#30613: Breast Cancer

The most significant nonmodifiable risk factor for the development of breast cancer is female sex. As discussed, women comprise 99% of breast cancer diagnoses and deaths [19]. Male rates are higher in some countries but are not ever recorded to be greater than 15% of female cases.

Aging increases a woman's risk of developing breast cancer, with age-specific incidence increasing throughout a woman's lifetime and correlating with decreased ovarian activity. The probable cause of a breast cancer diagnosis before 40 years of age is a genetic predisposition. For most women with an average risk, the usual age of onset is after 50 years of age, with most cancers diagnosed in women between 62 and 79 years of age [13,19,20].

As noted, breast cancer incidence and mortality rates vary significantly across racial/ethnic groups. According to data from the Surveillance, Epidemiology, and End Results (SEER) program, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women have higher odds of presenting with stage IV breast cancer compared to non-Hispanic White women [21]. Almost all groups were more likely to be diagnosed with ER/PR-negative disease, with Black and Puerto Rican women having the highest odds ratios (2.4- and 1.9-fold increases, respectively) compared with non-Hispanic Whites. Lastly, Black, Hawaiian, Puerto Rican, and Samoan patients had 1.5- to 1.8-fold elevated risks of breast cancer-specific mortality [21].

Overall, BRCA1 mutations are estimated to be present in 1 in 500 to 1 in 800 women. However, in Jewish women of Ashkenazi descent, the risk runs much higher at 1 in 40. For Jewish women diagnosed with breast cancer before 40 years of age, at least 20% will have the BRCA1 mutation [22,23].

Inherited gene mutations are a significant risk factor for the development of breast cancer [19]. An experienced healthcare professional will quickly associate the probability of a genetic mutation with a family history revealing several first- and second-degree relatives reportedly having been diagnosed with ovarian and/or breast cancer. A breast cancer diagnosis established in a younger family member, reports of bilateral breast cancer, or the unusual occurrence of a male family member developing breast cancer implicate a genetic mutation, particularly when the history illustrates no identifiable environmental factors [12,24].

Breast cancer susceptibility genes BRCA1 and BRCA2 are autosomal dominant tumor suppressor genes responsible for 5% to 10% of all cases [23]. BRCA1 is located on chromosome 17q21, consisting of 1,863 amino acids within 24 coding regions. BRCA2 was identified on chromosome 13ql2. It has 27 coding regions, producing a protein more prolific than BRCA1, with 3,418 amino acids [12,14,23,25].

Carriers of mutated BRCA1 and BRCA2 are reduced to one functioning allele on the genes, as one of the wild type (normal) alleles has been lost [23]. When BRCA1 or BRCA2 is unable to repair damaged DNA, mutations can potentially result in one or more malignancies.

BRCA1 and BRCA2 are high penetrance genes, but not 100%. They are seen more predominately in Eastern European populations. As discussed, Jewish women of Ashkenazi descent possess what is termed the "founder effect." This founder effect mutation has stayed within a certain population that has been geographically or culturally isolated; outsiders have not been integrated within this specific population. Three founder mutations have been located with BRCA1 (187delAG and 5385insC) and BRCA2 (617delT). Populations possessing a founder effect have been identified in Sweden, Holland, Iceland, Hungary, and France; ethnic groups include African Americans and Hispanics [14,22,23].

According to the American Society of Clinical Oncology, women at high risk for familial breast cancer syndromes should be referred for genetic counseling. Criteria to recommend referral include: Ashkenazi Jewish heritage; history of ovarian cancer at any age in the patient or any first- or second-degree relatives; any first-degree relative with a history of breast cancer diagnosed before 50 years of age; two or more first- or second-degree relatives diagnosed with breast cancer at any age; patient or relative with diagnosis of bilateral breast cancer; and history of breast cancer in a male relative.

(https://ascopubs.org/doi/full/10.1200/JCO.2012.45.9859 Last Accessed: July 21, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

BRCA1 and BRCA2 are inherited by both men and women (i.e., are not in sex-linked chromosomes) and confer a 50% chance any offspring will inherit the mutation [23]. For reasons as yet unknown, not everyone who inherits the mutation will go on to develop hereditary breast or ovarian cancer. In these individuals, the risk then becomes comparable to that of the general population. This germ line (inherited) mutation cannot skip a generation. Even if the mutation does not manifest as breast cancer, it is still passed on [18].

Women who inherit the breast or ovarian cancer gene have a lifetime risk of 50% to 85% of developing breast cancer. There is an 11% additional risk of developing a contralateral breast malignancy within five years, rising to 25% to 27% by 10 years after diagnosis [24,26]. First-degree relatives have a 50% chance of inheriting the gene, and second-degree relatives have a 25% chance of this inheritance [18]. BRCA1 mutations confer an additional risk of uterine, pancreatic, cervical, and gastric cancers. BRCA2 risks include pancreatic, stomach, gallbladder, and bile duct cancers [23,25].

Genes other than BRCA1 and BRCA2 have also been implicated in increased breast cancer susceptibility [27]. Rarer inherited genetic mutations include those associated with Cowden, Li-Fraumeni, and Peutz-Jeghers syndromes and ataxia telangiectasia [4,28]. Of these, Cowden and Li-Fraumeni syndromes are the most common [29].

Cowden Syndrome

Cowden syndrome, also known as multiple hamartoma syndrome, is a rare autosomal dominant disorder. The tumor suppressor gene is the major phosphatase and tensin homolog gene (PTEN) located on chromosome 10q23.3. Although it is a benign disease, considerable morbidity is experienced. Several distinct features characterize this disease, including macrocephaly and hamartomas, benign tumors that manifest on various sites. These tumors include trichilemmomas (roughened papules) on the face, papillomas on the lips and mucous membranes, acral skin keratosis, and palmar-plantar lesions. In all, 90% of individuals with inherited PTEN mutations exhibit skin changes by 20 years of age.

Hamartomas may also develop on the thyroid gland, with early-onset thyroid cancer common. Most women with Cowden syndrome (75%) will develop fibrocystic breasts, fibroadenomas, ductal hyperplasia, and/or lobular atrophy. In premenopausal women, 25% to 50% will develop breast cancer, usually invasive ductal, with the potential for bilateral and multifocal lesions [14,18,23,25,30].

Vigilance is required with screening for men and women. Beginning with a very thorough physical examination at 18 years of age, or five years previous to the reported age a family member was diagnosed, a clinical breast examination (CBE) should occur every six months starting at 20 years of age, followed by an annual mammogram and magnetic resonance imaging (MRI) beginning at between 30 and 35 years of age. Genetic screening and counseling should be offered [30].

Li-Fraumeni Syndrome

Li-Fraumeni syndrome was initially identified in 1969 in young adults with sarcomas. Early-onset breast cancer, soft tissue and bone sarcomas, brain tumors, and leukemia are associated with this syndrome. In 1990, the tumor suppressor gene TP53, located on chromosome 17p13.1, was implicated in this condition. In patients with Li-Fraumeni syndrome, 70% have the TP53 mutation. TP53 plays a vital role in slowing the progression of the cell cycle when damaged DNA is in need of repair.

This autosomal dominant mutation is highly penetrant, with a lifetime risk for women of 100%. Breast cancer can occur as early as 15 years of age for patients with Li-Fraumeni syndrome, and tumors are human epidermal growth factor receptor-2 (HER2)-positive in the majority of cases.

Beginning at 18 to 20 years of age, an annual physical and neurologic examination is necessary. Monthly breast self-examination (BSE) and bi-annual CBE are also recommended. Annual mammogram should begin at 20 to 25 years of age.

If breast cancer is diagnosed, full mastectomy is advised rather than partial mastectomy (lumpectomy) and radiation in order to decrease the risk of a secondary primary and/or subsequent radiation-induced malignancy. Genetic counseling is essential due to the complexity of genetic heterogeneity [14,18,22,25,31,32].

Years of exposure to endogenous estrogen and progesterone, plus sporadic changes in breast tissue, play a major role in the risk of developing breast cancer. Early menarche and late menopause increase the risk, implicating the total number of menstrual cycles women experience as the contributing factor [5,13,33].

Breast density has been established as a predicted risk for breast cancer, with very dense tissue increasing the risk three- to fivefold. Adding to this increased risk is the impact of greater breast density on the interpretation of imaging studies. Dense breast tissue images as white enhancements on mammograms, as opposed to black, posing a challenge to identifying masses [13,15,26,34,35].

Women who received mantle radiation to the chest before 15 years of age (typically for Hodgkin lymphoma) are at increased risk for developing breast cancer. Younger age at exposure and a higher dose of radiation correlate with risk level. The risk continues for 25 years, with an estimated 12% to 20% of women developing breast cancer by 45 years of age. Childhood survivors of Hodgkin lymphoma mirror the disease course seen in women with BRCA1 mutations, with diagnosis usually occurring between 32 and 35 years of age [13,36,37,38].

Women who have had breast cancer have a three- to fourfold increased risk of developing a new cancer in the other breast or in another part of the same breast, which is considered different from a recurrence of the original malignancy. Invasive or in situ breast cancer can result in a contralateral breast malignancy, although estimates of this likelihood vary widely. Approximately 5% of women with in situ tumors will progress to an invasive contralateral malignancy within 10 years, with a greater risk in premenopausal than postmenopausal women [39].

Caution is warranted when discussing benign breast disease as a risk factor for cancer development, as it can cause unnecessary panic on the part of patients. Many documented benign breast diseases are purely benign and present no risk for malignancy. However, some conditions are linked to an increased risk, particularly those with histologic findings consistent with atypical hyperplasia [40]. Atypical hyperplasia, whether lobular or ductal, confers a risk more than four times greater than among women without breast disease. Proliferative lesions without atypia (e.g., fibroadenoma, sclerosing adenosis) raise a woman's risk of breast cancer slightly (about 1.5 times the usual risk). These changes can affect one or both breasts, and a familial history further increases the risk [4,28,40].

In postmenopausal women, overweight and obesity are risk factors for breast cancer. Increased adipose tissue correlates with greater circulating estradiol, although it is questionable as to the timing when excess weight may actually influence estrogen storage [41]. An additional concern is whether excess body fat can mask clinical findings, causing a delay in making a diagnosis, in particular with disease recurrence [42]. Higher mortality has been noted in inactive, obese women than active, slimmer women [3].

Consumption of two or more alcoholic beverages per day is associated with a 20% higher breast cancer risk in pre- and postmenopausal women, an effect attributed to alcohol's stimulatory action on the carcinogen acetaldehyde [41]. In addition, DNA repair is suboptimal when poor nutrition accompanies an excess intake of alcohol [4,13,14,29].

Women who are younger than 18 years of age when they deliver their first full-term infant have a lower risk of developing breast cancer than women who are 30 years of age or older when delivering their first full-term child. Risk increases after pregnancy for approximately 10 years, changing then to a more sustained protective effect. Overall, the relative risk is higher for women who give birth at an older age than for women who remain nulliparous [13].

Breastfeeding confers a protective effect against developing breast cancer. Research indicates the total amount of time breastfeeding correlates with risk level. One year or more of breastfeeding reduces the risk by 26%, with an additional 7% reduced risk with each live birth [14,43].

Postmenopausal women on combination hormone replacement therapy (HRT) appear to have an increased risk for the development of breast cancer, although those taking estrogen alone (and not progesterone) do not. Increased risk is seen in women in as little as two years after initiation of combination HRT. In addition, these women develop denser breast tissue, which presents a challenge with mammogram interpretation [14].

Empiric models are appropriate tools for assessing risk when it is improbable there is a hereditary predisposition, which would require genetic testing [4,45]. The National Cancer Institute (NCI) developed the familiar Breast Cancer Risk Assessment Tool (BCRAT), better known as the Gail model, in 1989. The BCRAT predicts the risk of invasive breast cancer within the next five years and up until 90 years of age by incorporating the following data [13,15,45,46,47]:

The established cut score for the BCRAT is 1.66%; women who score lower are considered at lower risk, while those who score at or above this are high risk.

Although the BCRAT has been validated for White women, Black/African American women, Hispanic women and for Asian and Pacific Islander women in the United States, it may underestimate risk in Black women with previous biopsies and Hispanic women born outside the United States. Additionally, because data on American Indian/Alaska Native women are limited, their risk estimates are partly based on data for White women and may be inaccurate [47]. Additional disadvantages of the BCRAT include that it is designed only for women 35 years of age or older. No questions are related to a personal or family history of ovarian cancer, and there is no inquiry into distant family members or the age of onset of those with a breast cancer diagnosis. The role of race/ethnicity for African American women and other specific populations is excluded. Finally, the pathology report pertaining to a biopsy is excluded, even though the biopsy report is significantly more valid than the fact a biopsy was performed [18,47].

The Claus model is well suited for risk assessment when there is a significant family history of breast cancer. This model calculates risk at 10-year increments based primarily on items assessing family history [23]. The Claus model has the disadvantage of excluding ethnicity, hormonal/reproductive factors, personal breast disease, and ovarian cancer. BRCA1 and BRCA2 mutations are not calculated [18].

The BRCAPRO is the most widely used and studied model to assess the probability of a genetic mutation, focusing on BRCA1 and BRCA2 plus any family history of breast cancer. The BRCAPRO combines components of several risk assessment models including the Couch model, the Claus model, the Shattuck-Eidens model, and the Frank model. The model cumulatively builds on several variables, including age at diagnosis and first- and second-degree family members with any relevant history of breast or ovarian cancer. Race/ethnicity is also incorporated into this model [4,18,22].

Premammogram instructions should discourage the use of deodorant, talcum powder, lotion, or perfume prior to the examination, as the presence of these substances can cause light particles on the images, mimicking calcifications [67]. Women are counseled that the actual time taking the images amounts to a few seconds, although it may feel longer due to discomfort of the breast tissue being so firmly compacted. Two views are taken of each breast: cranial-caudal and mediolateral-oblique [46].

Mammograms are interpreted through the Breast Imaging Reporting and Data System (BI-RADS). Women receive a written report of their mammogram results, in terms they can understand, within 30 days of their screening. The four descriptions of breast tissue range from fatty to dense. The detection of abnormalities (or lack thereof) is categorized as [67,68,69,70]:

Errors in mammogram interpretation do occur, with variations in breast density, extremes of body type (obese or underweight), HRT, and the skill of the radiologist all impacting the findings [67]. In particular, this modality has a general inability to distinguish cysts from solid masses. False-positive results requiring a follow-up study can provoke anxiety, not only during the time before the re-screening but also while waiting for the subsequent results. False-positive results can also result in an unnecessary biopsy and/or overtreatment of a non-aggressive benign lesion. In reality, of the 11% of mammograms requiring further investigation, 90% prove to be benign [62].

The cost of a mammogram is relatively inexpensive, at approximately $150, yet a large number of women continue not to be screened. There are many barriers other than cost that contribute to this discrepancy. Pain and embarrassment have been noted to contribute to lack of compliance with screening recommendations, with anxiety before appointments a significant factor [71]. Language barriers, lack of transportation, lack of health insurance, and low income have also been identified as impedances. In addition, long office wait times and lower mammography capacity have been found to decrease screening rates [72]. Some women have an exaggerated sense of the amount of radiation exposure from a mammogram. In reality, the amount of exposure is insignificant.

The majority of women who undergo mammography do so due to healthcare professionals' recommendations and endorsements [36]. If 5% more women underwent mammography each year, as many as 560 deaths could be prevented annually. Nurses and other healthcare professionals have an obligation to educate and endorse the guidelines for breast cancer screening recommendations in order to improve the screening rate and overall survival [35,71].

Counseling should begin at 20 years of age and include information on the early signs and symptoms of breast cancer and a recommendation for CBE at least every three years. This should continue until 45 years of age, after which annual CBE and mammography should begin. Women 40 to 44 years of age should have the opportunity to begin annual screening [65].

Beginning at 30 years of age, annual mammography and MRI are recommended for women if they have [65,73]:

The USPSTF recommends that high-risk women should receive genetic counseling and, if indicated after counseling, genetic testing for BRCA1/2 [74].

Women 25 years of age and older who received mantle radiation for childhood Hodgkin lymphoma should be followed very closely by a skilled healthcare professional. Intensified surveillance for survivors involves CBE every six to 12 months, continual breast awareness, and scheduled yearly mammograms. Mammograms should begin within eight to 10 years after the radiation ceased or at 25 years of age. Annual MRI is also recommended, although the efficacy of this continues to be debated [15,36,58].

Although the same scanner and technique apply to a diagnostic mammogram as with a screening mammogram, there is more deliberation with the diagnostic imaging. This involves taking a series of pictures of breast tissue, capturing as many nodes as possible. The radiologist, who may even be accompanied by a second radiologist for additional input, is present during the scanning, reading each image until a decision is reached to either schedule a follow-up appointment within three to six months or recommend proceeding with an ultrasound-guided biopsy. Ideally, the biopsy should be obtained as soon as possible following the diagnostic mammogram.

If a defined mass is known to be malignant, it is imperative to complete the mammogram before the biopsy, as changes occur in the breast tissue after the biopsy has been completed. For women with a history of breast-conserving surgery and prior radiation treatments, mammograms are less sensitive and more challenging to read due to scar tissue [61].

After the initial mammogram, an ultrasound may be completed, if necessary [86]. The main utility of ultrasound is its ability to distinguish a cyst from a solid mass. The order for an ultrasound should summarize the location of the detectable lump and describe the findings. If the mass is solid, the location (described by placement on a clock face) and distance from the nipple should be noted. The order should also indicate if the mass should be aspirated or biopsied.

Ultrasound is noninvasive and painless, although patients may experience some discomfort with pressure from the scanner if the breast is tender or inflamed. The patient is positioned in a semi-reclining position with her wrist over her forehead to enable the area of breast tissue to be thinned as much as possible. Women with larger breasts may need to sit more upright, allowing gravity to help with positioning of pendulous breasts. As with scheduling mammograms or breast examinations, the ideal time for ultrasound for premenopausal women is one to two weeks after their menstrual cycle. Having the radiologist present to evaluate the images in real time is preferable.

In patients with suspected inflammatory breast cancer, ultrasound is preferred over mammography. For these patients, ultrasound will determine if the lymphatic vessels and nodes are engorged and will ascertain the thickness of the skin [7,86].

MRIs are costly but invaluable in showing the extent of the breast tumor. MRI is used for both screening and diagnostic purposes, although the CDC and the ACS only recommend both annual mammogram and MRI for high-risk women [62,66]. Prior to an MRI being performed, patients are routinely screened for any implanted metal objects, questioned as to whether they are claustrophobic, and cautioned they will need to remain still. The scanner is loud, and patients are offered ear plugs or headphones to muffle the sound. If contrast is ordered with the MRI, a renal panel will be obtained to check creatinine and blood urea nitrogen. The contrast injected for the MRI is gadolinium diethylenetriamine penta-acetic acid (DTPA), which has the potential to cause nephrogenic sclerosing fibrosis if any renal impairment exists [61,68].

In patients with suspicious mammography findings or a palpable breast mass, biopsy may be indicated. An MRI-guided core biopsy requires the use of a breast biopsy coil and a specialized table for the procedure. For the biopsy, women are placed prone on the table and informed that additional time is required to move them in and out of the magnet field and to exchange metal with plastic equipment for safety within the scanner. A needle biopsy may be sufficient, or a vacuum-assisted device can be used when obtaining a larger tissue sample. After the biopsy has been obtained, a titanium clip is placed in the breast to mark the lesion. If the biopsy is highly suspicious for a malignancy, a repeat MRI may be necessary [87].

It is imperative that the images are captured within the first minutes after the gadolinium is injected, when the vascular tumor is highlighted and before there is any detectable uptake of the contrast by any benign lesions. The downside to using contrast with an MRI is that normal breast tissue may appear abnormal due to hormonal influence. Fibroadenomas, mastitis, necrotic areas, and atypical hyperplasia will also be highlighted, potentially resulting in an unnecessary biopsy being performed [68].

Percutaneous fine-needle aspiration (FNA) is used when a mass, usually a cyst, is palpable and does not require imaging to locate the site. An FNA is used to biopsy BI-RADS category 3, 4, or 5 lesions.

The procedure is minimally invasive and inexpensive, requiring small-gauge needles size 23 to 27 and a 10- to 20-mL syringe. The needle is inserted in the lesion and twisted to obtain cells. Once retrieved, the tissue is deposited in preservative solution and sent for cytology. The downside of FNA is its inability to distinguish between an invasive and an in situ lesion; it should not be performed for suspected DCIS. There is also a possibility of an insufficient number of cells being obtained, resulting in an equivocal diagnosis [88,89]. An estimated 10% to 20% of malignancies are undetected with FNA due to false-negative findings [90,91].

Caution is warranted when benign cysts are aspirated on a fairly regular basis (e.g., for women with cystic breasts). Fluid removed should be assessed for consistency and color and compared to any previously obtained aspiration. Any change in the color of the aspirate or the presence of blood indicates the fluid should be sent for cytology [91].

A core-needle biopsy is appropriate for BI-RADS category 4 lesions with suspicious, nonpalpable masses. A core sample is more substantial compared to the amount of tissue obtained with FNA. The procedure is minimally invasive, and anticoagulants do not need to be put on hold. The area is numbed with local anesthesia, and a large-gauge needle and an automated biopsy gun obtain the core tissue. Women generally prefer this method to the stereotactic biopsy, as it is less time consuming and no x-ray is required. Ultrasound can be used for guidance if needed [68,88,89,90].

A stereotactic biopsy may be performed for microcalcifications, nonpalpable lesions, locally advanced breast cancer, and DCIS. Some preparation is required prior to the biopsy being performed as it is a more extensive procedure.

Anticoagulants may be held a few days prior to the biopsy, under the guidance of the patient's primary care provider, with prothrombin time/international normalized ratio checked prior to the biopsy. Additionally, any routine use of vitamin E, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) should be halted. Prophylactic antibiotics may be required for patients with a history of mitral valve replacement. Patients with chronic back pain, chronic obstructive pulmonary disease, obesity, persistent cough, or history of anxiety may not be eligible for stereotactic biopsy.

When undergoing a stereotactic biopsy, patients are required to lie prone and must be able to remain still for approximately 15 to 20 minutes, or longer if an MRI scanner is used [92]. Of note, the table has a weight limit of 350 pounds. Lying prone, patients are shielded from seeing the equipment housed below the table. The patient is prepped for the sterile procedure, and the area is numbed with local anesthetic. A 14-gauge needle is inserted into the breast, running parallel to the chest wall to prevent needles being propelled into the chest wall and subsequent pneumothorax. Women with small breasts may require a different approach to achieve the 2-cm thickness of compressed breast tissue required to safely obtain the stereotactic biopsy [92]. A core-needle biopsy with a vacuum-assisted device, using 8- or 11-gauge needles, can be used if a number of sites are to be biopsied; the 8-gauge needle allows for a larger sample size of tissue to be evacuated. Clips are placed in the area of the mass to mark the biopsy site; this is particularly imperative if the entire mass is removed. Clips have the potential to migrate, so additional documentation of placement is necessary if future surgical intervention is planned [61,88,89,92,93].

Following the procedure, women should be instructed to avoid heavy lifting for a few days. Hematomas may form, and patients should be informed they will gradually resorb over time [68].

Incisional and excisional biopsies were historically mainstays of breast cancer diagnosis. Incisional biopsies require the removal of a wedge of tissue to be examined in pathology. These biopsies are seldom performed today, as more accurate and sophisticated methods have made the use of this invasive method nearly obsolete [90].

The goal of an excisional biopsy is to remove the entire mass; however, it is associated with a high probability of the lesion having to be re-excised. An excisional biopsy is no longer the preferred method or the standard of care to obtain a breast tissue biopsy. It was often perceived as a way to obtain a "quick answer" for the patient, but the less invasive options are the preferred first-line approaches. It is important to remember that women have the right to elect to undergo the procedure, having the benign tumor removed and minimizing their anxiety [90].

SLNB is an integral part of the diagnostic work-up. Major improvements have been made in mapping lymph nodes, a method used to determine if any metastatic disease has spread from the breast lesion to the lymph system in the axilla. An SLNB as a preoperative staging procedure is a very accurate prognostic indicator [94]. If the SLNB yields positive results, an ALND will follow, contingent on the treatment plan [95].

The axilla houses approximately 40 lymph nodes. Among these, three levels of lymph nodes have been identified [96]:

The number of positive nodes, as opposed to the location, is the prognostic indicator. Because lymph nodes lie buried in fatty tissue, a dye or radioisotope is required to highlight and track nodal location.

Different methods of SLNB can be utilized, with two types of dye, methylene blue or isosulfan blue vital dye, available. Various sites in the breast may be selected for injection: subareolar, subdermal, or peritumoral. Radioactive isotopes are an alternative mapping method, but uptake of the isotope can take up to 24 hours. In some cases, isotopes are injected the day prior to the procedure [88].

After being surgically prepped for the SLNB, 3–5 mL of dye is injected around the tumor, avoiding the mass or any previous biopsy sites. The breast is massaged to encourage the flow of dye and dilate the lymphatic vessels. Less than an hour is required for the uptake of the selected dye. Dye and radioisotope may be used simultaneously in order to increase the accuracy of identifying the sentinel node and decrease the likelihood of false-negative results.

The technique and accuracy in obtaining the biopsies relies on the skill and competency of the surgical team. Precision is needed to track any blue-stained lymph vessels leading to the designated nodes. Dye will not be taken up by any nodes that have been replaced by tumor. It is imperative that the node proximal to the tumor staining the bluest be identified as the sentinel node. If the nodes are negative, there is generally no need to pursue ALND. However, any palpable nodes in the axilla, even if they fail to stain, should be removed.

There are several advantages of SLNB, and it is considered the gold standard of lymph assessment. The procedure is minimally invasive, requiring a small incision and no drain. SLNB may be completed on men and women and is associated with less pain than more invasive procedures. It is considered accurate and is associated with decreased morbidity relative to a lower occurrence of lymphedema [94].

Current evidence does not support SLNB in pregnant or lactating women [94]. Preoperative education is necessary to prepare patients for the procedure, particularly potential side effects. The isosulfan dye causes discoloration of the skin. Urine will be tinged green, and changes in stool color may be observed. These changes will fade with time. Methylene blue dye can cause skin necrosis, although this is not common. Should it occur, silver sulfadiazine dressings are recommended.

Anaphylaxis can occur as a reaction to isosulfan blue dye, although this is a rare occurrence. Treatment involves IV fluids, corticosteroids, diphenhydramine hydrochloride, and epinephrine.

In the majority of cases, an ALND will be conducted after the sentinel node has been identified. However, ALND may supersede SLNB when nodes are palpable in the axilla or if inflammatory breast cancer has been diagnosed. With inflammatory breast cancer, the flow of lymph to the axilla is obstructed, which can result in a false-negative result with SLNB. Women who are pregnant or breastfeeding will require ALND, as they are ineligible for SLNB [94,96]. A decision not to pursue ALND may be appropriate if the plan is to proceed with a mastectomy while simultaneously removing the nodes.

ALND is a more involved procedure than SLNB and usually requires general anesthesia. If comorbidities prohibit this, moderate sedation is an acceptable alternative. Approximately ten level I and level II nodes are excised, and at least three positive nodes must be present for a definitive diagnosis [49].

Any level III nodes requiring excision should be removed individually to reduce morbidity, although this is rarely necessary. Patients undergoing ALND may require an overnight stay in the hospital if a mastectomy is scheduled to follow the dissection [49].

Prior to discharge, patients should be taught how to empty and record the drainage amount from their bulb-type wound drain. A timely return to normal activities is encouraged, with patients receiving instructions for shoulder and arm mobility and the amount of activity permitted [63].

There are several potential side effects that may arise after ALND. Intercostal brachial or thoracodorsal nerve injury can result in numbness in the axilla. Pain with loss of arm and shoulder movement arises from damaged latissimus dorsi or serratus anterior muscles; these injuries may require physical therapy. A seroma may develop after the drain has been removed, in which case, periodic aspiration may be required. Some patients may develop lymphedema or, infrequently, infection.

Axillary web syndrome can occur from trauma to the lymphatic and venous system. With this syndrome, superficial, painful "threads" run from the area of nodal dissection down the inner arm, with pain restricting arm movement. No treatment is necessary, and the complication resolves itself within eight weeks following surgery [63,96].

DCIS constitutes 20% of all newly diagnosed breast cancers [75]. The malignancy arises in the TDLUs; the malignant epithelial cells tend to grow in medium to larger-sized ducts but do not extend through the basement membrane [88,93].

DCIS is usually diagnosed between the ages of 49 and 69 years. The challenge with DCIS is not only whether the in situ mass will progress to an invasive tumor, but when the progression will occur. DCIS is considered a precursor to invasive breast cancer and is related to a mutation in the BRCA genes and the allied risk factors of familial breast cancer, obesity, increased breast density, and nulliparity. Survivors of childhood Hodgkin lymphoma are usually diagnosed with this form of tumor if they develop breast cancer [37].

The goal of treatment with DCIS is to prevent the in situ mass from progressing to an invasive breast cancer [75]. Depending on the amount of tumor involvement, the standard of care is total mastectomy or breast-conserving surgery followed by radiation therapy and endocrine therapy. An SLNB is not indicated in this plan of care [63,95].

The morphology of DCIS may be broadly categorized as either comedo or non-comedo. Non-comedo DCIS includes the subgroups of cribriform, papillary, micropapillary, and solid.

In comedo-type DCIS, the TDLU is filled with pleomorphic malignant cells. Invariably, calcifications formed from a central core of necrotic material are seen on mammogram. The extent of necrosis corresponds to the prediction of an increased risk of a recurrent ipsilateral malignancy, with a higher grade of malignancy predicting a higher rate of invasion. The cells usually lack estrogen and progesterone receptors, with an overexpression of HER2, a known proto-oncogene. A mutation in the TP53 tumor suppression gene is also detected [49,97].

As noted, there are several types of non-comedo DCIS, each with its own characteristic presentation and cytology. In the cribriform type, malignant cells are smaller and uniform, appearing in a pattern resembling a sieve. If any necrosis develops, it is found within small clusters of cells or within single cells. The TDLU is not full, as is seen in comedo-type DCIS. Papillary cancers are distinguished by neoplastic cells projecting intraluminally, with a fibrovascular core. Most papillary breast cancers eventually spread to the lymph nodes. In the micropapillary form, small clusters of cells extend into the lumens. The base of the papillae is small, expanding to a larger apex.

Solid non-comedo DCIS is characterized by breast ducts becoming solidly packed with malignant cells, causing distention. Cells range from small to large and are less defined. No necrosis is identified [49,97].

As with other breast lesions, lobular carcinoma in situ (LCIS) is often an incidental finding, discovered when biopsies are performed pursuing other diagnoses. The majority of women diagnosed with LCIS are premenopausal, usually between 40 and 50 years of age. Although infrequently diagnosed, the incidence has increased over the last 20 years in postmenopausal women [98]. The abnormal cells found in LCIS are not cancerous, and therefore, it is not a precursor or a type of breast cancer.

There are no clinical signs or mammographic findings typical of LCIS, and it is distinguished from atypical lobular hyperplasia only by degree of distention of involved spaces. The noninvasive in situ mass arises in the TDLUs of the breast tissue, and the carcinoma is usually found to be multifocal and bilateral. LCIS predicts risk for both lobular and ductal invasive carcinomas. The goal of treatment of LCIS is similar to DCIS: surveillance with timely intervention. If LCIS does progress to an invasive tumor, there is a greater possibility of it being ductal as opposed to lobular [98]. When necessary, intervention requires tumor removal and possible radiation therapy [97].

Although LCIS is classified as predicting risk and not as a precursor, the variant of pleomorphic LCIS (PLCIS) is much more likely to develop into invasive carcinoma. In PLCIS, the cells have central necrosis, calcification, and discohesive cells with lack of uniformity in the large nuclei; massive acinar distention is common. PLCIS has a worse prognosis than classic LCIS, with some suggesting that it should be treated more like high-grade DCIS [98,99]. Because it is so rare, treatment recommendations are not well defined. Complete excision with margins, nodal staging, and possibly adjuvant therapy are common approaches.

Invasive ductal carcinomas make up approximately 70% to 80% of all invasive breast cancers. With this breast cancer, malignant cells have extended beyond the ducts and the TDLUs into the breast parenchyma, and a dense mass is detectable on mammogram or ultrasound [97,100].

Breast examination may reveal a fixed, immobile mass. The firmness of the mass results from a fibrous response that ultimately produces the hard gritty tumor. Pathologically, the tumors have a gray-white appearance. The invasive ductal carcinomas are histologically graded as [88,97]:

Invasive carcinomas are subtyped in order to assist in developing a treatment plan and projecting a prognosis. Tubular carcinoma consists of very small, low-grade tumors that seldom metastasize and have a favorable prognosis. The stroma is infiltrated by tubular columns with protruding areas of cytoplasm. DCIS is detected in 75% of these tumors [49,88,97].

Medullary carcinoma is relatively rare, occurring in fewer than 2% of cases [101]. These soft, fleshy, tan-brown tumors with necrotic or hemorrhagic areas constitute a well-defined mass, presenting as an aggressive lymphoplasmacyte infiltrate. Although high-grade and poorly differentiated, tubular carcinomas have a more favorable prognosis than the infiltrating ductal type.

An estimated 1% to 2% of invasive cancers are mucinous (colloid), which is characterized by tumors composed of clumps of cells within pools of extracellular mucin. Masses are well circumscribed, with a slow growth pattern and favorable prognosis; there is less likelihood of metastasizing to the axilla. Tumors are ER/PR-positive and HER2-negative. There may also be cells from DCIS found within the tumor [49,88,97]. Mucinous carcinomas are most commonly diagnosed in women 60 to 70 years of age.

Invasive lobular carcinomas amount to approximately 6% to 9% of all invasive breast cancers [101]. Invariably, invasive lobular carcinoma is diagnosed in older women.

Reaching a definitive diagnosis of invasive lobular carcinoma with mammogram interpretation alone is a challenge. The problem arises when breast tissue is dense and there is no definable mass. Tumors form in an irregular pattern and may be found bilaterally and in several quadrants of breast tissue. The cells of the invasive lobular tumor and those of LCIS are identical. Approximately 60% of invasive lobular tumors progress from LCIS, but they can also stem from DCIS. This type has the distinguishing feature of preferential metastases to the meninges, gastrointestinal tract, and peritoneum. Pathologically, the distinguishable cells form a single line and invade the supporting stoma. Well-differentiated tumors rarely overexpress HER2 and are found to be ER/PR positive, but the reverse is found in poorly differentiated tumors. In families with a known E-cadherin (CDH1) gene mutation, there is a higher incidence of invasive lobular malignancies [49,88].

Paget disease of the breast accounts for 1% to 3% of breast malignancies in women and less than 1% in men. Paget disease is identified by ulcerated, raw, scaly vesicular lesions visible on the nipple and extending to the areola. Paget cells, classified as large, high-grade adenocarcinoma, are present within the nipple epidermis. Advanced disease may manifest with some nipple retraction, but this is an infrequent finding [49,69,88]. The malignancy is generally ipsilateral.

The average age at diagnosis is 50 to 60 years of age. Any appearance of eczematous skin changes, nipple involvement, or discharge from the nipple should be investigated to rule out the possibility of an underlying malignancy [69]. Initial symptoms of pain and itching may exist for months and precede any visible signs of the disease. Steroids or antibiotics may provide a temporary improvement in the skin appearance; a biopsy is necessary to confirm the diagnosis. In 85% to 88% of patients who present with typical symptoms, an invasive or in situ malignancy will be detected [90]. Roughly 50% have a detectable mass within 2 cm of the affected nipple. An estimated 25% have an intraductal occult malignancy, with no abnormality seen on mammogram and no detectable mass. Another 20% have no palpable mass but an abnormality is detectable on mammogram; this finding confers a greater risk for invasive cancer. Paget disease must be distinguished from malignant melanoma and Bowman disease, a type of squamous cell carcinoma [105].

The classification of the primary tumor is the same regardless of whether it is assessed by clinical or pathologic criteria or both (Table 1). Size prior to the removal of tissues for assessment should be measured to the nearest millimeter. If biopsies have been obtained and a significant amount of tissue removed, a reconstruction of the actual tumor size is necessary to avoid inaccurate staging and suboptimal treatment of the disease. If the tumor size is slightly less than or greater than a cutoff for a given T classification, the measurement should be rounded to the millimeter closest to the cutoff. Designation should be made with a subscript "c" or "p" modifier to indicate whether the classification was determined by clinical (physical or radiologic) or pathologic measurements, respectively. In general, pathologic determination of tumor size should take precedence over clinical determination.

The involvement of the regional lymph nodes is an important prognostic indicator. Staging is based on whether nodes are fixed or mobile, the area detected, and whether the determination is made by clinical examination, imaging, or SLNB (Table 2). The axillary lymph node status supersedes any other indicator in determining survival and likelihood of remaining free of disease. If no nodes test positive for disease, the 10-year survival rate is estimated to be 70% to 80%; this rate decreases by 50% when one to three nodes test positive, and drops to 10% to 15% when 10 or more nodes are detected [49].

The metastasis (M) classification is an expression of the spread of tumor cells, via blood or lymph, beyond the regional nodes (Table 3). The sites most commonly involved are the brain, liver, bone, and lung.

The combined TNM score is used to stage the breast cancer, which is used to guide treatment decisions and determine prognosis (Table 4). The higher stages have lower associated overall survival.

For the approximately 40% of patients electing to have breast reconstruction, it is essential to determine the expectations women have, what are they hoping to achieve, and what is realistically feasible [120]. Women should be cautioned that, with aging, the contralateral breast will naturally alter in shape, size, and ptosis and may no longer match the reconstructed breast. The sensation in a reconstructed breast will also be different. An excellent cosmetic outcome can be achieved but will never be as good as prior to surgery [138]. An earlier trend of allowing a grieving period to adjust to the loss of a breast while awaiting reconstruction is no longer advocated [120]. Instead, physicians should opt for earlier reconstruction, timed simultaneously with the surgery if possible [140].

The choice to undergo breast reconstruction is based primarily on a patient's desire to maintain body image, preserve sexuality, and negate the need for external prostheses, and the appearance of the breast is more natural [140]. For some women, reconstruction provides an opportunity for breast augmentation. Being able to wear attractive clothes may be an essential component of a patient's self-perception and femininity, and intact breasts may provide less of a reminder of the disease [122,123].

Factors that impact the decision to have breast reconstruction surgery include [56,63,120,122,123,138,139,141]:

Patients tend to have a better appreciation of what lies ahead if given the opportunity to meet with someone who has undergone reconstruction to discuss expectations [140,142]. Healthcare professionals should also have educational materials available with detailed explanations and graphics to help women understand the extent and time involved with the surgical procedures [63,123].

Transverse Rectus Abdominus Myocutaneous (TRAM) Flap

The pedicled transverse rectus abdominus myocutaneous (TRAM) flap is an autologous reconstruction requiring two areas of surgical intervention. Initially, a mastectomy, preferably a skin-sparing mastectomy in order to produce a superior cosmetic outcome, is performed. Then, a lower hip-to-hip transverse abdominal incision is made and a flap of muscle, fat, and skin is excised (similar to an abdominoplasty or "tummy tuck"). This resected flap is rotated, tunneled under the skin, and used to create the mound of the reconstructed breast or a pocket for an implant. Although the flap is separated from the lower abdomen, it remains attached to the rectus abdominus muscle, which will subsequently form the pedicle. The pedicle receives vascular support through an intact blood supply from the superior epigastric artery [63,120,124,136,139,141].

The pedicled TRAM flap has the advantage of being completed in one surgery and recreating a breast that appears and feels more natural than an implant. However, there are many drawbacks and potential complications as well. The surgery usually lasts four to six hours, and patients are required to remain at the hospital for three to five days, with at least eight weeks before the patient may return to work. Pain management is an issue, and chronic pain can be exacerbated with an existing history of low back pain. Drain and wound care are necessary after the procedure and can be extensive. Some patients will experience a pulling sensation in the abdomen [120,123].

Full or partial flap loss will occur in some patients, although full loss occurs in fewer than 1% of cases. Additional surgery may be required for the removal of necrotic tissue, but most patients can be managed with dressings. Nearly all patients will experience loss of abdominal strength to some degree, with an increased risk of hernia that may require surgery in the future; lifting over a certain weight must be avoided [63,120,122,138,141]. Seromas may also develop, although most reabsorb over time. Due to these potential complications, TRAM flap procedures have generally been abandoned for more effective and safer approaches [143].

Free TRAM Flap

Similar to the pedicled TRAM flap procedure, the free TRAM flap involves a mastectomy and resection of a portion of the lower rectus abdominus muscle, skin, and fat for the reconstructed breast. However, the tissue is fully resected and transplanted; no pedicle is included. Microvascular anastomosis connects the perforators to either the internal mammary or thoracodorsal blood vessels, enabling the transplanted breast tissue to remain viable [120,124].

This procedure is associated with longer surgery times and a risk for partial or total flap loss (2% to 5% of surgeries). It also requires specialized nurses to monitor for flap necrosis in the postoperative period. As with the pedicled TRAM flap, the free TRAM flap may result in seromas, hematomas, and abdominal wall weakness [120,122,136,138].

Reconstructive TRAM flap surgeries are complicated, and additional challenges arise with patients who are obese or who are long-term smokers. In patients with large breasts, harvesting the entire rectus abdominus muscle may be required to form the flap. Other factors that place patients at higher risk for complications include [144]:

Some institutions enforce strict smoking cessation guidelines, insisting patients be free of any nicotine products, including gum or patches, for a minimum of four to six weeks prior to surgery and confirming this with blood work preoperatively. For patients with a long history of smoking, the TRAM flap may be completed in two surgical procedures, with an interval of several days between. The first surgery would involve dividing and re-routing the inferior epigastric vessels to perfuse the subcutaneous tissue in the infraumbilical area. With an augmented blood supply, this tissue can then be resected to form the breast mound in the final surgery, completing the TRAM [63,120,122,138,139].

Deep Inferior Epigastric Perforator (DIEP) Flap

The deep inferior epigastric perforator (DIEP) flap procedure uses the lower transverse abdominal area of fat and skin to create a usable flap, but the rectus abdominus muscle remains intact. The deep inferior epigastric perforators are used, and the transplanted tissue is dependent on the perforators for viability; a variant uses the superficial inferior epigastric artery (SIEA flap) and tissue from the lower abdomen. If circulation is deemed to be inadequate during surgery, the DIEP can be converted to a TRAM flap procedure. A DIEP cannot be performed if there is a pre-existing history of liposuction; obesity and smoking may also be contraindications [120].

DIEP flap has the advantages of being less painful and resulting in less abdominal weakness (with a corresponding decrease in the risk of hernia). The recovery time is also shorter than with a TRAM procedure, but DIEP requires a lengthy surgery to establish microvascular connections. Patients may develop fat necrosis, seroma, or hematoma following the surgery [63,120,122,141].

Latissimus Dorsi Flap (LDF)

The latissimus dorsi flap (LDF) involves resecting the skin and fat from the upper back and tunneling it through the axilla. The latissimus dorsi muscle usually acts as a pedicled flap, with blood supply via the thoracodorsal artery and vein. The flap generally requires a saline or silicone implant to augment the muscle and provide contour to the breast, with tissue expansion prior to placement of the implant. However, in many patients, the flap can be used without an implant, restoring volumes of up to 1.5 L in larger patients or with the use of modified techniques [145]. This form of reconstruction is suitable for women ineligible for a TRAM flap due to obesity, smoking, or a previous breast reconstruction that resulted in flap failure. It is also of benefit in patients who previously have undergone irradiation. Contraindications include posterior thoracotomy, severe cardiac or pulmonary disease, or patient desire to avoid implants [145].

After LDF, patients will experience some loss of function, but it is usually insignificant. Over time, the muscle over the implant may atrophy, causing the implant to become very prominent. Within 10 years, as many as 50% of women will undergo additional reconstruction. Seroma, hematoma, and flap necrosis are potential complications [63,120,136,138,139].

Gluteal Free Flap

One alternative to using abdominal or back muscles is to use the gluteal muscle from the buttock to create a flap. This may be a good option for women with insufficient abdominal fat or who prefer a less visible scar.

The gluteal free flap procedure involves removing the superior or inferior gluteal fat, skin, and some muscle. The superior gluteal artery perforators will supply the superior muscle, and the inferior gluteal artery perforators supply the inferior muscle. Due to the proximity of the sciatic nerve, the microvascular anastomosis involved, and the repositioning required during surgery, the procedure is a lengthy one, totaling 8 to 10 hours. A long hospital stay (four to five days) and lengthy recovery time are common. If a bilateral reconstruction is planned, two separate procedures will be required. There is a good possibility the reconstructed breast will feel firmer than the natural breast [120,138].

Precision and expertise are required with this surgery to preserve the sciatic nerve and complete microvascular anastomosis, and nerve damage can occur. Even without damage, the sciatic nerve will have less protective padding after the procedure, and pain is common. If the superior gluteal muscle is used, there may be less contour to the hip. Similar to the other procedures, flap loss, seroma, and infection may develop [63,120,122,138].

Transverse Upper Gracilis (TUG) Flap

For women with insufficient lower abdominal fat and with smaller breasts, an alternative option for reconstruction involves use of the upper gracilis muscle. Although the lower buttock and upper thigh may have a minimum of fat, it may be sufficient for certain women.

The scars associated with TUG flap are less visible than on the abdomen, and hip contour should be maintained. A lengthy surgery is necessary to allow for microvascular anastomosis [63].

Patients at risk for or who have developed lymphedema should adopt habits to maintain healthy skin. A daily routine of lubricating skin to keep it supple and prevent cracks also provides an opportunity to inspect for cuts or scratches. Nail and cuticle care should be nontraumatic, and patients are advised to wear a thimble if sewing. Gloves are recommended for washing dishes and any outside garden work. Water not exceeding 102°F should be used for cleansing, and temperature should be tested with the elbow of the unaffected arm; soaking in hot tubs and taking very hot showers should be avoided. Clothing and jewelry should be loose and non-constricting. The affected arm should not hang in a dependent position for any longer than 30 minutes; carrying heavy bags should be discouraged [51,52,54,150,153,154,159].

If interstitial brachytherapy is desired, small hollow catheters are threaded through the breast tissue following lumpectomy. These catheters are placed either at the time of surgery or several days later in the outpatient setting. The area may require 15 to 20 catheters to encompass the tumor site, spaced 1 to 1.5 cm apart [164]. Although this method is accelerated, dosing is challenging and requires precision and expertise. Treatments are scheduled twice a day, with a six-hour interval in-between, for a total of five days. The catheters are loaded with iridium-192 for the defined treatment time. After the five-day course of radiation is completed, the catheters are removed [139,166].

The preferred timing for the insertion of an intracavity catheter or balloon for the delivery of brachytherapy is in the days to weeks following surgery. This closed technique affords ample time to review the final pathologic report and decreases the risk of infection. The balloon can also be placed during surgery, but there is an added risk of infection using this open method [135,164,165].

The dual lumen catheter is placed under CT, ultrasound, or stereotactic mammogram guidance. The catheter has a red port and blue port that remain positioned on the outside of the breast. The ports terminate in a balloon seated within the tumor cavity.

The dimensions must be evaluated to ensure correct placement of the balloon, with a goal distance of 7 mm from the skin and less than 10% of air or fluid around the balloon (i.e., a "snug" fit within the tumor space). The balloon is filled with saline or CT contrast via the blue port, while the red port accommodates the iridium-192 seed. Treatment takes approximately 10 minutes per session, twice a day for five days. Dressings over the exit site are changed daily by the nursing staff in the radiology department. The catheters are removed when treatment is completed [135,160,165,166].

Possible complications to intracavity brachytherapy include [160]:

Intraoperative brachytherapy is delivered with a one-time dose during surgery, targeting the margins and limiting exposure to the skin. This method is widely used in Europe and is gradually being used more often in the United States. The disadvantage of administering radiation therapy during surgery is the final pathologic report has not been reviewed, a longer time is required in the operating room, and there is less accuracy with the delivered dose [164].

Radiation may be delivered to the tumor bed during surgery via an applicator or a linear accelerator [166]. In the first case, an applicator is temporarily sutured into the cavity, where 20 Gy is administered directed at the surface where the applicator is placed. An additional 5 Gy is applied at 1 cm for approximately 20 to 45 minutes.

The alternative method involves the delivery of radiation therapy via the linear accelerator in a single 21 Gy dose. The chest wall and lungs are protected by a shield.

According to the literature, most women undergoing accelerated partial breast irradiation tolerate the placement of the catheters or balloon without problems. Relevant patient education includes reporting any fevers, malaise, or potential skin issues, and keeping scheduled follow-up appointments.

The use of tamoxifen has evolved over time, and today it is considered the criterion standard for the endocrine treatment of postmenopausal women with ER-positive tumors. Tamoxifen was initially used as a contraceptive, but starting in the 1970s, it has been used as a treatment for advanced breast cancer in postmenopausal women, gaining approval from the U.S. Food and Drug Administration (FDA) in 1977. By 1987, tamoxifen became a common adjuvant therapy for node-positive disease. Studies show that 30% to 40% of women with newly diagnosed metastatic disease remain stable for several years with no disease progression or regression if prescribed tamoxifen [180].

To date, tens of thousands of women worldwide have been enrolled in trials comparing various doses and durations of tamoxifen and regimens involving aromatase inhibitors (AIs) [107,181]. Despite the multitude of trials, there does not appear to be a definitive answer as to whether AIs should be administered prior to tamoxifen, alone or in combination, or the optimal time frame for combination therapy [182].

Tamoxifen is currently prescribed to men and pre- and postmenopausal women, regardless of age or node status, for [177,178,182]:

DVT, pulmonary embolism, atrial fibrillation, hypertension, transient ischemic attacks, and uncontrolled diabetes are considered contraindications for tamoxifen use [178].

Research indicates that five years of tamoxifen versus no treatment yields an annual reduction in the risk of recurrence of 41%. Risk reduction continues up to 10 years following completion of the treatment, although the cause of this continued efficacy remains unclear [160].

Treatment with tamoxifen is usually initiated after radiation therapy and chemotherapy are completed, approximately four to six weeks following surgery. The daily prescribed dose is 20 mg orally for up to five years [178]. Five years has been determined to be the optimal time for prolonging disease-free survival and overall survival in women with ER-positive cancer [107,175,183].

The benefits and risks associated with tamoxifen should be clearly outlined to patients. Yearly gynecologic check-ups are strongly encouraged, with patients instructed to report any new symptoms, including shortness of breath, pain and swelling in their legs, vaginal bleeding, or abdominal bloating and weight gain [68,107,177,183].

Mechanism of Action and Resistance

Tamoxifen is a nonsteroidal SERM that competitively binds to estrogen receptors on tumor cells and other tissue targets, decreasing DNA synthesis and inhibiting the systemic effects of estrogen. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents malignant cells from dividing but does not cause cell death, it is considered cytostatic rather than cytocidal [178].

The liver produces two drug metabolizing enzymes in the cytochromes, P450 2D6 (CYP2D6) and CYP3A4/5, that convert tamoxifen to the active metabolite endoxifen. Tamoxifen is metabolized initially to N-desmethyl-tamoxifen through the action of CYP3A4/5, and then converted to endoxifen via CYP2D6 [178]. As such, tamoxifen is a prodrug; it is the conversion of tamoxifen to endoxifen that allows for greater binding affinity to estrogen receptors.

Any reduction in an individual's ability to convert tamoxifen to endoxifen, either from a genetic predisposition or the co-administration of certain medications, results in little benefit being derived from this drug [107,184,185]. Medications that inhibit CYP2D6 function are often the cause of tamoxifen ineffectiveness, and this includes drugs prescribed to treat hot flashes and depression, such as selective serotonin reuptake inhibitors (SSRIs) [178]. The strong inhibitors of CYP2D6 include bupropion (Wellbutrin), fluoxetine (Prozac), and paroxetine (Paxil); moderate inhibitors are diphenhydramine (Benadryl), amiodarone (Cordarone), cimetidine (Tagamet), trazodone (Desyrel), sertraline (Zoloft), and duloxetine (Cymbalta) [107,185]. If possible, these medications should be avoided in patients taking tamoxifen.

Tamoxifen is a partial agonist, binding estrogen to estrogen and competing with estrogen receptors on tumors; however, tamoxifen also possesses antagonist properties and promotes estrogen activity. The agonistic effects contribute to bone mineral density, reducing the risk of osteoporosis and associated fractures. However, tamoxifen can cause serious adverse effects as a result of its antagonism, including a doubled risk for both endometrial cancer and thromboembolic events. Leg cramps and the development of cataracts may also occur [16,107,178,186,187].

Compliance

A major drawback of tamoxifen is the lack of compliance stemming from the long treatment period. An estimated 22% of women discontinue tamoxifen treatment within one year; by 3.5 years, 35% will have stopped, and only 49% of women complete the full five-year treatment plan. It is important to assure patients that half of all recurrences are halted and mortality is reduced by 65% when tamoxifen is taken for five years [1]. If women appreciate the positive results achieved with tamoxifen, there may be more of an inclination to continue treatment.

Aside from the daily reminder and time commitment, reasons stated for discontinuing the medication include the cost (approximately $22 per month) and the side effects experienced. In addition to the risk of endometrial cancer and thromboembolic events, side effects can also include [93,98,107,174,175,177,178,187,188]:

Raloxifene was initially designed for the treatment of osteoporosis, and its beneficial effects on bone health are one reason some prefer it to tamoxifen. Raloxifene has been determined to be as effective as tamoxifen, but it carries a smaller risk of endometrial cancer and thromboembolic side effects [183]. As a SERM, it has a similar action to tamoxifen, although it displays fewer estrogen-like effects than tamoxifen.

Raloxifene is appropriate for high-risk postmenopausal women (e.g., women with an intact uterus, a risk score of 1.66% or greater on the BCRAT, women treated for osteoporosis, and a history of LCIS), reducing the risk of recurrence in this population by 50%. Due to the potential teratogenicity, premenopausal women should not be prescribed raloxifene [58,98,107,177,178].

Side effects are reported in 35% to 50% of patients taking an AI and can manifest as early as four to 12 weeks after initiation of therapy. In many patients, activities of daily living are greatly impacted due to bone pain. Joints in the hands, wrists, feet, and ankles may become stiffened, resulting in as many as 10% to 15% of patients discontinuing treatment. Decreased estrogen levels increase patellar cartilage damage, resulting in joint erosion and pain [192]. A bisphosphonate may be prescribed concurrently to counter the adverse effects on bone mineral density and reduce skeletal morbidity.

Bone pain should not automatically be presumed to be a side effect from AIs; imaging may be necessary to rule out fractures and the possibility of bone metastases. Treating the symptoms may include physical therapy with range of motion exercises. Acetaminophen and NSAIDs may provide some relief, but if NSAIDs are prescribed, monitoring for gastric irritation is warranted. Low-impact bone strengthening exercise, such as walking, should be encouraged in moderation.

In addition to arthralgia and bone pain, patients may experience headaches, nausea, vomiting, and hot flashes. The risk for endometrial cancer or thromboembolic events is lessened with AIs compared to tamoxifen [16,107,177,184,191,193,194,195].

Focusing on nutrition and a healthy lifestyle is worth pursuing. Any vaginal bleeding not related to menstruation should be reported immediately in light of the risk of endometrial cancer. Patients may not feel comfortable discussing side effects impacting sexual activity (e.g., vaginal dryness, decreased libido), so creating a trusting relationship in which patients feel safe sharing their concerns can allow for an honest discussion. Referral to a counselor may prove beneficial [14,182,194].

In women who have undergone induced menopause, AIs may stimulate premenopausal levels of estradiol, with some patients reporting their menses have resumed. This is due to the negative feedback loop to the pituitary and hypothalamus. If menses begins, the agent should be discontinued. Although the side effects manifested from AIs differ from those of tamoxifen, they do have the potential to severely impact quality of life and treatment compliance [98,107,177,181,186,196].

Goserelin is administered as a tiny pellet implanted via a large bore needle into the subcutaneous abdominal tissue below the navel. The usual dose is 3.6 mg every 28 days [178]. To buffer the painful implanting of the pellet, a local anesthetic is applied prior to the procedure. Goserelin can cause hot flashes, headaches, depression, vaginal dryness, and edema.

More well known as an established treatment for prostate cancer, leuprorelin is being evaluated for its use in ovarian ablation in premenopausal women with breast cancer; as of 2019, this use was off label [178]. Leuprorelin is administered by intramuscular injection at a dose of 3.75 mg every 28 days or 11.25 mg every three months for up to 24 months [178]. Side effects include breast discomfort, hot flashes, increased perspiration, peripheral edema, and dizziness [107].

Lapatinib (Tykerb) is a reversible TKI capable of interrupting intracellular activity. Lapatinib is not a MoAb but is a small molecule that competes with adenosine triphosphate for binding sites, blocking signals to intracellular tyrosine kinase. The interrupted pathways include PI3K and EPK1/2 [199,209,210].

Lapatinib is currently prescribed for [107]:

Lapatinib is being investigated for its effectiveness in treating brain metastases as well [211].

Due to the targeted effect of lapatinib, less toxicity is experienced than seen with chemotherapy, but side effects do occur. Although the risk for congestive heart failure with lapatinib is low, any prior treatment with an anthracycline may cause some heart damage and predispose a patient to heart failure. A serious side effect experienced with lapatinib is severe diarrhea, requiring treatment with antidiarrheals and adequate fluid intake to combat dehydration [178]. Loperamide 4 mg initially followed by 2 mg after each loose stool, reaching a maximum of 16 mg in 24 hours, is recommended. Any diarrhea not responding to this regimen may require antibiotics [178].

An acriform rash (not acne) found on the upper trunk and face is a possible side effect. It may respond to simple moisturizing creams with frequent hygiene to prevent skin infections. If the rash becomes very troublesome, steroid intervention and antibiotics may be necessary; however, steroids produce additional side effects, with elevated blood glucose levels and weight gain. Fatigue, mouth sores, and palmar-plantar erythrodysesthesia (PPE) are less common side effects. Patients should be advised to take lapatinib one hour prior to meals or two hours after they have eaten [107,178,197,198,210,212].

Cyclophosphamide (Cytoxan) is cell cycle non-specific, effecting breaks in double-strand DNA and prohibiting DNA repair and replication. Cyclophosphamide, administered either orally or intravenously, is a major component of many regimens. Oral cyclophosphamide should be taken with an antiemetic in the early morning with plenty of fluids. Patients should be instructed to empty their bladder frequently and report any signs of blood in their urine, although it is unlikely with the dose prescribed for breast cancer that hemorrhagic cystitis would occur.

More common side effects include alopecia, nausea, and vomiting, with patients frequently reporting a metallic taste. The anticipated nadir occurs within 8 to 14 days. A potentially harmful side effect is a secondary hematologic malignancy with myelodysplastic syndrome potentially progressing to acute myelocytic leukemia, although this is dose dependent. Radiation to the chest area or any prior treatments with an anthracycline may potentiate some cardiotoxicity [93,107,133,184,199,218].

Anthracyclines prescribed to treat breast cancer are doxorubicin, liposomal doxorubicin (Doxil), and epirubicin (Ellence). Anthracyclines (antitumor antibiotics) are used frequently in combination regimens, definitely with a taxane as first-line treatment for metastatic breast disease. Anthracyclines are cell cycle non-specific, binding with DNA and interrupting the synthesis of DNA and RNA [107,133,178,195,218].

Doxorubicin is a vesicant administered preferably via a CVAD. Due to the potential cardiotoxicity, the lifetime cumulative dose is 550 mg/m² [219]. If radiation therapy or cyclophosphamide has been previously administered, the cumulative dose is reduced to 450 mg/m². The potential for heart damage may be lessened if doxorubicin is given as a continuous infusion over 96 hours or in lower doses administered more frequently. Higher doses of doxorubicin correlate with greater toxicity, resulting in irreversible heart damage. Early toxicity can occur during treatment and continue for one year; late-onset toxicity may occur years later, manifesting with worsening LVEF [178]. Additional side effects from doxorubicin include anemia, nausea and vomiting, anorexia, fatigue, alopecia, diarrhea or constipation, and neutropenia [93,107,219]. Due to the potential cardiotoxicity associated with doxorubicin, a cardiac MRI (preferred) or baseline MUGA scan must be obtained [178,219].

Liposomal doxorubicin, equally as effective as the nonliposomal agent, helps reduce cardiotoxicity, although even in this form elderly patients may require a dose reduction. Similar side effects to doxorubicin are experienced; a higher incidence of PPE, also known as hand-foot syndrome, and mucositis occur with the liposomal form of the drug [107,178]. Liposomal doxorubicin for the treatment of metastatic breast cancer is an off-label use in the United States [178].

When doxorubicin and trastuzumab are prescribed concurrently, nurses should be cognizant that trastuzumab can increase the risk for heart damage [178]. Healthcare professionals should assess other medications prescribed for comorbidities for their role in potentiating or decreasing the action of doxorubicin; several classes of drugs are implicated [199,220].

Dexrazoxane is a cardioprotectant given prior to dosing with doxorubicin when the dose accumulates to 300 mg/m², thereby enabling therapy to continue. It is selected for patients who have previously been heavily treated with other cytotoxic agents. Dexrazoxane is dosed at a 10:1 ratio and infused within 30 minutes of doxorubicin or epirubicin administration [178,199].

As approximately 5% of doxorubicin is excreted via the kidneys, patients should be cautioned their urine will be reddish tinged from the coloring of the drug. Any signs or symptoms of congestive heart failure, including weight gain, shortness of breath, edema, or chest pain, must be reported. Liver function studies should be monitored regularly. The usual nadir with doxorubicin is between 10 to 14 days [178]. It is imperative to monitor for fever or chills, as the possibility of infection is greatest at this time. Nausea and vomiting, diarrhea, alopecia, and hyperpigmentation of the nail beds can also occur. Dietary instructions should focus on limiting sodium intake and avoiding alcohol. Emphasizing the need to refrain from smoking remains a constant.

Epirubicin is an anthracycline given in combination with other agents. It is dosed at 60–90 mg/m² over 10 minutes every 21 days [178]. The side effects are similar to those of doxorubicin, but with less severity. A dose reduction is required with any known hepatic disease. Caution is required with epirubicin and cimetidine, as there is a potential for increased toxicity [199].

The antimetabolites gemcitabine (Gemzar), capecitabine (Xeloda), 5-fluorouracil (5-FU or brand name Adrucil), and methotrexate (MTX) are cell cycle-specific antimetabolite chemotherapy agents. These drugs interfere with DNA and/or RNA synthesis via various actions and ultimately inhibit cell growth.

Gemcitabine is administered by IV weekly, either as monotherapy or in combination with other agents. When given with paclitaxel, the regimen is 1,250 mg/m² over 30 minutes on days 1 and 8, repeating the cycle every 21 days. The monotherapy dose, which is off label, is 800 mg/m² over 30 minutes on days 1, 8, and 15 of a 28-day treatment cycle [178]. Dose limiting may be necessary in anticipation of thrombocytopenia. Additional side effects include nausea and vomiting, rash, and flu-like symptoms [107].

Capecitabine is a fluorouracil pro-drug converted through the actions of enzymes to 5-FU. Tumor tissue has elevated levels of thymidine phosphorylase, which completes the conversion of capecitabine to 5-FU. This oral medication is administered twice daily for 14 days and cycled every three weeks, which produces less toxicity than if administered IV but is equally efficacious [88,178]. Patients older than 65 years of age may require a dose reduction. Capecitabine is given as monotherapy for women with metastatic disease who have failed anthracycline and taxane therapy. The usual dose is 1,000–1,250 mg/m² twice daily on days 1 to 14, with the cycle repeated every 21 days [178]. Side effects include nausea and vomiting and PPE; alopecia and myelosuppression seldom occur. Capecitabine should be taken following a meal and with plenty of water. It is imperative to monitor for any interactions with capecitabine, phenytoin, folates, or warfarin. Renal function should also be monitored [107,178,221].

5-FU is administered IV in combination with other agents. The dose varies dependent on the regimen chosen, but ranges from 500–600 mg/m² on days 1 and 8 of a 21- or 28-day cycle [178]. Adequate hydration and nutrition are essential, and patients are urged to report diarrhea not responding to antidiarrheal medications. Diarrhea caused by 5-FU can be severe and debilitating, leading to dehydration, hypotension, weakness, and dizziness; a similar protocol with loperamide prescribed for patients taking lapatinib should be followed. Mucositis is problematic, further compounding the potential for dehydration. A darkened streak on the skin tracking the vein where the drug was infused is a possible side effect, along with alopecia, photosensitivity, and PPE. A nadir at around 10 to 14 days is normal [178,199].

Methotrexate, one of the oldest of the antimetabolites, is an analog of folic acid. It is seldom used as a single agent and is generally combined with cyclophosphamide and 5-FU. If it is chosen, the dose is 30–60 mg/m² on days 1 and 8 every three to four weeks [178]. Any renal impairment should be closely observed in patients taking this agent, with attention to potential drug-drug interactions with several classes of drugs, including aminoglycosides, NSAIDs, and phenytoin [107,199].

Vinorelbine (Navelbine) is a vinca alkaloid and a microtubular inhibitor that prevents cell replication. Vinca alkaloids (spindle poisons) do not mimic the actions of taxanes and are prescribed for patients previously treated with anthracyclines and taxanes. Vinorelbine as a single agent is administered at 25 mg/m² every 7 days; when used with trastuzumab, it is given at 30–35 mg/m² on days 1 and 8 every three weeks [178]. It is considered relatively safe for elderly patients with comorbidities. The most frequently experienced side effect is neutropenia, with nausea/vomiting and alopecia being insignificant [88,178,199].

The taxanes are microtubule stabilizers, binding to B tubulin proteins. Taxanes available for the treatment of breast cancer include paclitaxel (Taxol), docetaxel (Taxotere), and nab-paclitaxel (Abraxane). Taxanes administered intravenously require polyethylene-lined tubing with an in-line filter.

Paclitaxel is an established agent for first- or second-line therapy, as a single or combined agent, and for recurrent or metastatic disease. Premedications are required when paclitaxel is used due to the medium polyoxyethylated castor oil used to reconstitute the drug. Frequent monitoring during the infusion is required, and the majority of adverse reactions occur within the first 10 minutes. Bradycardia, hypotension, dyspnea, wheezing, or complaints of chest pain require the infusion be stopped and treated appropriately with steroids, IV fluids, and antihistamines. If appropriate, the drug can be slowly restarted when the patient recovers. However, patients who experience severe reactions should not be re-challenged with the drug [107,178,215].

Nab-paclitaxel can be administered for subsequent treatments following a hypersensitive reaction to paclitaxel. Nab-paclitaxel does not require premedication, but it is considerably more expensive than paclitaxel [107,178,199,215]. Potential side effects include alopecia, myelosuppression, and neurotoxicity producing peripheral neuropathy.

Docetaxel is administered 60–100 mg/m² IV over one hour every three weeks. In order to help counteract the side effects of fluid retention, weight gain, and respiratory difficulties, patients may be prescribed 8 mg of dexamethasone for a total of three days: one day prior to treatment, the day of treatment, and the day after. Nausea and vomiting, mucositis, peripheral neuropathy, and PPE are potential side effects. Onycholysis of the fingers and toes can be unsightly and painful [107,178,199].

In 2007, the FDA approved ixabepilone (Ixempra) for patients who developed resistance to anthracyclines, taxanes, and capecitabine. Ixabepilone is the first of the epothilones, a class of drugs that acts like an antitubular agent but can target cells that have developed a resistance to the taxanes. Ixabepilone is given as 40 mg/m² over three hours every three weeks as monotherapy or in conjunction with capecitabine [178]. It has a six-hour window of stability once reconstituted. Similar to the taxanes, premedication and close monitoring are required for possible hypersensitive reactions [178]. Studies have shown that epothilones may have better efficacy and milder adverse effects than taxanes [107,215].

In 2018, olaparib was approved by the FDA for the treatment of HER2-negative metastatic breast cancer with a germline BRCA mutation [222]. Olaparib, the first PARP inhibitor approved for the treatment of breast cancer, acts by blocking an enzyme involved in repairing damaged DNA, allowing cells with damaged BRCA genes to die and potentially slowing or stopping tumor growth. This agent is administered orally 300 mg twice daily until disease progression or unacceptable toxicity. Also in 2018, a second PARP inhibitor, talazoparib, was approved by the FDA for patients with HER2-negative locally advanced or metastatic breast cancer with a germline BRCA mutation. Patients must be selected for therapy based on an FDA-approved companion diagnostic for talazoparib [178,223]. Talazoparib is administered orally 1 mg daily until disease progression or unacceptable toxicity [178]. The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Common adverse reactions include fatigue, anemia, nausea and vomiting, neutropenia, thrombocytopenia, and decreased appetite [178].

Chemotherapy-induced nausea and vomiting (CINV) has historically been one of the most highly anticipated side effects associated with chemotherapy [139,216]. Although nausea and vomiting still present a challenge, it is a treatable condition.

CINV is invariably more problematic in younger women, women with a history of motion sickness or morning sickness, and women prone to anxiety. Nausea and vomiting occur when the release of dopamine-2, neurokinin-1, or serotonin 5-hydroxytryamine (5-HT) triggers the vagus nerve to stimulate the chemoreceptor trigger zone. Due to the complexity of various signals and triggers, a combination of antiemetics is often required for effective prevention and treatment [107,148,224,225].

The majority of chemotherapy agents administered for breast cancer fall into the moderate-to-high range of emetogenicity, including 5-FU, cyclophosphamide, paclitaxel, epirubicin, and docetaxel. Cyclophosphamide, doxorubicin, and methotrexate fall into the moderate category, and 30% to 60% of patients taking these medications will experience CINV without premedication. High-dose cyclophosphamide (>1,500 mg/m²) and the anthracyclines fall into the highly emetogenic category, with as many as 90% of patients experiencing CINV if insufficient premedication is administered. The lowest potential risk (10% to 30%) for CINV results from the administration of the taxanes, 5-FU, and gemcitabine [2,224,225].

CINV is further classified by the timing and intervals of occurrence. Acute CINV, as implied, can manifest with chemotherapy initiation, lasting up to 24 hours. Combined agents and those rapidly infused may potentiate a more severe emetogenic response compared to single agents or infusions given over longer periods of time.

As many as 54% of patients experience anticipatory nausea and vomiting as a result of initial treatments being poorly controlled. Investigating the triggers associated with anticipatory CINV, such as the smell of food, can provide some insight. For hospitalized patients, having meal trays "aired out" prior to being delivered to their room may prove beneficial. Incorporating alprazolam and lorazepam into a patient's medication regimen is warranted to reduce anxiety.

Delayed nausea and vomiting can continue for approximately one week, with the onset beginning 24 hours after the completion of chemotherapy. Two agents known to cause delayed CINV are cyclophosphamide and doxorubicin. Breakthrough nausea and vomiting may require around-the-clock dosing with antiemetics with a thorough investigation into previously administered antiemetics clearly proven to be ineffective.

The American Society of Clinical Oncology asserts that adult patients who are treated with cisplatin and other high-emetic-risk single agents should be offered a four-drug combination of a neurokinin 1 (NK1) receptor antagonist, a serotonin (5-HT3) receptor antagonist, dexamethasone, and olanzapine.

(https://ascopubs.org/doi/10.1200/JCO.2017.74.4789 Last Accessed: July 21, 2022)

Strength of Recommendation/Level of Evidence: Strong/High

CINV can be controlled and managed with effective antiemetics. According to American Society of Clinical Oncology guidelines, a 5-hydroxytryptamine type 3 (5-HT3) antagonist, dexamethasone (Decadron), olanzapine (Zyprexa), and a neurokinin 1 (NK1) receptor antagonist (such as aprepitant [Emend]) should be used as prophylaxis for a highly emetic chemotherapy agent or combination (e.g., an anthracycline and cyclophosphamide) [226]. Palonosetron (Aloxi), in combination with dexamethasone, is recommended for patients taking chemotherapy agents with moderate emetic risk, and dexamethasone is recommended before the first dose of chemotherapy with a low emetic risk. In addition to pharmacologic management of nausea and vomiting, other supportive approaches include maintenance of oral hygiene, regular baths to reduce unpleasant odors, and small meals at regular intervals. Cold foods may be better tolerated than hot foods because of decreased smells.

Overall quality of life is impacted if CINV is not controlled; patients are less productive, and work and home life are disrupted. Patients should be reassured they will receive antiemetics prior to treatments, throughout the course of therapy, and as needed to use at home [56,181,224,225].

Alopecia, a very visible side effect of chemotherapy, can be daunting. Hair loss typically begins as early as two to three weeks into treatment, and in addition to the head and eyebrows, hair is also lost from the pubic and axillary areas as well. Although alopecia may significantly impact quality of life, most women appear to adapt well, opting to wear a head covering or wig. A short haircut early in the course of treatment prevents hair from being noticeably shed on clothing and bedding and falling into food or meal trays. For all women, undoubtedly, new hair growth will begin after treatments are completed, although hair color or texture may be different [2,107,139,181,216].

Chemotherapy-induced peripheral neuropathy results from agents targeting microtubules, which includes the taxanes, vinca alkaloids, and epothilones [139,227,228]. Approximately 40% to 70% of women will develop this debilitating side effect, with patients with pre-existing neuropathy caused by diabetes or alcohol abuse at risk for more severe symptoms. Patients may be reluctant to report chemotherapy-induced peripheral neuropathy, as one of the interventions to relieve symptoms is a dose reduction or lengthening of the time interval between treatments. Patients understandably fear that if they miss a treatment, it could allow for disease progression. Reassurance should be given this is not an accurate assumption.

Early symptoms begin with numbness or tingling in the toes or fingers [215,228]. Neuropathy is painful, and the numbness and tingling result in the loss of fine motor skills, making simple tasks such as buttoning clothes a challenge. Skin sensations are diminished, posing a danger of injury. Gait disturbances create safety issues with ambulation, requiring physical therapy and the use of assistive devices [227].

Remedial efforts, such as dose reduction or retiming treatments, are the mainstay in treating chemotherapy-induced peripheral neuropathy. In approximately one-third of patients, long-term chemotherapy-induced peripheral neuropathy may be relieved with amitriptyline, gabapentin, and glutamine taken on a regular basis. Topical analgesics and creams may afford some relief, but focusing on safety becomes a priority [2,181,216,228].

Chemotherapy-induced cognitive impairment (CICI) or dysfunction, also termed "chemo brain" or "chemo fog," occurs in up to 23% of women undergoing chemotherapy for breast cancer; overall, the estimated prevalence of CICI varies from 15% to 82% depending on the patient population and the definition of impairment [229,230]. It manifests as an alteration in cognitive abilities, with a decreased attention span and ability to learn, word-finding difficulty, and short-term memory loss [139,231]. The mechanism responsible for CICI is not fully understood. Many possibly etiologies have been described, and the underlying mechanism is believed to be multifactorial [230,232]. The direct neurotoxic effects of chemotherapy may cause damage to neurons or surrounding cells, with some studies indicating structural changes in white matter [233]. Oxidative stress and DNA damage may cause a slowing of cell division in the subventricular zone, impairing cognition. Changes in hormone levels and/or immune dysregulation may also contribute [232]. Genetic predisposition (e.g., impaired DNA repair capability) may result in an exaggerated level of cognitive impairment. Other factors include the possibility of brain metastases, electrolyte or metabolic imbalances, and polypharmacy [56,216,234,235,236]. Cognitive impairments have also been shown to occur prior to chemotherapy, making it difficult to determine causality [229,237,238,239]. CICI may also be a result of common problems faced by cancer survivors (e.g., pain, insomnia, depression, fatigue) [240].

It is possible that this side effect will continue in some women for as long as 10 years after treatment. Alerting patients to the possibility of CICI and helping to prepare them with suggested coping strategies may relieve some of the frustration experienced. Restructuring the day, compiling lists and calendars, and learning to pace activities are useful approaches that can enable patients to continue with life as normal as much as possible. Being driven to appointments and help with running errands can provide a safety net for affected women. However, careers can be significantly challenged [241,242,243].

There are no defined modalities to reverse this impairment. Coping mechanisms and support are crucial. Adequate rest is also important, as fatigue may contribute to CICI cycling with depression. If anemia is present, it should be addressed fully. Methylphenidate and modafinil have been suggested for the treatment of CICI, and research regarding the utility of these drugs for such patients is ongoing [231,236,244]. Various nonpharmacologic approaches to managing CICI have been suggested, including mental exercises, yoga, meditation/guided imagery, exercise, stress management techniques, probiotic supplementation, and acupuncture. Although evidence supporting any of these approaches is lacking, many survivors report that they find them to be helpful and empowering [239].

Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is further classified based on the factor affected as anemia, thrombocytopenia, or neutropenia. These are anticipated side effects from chemotherapy, but they can be addressed and corrected. Patients should report any shortness of breath, dizziness, tachycardia, or headaches indicative of anemia. When myelosuppression is present, there is a heightened risk for infection during patients' nadirs, so reporting 100.4°F or higher and other signs of infection is important. Febrile neutropenia requires hospitalization, with fever work-up to determine the cause and subsequent treatment with appropriate IV antibiotics. Crowds should be avoided during the nadir period; if this is not feasible, patients should be advised to wear a mask when in public.

The treatment of anemia can be complicated. Many studies have provided evidence to recommend the use of erythropoiesis-stimulating agents (e.g., erythropoietin [Epogen], darbepoetin [Procrit]) for anemia in people with cancer because of the benefits of increasing the hemoglobin level, improving exercise tolerance, reducing symptoms, and decreasing the need for blood transfusions [245; 246]. However, safety concerns led the FDA to require a boxed warning on the label of erythropoiesis-stimulating agents regarding the increased risk of several adverse events (e.g., death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence) among people with chronic kidney disease or cancer [178; 247]. The FDA recommends using the lowest dose sufficient to avoid red blood cell transfusion [178; 247]. The overall goal is to protect patients against infection, maintain safety when there is a potential risk for bleeding, and keep patients on track with the scheduled treatment plan [139; 181; 212; 216; 235; 247].

Fatigue has been suggested to be the sixth vital sign for cancer patients and can severely impact quality of life [248]. Fatigue experienced during and following cancer treatments is multifactorial, with physical, psychologic, and emotional manifestations [148,171,216,249]. As many as 70% to 100% of patients undergoing chemotherapy will experience fatigue, and it has been known to persist up to five years in 30% to 40% of women; for some, this debilitating side effect may last as long as 10 years [2,56,171,181,249]. Fatigue is more pronounced with higher doses of chemotherapy, dose density scheduling, and concurrent administration of chemotherapy and radiation.

Ideally, all patients should be assessed prior to starting chemotherapy for any existing fatigue, but this is often overlooked in the push toward starting treatment [169,171,181]. Fatigue experienced prior to the beginning of any treatment is a predictor of increased severity with ongoing therapy [234]. The NCCN has established guidelines for screening and treatment of cancer- and chemotherapy-related fatigue [250].

Anemia is a major cause of fatigue, although its treatment is a complex issue, as discussed. Shortness of breath and profound weakness can cause significant increases in fatigue and anxiety, with some presuming this signals disease progression. Focusing on nutrition, iron supplements, and pharmacologic management to correct deficiencies will add to a sense of well-being and decrease fatigue [171]. Electrolyte imbalances (e.g., hypercalcemia, hyponatremia, hypokalemia, hypothyroidism) should be assessed and corrected appropriately.

When medications are the underlying cause of the fatigue, nonessential medications should be discontinued, and changing medications or the time of dosing may reduce tiredness during the day. Appropriate management of infection, cachexia, depression, and insomnia may also help reduce fatigue [246,250,251].

Most patients will try to manage fatigue by resting and/or sleeping more often, and many healthcare professionals will also recommend this strategy. However, additional rest and/or sleep usually does not restore energy in patients who have fatigue related to cancer or cancer treatments; continued lack of exercise may even promote fatigue [246]. Aerobic exercise has been found to alleviate fatigue among cancer survivors. A meta-analysis demonstrated a significant effect of exercise in the treatment of fatigue during and after cancer treatment [252]. An update of the meta-analysis confirmed this finding but concluded that additional research is needed to determine the optimal type, intensity, and timing of exercise as an intervention for cancer-related fatigue [253].

Although an exercise program is recommended, decreasing activity to conserve energy is also encouraged [246]. Clinicians should talk to the patient and family about the importance of the patient conserving energy by adjusting daily activities to correspond to times of peak energy, setting priorities for activities, following a normal wake-sleep cycle, using assistive devices, and delegating less important tasks [246].

Pharmacologic treatment of fatigue should be undertaken only after potential causes of fatigue have been ruled out [246,250]. Methylphenidate may reduce fatigue, and the NCCN recommends it as a first-line option in the cancer care setting [250]. This recommendation is based on systematic reviews showing a significant effect of methylphenidate for the treatment of fatigue in people with cancer or HIV/AIDS or for opioid-induced sedation [246,246]. An optimal dose of methylphenidate has not been defined, but an initial dose of 5–10 mg (given in the morning) has been used, with the dose titrated to 40–60 mg per day (given once in the morning and once at midday) [246,250]. Among the side effects are nervousness, jitteriness, agitation, arrhythmia, and tachycardia. Though used in the past, modafinil is no longer recommended by the NCCN for the treatment of cancer-related fatigue [250].

PPE is an inflammatory process of unknown etiology that begins on the soles of the feet and the palms of the hands. Early manifestations are usually painless, itchy patches of dry skin, but the condition progresses to edematous, painful areas affecting activities of daily living and quality of life; intervention is necessary. Some relief from the discomfort can be achieved by elevating the extremities, limiting pressure on the soles of feet, avoiding heavy bedcovers, applying cold compresses and/or creams, and using corticosteroids and analgesics. The drugs capecitabine and pegylated doxorubicin are the major causal agents in PPE, and if these are part of a patient's chemotherapy, dose reduction may be necessary to control symptoms [88,107,199,212].

It is essential for patients undergoing chemotherapy to optimize overall health and avoid illness if at all possible. Health maintenance goals should be set as part of the treatment protocol and reinforced during patient teaching. Avoiding infection is key during chemotherapy, particularly during patients' nadirs. This entails adhering to proper hand hygiene, avoiding crowded areas (especially during flu season), and being vigilant for signs of infection.

Patients should check their temperature at around the same time daily and report any temperatures of 100.4°F or greater. Signs and symptoms of infection of the skin surrounding a CVAD site (e.g., pain, redness, swelling, drainage) should also be reported.

Teeth or dentures should be brushed after every meal; mouth rinses may help to remove any food debris. Mouth sores, a sore throat, or symptoms of mucositis should be promptly reported.

Nutrition must be adequate, with plenty of fluids and the avoidance of alcohol. Protein supplements may be ordered to augment intake. Diarrhea can lead to dehydration and electrolyte imbalance if not controlled. Any sudden weight gain or edema should be reported. Smoking cessation and mobility and exercise within safe boundaries are strongly encouraged [38,139,212,220].

Timely reporting from patients as they experience side effects ensures prompt intervention and treatment, preventing toxicities from accelerating to more serious complications. As such, reporting symptoms is a large aspect of patient teaching. Pain, redness, or swelling in the upper or lower extremities may be indicative of thrombosis and should be addressed. Any new onset of increased shortness of breath indicating cardiac toxicity or the possibility of a pulmonary embolism requires immediate reporting. It is understandably difficult for patients to comprehend and retain everything they hear from one or two teaching sessions. With ongoing treatments and as side effects emerge, teaching should be reiterated. Having patients repeat what they have heard is an excellent way of determining how much they comprehend.