and/or radiation therapy.321

Although silicone gel implants are superior to saline implants in terms of offering a more natural

contour and texture, the use of silicone implants remains controversial secondary to unsubstantiated

claims of a link between silicone implants and autoimmune disease first reported in 1992. Since that

time, no studies have shown a causative relationship and the American College of Rheumatology and

the FDA have concluded that there is no additional risk of connective tissue disease in patients with

silicone implants.322–324

A few case reports have noted an association between breast implants (saline or silicone) and

anaplastic large cell lymphoma of the breast. There have been 60 cases of ALCL reported among an

estimated 5 to 10 million women with breast implants. Although a causal relationship is not proven and

the potential risk is extremely low, the FDA does require breast implant manufacturers to include this

finding in the product labeling.325

Figure 74-26. Breast reconstruction with tissue expanders. Although the breasts are not identical, this is not evident when a bra is

worn.

The primary benefit of autologous tissue breast reconstruction is that the reconstructed breast appears

and feels more natural than following implant-based breast reconstruction. In addition, autologous

tissue breast reconstruction may be the only option in patients who have undergone chest wall

radiation, as skin fibrosis may preclude implant-based breast reconstruction. A common procedure is the

free TRAM flap, which involves removing skin, subcutaneous fat, muscle, and associated blood supply

from the lower abdomen. The blood supply includes the deep inferior epigastric artery and vein, which

are anastomosed to the internal mammary or thoracodorsal arteries and veins. The TRAM flap is

contoured to replicate the native breast. Similar to the TRAM flap, the DIEP flap uses the same lower

abdominal skin and subcutaneous fat but spares the rectus abdominis muscle. In both methods, the

donor site is closed as a modified abdominoplasty.

Radical Mastectomy

In 1907, Halsted presented to the American Surgical Association his results of 232 patients who

underwent his radical mastectomy at Johns Hopkins. Halsted’s radical mastectomy involved wide

excision of skin via a teardrop incision extending across the deltopectoral groove, excision of the entire

pectoralis major muscle, resection of the pectoralis minor muscle to expose the axillary contents for

dissection, and excision of the supraclavicular lymph nodes. In certain cases, he also removed the

mediastinal nodes. Immediate skin grafting was performed to close all of the wounds.326 With advances

in breast cancer screening, adjuvant medical therapy, and radiation therapy, a concomitant evolution

toward less radical surgery has ensued. A report by the American College of Surgeons Commission on

Cancer demonstrated a dramatic decline in the use of the radical mastectomy from 47.9% of breast

cancer cases in 1972 to 3.4% of cases in 1981.327 Furthermore, the modified radical mastectomy,

which consists of a simple mastectomy and ALND, was considered a satisfactory alternative to the

radical mastectomy by 1980.328 A randomized, prospective clinical study by W.A. Maddox in 1983

showed no significant differences in disease-free survival, overall survival, or local recurrence rates at 5

years for modified radical versus radical mastectomy. These differences are likely secondary to the

routine use of chemotherapy for patients with involved axillary lymph nodes by this time period.329

When patients are not candidates for breast conservation and SLNB, a modified radical mastectomy is

indicated. See the section on Axillary Lymph Node Dissection above.

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Radiation Therapy

The primary indication for the use of radiation therapy in breast cancer is to reduce the risk of a

locoregional recurrence following surgery and potentially improve survival by eradicating persistent

locoregional disease that may be resistant to systemic therapy.

The standard approach for patients who undergo breast-conserving surgery is to deliver whole breast

radiation therapy with a dose of 50 to 60 Gy. The regimen is often given in 2 Gy fractions 5 days a

week for a total of 5 weeks. A 60 Gy regimen, which also includes a 10 Gy boost to the tumor bed, was

found to be more effective for patients 45 years of age or younger, with a local relapse rate of 14% (60

Gy) compared to 28% (50 Gy) (p < 0.0001).330 Alternative radiation therapy strategies are currently

under investigation including the use of rapid fractionation schedules, such as the delivery of 41 to 42

Gy over 15 fractions and accelerated partial breast radiation. Early results show excellent clinical

outcomes.331–333

Although most women do not require radiation therapy following mastectomy, postmastectomy

radiation therapy is often recommended for women at high risk for locoregional recurrence, including

women with four or more positive lymph nodes, tumor size greater than 5 cm, or with positive surgical

margins. In these instances, postmastectomy radiation can reduce the rate of chest wall recurrence by

65% to 75%.70,334–337

11 Of note, optimal locoregional management of the axilla remains to be defined. Both surgery and

radiation therapy can be used to treat disease in the axilla. Previously, ALND was the preferred

treatment modality for prevention or treatment of axillary disease. More recent studies suggest that

radiation therapy may be equally effective with less morbidity. The EORTC AMAROS trial randomized

patients with clinical T1-T2 N0 breast cancer to ALND or radiation therapy to the axilla after a positive

SLNB.338 The two arms had comparable axillary control, but patients in the radiation therapy arm had

significantly less morbidity. At 5 years, 23% of patients in the ALND arm had lymphedema compared to

11% in the radiation therapy arm. Currently, in patients with clinical T1-T2 N0 disease who undergo

mastectomy with a positive SLNB, ALND is the standard approach as these patients were not included in

the Z0011 study. However, findings from the AMAROS trial suggest that in this group of patients,

radiation therapy may provide similar locoregional control with less morbidity.

Chemotherapy

The role of medical therapy is to eradicate breast cancer cells at the primary tumor site or at any other

site in the body. Systemic therapies include but are not limited to chemotherapy, endocrine therapy, and

targeted therapy.

The decision as to whether or not to treat patients with breast cancer with chemotherapy is complex.

Considerations include patient age, menopausal status, AJCC TNM stage, histologic grade, biomarker

profile, proliferation index, and medical comorbidities. Online calculators exist to estimate the risks and

benefits of chemotherapy and other adjuvant therapies. Adjuvant! Online is a popular risk-benefit

calculator that is based on population-wide data that focuses on recurrence risk and probability of

survival. This is a Web-based program that is generated from collective data from the SEER database,

the Early Breast Cancer Trialists Collaborative Group (EBCTCG), individual clinical trial results, and

published literature.339 Other calculators include Cancermath.net340 and FinProg project.341 Molecular

profiling using Oncotype DX or similar molecular assay can be used for patients with node-negative

ER+/HER2− breast cancers. For Oncotype DX, a score of ≥31 is associated increased risk of recurrence

with a recommendation for administration of chemotherapy.

Adjuvant chemotherapy is often initiated 4 to 6 weeks after surgery. Although treatment earlier is not

beneficial, a delay of greater than 12 weeks may be detrimental. If adjuvant radiation therapy is

indicated, it is administered starting 3 to 4 weeks after completion of chemotherapy.

Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin)

These compounds are derived from Streptomyces bacteria and function by inhibiting DNA and RNA

synthesis by intercalating between base pairs of the DNA/RNA strand, blocking DNA transcription and

replication by inhibiting topoisomerase II enzyme, generating free oxygen radicals, and by inducing

histone eviction form chromatin. The main adverse effect is cardiotoxicity.

Taxanes (Paclitaxel, Docetaxel)

These compounds are derived from plants of the genus Taxus (yews) and function by disrupting

microtubule formation and inhibiting mitosis. The main adverse effect is peripheral neuropathy. Given

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that these compounds are not water soluble, allergic reactions to the diluent may result.

Cyclophosphamide

This compound is a nitrogen mustard alkylating agent that functions by adding an alkyl group to the

guanine base of DNA, resulting in intrastrand and interstrand DNA cross-links and, therefore, interferes

with DNA replication. The main adverse effects include acute myeloid leukemia, bladder cancer,

hemorrhagic cystitis, and infertility.

5-Fluorouracil

This compound is an antimetabolite that works as an irreversible inhibitor of thymidylate synthase and,

therefore, interferes with DNA synthesis. The main adverse effect is mucositis.

Methotrexate

This compound is both an antimetabolite and an antifolate that blocks dihydrofolate reductase and,

therefore, inhibits the synthesis of folic acid, which is essential for DNA, RNA, thymidylate, and protein

synthesis. The main adverse effect is ulcerative stomatitis.

Platinum Agents (Carboplatin or Cisplatin)

These compounds bind to and cause cross-links in DNA, triggering apoptosis. The main adverse effects

are nephrotoxicity, neurotoxicity, and ototoxicity.

Endocrine Therapy

Patients with all stages of breast cancer that express the ER or PR are candidates for endocrine therapy.

In the premenopausal setting, the focus is on blocking ovarian function and the effects of estrogen. In

postmenopausal women, the ovaries are no longer the predominant source of estrogen, but instead

estrogen is synthesized mainly from nonglandular sources such as subcutaneous fat. As such, blocking

estrogen production is very effective in the postmenopausal population.

Blocking Ovarian Function (Leuprolide, Goserelin, Buserelin)

As the ovaries are the main source of estrogens in premenopausal women, ovarian ablation can be

achieved either surgically by removal of the ovaries or through medical therapy with luteinizing

hormone-releasing hormone agonists such as goserelin or leuprolide. These compounds function by

binding to the gonadotropin-releasing hormone receptor, resulting in initial FSH and LH release.

However, with prolonged drug exposure, desensitization of the pituitary occurs whereby the levels of

LH and FSH become profoundly suppressed. This results in inhibition of the growth of ovarian follicles

and steroidogenesis.

Blocking Estrogen at the Receptor (Tamoxifen, Raloxifene, Fulvestrant)

As SERMs, tamoxifen and raloxifene competitively bind to the ER and prevent estrogen from binding.

As a selective estrogen receptor down-regulator (SERD), fulvestrant binds to the ER and targets it for

destruction. Fulvestrant is used in postmenopausal women who have hormone receptor-positive

metastatic disease who experience progression following endocrine therapy.

Blocking Estrogen Production (Anastrozole, Letrozole, Exemestane)

The enzyme aromatase converts androgenic substrates to estrogen, and, therefore, its inhibition can

effectively decrease plasma levels of estrogen. Nonsteroidal AIs include anastrozole and letrozole,

whose binding activity can be reversed. Exemestane is a steroidal AI that irreversibly binds aromatase

and permanently inactivates it.

Targeted Therapy

Targeted Therapy for HER2+ Breast Cancers

Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) is present in

approximately 20% of primary breast cancers. Given that effective targeted therapies exist for these

patients, all newly diagnosed breast cancers are routinely tested for HER2 expression/amplification.

Trastuzumab is a monoclonal antibody that targets HER2+ breast cancers by multiple mechanisms

including (1) interfering with the homo- and heterodimerization of HER2 and inhibiting mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) signaling pathways, (2)

immune-mediated killing of tumors that overexpress HER2 by a mechanism referred to as antibody2081

dependent cellular cytotoxicity (ADCC), and (3) triggering HER2 internalization and degradation

through promoting the activity of tyrosine kinase-ubiquitin ligase c-Cbl.

Pertuzumab is a monoclonal antibody that interferes with the dimerization of HER2 to HER3,

therefore, interfering with MAPK and PI3K pathway activation. It also induces antibody-dependent cellmediated cytotoxicity (ADCC).

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that consists of trastuzumab linked

with the cytotoxic agent mertansine (DM1). While trastuzumab binds to the HER2 receptor, mertansine

enters the cell and destroys it by binding to tubulin. This allows toxin to be targeted specifically to the

cancer cell.

Targeted Therapy for Triple Negative Breast Cancers (Experimental Options)

Although patients with TNBC often have an excellent response to chemotherapy, overall outcomes are

worse compared to patients with ER+ and/or HER2+ disease.236,342,343 The lack of effective targeted

therapies for TNBCs likely contributes to this disparity in outcome. Drugs-targeting TNBCs are in

clinical trials and include inhibitors targeted to the epidermal growth factor receptor (cetuximab),

angiogenesis (bevacizumab), DNA damage or poly adenosine diphosphate-ribose polymerase (olaparib,

veliparib, iniparib), the proto-oncogene Src (dasatinib), and histone deacetylase (vorinostat). Given the

heterogeneity of TNBC, multitargeted therapy will likely be needed to eradicate this disease.

Treatment Regimens

Adjuvant Medical Therapy for Hormone Receptor-Positive or Negative, HER2-Negative

Breast Cancer

For patients at high risk for recurrence, a regimen based on the combination of an anthracycline and

taxane has been proven to be the most effective. This combination is commonly given in a dose-dense

fashion (whereas traditional chemotherapy is given every 3 weeks, this requires administration every 2

weeks) with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for four cycles, followed by

paclitaxel (175 mg/m2) every 2 weeks for four cycles. The data to support this regimen come from an

EBCTCG meta-analysis. In this study published in 2011, anthracycline-based regimens were compared to

CMF (cyclophosphamide, methotrexate, and 5-Fluorouracil), and to no treatment. Both chemotherapy

regimens resulted in a significant decrease in the risk of recurrence and a reduction in both breast

cancer and overall mortality versus no treatment at 10 years. There was no difference between the

anthracycline and CMF treatment regimens with standard doses of doxorubicin (four cycles with 60

mg/m2 with a cumulative dose of 240 mg/m2). However, at higher doses of anthracyclines (>240

mg/m2), there was a reduction in the risk of recurrence (absolute difference of 2.6%), a reduction in

breast cancer mortality (absolute difference of 4.1%), and a reduction in overall mortality (absolute

difference of 3.9%) at 10 years. By 2012, taxanes were routinely combined with anthracycline-based

therapies (ACTHs) and the combination regimen resulted in a reduction in the risk of recurrence

(absolute difference of 4.6%), a reduction in breast cancer mortality (absolute difference of 2.8%), and

a reduction in overall mortality (absolute difference of 3.2%). In addition, the benefits of taxanes were

independent of age, nodal status, tumor size, tumor grade, and ER status.344,345

Although AC-T has been shown to result in the greatest improvement in outcome, there is no single

chemotherapy regimen that is the standard of care as preferred combinations vary by institution,

geographic region, and by medical oncologist. Other anthracycline-based regimens include FEC

(fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) given every 3

weeks for six cycles and FEC-Taxane (FEC every 3 weeks for three cycles, followed by docetaxel 100

mg/m2) for three cycles or FEC for four cycles, followed by weekly paclitaxel (100 mg/m2) for 8

weeks. For patients who are not candidates for anthracycline-based regimens, TC can be administered

(docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2) for four cycles given every 3 weeks. CMF

(cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 IV days 1 and 8, and 5-

fluorouracil 600 mg/m2 IV days 1 and 8) for six cycles every 4 weeks is another alternative regimen.

After chemotherapy, for patients with ER+ breast cancer, endocrine therapy should be initiated, as

multiple meta-analyses have consistently shown improved survival outcomes with its use. The choice of

endocrine therapy is dependent on menopausal status, with menopause being defined as the lack of

menstruation for at least 12 months in the absence of tamoxifen, chemotherapy, or ovarian suppression.

Menopause can also be achieved surgically with the removal of both ovaries.70 In premenopausal

women, the preferred agent is tamoxifen, which is a SERM that inhibits the growth of breast cancer

cells. In the 2011 EBCTCG meta-analysis, women who took tamoxifen for 5 years had a significant

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reduction in the risk of breast cancer recurrence (40%) and breast cancer mortality (30%) at 15

years.346 For premenopausal women who cannot tolerate tamoxifen secondary to side effects, ovarian

suppression should be considered and can be accomplished through surgical resection of both ovaries or

by administration of a luteinizing hormone-releasing hormone agonist such as leuprolide or goserelin.

Although not as effective as tamoxifen therapy, ovarian suppression results in a significant reduction in

the risk of recurrence (25%) and a significant reduction in breast cancer mortality (29%) compared with

observation.265

In postmenopausal women, AIs have consistently been shown to be superior to tamoxifen, as

supported by an intention to treat meta-analysis that included 37,000 postmenopausal women with ER+

breast cancer. The AI treatment group had a significant reduction in breast cancer recurrence and breast

cancer mortality.347 Furthermore, in the NCIC CTG MA.17 trial that included more than 5,000

postmenopausal women, who had completed a 5-year course of tamoxifen, followed by an additional

course of letrozole or placebo – the letrozole treatment group at follow-up of 64 months had

improvement in disease-free survival and overall survival.348–350 The different AIs have been shown to

have similar efficacies and as such there is not one that is preferred. Postmenopausal women, who

cannot tolerate an AI because of osteoporosis, AI-associated musculoskeletal syndrome, or cardiac

disease, can be treated with tamoxifen. Premenopausal women should not be treated with an AI as it

can result in reactivation of ovarian function.351,352

The optimal duration of endocrine therapy has also recently been studied. In the Adjuvant Tamoxifen:

Longer Against Shorter (ATLAS) trial, 15,000 women were assigned to treatment with tamoxifen for 5

years or 10 years. It was found that the group receiving tamoxifen for 10 years had a reduction in the

risk of recurrence, significant reduction in breast cancer mortality after year 10, and a significant

reduction in the incidence of contralateral breast cancer. However, this was also associated with an

increased cumulative incidence of endometrial cancer (3.1% vs. 1.6%), pulmonary embolus (1.2% vs.

0.6%), and ischemic heart disease (4% vs. 2%).353 Further supporting the use of tamoxifen for 10 years

is the Adjuvant Tamoxifen-To Offer More trial that enrolled 7,000 women. The 10-year tamoxifen

treatment group had a significant reduction in the risk of recurrence and a trend toward a reduction in

mortality. However, there was an increased cumulative incidence of endometrial cancer and deaths

from endometrial cancer. As such, women with more aggressive ER+ breast cancers (high grade, tumor

size >2 cm, pathologically involved lymph nodes) should be offered tamoxifen for 10 years,

understanding the associated risks.354 Similarly, in the MA.17R trial extending the use of AIs to 10 years

has been shown to decrease the rate of breast cancer recurrence and the development of primary breast

cancer in the contralateral breast.355

For patients with ER-/PR-/HER2- or TNBC, chemotherapy is critical as no targeted therapies exist for

these patients. Adjuvant chemotherapy has been shown to provide a larger benefit for patients with

TNBC than for those with hormone-positive disease, with a larger reduction in the risk of recurrence

and subsequently a higher absolute improvement in disease-free survival (23% vs. 7%). Furthermore,

there was a larger reduction in the risk of death and as such a higher absolute improvement in overall

survival (17% vs. 4%).356 There is no standard chemotherapeutic regimen for patients with TNBC;

however, anthracycline- and taxane-based therapies remain the most commonly used. Taxanes are

known to be associated with a significant improvement in disease-free survival for patient with TNBCs

at 7 years, as seen in the GEICAM 9906 trial comparing FEC versus FEC, followed by paclitaxel.357 In

addition, the use of platinum agents has been introduced for patients with TNBC. As most breast cancers

that arise in the setting of a germline mutation in BRCA1 are triple negative and the role of BRCA1

relates to DNA damage response and cell cycle checkpoint control, it has been hypothesized that

platinum agents (as DNA-damaging agents) would have a role in BRCA1-induced breast cancers. In one

clinical trial involving 107 women with stage I to III breast cancers treated with cisplatin for four cycles

prior to neoadjuvant chemotherapy, the pathologic complete response was 61%.358 Given that it is

known that pathologic complete response in patients with TNBCs is associated with an improvement in

disease-free survival, platinum-based therapy is very promising.359,360 However, it is not currently

known how platinum agents impact survival.

Patients with TNBC have a poorer prognosis compared with patients with other breast cancer

subtypes. These patients have a worse breast cancer-specific survival, worse overall survival, and a

dramatic increase in death within 2 years of diagnosis. However, this risk declines substantially over

time.361 Given these risks, chemotherapy is now commonly given in the neoadjuvant setting, especially

for patients with locally advanced TNBCs.

Adjuvant Medical Therapy for HER2-Positive Breast Cancer

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