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and progesterone receptor (PR)-positive disease. Human

epidermal growth factor receptor (HER2) testing of the

tumor was negative. What prognostic factors are evaluated

in all breast cancer patients?

In addition to staging, other prognostic factors should be

evaluated to help determine a patient’s treatment course. Prognostic factors such as size of the tumor and lymph node status

are important. Large tumor size leads to worse prognosis than

smaller tumor size, and presence of disease in the lymph nodes

leads to worse prognosis than disease-negative nodes. Further,

presence of a high number of positive lymph nodes is directly

related to a poorer prognosis. Pathologic testing of the breast

tumor gives important prognostic factors such as ER and PR

and HER2 status.22 Tumors that are ER or PR positive tend to

denote a slower-growing, indolent disease and have a more favorable prognosis than ER/PR-negative disease. Approximately twothirds of breast cancer patients diagnosed have ER/PR-positive

disease. If a patient has ER/PR-positive disease, hormonal therapy

is a treatment option. Tumors that are HER2-positive generally

denote more aggressive disease. Approximately 25% of breast

cancers test positive for HER2 gene amplification. Although this

is indicative of a more aggressive disease, it is a positive predictor

for response to trastuzumab therapy (which targets the HER2

protein).23

HER2 positivity is determined by two different methods,

immunohistochemistry or fluorescence in situ hybridization

(FISH). Either method could be used to determine HER2 status. Immunohistochemistry determines the overexpression of

the HER2 protein and results are reported as 1+, 2+, and

3+. Patients with 3+ overexpression are considered positive for

HER2 and will respond to trastuzumab therapy. If a patient is

determined to have 2+ overexpression (an equivocal test), then

further testing would be conducted with FISH. FISH testing

evaluates the HER2 gene amplification by denoting a ratio of the

number of gene copies of HER2 compared to the control and

only those patients with positive FISH testing will respond to

trastuzumab therapy.22,23

Other pathologic tests are completed such as nuclear grade

(which determines the degree of differentiation of the tumor

cells) as well as tests to evaluate the growth fraction of the disease

(such as S-phase fraction, Ki-67, and mitotic index). Clinicians use

all of these factors (positive and negative) to determine a patient’s

prognosis and treatment course.

Other tools allow clinicians to make a more individualized

approach (i.e., hormonal therapy alone, chemotherapy alone, or

a combination of chemotherapy and hormonal therapy) to treatment. One such tool is Adjuvant!online (www.Adjuvantonline.

com), which can be used in early-stage breast cancer patients

after surgery to evaluate their individual risk factors and determine treatment benefit versus risk of recurrence. The tool uses

clinical factors to estimate an individual’s percent risk reduction

in recurrence after adjuvant treatment (the benefit with hormonal therapy alone versus the benefit of hormonal therapy and

chemotherapy). In addition, genetic profiling has led to the creation of gene arrays to evaluate a patient’s risk of recurrence

based on their treatment course. Many patients today present

with early-stage disease, which is highly curable. Clinicians can

use these tests to determine which patients should receive more

or less therapy based on their recurrence score. One such test

is the Oncotype DX assay for patients with ER/PR-positive and

lymph node negative disease and assigns a patient a recurrence

score. Based on the score, clinicians and patients can decide the

best treatment course such as hormonal therapy alone versus

the combination of hormonal therapy and chemotherapy.24

Treatment

CASE 93-3, QUESTION 6: C.D. was diagnosed with a stage

II, ER-positive and PR-positive, HER 2-negative, invasive

ductal carcinoma of the left breast. Her staging workup was

negative as indicated previously with a negative CT scan of

the chest, abdomen, and pelvis and a negative bone scan.

Based on this information what would be C.D.’s treatment

course?

LOCAL TREATMENT (SURGERY AND

RADIATION THERAPY)

Surgery is the definitive treatment in early-stage breast cancer.

Many years ago, a more radical approach to the surgical removal

of breast cancer was used. This approach, called a radical mastectomy, involved the removal of the entire breast, both the major

and minor pectoralis muscle, and a full axillary lymph node dissection on the side of the breast cancer. Increased morbidity was

associated with this approach such as shoulder dysfunction and

a poor cosmetic appearance. Today, a modified radical mastectomy is used that removes the entire breast along with an axillary lymph node dissection while leaving the pectoralis muscles

intact. This approach leads to equivalent survival compared with

the radical surgery.25 Radiation may be offered in addition to a

modified radical mastectomy if the tumor is greater than 5 cm

in size, if the patient has greater than four positive lymph nodes,

or if positive tissue margins were present after surgery.26,27 This

further improves the local control of the disease.

Conservative approaches to surgery, such as lumpectomy, segmental mastectomy, or quadrantectomy, are also available. If a

patient has a small tumor and wishes to preserve the breast,

this surgical approach could be used; however, not all patients

are candidates for this procedure. Those who are not candidates

2203Breast Cancer Chapter 93

can include those with multicentric disease (numerous tumors

throughout the breast), large tumors in relation to the size of

the breast, and inflammatory breast cancer.18 If the decision

is to proceed with breast-conserving surgery, the patient must

also undergo adjuvant radiation therapy. Because the surgery

only removes the primary tumor, the rest of the breast should

be treated with radiation therapy to prevent recurrence of disease. Similar survival rates are observed with modified radical mastectomy versus breast conserving surgery plus radiation

therapy.25,28 C.D. could either undergo breast-conserving

surgery plus radiation therapy or a modified radical mastectomy,

but with C.D.’s family history she may also choose to undergo

bilateral mastectomies to prevent the development of contralateral breast cancer.

Larger tumors do not preclude a patient from undergoing

breast-conservative surgery. However, to be eligible for this

surgery, patients would receive neoadjuvant chemotherapy to

help shrink the tumor to a size conducive to breast-conserving

techniques. Neoadjuvant chemotherapy also allows the oncologist to assess response to treatment while the tumor is still

in place and allows the opportunity to discontinue a particular

chemotherapy regimen if the patient is not responding. Most

patients will respond to chemotherapy; however, for those who

do not, further chemotherapy (with a different regimen) or radiation therapy may be offered.29

The presence and extent of nodal disease is assessed through

an axillary lymph node dissection. This involves the removal

of at least ten lymph nodes on the same side of the primary

tumor to assess for the presence of breast cancer. Lymph node

dissection may result in lymphedema, thromboembolism, and

infection.30,31 Sentinel lymph node biopsy is one way to avoid

the comorbidities associated with the axillary lymph node dissection. In this procedure, a blue dye (labeled with a radiocolloid)

is injected around the breast tumor. Time is given for the dye to

drain from the tumor to the lymph nodes. The surgeon is able to

identify the sentinel nodes because of the presence of radiocolloid and the blue color. The breast (and presumably the cancer)

drains first into the sentinel lymph nodes. Only one or two of

the sentinel lymph nodes will be removed, reducing the risk of

lymphedema, thromboembolism, and infection.

For a video discussing sentinel lymph node

biopsy, courtesy of CancerQuest http://

www.cancerquest.org), go to http://

thepoint.lww.com/AT10e.

Many consider this procedure the standard of care for assessment of the axillary lymph nodes.29,32–34

SYSTEMIC THERAPY (CHEMOTHERAPY, HORMONAL

THERAPY, AND BIOLOGIC THERAPY)

Surgery and radiation therapy eradicates most tumor cells; however, microscopic disease is difficult to detect and treat locally.

Microscopic cancer deposits can migrate through the body and

serve as sites for disease recurrence. To diminish the chance of

recurrence, systemic adjuvant chemotherapy, hormonal therapy,

or biologic therapy is given. The determination of which single

modality or combination of therapies is based on the patient’s

prognostic factors: ER/PR status and HER2 positivity. As mentioned earlier, tools such as the Oncotype DX genetic assay can

estimate risk recurrence based on these tumor specific characteristics and assist in determination of therapy.

The size of the tumor and other prognostic factors are also

evaluated to determine the course of therapy; see Table 93-3.

The National Comprehensive Cancer Network provides treatment guidelines to help guide treatment planning.29 Patients

with small tumors (0.6–1 cm) and negative lymph nodes can

be further divided into two groups based on favorable and

unfavorable prognostic features. Favorable prognostic features

would include hormone-positive disease. These patients can be

offered hormonal therapy without chemotherapy. Those individuals with poor prognostic features (tumors with lymphatic invasion, high nuclear grade, hormone-receptor–negative, or HER2-

positive disease) would be offered chemotherapy with or without

trastuzumab therapy.18

Tumors greater than 1 cm in size are generally treated with

systemic chemotherapy. Patients with ER/PR-positive disease are

usually also treated with hormonal therapy. Biologic therapy

with trastuzumab is added to chemotherapy if the patient has

HER2-positive disease and assuming there are no contraindications such as cardiac disease. Patients should be fully informed

of the absolute benefit of chemotherapy, because in those with

early-stage disease the benefit from chemotherapy could be as

low as 2% to 3%. The Early Breast Cancer Trialists Collaborative Group conducts an overview analysis every 5 years on the

effects of chemotherapy and hormonal therapy in breast cancer

randomized trials. In 2005, the 15-year survival updates were published. Although no standard regimen has been identified, combination regimens are superior to single-agent therapy (recurrence

rates and mortality for combination chemotherapy, respectively:

hazard ratio [HR], 0.77; p <0.00001 and HR, 0.83; p <0.0001,

respectively; single-agent therapy recurrence rates and mortality: HR, 0.86; p = 0.001 and HR, 0.96; p = 0.4, respectively).35

Looking back at C.D.’s tumor characteristics, she has stage II

(2.2 cm with lymph node involvement), ER-positive, PR-positive,

and HER2-negative breast cancer. Based on this information,

C.D. would be a candidate for surgery and chemotherapy (based

TABLE 93-3

Overview of the Selection of Adjuvant Treatment

Adjuvant Hormonal Therapy Adjuvant Chemotherapy†

Lymph node negative

disease

ER/PR (+) ER/PR (–)

<0.5 cm Yes No No

0.6 – 1 cm∗ Yes No Consider

>1 cm Yes No Yes

Lymph node positive disease ER/PR (+) ER/PR (–)

Yes No Yes

∗Consider Oncotype DX testing: Low recurrence score (<18) = adjuvant hormonal therapy; intermediate recurrence score (18–30)

= adjuvant hormonal therapy +/– chemotherapy; high recurrence score (≥ 31) = adjuvant hormonal therapy + chemotherapy

†Give trastuzumab therapy if the patient is HER2 (+) and no contraindications

Source: National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Breast Cancer. v2. http://www.

nccn.org. Accessed June 20, 2011.

2204Section 17 Neoplastic Disorders

on the tumor size and lymph node–positive disease), followed by

hormonal therapy due to her ER/PR-positive disease.

ADJUVANT CHEMOTHERAPY

CASE 93-3, QUESTION 7: C.D. underwent a left modified

radical mastectomy and axillary lymph node dissection. She

had 2 of 15 lymph nodes positive for disease. Her adjuvant

treatment will consist of chemotherapy (due to the larger

size of the tumor and positive lymph nodes). What are typical adjuvant chemotherapy regimens for the treatment of

early-stage breast cancer, and what should C.D. receive?

Many different combination chemotherapy regimens are used

in the adjuvant setting (Table 93-4). Anthracycline-containing

regimens are commonly used. Doxorubicin or epirubicin in

combination with an alkylating agent, cyclophosphamide plus

or minus fluorouracil are typical regimens. In the most recent

Early Breast Cancer Trialist Cancer Group analysis, anthracycline regimens had significantly lower recurrence rates and death

compared to traditional cyclophosphamide, methotrexate, fluorouracil (recurrence rate ratio, 0.89; p = 0.001 and cancer death

rate ratio, 0.84; p <0.00001, respectively).35 Taxane-containing

regimens are also used although the most recent analysis did

not include taxanes as this class of agents is relatively new in the

adjuvant setting. Future updated analyses will include results

with the use of adjuvant taxanes. A large pooled analysis demonstrated improved diseasefree (p <0.00001) and overall survival

(p <0.0001) with the addition of a taxane.36 The optimal taxane regimen has yet to be identified and the full benefit of the

utility of taxane therapy in lymph node–negative disease is yet

to be determined; however, the benefit is apparent in lymph

TABLE 93-4

Common Adjuvant Chemotherapy Regimens

Regimen

Schedule (No. of Weeks

Between Cycles) Number of Cycles

Cyclophosphamide (C)

Methotrexate (M)

5-Fluorouracil (F), classic (oral)

4 6

CMF (intravenous) 3 9–12

Cyclophosphamide (C)

Doxorubicin (A)

5-Fluorouracil (F) (oral)

4 6

Cyclophosphamide (C)

Doxorubicin (A)

5-Fluorouracil (F)

3–4 6

Cyclophosphamide (C)

Epirubicin (E)

5-Fluorouracil (F)

3 6

Docetaxel (T)

Doxorubicin (A)

Cyclophosphamide (C)

4 6

Doxorubicin (A) →

Cyclophosphamide (C)

Methotrexate (M)

5-Fluorouracil (F)

3 → 3 4 → 8

Doxorubicin (A)

Cyclophosphamide (C)

3 4–6

Doxorubicin (A)

Cyclophosphamide (C) → Paclitaxel (P)

3 → 3 4 → 4

Doxorubicin (A) →

Paclitaxel (P) →

Cyclophosphamide (C)

3 → 3 → 3 4 → 4 → 4

Dose dense∗

Doxorubicin (A)

Cyclophosphamide (C) → Paclitaxel (P)

2 → 2 4 → 4

Dose dense∗

Doxorubicin (A) →

Paclitaxel (P) →

Cyclophosphamide (C)

2 → 2 → 2 4 → 4 → 4

A, adriamycin; C, cyclophosphamide; E, epirubicin; F, fluorouracil; M, methotrexate; P, paclitaxel; T, docetaxel; →, followed by; ∗Dose dense, given every two weeks instead of every 3 weeks. See source document for specific dosing.

Source: National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Breast Cancer. v2. http://www.

nccn.org. Accessed April 22, 2011.

2205Breast Cancer Chapter 93

node–positive disease. Taxanes should be incorporated in the

treatment regimen of those with lymph node–positive disease.

Congestive heart failure is a well-known toxicity associated

with anthracycline chemotherapy. If a patient has heart failure or other pre-existing cardiac disease, anthracyclines must

be used cautiously. To avoid potential toxicity, taxane regimens

such as docetaxel and cyclophosphamide have been compared

to standard anthracycline-containing regimens, doxorubicin and

cyclophosphamide. After 7 years of follow-up, both diseasefree

and overall survival were significantly better in the taxane arm

compared with the anthracycline arm (81% vs. 75%; p = 0.033

and 87% vs. 82%; p = 0.032, respectively).37 Although the results

are encouraging, these data do not have the track record of the

anthracycline-containing regimens that are still considered the

mainstay of therapy for adjuvant chemotherapy in early-stage

breast cancer. Studies are currently underway to identify specific populations that may not respond to anthracycline therapy,

thereby avoiding the risk of cardiac toxicity in these individuals.38

If these specific cases are identified, more nonanthracycline-based

chemotherapy regimens will be incorporated into clinical practice. Based on C.D.’s lymph node–positive breast cancer, a typical

adjuvant chemotherapy regimen would consist of doxorubicin

and cyclophosphamide (AC) or fluorouracil and doxorubicin and

cyclophosphamide (FAC) given every 3 weeks for four cycles

followed by a taxane such as paclitaxel weekly for 12 weeks

(see Table 93-4 for commonly used adjuvant chemotherapy regimens).

Trastuzumab therapy can be incorporated into a patient’s

adjuvant chemotherapy regimen if the tumor is HER2-positive.

Trastuzumab was first studied in the metastatic setting and

demonstrated improved overall survival when added concurrently with chemotherapy.39 Because of its robust activity in the

metastatic setting, it was then studied in early breast cancer to see

if the same benefit could be achieved. Two large trials were conducted concurrently addressing different questions regarding the

use of concurrent, sequential, and maintenance trastuzumab.40

Patients received the classic AC regimen for four cycles followed

by paclitaxel weekly either given sequentially or concurrently.

Trastuzumab therapy was started after the completion of the AC

regimen to reduce potential cardiac toxicities associated with

doxorubicin and trastuzumab.40 The results of these trials were

combined and published in full. Diseasefree and overall survival

were significantly improved with the addition of trastuzumab

(52% decrease in recurrence rates, p <0.0001; and 33% reduction in mortality, p = 0.015, respectively).40 Four-year follow-up

data continued to demonstrate significant improvements with

trastuzumab compared to chemotherapy alone. Based on these

data, trastuzumab was approved for use in early-stage, HER2-

positive disease after the completion of AC therapy followed by

sequential paclitaxel therapy for 1 year.40 The use of maintenance trastuzumab is being further studied in the HERA Trial

(Herceptin Adjuvant Trial).41 In that trial, patients are randomly

assigned to complete 1 or 2 years of maintenance trastuzumab

therapy. Results have not been published to date. One year of

trastuzumab therapy is the current standard of practice for maintenance therapy in the adjuvant setting. Because C.D. does not

have HER2-positive disease, trastuzumab therapy should not be

used.

CHEMOTHERAPY TOXICITY

CASE 93-3, QUESTION 8: C.D. is to undergo four cycles

of AC chemotherapy followed by weekly paclitaxel for 12

weeks. What are the common toxicities associated with this

treatment course? If the tumor was HER2-positive and C.D.

received trastuzumab, what toxicities would be associated

with its use?

Doxorubicin is an anthracycline chemotherapy. It works

through multiple mechanisms, but inhibition of topoisomerase

II may be most important.42 By inhibiting this enzyme, doublestrand DNA breaks occur. Common toxicities include myelosuppression, nausea/vomiting, and alopecia. A well-known toxicity of anthracyclines is the risk of cardiomyopathy due to the

formation of oxygen free radicals and doxorubicin metal complexes. These toxicities can be acute (with symptoms similar to an

arrhythmia or myocardial infarction) or chronic (with a patient

demonstrating symptoms of congestive heart failure).43 The risk

of cardiotoxicity increases with larger anthracycline cumulative

doses.44 With the typical doses of anthracyclines used in the

adjuvant setting, a patient will not reach the cumulative doses

known to increase the risk of cardiotoxicity. If a patient has underlying cardiac dysfunction, baseline evaluation of ejection fraction

either through an echocardiogram or multigated acquisition scan

should be completed.45,46 Other known risk factors for the development of anthracycline-induced cardiotoxicity include age older

than 70 years, hypertension, pre-existing coronary artery disease,

and previous cardiac irradiation, or previous anthracycline exposure, and may warrant cardiac evaluation.47

Cyclophosphamide is an alkylating agent that works by

forming cross-links in DNA, thus inhibiting DNA synthesis.42

Common toxicities are nausea/vomiting, myelosuppression, and

alopecia. The alkylating agents, although rare, are also associated

with a risk of secondary leukemias.

Paclitaxel, a taxane chemotherapy, derived from the Pacific

yew tree, works by binding to the β-tubulin subunit of microtubules preventing disassembly and ultimately causing inhibition

of mitosis. Common toxicities associated with paclitaxel include

nausea/vomiting, myelosuppression, neuropathy, and hypersensitivity reactions due to the cremaphor solvent in paclitaxel. All

patients should be premedicated with dexamethasone and H1

and H2 blockers to prevent hypersensitivity.48

Trastuzumab is a monoclonal antibody targeted against

the extracellular HER2 protein. The classic toxicity associated

with trastuzumab is cardiac toxicity, but is different than that

with anthracyclines. Trastuzumab cardiotoxicity is considered

reversible and believed to be a result of HER2 blockade (HER2

signaling is responsible for cardiomyocyte growth, repair, and

survival).49–51 In those patients who will receive long-term

trastuzumab therapy, baseline cardiac function should be evaluated similar to doxorubicin and then periodically with echocardiogram or multigated acquisition scan during therapy. C.D. does

not have a history of cardiac disease, so a baseline cardiac evaluation before AC therapy may not occur. C.D. should be counseled

on the common toxicities associated with her chemotherapy,

such as myelosuppression, nausea/vomiting, alopecia, neuropathy, cardiomyopathy, and hypersensitivity reactions.

HORMONAL THERAPY

CASE 93-3, QUESTION 9: After the completion of adjuvant

chemotherapy, C.D. will receive hormonal therapy because

her disease is ER/PR-positive. What are the common adjuvant hormonal regimens used? What regimen would be

appropriate for C.D.?

Breast cancer is a hormonally mediated disease and therapies that alter hormonal levels are an integral component to the

treatment plan. This therapy is offered to patients with ER/PRpositive disease. Therapeutic options include SERMs, luteinizing

hormone–releasing hormone (LH-RH) agonists, and aromatase

2206Section 17 Neoplastic Disorders

TABLE 93-5