromboembolic events.
Aromatase inhibitors (AIs)
• Exemestane and anastrozole taken for 5 years significantly reduced
the rates of invasive breast cancers in postmenopausal women with
tolerable adverse events.
• Risk reduction strategies include mastectomy, oophorectomy, and
pharmacologic agents.
• Clinical guidelines recommend the use of tamoxifen, raloxifene,
anastrozole, or exemestane for postmenopausal women at high
risk.
CLINICAL PRESENTATION
• A painless, palpable lump is the initial sign of breast cancer in
most women.
• The typical malignant mass is solitary, unilateral, solid, hard,
irregular, and nonmobile.
• Nipple changes are less commonly seen.
• 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 should include a careful history, physical
examination of the breast, three-dimensional mammography,
and, possibly, other breast imaging techniques, such as
ultrasound and magnetic resonance imaging (MRI).
• Breast biopsy is indicated for a mammographic abnormality that
suggests malignancy or for a palpable mass on physical
examination.
Staging
• Stage (anatomical extent of disease) is based on
primary tumor extent and size (T ),
1–4
presence and extent of lymph node involvement (N ), 1–3
and presence or absence of distant metastases (M ).0–1
• The staging system determines prognosis and assists
with treatment decisions.
• ✔ Early breast cancer
• Stage 0: Carcinoma in situ or disease that has not
invaded the basement membrane
• Stage I: Small primary invasive 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 the node or tumor is fixed to the
chest wall
Advanced or metastatic breast cancer
• Stage IV: Metastases in organs distant from the primary
tumor
• Staging for breast cancer is separated into clinical and pathologic staging.
• The clinical stage is assigned before surgery and is based on
physical examination (assessment of tumor size and presence of axillary
lymph nodes),
imaging (eg, mammography, ultrasonography), and pathologic
• examination of tissues (eg, biopsy results).
• Pathologic staging occurs after surgery and adds data from surgical
exploration and resection.
Pathologic Evaluation
• Development of malignancy is a multistep process involving preinvasive (or
noninvasive) and invasive phases.
• The goal of treatment for noninvasive carcinomas is to prevent the
development of invasive disease.
• Pathologic evaluation of breast lesions establishes the histologic diagnosis
and confirms the presence or absence of prognostic factors.
• Most breast carcinomas are adenocarcinomas and are classified as ductal
or lobular
Prognostic Factors
• The ability to predict prognosis is used to design personalized treatment
recommendations.
• Age at diagnosis and ethnicity can affect prognosis.
• Tumor size and presence and number of involved axillary lymph nodes are
independent factors that influence the risk for breast cancer recurrence and
subsequent metastatic disease.
• Other disease characteristics that provide prognostic information are histologic
subtype, nuclear or histologic grade, lymphatic and vascular invasion, and
proliferation indices.
• Hormone receptors (estrogen [ER] and progesterone [PR]) are not strong
prognostic markers but are used clinically to predict response to endocrine
therapy.
• HER2 overexpression occurs in about 20%–30% of breast cancers and is
associated with increased tumor aggressiveness, increased rates of
• recurrence, and increased rates of mortality.
• Genetic profiling tools provide additional prognostic information to aid in
treatment decisions for subgroups of patients with otherwise favorable
treatment
TREATMENT
Goals of Treatment: Adjuvant therapy for early and locally
advanced breast cancer is administered with curative intent.
Neoadjuvant therapy is given to eradicate micrometastatic
disease, determine prognosis, and potentially conserve breast
tissue for a better cosmetic result.
Palliation is the desired therapeutic outcome in the treatment of
MBC.
Early Breast Cancer (Stage I and II)
• Local-Regional Therapy
• Surgery alone can cure most patients with in situ cancers, 70%–80% of
stage I cancers, and approximately one-half of those with stage II cancers.
• Breast-conserving therapy (BCT) is an appropriate primary therapy for most
women with stages I and II disease and is preferable because it provides
survival rates equivalent to modified radical mastectomy.
• BCT includes removal of part of the breast, surgical evaluation of axillary
lymph nodes, and radiation therapy (RT) to prevent local recurrence.
• RT is administered to the entire breast over 3–5 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.
• Multiple sites of cancer within the breast and the inability to attain
negative pathologic margins on the excised breast specimen are
indications for mastectomy.
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.
• Administration of chemotherapy, endocrine therapy, targeted therapy, or
some combination of these agents results in improved disease-free
survival (DFS) and/or overall survival (OS) for high-risk patients in specific
prognostic subgroups.
Adjuvant Chemotherapy
• Early administration of effective combination chemotherapy at a time of
low tumor burden should increase the likelihood of cure and minimize the
emergence of drug-resistant tumor cell clones.
• Combination regimens have historically been more effective than single-
agent chemotherapy.
• Anthracycline-containing regimens (eg, doxorubicin and epirubicin) reduce
the recurrence and death rate compared to regimens that contain
cyclophosphamide, methotrexate, and fluorouracil.
• The addition of taxanes, docetaxel, and paclitaxel, to adjuvant regimens
comprised of the drugs listed above resulted in a reduced risk of distant
recurrence, any recurrence, and breast cancer mortality compared with a
nontaxane regimen in node-positive breast cancer patients.
• Initiate chemotherapy within 12 weeks of surgical removal of the primary
tumor.
• The optimal duration of adjuvant treatment is unknown but appears to be 12–
24 weeks, depending on the regimen used.
• Dose intensity refers to the amount of drug administered per unit of
time, which can be achieved by increasing the dose, decreasing the
time between doses, or both.
• Dose density is one way of achieving dose intensity by decreasing the
time between treatment cycles.
Adjuvant Biologic or Targeted Therapy
• Trastuzumab in combination with or sequentially after adjuvant
chemotherapy is indicated in patients with early-stage, HER2-
positive breast cancer.
• The risk of recurrence was reduced by up to 50% in clinical trials.
Adjuvant Endocrine Therapy
• Tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing
hormone-releasing hormone (LHRH) agonists, and Aromatase inhibitors (AIs)
are hormonal therapies used in the treatment of primary or early-stage breast
cancer.
• Tamoxifen was the gold-standard adjuvant hormonal therapy for three
decades and is generally considered the adjuvant hormonal therapy of choice
for premenopausal women.
• 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.
• It is usually well tolerated; however, symptoms of estrogen
withdrawal (hot flashes and vaginal bleeding) may occur but
decrease in frequency and intensity over time.
• Tamoxifen reduces the risk of hip radius and spine fractures.
• It increases the risks of stroke, pulmonary embolism, deep vein
thrombosis, and endometrial cancer, particularly in women aged 50 years
or older.
• Administration of tamoxifen for 10 years in patients with a higher risk of
recurrence is supported by recent studies.
• Premenopausal women benefit from ovarian ablation with LHRH agonists
(eg, goserelin) in the adjuvant setting, either with or without concurrent
tamoxifen.
• Guidelines recommend incorporation of AIs into adjuvant hormonal therapy
for postmenopausal, hormone-sensitive breast cancer.
• Experts believe that anastrozole, letrozole, and exemestane have similar
antitumor efficacy and toxicity profiles.
• Adverse effects with AIs include bone loss/osteoporosis, hot flashes,
myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea.
• The optimal drug, dose, sequence, and duration of administration of AIs in
the adjuvant setting are not known.
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 an anthracycline- and taxane-
containing regimen is recommended.
• The use of trastuzumab and pertuzumab 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.
Metastatic Breast Cancer (Stage IV)
• Treatment of MBC with cytotoxic, endocrine, or targeted therapy
often results in regression of disease, improvements in quality of
life, and improved OS with the addition of some biologic or
targeted therapies.
• The choice of therapy for MBC is based on the extent of disease
involvement and the presence or absence of certain tumor or
patient characteristics.
• The most important predictive factors are the presence of HER2, ER,
and PR receptors in the primary or metastatic tumor tissue.
• Consider adding bone-modifying agents (eg, pamidronate, zoledronic
acid, or denosumab) to treat breast cancer patients with metastases to
the bone to decrease rates of skeletal-related events, such as fractures,
spinal cord compression, and pain, and the need for radiation to the
bones or surgery.
Biologic or Targeted Therapy
• 15% to 20% of patients with MBC overexpress HER2.
• anti-HER2 agents are available: trastuzumab, lapatinib, pertuzumab, ado-
trastuzumab emtansine, and neratinib.
• First-line therapy with a pertuzumab-trastuzumab-taxane combination is the
preferred option for HER2-overexpressing MBC in patients who have not
received pertuzumab in the neoadjuvant or adjuvant setting.
• Second-line HER2-targeted therapy for MBC depends on the specific agent
given as first-line therapy.
• Subsequent therapy (third-line) for HER2-positive MBC is controversial.
• Consider combination endocrine plus HER2-directed therapy when
chemotherapy is not tolerated or after achieving maximal response with the
chemotherapy-HER2 therapy approach.
• All HER2-targeted therapies are cardiotoxic with the type of toxicity differing
among agents. The incidence of heart failure is ∼5% with single-agent
trastuzumab and unacceptably high in combination with an anthracycline.
• Other targeted agents including mTOR inhibitors (eg, everolimus) and cyclin-
dependent kinases (CDK) (eg, abemaciclib, palbociclib, and ribociclib) are used in
combination with endocrine agents to improve outcomes.
• To date, CDK inhibitors have improved progression-free survival in combination
with AIs (as first-line therapy), fulvestrant (as first- and second-line therapy), and
tamoxifen (as first-line therapy)
Endocrine Therapy
• Consider endocrine therapy in combination with a targeted agent when
feasible although this increases the risk of adverse events that require
supportive management strategies.
• The choice of endocrine therapy is based on the menopausal status of
the patient, prior therapies and previous response, duration of response,
or disease-free interval.
• 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.
• No one endocrine therapy has superior survival benefits.
• Choice of agent is based primarily on mechanism of action, toxicity, and
patient preference.
• AIs are generally first-line therapy in postmenopausal women. AIs reduce
circulating and target organ estrogens by blocking peripheral conversion from
an androgenic precursor, the primary source of estrogens in postmenopausal
women.
• The third-generation AIs was anastrozole.
• letrozole and exemestane are more selective and have an improved toxicity
profile.
• When compared with tamoxifen, patients receiving AIs had similar response rates
as well as lower incidence of thromboembolic events and vaginal bleeding.
• Tamoxifen, an estrogen agonist/antagonist, is the preferred initial agent when
metastases are present in premenopausal women except when metastases occur
within 1 year of adjuvant tamoxifen. In addition to the side effects described for
adjuvant therapy, tumor flare or hypercalcemia occurs in approximately 5% of
patients with MBC
• Toremifene, also an estrogen agonist/antagonist, 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 with anastrozole or exemestane in patients who
progressed on tamoxifen.
• Surgical or chemical ovarian ablation is considered by some experts 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
Chemotherapy
• Chemotherapy is used as initial therapy for women with hormone receptor-
negative tumors, triple-negative tumors, and after failure of
endocrine/targeted therapy regimens.
• Chemotherapy is chosen based on overall efficacy, the risk of toxicity,
performance status and presence of comorbidities in the patient, the
aggressiveness of disease (eg, indolent vs. visceral crisis), and patient
preferences related to chemotherapy schedules, dosing route (eg, oral vs.
intravenous), and frequency (eg, weekly vs. every 3 weeks).
Immunotherapy
• Pembrolizumab (mAb against programmed cell death protein 1
[PD1]) is approved in combination with album-inbound paclitaxel,
paclitaxel, or the combination of carboplatin + gemcitabine.
• Atezolizumab (mAb against programmed death ligand [PDL1]) is
approved in combination with albumin-bound paclitaxel.
• Response rates are high with combination chemotherapy, but
sequential use of single agents is an effective strategy and may be
preferred due to decreased rates of adverse events. In the palliative
setting, when efficacy is similar, the least toxic approach is preferred.
• Treatment with sequential single agents is recommended over
combination regimens unless the patient has rapidly progressive
disease, life-threatening visceral disease, or the need for rapid
symptom control.
EVALUATION OF THERAPEUTIC OUTCOMES
• Early Breast Cancer
• The goal of adjuvant therapy, chemotherapy, biologic or targeted therapy,
and endocrine therapy, in early-stage disease is cure.
• Adjuvant therapy is intended to eradicate micrometastases and thus cure
the patient of breast cancer, which cannot be fully evaluated for years
after initial diagnosis and treatment.
• In addition, because disease cannot be detected at the time adjuvant
therapy is started, an assessment of disease response is not possible.
• Adjuvant chemotherapy can cause significant toxicity. Optimize supportive
care measures such as antiemetics and growth factors to maintain dose
intensity.
• 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.
• Metastatic Breast Cancer
• Palliation is the therapeutic end point in the treatment of MBC.
Optimizing quality of life is an important therapeutic end point.
• Valid and reliable tools are available for objective assessment of quality
of life in patients with breast cancer.
• 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 changes in laboratory tests, diagnostic
imaging, or physical signs or symptoms.
The End
