Approximately 20% of women diagnosed with primary invasive breast cancer will have either an

amplification or overexpression of the HER2. Since the introduction of trastuzumab to adjuvant

chemotherapy, women with early and locally advanced HER2 positive disease have had tremendous

improvements in both disease-free survival (HR for recurrence, 0.60; 95% CI, 0.50 to 0.71) and overall

survival (HR for mortality, 0.68; 95% CI, 0.57 to 0.77), as evidenced in a meta-analysis of eight trials

involving approximately 12,000 women that compared trastuzumab plus chemotherapy versus

chemotherapy alone. The risks associated with trastuzumab therapy include congestive heart failure and

a decline in left ventricular ejection fraction.362 Trastuzumab is the only HER2-targeted therapy to

result in a survival benefit when administered with chemotherapy in the adjuvant setting. Based on

collective data from the Herceptin Adjuvant (HERA) trial363 and the Protocol for Herceptin as Adjuvant

therapy with Reduced Exposure (PHARE) trial,364 the duration of adjuvant trastuzumab treatment

should be 1 year.

It is recommended that women with HER2 positive, node-positive breast cancer and women with

HER2-positive, node-negative tumors >1 cm in size receive both adjuvant chemotherapy and

trastuzumab. Chemotherapy regimens include both anthracycline-based (ACTH: doxorubicin 60 mg/m2

and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles, followed by docetaxel 100 mg/m2

every 3 weeks and trastuzumab [weekly during chemotherapy and then every 3 weeks for 1 year]) and

non–anthracycline-based therapies (TCH: docetaxel 75 mg/m2 plus carboplatin every 3 weeks for 6

cycles, with trastuzumab [weekly during chemotherapy and then every 3 weeks for 1 year]). The

effectiveness of anthracycline-based chemotherapy has been validated with the National Surgical and

Breast and Bowel Project (NSABP B-31) trial and the North Central Cancer Treatment Group (NCCTG)

N-9831 trial. With a median follow-up of approximately 4 years, chemotherapy plus adjuvant

trastuzumab resulted in superior rates of disease-free survival and overall survival.365 Non–

anthracycline-based therapy (TCH) has been contrasted with ACTH in the Breast Cancer International

Research Group 006 (BCIRG-006) trial, and it was determined that ACTH demonstrated a trend toward

improved disease-free and overall survival that did not reach statistical significance. However, ACTH

had greater toxicity than TCH.366 As such, both ACTH and TCH are reasonable options for women with

HER2-positive breast cancer.

Although trastuzumab has significantly improved survival outcomes for patient with HER2+ breast

cancer and has paved the way for the era of targeted therapy in breast cancer treatment, inherent or

acquired mechanisms of resistance to trastuzumab therapy can occur, resulting in the need for more

effective anti-HER2 therapies.367 A once promising HER2- directed therapy that has recently been

shown to have no effect in the adjuvant setting is lapatinib, a tyrosine kinase inhibitor that has dual

effects against both HER2 and the epidermal growth factor receptor. In a placebo-controlled,

multicenter, randomized phase III trial, women with HER2-positive early- breast cancer who had

previously received adjuvant chemotherapy but not trastuzumab were randomly assigned to receive

daily lapatinib or placebo for 12 months. At a median follow-up of 48 months, there were no differences

in mortality or in local/distant recurrences.368 Furthermore, as presented in the 2014 ASCO meeting,

the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation Study (ALTTO) showed a lack of

benefit for combining lapatinib with trastuzumab as there was no impact on disease-free survival

compared with adjuvant trastuzumab alone.369 Novel HER2-targeted therapies include pertuzumab,

which has been approved for HER2-positive breast cancer in both the neoadjuvant and metastatic

settings in conjunction with chemotherapy and trastuzumab.70 Overall survival benefits are not known

at this time and the benefits of adjuvant pertuzumab is being explored in randomized trials. Another

promising HER2-targeted therapy under clinical investigation is TDM1, which consists of trastuzumab

linked with the cytotoxin mertansine, which should result in more specific and robust targeting of

HER2-positive breast cancer cells.370

SPECIAL ISSUES IN BREAST CANCER TREATMENT

Inflammatory Breast Cancer

A common clinical presentation for IBC is peau d’orange, characterized by edema, warmth, and

erythema. Unlike other types of breast cancer, patients with IBC often have associated pain and

tenderness with an enlarged and firm breast. The nipple can also be involved with flattening, erythema,

crusting, blistering, and retraction. Despite the reference to inflammation, the skin changes are not

secondary to an inflammatory process but rather secondary to tumor emboli within the dermal

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lymphatics.371 As noted by Sir Charles Bell in 1812, these cancers tend to be much more aggressive

—“when a purple color is on the skin over the tumor accompanied by shooting pains, it is a very

unpropitious beginning.”372 By 1924, Lee and Tannenbaum373 described 28 cases of women presenting

with a rare, rapidly progressive breast cancer with inflammatory features and introduced the term

“inflammatory breast cancer.

IBC is an aggressive form of LABC that effects approximately 1% to 5% of women with breast

cancer.374 It is designated as primary tumor stage T4d. The consensus-based criteria for the diagnosis of

IBC was determined by an international expert panel who proposed the following features: (1) rapid

onset of breast erythema, edema, and/or peau d’orange, and/or warm breast, with or without an

underlying palpable mass, (2) duration of history no more than 6 months, (3) erythema occupying at

least one-third of the breast, and (4) pathologic confirmation of invasive carcinoma.375 Furthermore,

although dermal lymphatic involvement supports the diagnosis of IBC, which can be obtained with a

full-thickness skin punch biopsy, it is neither necessary nor sufficient in the absence of the classical

clinical findings. The diagnosis of IBC is made with clinical examination findings, followed by breast

imaging, which includes mammography and ultrasound to help detect sites within the breast that can be

biopsied to confirm the breast cancer. To determine extent of disease, we routinely obtain a breast MRI.

A skin punch biopsy can then be performed but is not required for diagnosis. As IBC is a clinically and

pathologically distinct form of LABC that is particularly fast growing, invasive, and angiogenic, nearly

all women have lymph node involvement at the time of presentation and approximately a third of

patients will have distant metastases.376,377 As such, all women with IBC need to undergo complete

staging including a chest/abdomen/pelvic CT scan and bone scan. Head CT should be considered if

symptoms are present.

The treatment of IBC is based on multimodality treatments, similar to those described for women

with LABC. However, BCT, SLN biopsy, and immediate breast reconstruction are generally considered

inappropriate for patients with IBC. Treatment often consists of neoadjuvant chemotherapy that is

anthracycline- and taxane-based until all signs of skin inflammation have resolved and the breast and

axillary masses are deemed operable. Surgical management with a modified radical mastectomy is then

performed with delayed breast reconstruction, if appropriate. Adjuvant radiation therapy follows using

standard fields determined by CT planning, ensuring that the chest wall, supraclavicular, infraclavicular,

and the internal mammary lymph nodes are radiated.375 Radiation therapy to the axillary bed after

axillary dissection is often individualized. However, if the patient still remains inoperable after

neoadjuvant chemotherapy, then radiation therapy ensues, with the goal that the patient will thereafter

become operable. For ER+ IBC, adjuvant endocrine therapy is given. For HER2+ IBC, trastuzumab (+/

− pertuzumab) is added to the neoadjuvant regimen and adjuvant trastuzumab is given to complete 1

year of treatment.

Currently, there is no optimal systemic regimen (chemotherapy or targeted therapy) identified for

IBC. However, patients who obtain a complete pathologic response from chemotherapy have a

significantly higher disease-free survival and overall survival.378,379 Despite the combination of surgery

and radiation therapy improving locoregional control, there is no impact on overall survival.380 Even

with multimodality treatments, the prognosis for patients with IBC remains poor with 5-year diseasefree survival rates of 20% to 45% and an overall survival of 30% to 70%.378,380–383

Breast Cancer in the Elderly

In the United States, approximately half of newly diagnosed breast cancers are in older women,

typically defined as aged 65 years or older. Older patients tend to receive less than standard therapy

worldwide,384–387 with decreased rates of surgery and use of adjuvant radiation therapy, but with

increased use of primary endocrine therapy.388 This may be secondary to more indolent tumors present

in elderly women versus younger women.379 However, after controlling for confounding factors such as

comorbidity, social support, and functional status, older women are still treated less aggressively than

their younger counterparts. In general, treatment approaches should not be altered for medically fit

older women, except for the use of SLNB and/or radiation therapy in early ER+ disease.

The ability to omit axillary surgery without an adverse effect on outcome in older women (age ≥70

years) with favorable breast cancers has been well studied and supported by multiple randomized trials.

These women had clinically negative axillary examinations, small (<2 cm) ER+ breast cancers, and

were all treated with adjuvant endocrine therapy.390–392

The ability to omit adjuvant radiation therapy in older women who have undergone partial

mastectomy for early ER+ breast cancer is supported by CALGB 9343. This phase III study involved 636

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women (age ≥70 years) who had T1N0M0 ER+ breast cancer who were treated with partial

mastectomy and then randomly assigned to receive either radiation therapy plus tamoxifen (317

women) or tamoxifen alone (319 women). The primary end points studied included time to local or

regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant

metastasis, and overall survival. At 10 years, 98% of patients receiving radiation therapy plus tamoxifen

compared with 90% of those receiving tamoxifen alone were free from local and regional recurrences.

However, there were no significant differences in time to mastectomy, time to distant metastasis, breast

cancer–specific survival, or overall survival between the two groups. Ten-year overall survival was 67%

(95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%), respectively.393 This led to breast-conserving

surgery and endocrine therapy alone being incorporated as a category I recommendation in the current

NCCN Guidelines for older women.

For older women with comorbidities, functional status limitation, or frailty, the Comprehensive

Geriatric Assessment (CGA) can serve as an objective measure to aid in treatment decisions. The CGA

has been used in elderly patients with cancer including those with breast cancer and ranges from 44 to

84 questions. The ELCAPA study looked at how the CGA could alter an initial treatment plan in 375

patients aged 70 years and older. Treatment plans were modified in 20.8% of cases, with most plans

changed to decrease treatment intensity, although there were some regimens (10.8%) that were

intensified.394 Given how extensive the full CGA can be, other screening tools that have been developed

include the Vulnerable Elders Survey-13, Barber Questionnaire, Geriatric 8, Cardiovascular Health

Study, and the abbreviated CGA.

For medically frail patients, surgical management, followed by observation is commonly offered,

especially if a patient’s life expectancy is limited. If surgical intervention is not an option, endocrine

therapy can be offered to patients with ER+ disease and single agent chemotherapy for those with ER−

disease. In the presence of HER2+ disease, single agent HER2-directed therapy or its addition to

systemic therapy can be prescribed, understanding that the latter approach carries additive risks of

toxicity. Radiation therapy is not recommended unless local control of disease is needed for symptom

management. Finally, palliative and supportive care services need to be offered to patients who wish to

avoid both surgical and systemic therapies.

Breast Cancer during Pregnancy

Gestational breast cancer is a rare disease affecting approximately 1 in 1,000 pregnancies but may

become more common as women delay childbearing.395–398 It is defined as breast cancer that is

diagnosed during pregnancy, within the first postpartum year, or anytime during lactation. Similar to

nonpregnant women, women with gestational breast cancer present most often with a breast mass or

skin thickening. Any mass that persists for greater than 2 weeks needs diagnostic imaging and possible

biopsy.

The breast becomes engorged and hypertrophied during pregnancy making imaging more difficult.

When women present with a mass in pregnancy, ultrasound is first obtained, which can differentiate

between a simple cyst, a complex cyst, or a solid tumor. The majority of gestational breast cancers

present as a focal solid mass.399,400 In the presence of an abnormal ultrasound, a diagnostic

mammogram can then be obtained to further determine the extent of disease and has been shown to be

safe in pregnancy as long as abdominal shielding is used.401 Although MRI with gadolinium has been

shown to be more sensitive than mammography for detecting invasive breast cancer, gadolinium is

contraindicated in pregnancy. MRI has also not been systemically studied for the evaluation of breast

masses in pregnancy or lactation. All suspicious masses must be biopsied, even in the presence of

normal imaging studies, through core needle biopsy, incisional biopsy, or excisional biopsy. In a patient

who has a concerning axillary examination, FNA biopsy is indicated.

The most common histologic type of gestational breast cancer is IDCs that are poorly differentiated

and diagnosed at an advanced stage. Compared to nonpregnant women, women with gestational breast

cancers have less hormone receptor-positive breast cancers (approximately 25% vs. 55% to 60%).402,403

The association between HER2 disease and gestational breast cancer is not currently known. For

pregnant or lactating women with locally advanced disease, staging evaluation is necessary. Given the

large cumulative radiation dose that can be associated with computed tomographic scans and the

contraindication for gadolinium use (therefore limiting the utility of MRI) in pregnancy, staging

imaging for pregnant women commonly includes chest radiography, an abdominal ultrasound of the

liver, and a “low-dose” bone scan or a skeletal MRI.

For women diagnosed with breast cancer at an early gestational age, pregnancy termination is an

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option. However, studies have not shown better outcomes with early termination. In a study involving

176 patients, pregnancy did not directly affect the prognosis of breast cancer, instead poor survival was

related to younger age (younger than 40 years) and to the large number of ER-negative tumors

(71%).404 Multiple subsequent studies have shown that pregnancy does not have a negative impact on

overall survival.405–407 In 2012, a meta-analysis involving 3,000 patients with gestational breast cancer

who were compared to 37,100 controls found that gestational breast cancer was associated with a

higher risk of death. However, this was limited to women diagnosed in the postpartum period.408

The treatment for breast cancer for women diagnosed in the postpartum or lactational period does not

differ from that recommended for nonpregnant patients. However, for patients receiving chemotherapy,

trastuzumab, or endocrine therapy, breast-feeding is not recommended given the potential toxicity to

the infant. The treatment for pregnant women does not differ significantly from established guidelines

but includes modifications to ensure the safety of the developing fetus. During any trimester of

pregnancy, surgical and anesthetic risks to the fetus have been shown to be minimal.409–412 Mastectomy

can be performed and for early breast cancers, this can eliminate the need for radiation therapy as it is

contraindicated in pregnancy. Typical radiation doses used for breast cancer range from 46 to 60 Gy,

which has been shown to convey a first trimester fetal dose of 0.04 to 0.15 Gy or a third trimester dose

as high as 2 Gy.406,413 The threshold determined for prenatal radiation exposure for fetuses under 16

weeks of gestation is 0.10 to 0.20 Gy and after 16 weeks 0.50 to 0.70 Gy to avoid risk of congenital

malformations.414 As such, breast-conserving treatment (which necessitates radiation therapy) remote

from delivery is not a feasible option. Otherwise, the choice between breast-conserving surgery and

mastectomy can be guided by a patient’s preference and the biology of the tumor.

Although the efficacy and safety of SLN biopsy has not been well established in pregnant women with

invasive breast cancers, most institutions do perform SLN biopsy for axillary staging. Isosulfan blue dye

is contraindicated in pregnant women, and methylene blue when used in amniocentesis has been

associated with fetal complications. However, a small series of studies using methylene blue or doublefiltered technetium sulfur for SLNB have suggested its safety and success in pregnant women.415–418

Given the small number of pregnant patients included in these studies, the potential risks of methylene

blue and technetium sulfur to the fetus along with the potential inaccuracy of SLNB in pregnancy need

to be discussed with the patient preoperatively. At our institution, single agent technetium sulfur is used

for SLN mapping in pregnant patients.

The most common regimens used in gestational breast cancers are anthracycline-based, AC

(doxorubicin plus cyclophosphamide), or FAC (fluorouracil plus AC). The exposure of the fetus during

organogenesis or the first trimester to chemotherapy can be detrimental and conveys risks including

congenital abnormalities, chromosomal abnormalities, and miscarriage. Although chemotherapy

exposure in the second and third trimesters is not associated with organogenesis, risks of intrauterine

growth restriction, lower gestational age at birth, and low birth weight occur in about half of exposed

infants.419–422 As such, chemotherapy is often initiated after the first trimester and given its association

with transient neonatal myelosuppression, it should be avoided 3 to 4 weeks prior to delivery. When

possible, timing of delivery is restricted to 34 or more weeks of gestation and requires confirmation of

fetal lung maturity to minimize complications associated with prematurity. Given that gestational breast

cancer can present as locally advanced disease, neoadjuvant chemotherapy can be first given, followed

by surgery in the postpartum period, and if indicated, adjuvant radiation therapy and endocrine therapy

can then be initiated. For women who are diagnosed late in pregnancy or the postpartum/lactational

period, prior to commencement of chemotherapy, which may impair infertility, these women should be

offered consultation with a reproductive endocrinologist to discuss fertility-preserving options.

Trastuzumab is contraindicated in pregnancy given its association with oligohydramnios, which can

result in fetal death, pulmonary hypoplasia, and fetal developmental abnormalities.423,424 The use of

methotrexate and endocrine therapy is also contraindicated during pregnancy. These therapies can be

initiated in the postpartum period.

Given that the majority of women diagnosed with gestational breast cancers are of reproductive age,

many desire additional pregnancies. In a meta-analysis of 14 studies, 1,244 women who became

pregnant following breast cancer were compared to 18,145 control patients. Pregnancy in breast cancer

survivors did not convey a worse survival but suggested a protective effect. Some suggest that

pregnancy may have an unknown biologic antitumor effect, although more likely this is secondary to

healthier women with better prognosis choosing to reproduce over their sicker peers and, therefore,

resulting in a bias toward improved survival. As most recurrences happen within the first 2 years after

diagnosis and treatment, it is generally recommended that pregnant women wait 2 years before

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contemplating another pregnancy.

Breast Cancer in Men

Male breast cancer in the United States accounts for 0.5% to 1% of all breast cancers diagnosed

annually.425 Risk factors for male breast cancer include family history of breast cancer and genetic

mutations including BRCA1 and BRCA2. BRCA2 is more commonly associated with male breast cancer

and conveys a 6% lifetime absolute risk, which is an approximately 100-fold higher risk than that in the

general male population.426As such, all men diagnosed with breast cancer need genetic counseling and

BRCA testing. Other genetic mutations include PTEN, which is linked to Cowden syndrome, TP53, which

is associated with Li–Fraumeni syndrome, mismatch repair genes that are linked to hereditary

nonpolyposis colorectal cancer (Lynch syndrome), and PALB2 mutations.427,428 Other risk factors include

those that increase circulating estrogens such as hormonal therapies, hepatic dysfunction, obesity,

marijuana use, and thyroid disease. It is also associated with Klinefelter syndrome, which is

characterized by 47XXY genotype. These male patients have atrophic testes and gynecomastia. In

addition, they have high-serum concentrations of gonadotropins (follicular-stimulating hormone,

luteinizing hormone) and a low-serum testosterone level, resulting in a high ratio of estrogen to

testosterone. Those with Klinefelter syndrome have a 19.2- and 57.8-fold increase in the incidence of

and mortality from breast cancer.429 Primary testicular conditions (orchitis, undescended testes,

testicular injury) are associated with an increased risk of male breast cancer as it can result in lower

androgen production and, therefore, result in a higher than normal estrogen to androgen ratio.430,431

Unfortunately, men are often diagnosed with breast cancer at an advanced stage. They commonly

present with a firm retroareolar mass that is painless. Workup for a suspicious breast mass in men is

similar to that for women and includes a mammogram and biopsy. Ultrasound is typically less

informative. The most common histologic subtype is invasive ductal carcinoma (90%). Lobular

carcinoma is rarely diagnosed in men. DCIS is also less frequent in men versus women. Most male

breast cancers are ER+ (81.5%).432 The staging system for male breast cancers is similar to that for

women and is classified according to the TNM AJCC staging system.

The treatment of early stage male breast cancer has generally been a modified radical mastectomy.

However, for a man with a clinically negative axillary examination, an expert panel from the American

Society of Clinical Oncology considers SLN biopsy to be an “acceptable” method.248 It is generally

accepted that in men who have no evidence of disease in the SLN biopsy, no further axillary surgery is

needed. For men who have a positive SLN, given there is a lack of data for men, they should be treated

similarly to women with positive SLN biopsies. There are limited data regarding the use of breastconserving surgery in men. A retrospective study of seven men treated with breast-conserving therapy

followed for a median of 67 months reported that there was no recurrence of disease. If men do elect

for a partial mastectomy, adjuvant radiation therapy is essential and is based on results showing that

adjuvant radiation therapy after breast-conserving surgery for women conveys a survival advantage.433

For men with LABC (T3N0, N1-2, or T2N2) or IBC, treatment plans are similar to that for women.

Consideration for neoadjuvant chemotherapy prior to surgery should be made. The treatment of

metastatic breast cancer in males should parallel that for females.

Adjuvant chemotherapy, radiation therapy, anti-HER2 therapy, and endocrine therapy should mirror

those for women. As the majority of male breast cancers are ER-positive, endocrine therapy with

tamoxifen should be given. In a limited study involving 39 men, those treated with tamoxifen had

better 5-year actuarial survival (61% vs. 44%) and disease-free survival (56% vs. 28%).434 Although

there are limited data, tamoxifen appears to be superior to AIs in the adjuvant setting for male breast

cancer.435 Extrapolating from the ATLAS trial for women,353 for men with higher risk of breast cancers,

consideration toward extending tamoxifen to 10 years should be considered.

Male patients with breast cancer should undergo similar posttreatment surveillance as that

recommended for females. However, the role of screening mammography for the contralateral breast in

these men has not been explored. It is important to recognize that male patients with breast cancer are

at risk for developing secondary cancers such as those of the small intestine, rectum, skin

(nonmelanoma), pancreas, and prostate.436

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