Breast cancer is diagnosed more frequently in women than any other cancer (with the exception of skin cancer) and carries the second highest mortality rate after lung cancer [3,4,5,6,7]. An estimated 287,850 women will be diagnosed with an invasive breast cancer in 2022, and an additional 51,400 women will be diagnosed with carcinoma in situ (CIS) breast cancer [3].

Certain risk factors associated with breast cancer cannot be modified, including age, sex, ethnicity, family history/inherited gene mutations, and hormonal influences. The most significant risk factors for developing breast cancer are female sex, increasing age, and familial breast cancer [4,12,14,15,16].

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].

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].

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].

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].

Approximately five weeks after conception, embryonic breast tissue begins to develop. Cells at this early stage appear as little more than a ridge or thickened area of tissue. At approximately 10 to 16 weeks, more defined tissue forms the foundation for glands for milk production. Muscle cells form the nipple, with the darkened area of areola containing sebaceous glands surrounding the nipple protrusion. As pregnancy advances with hormonal influence from placenta to fetus, the glands with the ability to produce milk form as lobules. From birth to puberty, the 10 to 12 rudimental ducts formed beneath the nipple and areola slowly continue to form into more mature ductal structures.

Lymphatic vessels differ from those of the circulatory system, as they function within a low pressure system supported by the close proximity of pulsating arteries (with smooth muscle within the larger lymphatic vessels promoting peristalsis). The valves (lymphangions) within the vessels permit the lymph to be transported in one direction only.

The body is divided into the right and left lymphatic systems. The right lymphatic duct receives lymph from the right side of the head and neck, the right arm, and the right side of the upper trunk. This lymphatic duct then drains into the right venous angle, located between the right internal jugular and right subclavian vein. The right subclavian vein returns lymph to the heart, where it subsequently flows back into the systemic circulation as plasma. The left side of the lymphatic system carries a far greater load and is responsible for the lower extremities, the pelvic area, the left side of the head and neck, the left chest, and the left arm. Lymph returning from the lower extremities and pelvis collects into the cisterna chyli in the mid-abdominal region before being propelled on to the thoracic duct. From the thoracic duct, the lymph continues to the final drainage area in the left venous angle. Parallel with the right, the left subclavian vein returns lymph to the circulation as plasma [52,53,54,55,56,57].

There are approximately 600 to 700 lymph nodes throughout the body, and damaged nodes cannot regenerate. When a malfunction occurs in the lymphatic system, caused by injury from a surgical intervention or as a side effect from radiation therapy, lymphedema can result. Lymphedema occurs in 5% to 9% of patients undergoing sentinel lymph node biopsy (SLNB) and up to 40% of patients who have had axillary lymph node dissection (ALND) [51,52,54].

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].

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

Fibrocystic changes are identified more frequently than any other benign breast mass, and fibroadenoma, comprised of both glandular and structural tissue, is the most common type of benign tumor diagnosed in women 20 to 35 years of age. These tumors arise in the intralobular fibrous stroma of breast tissue. Surveillance with routine screening is usually sufficient treatment if there is absolute assurance that it is not a phyllodes tumor [77].

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.

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.

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].

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

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.

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].

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]:

The criteria established by the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control for the diagnosis of inflammatory breast cancer include [73,102,103]:

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].

Triple-negative breast cancers are more common among premenopausal women and are diagnosed with greater frequency in African American and Hispanic women [111]. Other risk factors, some of which are modifiable, include:

The majority of breast cancers are diagnosed at stage I or stage II, but approximately 10% are at a more advanced stage when they are identified. Women with locally advanced breast cancer (stage III) generally require neoadjuvant chemotherapy and/or radiation prior to any surgery to promote tumor shrinkage and allow for a more manageable surgical procedure [62,63,118]. Surgery may also be indicated for metastasized stage IV breast cancer, but primarily only for palliation of pain or prevention/amelioration of symptoms of the disease. It is important to note that surgery with radiation therapy is generally not curative for these patients.

Mastectomies may be radical, modified radical, or simple. Radical mastectomy is rarely performed today due to the morbidity associated with removal of the entire breast and skin. With this approach, level I, II, and III axillary nodes plus the pectoralis major and minor muscles are removed. A modified radical mastectomy involves removal of the entire breast, the fascia underlying the pectoralis major muscle, and level I and II axillary nodes. A modified radical mastectomy is appropriate for patients with two or more primary tumors in the same breast but in separate quadrants and malignant micro-calcifications in diffuse areas. The tumor(s) should be large in relation to the area of breast tissue. Re-excision of breast tissue that fails to produce negative margins is an indication for this type of surgery. It is the surgical intervention of choice for patients previously administered radiation therapy for breast cancer or mantle radiation therapy for childhood Hodgkin lymphoma.

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].

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.

Lymphedema occurs when the volume of interstitial lymph exceeds the capability of the lymphatic transporting system. It is a frequent complication of surgical interventions and radiation therapy administered for the treatment of breast cancer, an association that was documented as early as 1898. When radical mastectomies were the primary surgical treatment option for breast cancers, 80% of women developed lymphedema. Today, the prevalence of lymphedema two years following breast cancer treatment is 20% to 36%, increasing to 30% to 45% after 15 years [34,139,148,149].

The International Society of Lymphology uses a staging system to help guide treatment decisions and prognosis for lymphedema. The established stages are [51,53,54,150,155]:

The initial goal is to maintain the integrity of the skin and underlying structures, reducing the fluid volume in the affected arm until a plateau is reached. Manual lymphatic drainage is a massage therapy designed to gently propel fluid forward, allowing superficial lymph vessels to fill and larger conduits to open, thereby promoting drainage of lymph back into the circulation. This generally requires treatment sessions five days per week for two to four weeks. Therapy begins with the lower forearm, gradually working upwards to the axilla and shoulder. Compression bandages may be worn overnight, but are removed prior to therapy [158].

Contraindications for manual lymphatic drainage include any signs or symptoms of infection, cellulitis, thrombosis, and heart failure. Caution should be exercised when considering manual lymphatic drainage for patients with pre-existing comorbidities. For example, diabetes patients with neuropathy may be unable to identify bandaging that is too constricting, causing further damage. For patients with asthma, therapy is initiated slowly, building up gradually to the normal treatment protocol. Hypertension should be monitored and treatment tailored. Caution is required with any existing paralysis and contractures to prevent further constriction of lymph flow and drainage [51,52,54,150].

Having successfully undergone surgery, the next step for many patients is radiation therapy. Radiation therapy with whole breast irradiation has been the mainstay of breast cancer treatment for nearly 100 years. But in a manner similar to surgery, radiation treatment has evolved to focus more on breast conservation [132]. Morbidity and mortality rates have decreased as a result of earlier detection, allowing for less invasive procedures and increased control of microscopic disease. Breast-conserving surgery followed by radiation therapy has become the standard of care for stage I, stage II, and locally advanced stage III breast cancers [133,139,160].

While the majority of women are able to make decisions that reflect their personal preferences, others are ineligible due to absolute or relative contraindications relating to existing health issues. Absolute contraindications to radiation therapy include [118,139]:

Radiation dermatitis can vary widely in severity. Pruritus occurs after about three weeks of treatment of 30 Gy. In some cases, sebaceous glands are damaged, resulting in less perspiration. Dry desquamation results from damaged stem cells in the epidermis. This can progress to moist desquamation as it invades the dermis, usually with doses of 45 to 60 Gy. Chemotherapy and friction in skin folds can exacerbate these symptoms. In severe cases, patients may require a break in radiation therapy until symptoms subside [173]. Extreme moist desquamation seldom occurs, but it can be a cause of tissue necrosis.

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].

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].

Male breast cancer has not been extensively studied, and research is difficult because of the small numbers of men with the disease. Reviews of the literature have been helpful in identifying risk factors, clinical and pathologic characteristics, and the role of genetics [255,256,258]. Studies have shown that male breast cancer differs from female breast cancer in many ways. For example, some risk factors unique to men include [257,258]: