Mammography

Mammography is utilized for two major purposes: (1) to screen asymptomatic women for breast cancer and (2) to evaluate breast problems or abnormalities. Although the United States does not have a government-funded screening program, the screening guidelines recommended by the National Cancer Institute advise that women 40 years and older who are at average risk of breast cancer undergo screening mammography every 1 to 2 years.¹¹ Since the introduction of screening mammography, the number of deaths from breast cancer has declined in every age and racial group of women in the United States.¹² Some investigators attribute this decline to mammography screening, whereas others believe it is related to advances in therapy. The 2002 Swedish screening trial reported that screening mammography reduced breast cancer mortality by 30%, supporting the concept that the decline in breast cancer mortality rates is related to the utilization of screening mammography.¹³ Today, the benefits of screening mammography for women between the ages of 50 and 69 years is universally accepted whereas screening for women between the ages of 40 and 49 years remains controversial despite the statistically significant reduction in breast cancer mortality¹⁴ and significant increase in survival rates¹⁵ reported.

Screening mammography consists of mediolateral oblique and craniocaudal views of each breast. In the United States, a standardized terminology for interpreting mammograms, the Breast Imaging Reporting and Data System (BI-RADS), has been developed by the American College of Radiology to help facilitate uniformity in mammography reporting across facilities.¹⁶

Currently, mammography studies are performed using either film screen or full-field digital mammography (FFDM) technologies. FFDM technology has slowly replaced film screen mammography because FFDM provides a lower radiation dose in large breasts; increased image quality associated with a higher contrast resolution; shorter examination times, and higher patient throughput; elimination of costs associated with film such as film storage, film, and processing; and facilitation of teleradiology for mammography.¹⁷ Furthermore, cancer detection rates with current FFDM technology are equivalent to those with film mammography.¹⁷ In addition to advancing detector and processing technology, advanced techniques that operate in conjunction with FFDM, such as digital tomosynthesis, computer-assisted diagnosis algorithms, and contrast-enhanced mammography, are current areas of research that may improve the detection of small early-stage cancers and decrease the false-positive recall rate (Figure 27-1).

Figure 27-1 A 53-year-old woman had a screening mammogram (A, craniocaudal [CC] view and B, mediolateral [ML] view) that demonstrated a cluster of suspicious microcalcifications at the 12 to 1 o’clock position of the left breast, measuring 10 mm. C, Computer-assisted diagnosis software digitally annotated the suspicious calcifications (asterisk). D and E, Magnification CC and ML views confirm that the calcifications (arrows) have suspicious characteristics. Stereotactic-guided biopsy confirms that the calcifications represent intraductal carcinoma, grades 1 to 2.

The potential role of physician-performed screening ultrasonography, as an adjunct to mammography screening, has been evaluated in a multi-institutional trial that demonstrated many barriers to widespread implementation, such as high false-positive rates and low reimbursement rates.¹⁸ In high-risk populations, such as women with a genetic predisposition for breast cancer, MRI has been reported to have a higher sensitivity than either ultrasonography or mammography for the detection of breast cancer; therefore, MRI is a more appropriate adjunct to screening mammography in these cases.

Magnetic Resonance Imaging

Use of screening mammography in the general population has been shown to reduce mortality associated with breast cancer by at least 24%.¹⁹ Women at high risk of breast cancer owing to a known genetic predisposition should be engaged in aggressive surveillance and screening, which should begin at a younger age than screening for women in the general population because of the potential for early onset associated with familial breast cancer. Current surveillance protocols for screening women with a BRCA1 or BRCA2 mutation include a clinical breast examination every 6 months and annual mammography and MRI.²⁰

Multiple studies have demonstrated higher cancer detection rates with MRI than with mammography, although the differences were not statistically significant.^21–23 Despite variations in breast cancer screening techniques between facilities, MRI is consistently reported to have a higher sensitivity (77-100%) than mammography (25-40%).^24–26 MRI detects more breast cancers than either mammography or sonography.^24–26 However, MRI also consistently demonstrates a higher false-positive rate and, thus, is associated with a higher biopsy rate—8.2%—than mammography (2.3%) or sonography (2.3%).²⁶ The majority of breast cancers detected on MRI screening demonstrate the typical conspicuous morphologic and dynamic enhancing patterns expected for malignant lesions (Figure 27-2). However, in a trial studying patients at high risk of breast cancer, 20% of the breast cancers detected on MRI screening presented with non-masslike enhancement and 33% presented with an enhancing pattern typical for benign lesions.²⁷ This lack of specificity associated with current morphologic and kinetic MRI features makes MRI detection of breast cancers in high-risk patients challenging. A study by Kuhl and coworkers²⁸ compared clinical breast examination, mammography, sonography, and MRI in 529 study participants. The combination of mammography and MRI yielded the highest sensitivity (93%), which agrees with the findings from other published trials. In this trial, MRI and mammography had the same specificity (97%), as opposed to a higher specificity for mammography than MRI reported in prior studies. This improved specificity of MRI may be due to improved imaging techniques.²⁸

Figure 27-2 A 49-year-old woman with a history of right segmentectomy for breast cancer 3 years before this screening magnetic resonance imaging (MRI) study. The recent screening mammography examination was negative for cancer. Sagittal T1-weighed contrast-enhanced image (A) and kinetic curve analysis image (B) of the right breast revealed a 6-mm invasive ductal carcinoma (arrow in A) with initial rapid enhancement and delayed wash-out pattern.

While the role of MRI in breast screening programs continues to evolve, the full impact of modern MRI screening technology on mortality from breast cancer is still unknown. Patients for whom MRI is being considered should be informed of the current status of MRI in the detection of breast cancer, and appropriate management strategies are best determined on an individual basis. At the present time, no consensus exists as to the appropriateness of MRI as an adjunct to screening mammography in the general population.

Anatomy

The breast is composed of 15 to 20 lactiferous ducts that extend from the lobules or glandular epithelium to the ductal opening in the subareolar tissue. The areolar tissue and nipple contain smooth muscle fibers, sensory nerve cell endings, sebaceous glands, sweat glands, and accessory areolar glands (also called Montgomery glands). In general, the upper outer quadrant of the breast contains more glandular tissue than the other quadrants.

The breast is located in the superficial fascia and is attached to the skin by fibrous connective tissue and suspensory structures, called Cooper’s ligaments. Fibrous connective tissues interdigitate between the Cooper ligaments and the glandular tissue within the breast. Posterior to the breast tissue is the retromammary bursa, located between the deep layer of the superficial fascia and the deep layer of the pectoralis major muscle.²⁹ The breast extends from the second or third rib to the sixth or seventh rib, or inframammary fold. The muscles that the breast rests on are the pectoralis major, serratus anterior, and external abdominal oblique muscles and the upper extent of the rectus sheath. The growth of the mammary gland is influenced by the levels of estrogen, progesterone, and adrenal corticoids; during pregnancy or lactation, growth of the mammary gland is also influenced by prolactin (from the adenohypophysis) and somatomammotropin (from the placenta).

The axilla contains many important structures, such as the great vessels and nerves, connective tissue, and lymph nodes. The boundaries of the axilla include four walls, the apex, and the base. The four walls are the anterior wall (pectoralis major and minor muscles and associated fasciae), posterior wall (subscapularis muscle, teres major, and latissimus dorsi muscles and associated tendons), lateral wall (humerus and bicipital groove), and medial wall (serratus anterior muscle). The apex is the aperture into the cervicoaxillary canal, whose borders consist of the clavicle, scapula, and the first rib. The base consists of the axillary fascia and skin.

Pathology

Breast cancer is a heterogeneous disease and has been traditionally categorized as in situ lesions (DCIS and lobular carcinoma in situ [LCIS]) or invasive cancers. The in situ or noninvasive disease encompasses a spectrum of lesions and is not as simple as the original definition implies³⁰; in situ lesions develop in a linear progression from normal breast tissue to atypical ductal hyperplasia, DCIS, and invasive cancers. DCIS predominantly arises from the terminal ductal-lobular unit and may extend into the extralobular ducts.

The conventional pathologic classifications of invasive breast cancers by morphology include invasive ductal carcinoma, invasive lobular carcinoma, tubular carcinoma, mucinous carcinoma, medullary carcinoma, papillary carcinoma, metaplastic carcinoma, and other less common types. Tubular carcinoma accounts for 3% to 5% of all invasive breast carcinomas. It is a low-grade cancer with an excellent prognosis and usually occurs in older women.³¹ Mucinous or colloid carcinoma is characterized on histologic examination as having extracellular pools of mucin and low-grade tumor aggregates. Pure mucinous carcinoma also has a very favorable prognosis, with a 10-year survival rate of 90%.³¹ Medullary carcinoma is commonly seen on imaging as a circumscribed mass consistent with the distinctive smooth pushing border seen on pathology.³² Medullary carcinoma also has a favorable prognosis, but it is not observed as frequently as tubular and mucinous carcinomas. This type of carcinoma comprises a higher proportion of BRCA-related breast cancers than sporadic cases but still represents a minority of the breast cancers in women with BRCA mutations. Metaplastic carcinomas include tumors that show both epithelial and mesenchymal features. Although there are conflicting data on the biologic behavior of these tumors, many exhibit an aggressive clinical course with sarcoma-like behavior.³³ Inflammatory breast cancer is a rare but aggressive disease with a poor prognosis; it is usually diagnosed clinically owing to the inflammatory symptoms. In addition to the type of breast cancer, the receptor or tumor marker status of the cancer (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2] receptor) is very important for determining the treatment options in patients with invasive breast carcinoma. The status of these receptors is also important for patients with in situ disease who are considering hormone therapy.

Even though genetic profiling has not been widely used in clinical practice, the research on this technology has resulted in a molecular classification of breast cancer with the hope of offering insight on the prognosis and response of tumors to specific therapy. Based on genetic profiling, breast cancers are divided into five subtypes: luminal A, luminal B, normal breast–like, HER2+, and basal-like carcinomas.³⁴ Luminal A breast cancer is characterized by the high expression of ERs and PRs. These cancers tend to be of a lower grade and have a better prognosis than the other subtypes. Luminal B breast cancers not only express ERs and/or PRs but also overexpress HER2. They are more aggressive, with high tumor grade. The normal breast–like type or unclassified subtype is a triple-negative tumor with a molecular profile similar to that of basal-like carcinoma; however, normal breast–like carcinoma has a better prognosis than basal-like carcinoma. The HER2+ subtype includes ER-negative and ER-positive types and is often associated with DCIS. The basal-like breast carcinomas lack ER, PR, and HER2 expression and, therefore, are often called triple-negative tumors. These tumors show a high rate of p53 mutations and are common in BRCA mutation carriers. Triple-negative cancers tend to be more sensitive to chemotherapy but have a worse prognosis than other subtypes.^2,35 However, not all triple-negative breast cancers are basal-like tumors. Some data suggest that 76% of triple-negative breast cancers are basal-like, and 77% of the basal-like tumors are triple negative.³¹ This molecular classification will likely be further modified as additional molecular features are discovered. Future classifications should help predict the sensitivity of particular tumors to targeted therapies, thereby improving the selection of patients for specific therapeutic approaches.

Primary Tumor

Breast imaging is used to detect primary or recurrent breast cancer, determine the extent of disease in the affected breast, evaluate regional lymph nodes, and identify distant metastatic disease. Cancer within the affected breast may be described as unifocal (Figure 27-5), multifocal (two or more lesions in the same quadrant [Figure 27-6]), or multicentric (lesions in two or more quadrants [Figure 27-7]). Currently, mammography, ultrasonography, and MRI are the primary modalities indicated in the detection and staging of breast cancer.

Figure 27-5 A, A 52-year-old woman with a newly diagnosed unifocal invasive ductal carcinoma in the right breast (arrow), measuring 1.8 cm. B, The kinetic analysis demonstrates the rapid initial enhancement with delayed wash-out pattern, typical for malignancy.

Figure 27-6 A 46-year-old woman who has a newly diagnosed 3.2-cm invasive ductal carcinoma in the left breast seen on mammography and ultrasound. Sagittal postcontrast fat-suppressed T1-weighted gradient echo MRI study of the left breast revealed multifocal disease with the known carcinoma (thick arrow) and additional enhancing foci extending toward the nipple in a ductal distribution (thin arrows). The high T1-weighted signals within the ducts in the inferior breast are related to fibrocystic changes; no malignancy was seen on pathology of the mastectomy.

Figure 27-7 A 45-year-old woman who has newly diagnosed multicentric invasive ductal carcinoma in the left breast. The ML (A) and CC (B) mammography views showed multiple obscured masses in the left breast, measuring at least 7.7 cm (thin arrows), with global skin thickening (thick arrows in B). C and D, The postcontrast maximum intensity projection (MIP) and colorized MRI studies revealed multiple rim-enhancing masses (arrows) in all four quadrants of the left breast, compatible with locally advanced multicentric carcinoma.

Mammography

Diagnostic mammography or problem-solving mammography is performed when a patient presents with a palpable finding or when a suspicious finding is detected with screening mammography. A radiopaque BB or skin marker is placed directly over the suspicious region before the mammogram is obtained. In addition to the mediolateral oblique and craniocaudal views, described earlier, additional views may be indicated to properly evaluate the abnormality. A 90-degree lateral view can assist in triangulating the abnormality. Spot compression views in craniocaudal and lateral projections are incorporated to evaluate a possible mass, asymmetrical density, or superimposition of normal breast parenchyma. Magnification views, commonly performed in craniocaudal and lateral projections, facilitate characterization of microcalcifications. Slowly, conventional analog technology is being replaced by digital mammography. However, standard mammography projections remain unchanged. With advances in digital acquisition and processing technology, digital tomosynthesis is being incorporated into mammography systems and may provide a solution to the problem of distinguishing overlapping structures in the breast, increasing the sensitivity and specificity of mammography for cancer detection and diagnosis.⁴¹ Clinical trials are currently under way to establish the efficacy of digital breast tomosynthesis and to define its role in future practice.

Mammography is also used to guide breast interventions, including a stereotactic-guided core biopsy using vacuum-assisted devices and an image-guided needle localization of a lesion prior to surgery. Immediately after resection of the targeted lesion, the biopsy or resected specimen can be imaged while the patient is still under anesthesia in order to verify the margins. This “specimen radiography” provides additional information in patients who had a complete response to preoperative chemotherapy because the only image-detectable finding is often the biopsy clip placed at the time of the initial biopsy or residual calcifications (Figure 27-8).

Figure 27-8 A 37-year-old female with multifocal invasive ductal carcinoma in the left breast. A, On the ML view of the pretreatment mammogram, two biopsy clips are associated with the spiculated 2.5-cm mass and satellite lesion (arrows). After neoadjuvant chemotherapy, the masses have decreased in size. B, The left segmentectomy specimen radiograph confirmed resection of the targeted biopsy clips with associated residual subcentimeter nodules (arrows). A third biopsy clip (circle) is seen, related to location of an ultrasound-guided biopsy denoting a satellite lesion.

Sonography

Currently, breast sonography is considered a diagnostic tool for characterization of lesions detected via mammography or clinical examination and for staging of newly diagnosed breast cancer. The Breast Imaging Reporting and Data System (BI-RADS) risk assessment categories should be adhered to in the reporting of breast ultrasound findings.¹⁶ A linear array transducer should be used to perform the examination, utilizing the highest center frequency (7.5-15 MHz) possible that still penetrates to the chest wall in order to provide high-resolution images of the breast. Both longitudinal and transverse planes are commonly used to characterize findings.⁴² However, a radial and orthogonal antiradial pattern has been demonstrated to be superior and is preferred.⁴² When investigating a suspicious finding, the entire ipsilateral breast should be scanned to determine the full extent of the index lesion and assessed for any satellite or synchronous lesions. Breast tumors are usually hypoechoic solid masses, with irregular margins, posterior acoustic shadowing, and internal vascularity on color Doppler imaging (Figure 27-9). Sonography of the ipsilateral axilla should be conducted for all newly diagnosed breast cancer cases to assess for morphologically abnormal nodes. Upon detection of an abnormal lymph node, confirmation of malignancy by ultrasonography-guided core biopsy or fine-needle aspiration biopsy may assist the surgeon in the decision to proceed directly to an axillary dissection as opposed to a sentinel node biopsy. A radiologic marker placement at the time of the ultrasonography-guided biopsy can aid in facilitating subsequent confirmation of proper node recovery or ensuring the complete removal of the breast cancer that has disappeared after the completion of neoadjuvant chemotherapy. At our institution, the infraclavicular and internal mammary regions are also evaluated during the staging sonographic examination of all new breast cancer cases (Figure 27-10).

Figure 27-9 Ultrasonography of the right breast in a 41-year-old woman with newly diagnosed invasive ductal carcinoma demonstrates an ill-defined hypoechoic mass with irregular margins (blue arrow) and posterior acoustic shadowing (green arrow).

Figure 27-10 A, Gray-scale ultrasonographic image of a biopsy-proven malignant infraclavicular lymph node (n; arrow) diagnosed at the staging ultrasound examination of a 44-year-old woman with newly diagnosed right breast invasive mucinous carcinoma. The node is deep to the pectoralis muscle (p). B, Gray-scale ultrasonographic image of an enlarged metastatic internal mammary lymph node (arrow) in a 41-year-old woman with locally advanced invasive ductal carcinoma and ductal carcinoma in situ of the right breast. R, ribs.

Magnetic Resonance Imaging

A breast MRI is performed with the patient lying in a prone position within a 1.5-Tesla or higher magnetic field strength scanner. Only breast-dedicated multiphase array coils should be used to ensure adequate spatial resolution. The examination usually utilizes bilateral imaging techniques for several reasons, including the ability to assess asymmetrical enhancement between the breasts as well as evaluation for contralateral carcinoma in patients with newly diagnosed breast cancer. Common sequences of a standard examination include a precontrast T1-weighted pulse sequence to delineate fat from a lesion or lymph node, a precontrast T2-weighted pulse sequence with or without fat suppression to separate cysts from most solid masses, a time series of contrast-enhanced T1-weighted sequences to detect enhancing breast masses, or a dynamic contrast-enhanced series. This series usually consists of a minimum of three time points after the intravenous administration of the contrast medium over a 6- to 8-minute period. The minimal imaging parameter requirements for the dynamic acquisition recommended by the American College of Radiology include a slice thickness of mm or less and in-plane resolution of 1 mm or less to facilitate the evaluation of essential morphologic details such as lesion margins, spiculations, and internal enhancement. Interpretation is based on the descriptors from the BI-RADS MRI lexicon.

Over the past several years, the increased use of preoperative breast MRI in the staging of breast cancers has been heavily scrutinized, and the role of MRI in staging remains a source of considerable discussion and research.⁴³ In experienced hands, MRI used in conjunction with a computer-aided detection software can be helpful in defining the extent and size of the primary breast carcinoma and has been used to detect additional foci of malignancy within the ipsilateral breast in up to 16% of patients and malignancies that were occult on mammography within the contralateral breast in up to 4% of patients.^44,45 A recently published meta-analysis of 19 studies and prospective randomized trials, such as the randomized Comparative Effectiveness of Magnetic Resonance Imaging in Breast Cancer trial, reported that MRI demonstrated no benefit on the reoperation rate but did result in more extensive breast surgery.^44,46 However, the impact of these findings on patient management decisions and outcomes has yet to be rigorously evaluated. Although these publications indicated that the preoperative MRI is not necessarily indicated in every patient, the ability of MRI to detect additional tumor foci and contralateral cancer that are not detected via physical examination or mammography should not be discounted. The impact of preoperative MRI-based decisions on recurrent disease or overall survival remains unanswered and is a subject for future clinical research.

For less common and more aggressive invasive breast cancers, such as invasive lobular carcinoma or inflammatory breast cancer, MRI can provide useful information regarding tumor extension as well as involvement of skin, nipple, or chest wall.^47,48 Because of the diffuse infiltrative growth pattern of invasive lobular carcinoma, a prebiopsy MRI may be helpful in accurately localizing the disease and facilitating a more effective biopsy and surgical plan (Figure 27-11). In patients who present with adenocarcinoma in the axilla without a diagnosis of a primary carcinoma, MRI has been demonstrated to be beneficial in identifying the primary tumor.⁴⁹ When a primary breast lesion can be detected (Figure 27-12), proper staging can be performed, facilitating targeted therapy or consideration for breast-conservation therapy in conjunction with radiotherapy, depending on the stage of the carcinoma.

Figure 27-11 A 60-year-old woman with a newly diagnosed right breast invasive ductal carcinoma, who had a preoperative staging MRI study. A, A sagittal MIP MRI study of the right breast revealed an irregular 2.1-cm carcinoma (arrow). B, A sagittal MIP MRI study of the left breast revealed a 6-mm enhancing focus (arrow). C and D, The kinetic analysis (D) demonstrated that the left breast lesion has rapid initial and delayed progressive enhancing patterns. MRI-guided biopsy confirmed the left breast lesion (arrow in C) to be a contralateral invasive ductal carcinoma.

Figure 27-12 A 40-year-old woman with diagnosis of metastatic axillary lymphadenopathy from an excisional biopsy. A, The mammogram (ML view) and initial breast ultrasound did not reveal a suspicious finding for malignancy. B, An MRI study of the right breast (sagittal T1-weighted after intravenous contrast) demonstrated a 4-mm irregular enhancing focus with a linear enhancement toward the nipple (arrow). C, A targeted breast ultrasound, performed after the MRI examination, revealed a 4-mm hypoechoic mass (arrow). A core biopsy was performed and confirmed an invasive ductal carcinoma.

DCIS is a noninvasive malignancy, and the patient is often asymptomatic. However, DCIS is associated with increased risk of developing invasive carcinoma that can involve multiple sites and intervening normal tissue. The prevalence of DCIS diagnoses in the United States has increased with the introduction of screening mammography and currently accounts for 25% to 30% of all reported breast cancers. However, mammography tends to underestimate both the size and the extent of DCIS, especially when the DCIS is not associated with the characteristic pleomorphic microcalcifications.⁵⁰ MRI, conversely, has a reported sensitivity of 67% to 100% for the detection DCIS whereas mammography has a sensitivity of 70% to 80%.^51,52 Common MRI features indicative of DCIS include clumped or heterogeneous enhancement in a linear, ductal, or segmental distribution (Figure 27-13). Despite these highly specific morphologic features, current MRI techniques poorly differentiate benign proliferative disease from DCIS; thus, the specificity of MRI in the detection of DCIS remains low due to a high rate of false-negative findings.⁵³ Ultimately, MRI may be useful in cases where mammography, sonography, and clinical findings are inconclusive and no focal finding is apparent; currently, approximately 95% of DCIS cases are diagnosed via calcifications identified on mammography.

Figure 27-13 A 42-year-old woman with a new diagnosis of advanced left breast carcinoma who received an MRI examination for staging assessment. A, Sagittal postcontrast T1-weighted MRI study demonstrated non-masslike and ductal enhancement in a segmental distribution (arrows) concerning for ductal carcinoma in situ (DCIS) within the contralateral or right breast. B, The corresponding magnification mammographic views revealed a few small clusters of microcalcifications (arrows) in the area of abnormal enhancement seen on MRI. The entire area of abnormal enhancement corresponds to high-grade DCIS at surgery.

Unconventional Breast Imaging

In contrast to conventional breast imaging tools (mammography, sonography, and MRI) that focus primarily on anatomic and morphologic detail, many molecular imaging approaches are being investigated to aid in the differentiation of normal and cancerous tissues by evaluating functional differences between tissues, such as metabolism. These unconventional breast imaging tools include breast-specific gamma imaging (utilizing technetium-99m-sestamibi), positron-emission mammography (utilizing [¹⁸F]-fluorodeoxyglucose), and magnetic resonance spectroscopy (MRS).

Breast-specific gamma imaging has exhibited strong potential as an additional problem-solving tool. However, the radiation dose associated with this technology is currently prohibitive, and results from an on-going, multicenter, prospective clinical trial are needed to better determine the potential role of gamma imaging in breast imaging.

A high-resolution [¹⁸F]-fluorodeoxyglucose PET scanner, a positron-emission mammography flex device (Naviscan PET Systems Inc., San Diego, CA), was recently approved by the U.S. Food and Drug Administration (FDA) for imaging the breast or other small body parts in contrast to the whole body imaging of PET (Figure 27-14). In one published breast cancer study of 77 women with 92 lesions from four centers, positron-emission mammography was reported to have a sensitivity of 90%, with a specificity of 86% in detecting breast cancer.⁵⁴

Figure 27-14 Positron-emission mammography. A-C, A 58-year-old female who presented with two biopsy-proven invasive ductal carcinomas of the left breast, as denoted by the biopsy clips at both sides (white arrows). The PEM confirms the presence of another lesion suspected on mammography, but subtle on MRI sagittal image (yellow arrows).

The purpose of breast MRS is to detect an increase in the concentration of choline, a metabolic byproduct of cellular proliferation, within a suspicious lesion because elevated choline concentration tends to be indicative of a malignant process. As an adjuvant tool to breast MRI, MRS may improve the specificity of MRI, reducing the number of MRI-detected lesions requiring biopsy.⁵⁵ Currently, only single-voxel 1H MRS acquisition is commercially available for interrogating breast lesions. Such acquisitions are limited in resolution and are generally successful only in lesions greater than 1.5 cm; also, MRS allows the evaluation of only one lesion at a time.⁵⁶ These and other acquisition and processing oriented technological hurdles currently limit the usefulness of MRS in breast imaging (Figure 27-15).

Figure 27-15 A and B, A 44-year-old woman with locally advanced right breast invasive ductal carcinoma and DCIS, with global skin thickening and global breast enlargement. Magnetic resonance spectroscopy was performed on the index largest breast mass in the lateral right breast (arrow in A), and demonstrated the presence of a choline peak (arrows in B).

Numerous other emerging technologies, such as dedicated breast CT and optical coherence tomography, are still being developed and are currently at the preclinical or early clinical investigational stages. Very promising preliminary results have been demonstrated in studies performed with full-breast dedicated CT scanners that provide high-resolution, three-dimensional, cross-sectional imaging of the breast with a radiation dose similar to the dose of a two-view mammography; this type of CT study is likely to compete directly with digital mammography and tomography techniques in the future⁵⁷ (Figure 27-16).

Figure 27-16 A, The spectrum of normal lymph node appearance includes a thin cortex (arrows) with echogenic hilum. Abnormal lymph node secondary to tumor infiltration or replacement of the lymph node by metastatic disease can have variable ultrasonographic appearances such as cortical thickening (B) and irregularity (arrows in B) or complete mediastinal obliteration and rounding of the lymph node (arrows in C).

Nodal Disease

Evaluation of locoregional nodal disease is the single most important prognostic factor in the staging of newly diagnosed breast cancers, because this information can help guide local and systemic treatment decisions. Cancer cells in the lymphatic fluid from the breast can drain directly into the regional lymph nodes or can bypass the nodes and enter the bloodstream. The axillary lymph nodes are the nodes most commonly involved in breast cancer. The internal mammary lymph nodes may also be involved when the primary breast cancer is in the inner quadrants of the breast.⁵⁸

The status of the axillary lymph nodes has been traditionally evaluated with axillary lymph node dissection. However, axillary lymph node dissection is associated with lymphedema, nerve injury, paresthesias, and other morbidities. Sentinel lymph node biopsy, in place of axillary lymph node dissection, may be an alternative option for women with node-positive breast cancer at initial diagnosis because sentinel lymph node biopsy is associated with less morbidity. An on-going multi-institutional trial is evaluating sentinel lymph node biopsy as an alternative to axillary lymph node dissection for axillary staging after preoperative chemotherapy.⁵⁹ Other clinicians are also considering the role of preoperative axillary sonography in combination with fine-needle aspiration biopsy or core needle biopsy in evaluating metastasis or residual nodal disease after preoperative chemotherapy. In a meta-analysis of 16 selected studies, axillary sonography combined with biopsy had a specificity of 88% to 98% in diagnosing axillary metastasis.⁶⁰

Sonographic evaluation of the regional lymph nodes, including the axillary, infraclavicular, and internal mammary regions, is a part of all staging breast sonography examinations performed at our institution. Lymph nodes are assessed for both size and morphology. A short-axis, or minimum diameter larger than 1 cm, has been suggested as the threshold criterion for an abnormal lymph node diagnosis.⁴² However, many nodes that are normal or fatty can measure over 1 cm, while a malignant node can be less than 1 cm. For this reason, the morphologic findings of the lymph node are crucial for an accurate diagnosis. Morphology suggestive of a malignant node includes a diffuse or focal hypoechoic and thickened cortex of 3 mm or more, partial or complete hilar compression or displacement, and perinodal invasion (Figure 27-17). If a suspicious lymph node is detected, a biopsy can be performed using a hypodermic needle (21- to 23-gauge attached to a 10-mL syringe). Papanicolaou staining or air-dried Diff-Quik staining is performed,⁶¹ and preliminary results can be available to the patient at the same appointment. The management of internal mammary nodes remains controversial, and many medical centers do not perform ultrasound-guided or surgical percutaneous biopsies owing to concerns about morbidity and the lack of a demonstrated impact on survival.

Figure 27-17 Abnormal bone scan in an 83-year-old woman with newly diagnosed breast cancer. A, A bone scan demonstrated multiple foci of increased radiotracer technetium-99m-methylene diphosphate (MDP) uptake in the bilateral ribs, sternum, vertebral bodies, and iliac bones. B, Computed tomography (CT) scan of the chest demonstrates corresponding osteolytic lesions throughout the ribs and sternum (arrows).

Metastatic Disease

Metastatic disease of the breast is a heterogeneous disease and ranges from a solitary metastasis to diffuse disease within multiple organs. Despite the medical advances in the detection and diagnosis of breast cancer at an early stage, approximately 30% of patients with early-stage breast cancer will develop a distant metastasis.⁶² A subset of oligometastatic disease refers to a few metastatic lesions within one organ and has a more optimistic prognosis than the cases with diffuse disease when treated with an intensified multidisciplinary therapeutic approach.⁶³ Currently, we do not have a clear understanding of the patterns of spread or specific sites of recurrence. Advances in whole body imaging may aid in the early detection of metastases and in facilitating a better understanding of how and why breast cancer spreads in spite of therapy.

Bone Metastases

Metastases develop in approximately 69% of patients with advanced stage or recurrent breast cancer, and bone is the most common site of distant metastases from breast cancer.⁶² Imaging modalities commonly indicated for the detection and management of osseous metastases include plain-film radiography, skeletal scintigraphy, CT, MRI, PET, and single-proton emission radiography, as well as combination techniques such as PET/CT, dual-modality single-photon emission CT, and whole-body MRI.⁶⁴ For a newly diagnosed breast cancer patient with no bone symptoms, skeletal scintigraphy is the modality of choice for screening for osseous metastases (Figure 27-18). If focal bony symptoms are present, plain film radiography of the symptomatic area(s) would be helpful to visualize the bony anatomy. If the radiography fails to identify osteolysis, CT can be performed to evaluate the cortex and associated soft tissue calcifications. CT is also preferred over MRI for rib lesions. When evaluation of bone marrow or soft tissue is indicated, high-contrast MRI is the preferred imaging modality. MRI carries the added advantage of being able to differentiate metastatic breast cancer from osteoporotic compression fractures (Figure 27-19). If radiography, CT, or MRI studies remain discordant in the presence of highly suspicious clinical symptoms, PET/CT is indicated.

Figure 27-18 Ultrasound of liver metastases in a 61-year-old woman with a history of invasive ductal carcinoma of the right breast who subsequently developed liver metastasis. Ultrasonographic image demonstrates a 2.5-cm isoechoic liver mass with a hypoechoic halo (arrow), compatible with metastatic disease.

Figure 27-19 A 57-year-old woman with a history of left breast carcinoma who subsequently developed liver metastasis 3 years later. CT images of the abdomen revealed multiple irregular hypodense hepatic masses on the precontrast image (A), typical of hepatic metastasis from breast cancer. B, On the postcontrast image, the lesions mildly enhance along the periphery.

Liver Metastasis

Liver metastasis from breast cancer is less common than bone metastasis, yet liver metastasis is observed in 55% to 75% of autopsies in patients with breast cancer.⁶⁵ Common clinical presentation of liver metastasis includes hepatomegaly and abnormally elevated liver function tests. Imaging tests commonly incorporated to investigate these clinical symptoms include abdominal ultrasonography and contrast-enhanced CT, MRI, and PET studies.

Ultrasonography is the least expensive and most widely available modality, with a reported sensitivity of 94% in the detection of liver lesions larger than 2 cm and 56% for smaller lesions.⁶⁶ The examination of the liver should be performed with a sector or a curvilinear array transducer, with center frequencies between 2 and 5 MHz for deep penetration. Hepatic metastasis is usually presented as a hypoechoic focal lesion compared with normal liver parenchyma, or it may have a “target” appearance, displaying as an echogenic center surrounded by a hypoechoic halo (Figure 27-20). Diffuse hepatic metastases may present as a diffusely inhomogeneous liver parenchyma. Ultrasonography is primarily used for further characterization of liver lesions and for guiding biopsies; ultrasonography is not used as a surveillance tool for the detection of metastases owing to its poor ability in differentiating benign from malignant lesions, especially at medical centers where CT or MRI is available. However, ultrasonography is a strong alternative choice for patients with allergies or contraindications to CT or MRI contrast agents.

Figure 27-20 A 58-year-old woman with a history of invasive ductal carcinoma of the left breast. A, A staging CT of the abdomen demonstrated one indetermined hypodense liver lesion (arrow) and a few hepatic cysts. B and C, MRI studies performed for further tissue characterization demonstrate a hypointense liver lesion (arrows) with peripheral enhancement and wash-out on delayed-phase imaging.

Unlike ultrasonography, CT is not operator-dependent, is easily reproducible, and can detect subcentimeter liver lesions. Hepatic metastases from breast cancer typically present as irregular, ill-defined, hypodense masses on the precontrast image and during the portal venous phase. The periphery of the mass may demonstrate mild enhancement. Against the background of hepatic steatosis, hepatic metastasis can be difficult to detect on CT, and MRI is a superior modality for this clinical scenario. The liver may be shrunken or have the appearance of cirrhosis due to diffuse disease related to periportal fibrosis. Hepatic steatosis can also be a posttreatment appearance from tamoxifen or cytotoxic drugs.⁶⁷ Because of its usefulness in lesion detection and prevalence in interventional clinics, CT is also used to guide biopsies of suspicious lesions. For nonspecific liver CT findings, MRI may be useful in both confirming the presence of liver lesions and further characterization of the lesions.

Breast carcinoma has variable appearances on MRI, ranging from a military pattern with ring-enhancing masses to confluent segmental abnormalities. Metastases are typically hypervascular tumors that do not contain Kupffer cells. Therefore, the contrast agent does not accumulate in these lesions, and metastases tend to appear as hypointense lesions compared with liver parenchyma on delayed-phase imaging. Regardless of the imaging modality performed, information acquired from imaging of metastatic liver lesions includes the number and size of each liver lesion, the characteristics of the lesion, and the resectability or relationship to vital vessels.

Intrathoracic Metastasis

The thorax is a common site of metastasis and involves the lung, pleura or mediastinum, and airway. Pulmonary metastasis may be a single pulmonary mass, multiple pulmonary nodules, an airspace-pattern metastasis, a lymphangitic metastasis, or an endobronchial metastasis (Figure 27-21). The metastatic pulmonary nodules or masses can be irregular or circumscribed lesions and tend to be in the periphery of the lung. Centrally located metastases or mediastinal metastases can extend into the bronchial walls, resulting in endobronchial metastasis. The pulmonary metastases rarely cavitate or present as a consolidation or airspace pattern, mimicking pneumonia. Breast cancer cells can spread to the pulmonary lymphatic system, resulting in lymphangitic metastasis. This pattern of spread presents as a thickening and nodularity of the interlobular septa or Kerley B lines. Unilateral involvement is more common than bilateral involvement in metastatic breast cancer. Other intrathoracic metastases include pleural effusions, pleural thickening, or pleural-based masses. The effusion tends to be unilateral and ipsilateral to the primary breast cancer. Pleural metastasis is thought to be due to lymphatic dissemination of breast cancer.⁴⁰ The heart and pericardium can be involved by extrathoracic primary carcinoma from the breast. Most patients receive a chest radiograph at the initial staging evaluation, even though CT better delineates the metastatic pulmonary lesions, the endobronchial lesions, and the pleural nodules.

Figure 27-21 A 51-year-old woman with triple negative (estrogen receptor [ER]–negative, progesterone receptor [PR]–negative) invasive ductal carcinoma of the left breast who developed pulmonary metastasis 1 year later. CT image of the lungs revealed multiple masses bilaterally, compatible with pulmonary metastasis.

Abdominal Metastasis

Besides the liver, other organs that breast cancer cells can spread to include the spleen, adrenal glands, lymph nodes, and peritoneum (Figure 27-22). Splenic metastases tend to be microscopic rather than macroscopic disease, and on CT, splenic metastases appear similar to liver metastases with irregular, ill-defined hypodense lesions. If there is diffuse disease, splenomegaly may also be present. Metastases to the adrenal glands are more common than to other endocrine organs, such as the thyroid or pituitary glands. Adrenal metastases demonstrate similar morphologic appearances as in the liver or spleen, with irregular, ill-defined margins and lower attenuation than the normal adrenal gland. The metastases can be unilateral or bilateral; however, a new lesion is suspicious for metastases. Lymph nodes in the abdomen that can be involved by breast cancer cells include the retrocrural, para-aortic, retroperitoneal, and intrapelvic nodes. Ascites and peritoneal spread to the bowel wall, mesentery, and omentum are not uncommon, especially with invasive lobular carcinoma.⁶⁸ Other distant sites include the kidneys, ovaries, and uterus, although metastasis to the uterus is uncommon.

Figure 27-22 A 48-year-old woman with a history of right breast invasive ductal carcinoma and DCIS who developed lung metastasis, liver metastasis (A), malignant ascites (thick arrow in B), and peritoneal carcinomatosis (thin arrow in B) 3 years later.

Key Points The radiology report

What the Surgeon Needs to Know

• Tumor size, number, and total volume to be taken out en bloc.

• Tumor location.

What the Medical Oncologist Needs to Know

• Tumor size, skin or chest wall involvement, and absence or presence of regional lymph node involvement.

• Metastatic disease: location of metastasis, extent of disease, and related complications from the metastasis.

What the Radiation Oncologist Needs to Know

• Location of existing and resected gross disease.

• Location of adjacent vital structures, such as carotid vessels or the thyroid gland.

• Location of malignant lymph nodes.

Surgical Treatment

Surgical management of breast cancer involves the appropriate extirpation of the primary tumor as well as assessment of the regional lymph nodes. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-4 and B-6 trials clearly established that less extensive surgery is as effective in curing patients of their disease as more extensive surgery and opened the door to breast-conserving therapy.^33,70 Thus, most breast cancer patients have the option of undergoing breast-conserving surgery as an alternative to mastectomy for treatment of their primary tumor. Currently, oncologic exclusions to breast-conserving surgery include inflammatory breast cancer, multicentric breast cancer, and T4 tumors involving the skin. Breast-conserving surgery requires the complete removal of all macroscopic and microscopic disease, as determined by achieving negative margins; after surgery, the patient must undergo radiation therapy to the breast. Margin-positive excisions are clearly recognized as increasing the risk of local failure,⁷¹ which in turn may compromise long-term survival.⁷²

The second component in the surgical management of breast cancer is the evaluation of regional lymph nodes to provide accurate regional staging and prognostic data. Traditionally, this was accomplished by axillary dissection with its attendant morbidities, in particular lymphedema and paresthesia. In 1994, however, sentinel node biopsy was introduced as an accurate and less morbid means of staging the axilla⁷³ and has now become the standard practice for this purpose. Considerable debate remains about whether women with sentinel node metastasis require complete dissection because many will have no metastasis beyond the sentinel node.⁷⁴ Among the underlying issues in this debate is whether axillary dissection has therapeutic value in addition to providing prognostic information. At a minimum, it is becoming clear that, even if a survival benefit to completion node dissection cannot be proved, in-basin recurrences are higher if completion node dissection is omitted.^75,76 It is also theoretically possible that failure to remove additional foci of nonsentinel nodal disease may result in understaging of the patient and, potentially, undertreatment as well. Despite this ongoing debate, it should be noted that, although in individual cases a decision may be made to forego complete node dissection, the American Society of Clinical Oncology recommends node dissection for all women with micro- or macrometastasis in the sentinel lymph node.⁷⁷

For women who require a mastectomy, breast reconstructive surgery is offered to improve the physical and psychosocial effects of the physical deformity caused by mastectomy. The two broad categories of breast reconstruction are implant-based reconstruction and autologous tissue–based reconstruction. The types of breast reconstruction are listed in Table 27-3.

For implant-based reconstruction, the surgeon initially creates a breast mound by placing a prosthesis or tissue expander within the mastectomy skin pocket extending to the pectoralis major muscle. Patients with tissue expanders should avoid undergoing an MRI owing to the presence of metal in the infusion port. The decision to use either a silicone- or a saline-filled implant is largely based upon the patient’s preference. Silicone implants offer a more natural appearance and feel whereas saline implants are perceived as a safer choice, even though studies have not shown a difference in the safety profiles of the two types of implants.

Autologous tissue–based reconstructions, also described as flap reconstruction, are the second major classification of breast reconstruction.⁷⁸ Flaps are classified by both the source of their arterial perfusion and the method of their transfer (see Table 27-3). Pedicled flaps entail the transfer of skin and subcutaneous fat based on a vascular leash that remains attached to its source vessels. Free flaps are created when the vascular supply to the tissue is detached from the source vessels and the vessels are anastomosed under microscopic visualization to distant recipient vessels.⁷⁹

Chemotherapy

Chemotherapy treatment for breast cancer depends on disease stage, patient symptoms, and tumor features such as receptor status and grade. Chemotherapy may be administered after surgical resection (adjuvant therapy) to reduce the risk of developing metastatic disease in high-risk patients. Adjuvant therapy reduces the risk of breast cancer recurrence by 30% to 50%.^80,81 The administration of chemotherapy before surgical resection (neoadjuvant therapy) offers the same survival benefit as adjuvant therapy and is often considered in patients with locally advanced breast cancer to reduce tumor size, which results in a less extensive operative procedure in certain patients. Chemotherapy is also used to palliate symptoms in patients with metastatic breast cancer.

Many chemotherapy drugs have activity against breast cancer (Table 27-4). Anthracyclines, such as doxorubicin and epirubicin, are commonly used to treat breast cancer and exert their action by inhibiting topoisomerase II, an enzyme that relieves torsional stress during DNA replication and transcription.⁸² To increase cytotoxicity, anthracycline-based regimens usually include cyclophosphamide with or without fluoropyrimidines, such as 5-deoxyfluorouridine (5-FU).⁸³ Taxanes, such as paclitaxel, docetaxel, and nab-paclitaxel (an albumin-bound formulation of paclitaxel that reduces hypersensitivity reactions), exert their cytotoxic effects by binding to alpha-tubulin, stabilizing microtubule formation, and blocking the progression of mitosis.⁸⁴ Epothilones, such as ixabepilone, also bind to alpha-tubulin but have demonstrated activity in taxane-resistant cell lines.⁸⁵ Vinca alkaloids, such as vinorelbine, interfere with mitosis by exerting their effects on microtubule assembly.⁸⁶ Nucleoside analogues, such as 5-FU, capecitabine, and gemcitabine, induce apoptosis through their effects on DNA replication.^87,88 Alkylating agents, such as cyclophosphamide, or platinum salts, such as cisplatin and carboplatin, induce apoptosis by cross-linking DNA strands.

Table 27-4 Chemotherapy Agents Commonly Used to Treat Breast Cancer and Associated Toxicities

Common toxicities associated with chemotherapy drugs used to treat breast cancer are listed in Table 27-4. Anthracyclines and/or taxanes are the most frequently used neoadjuvant and adjuvant chemotherapy regimens and may also be used to treat patients with metastatic disease. Taxanes, nucleoside analogues, vinca alkaloids, and platinum salts are commonly combined with targeted agents, such as trastuzumab, bevacizumab, or lapatinib, to enhance their cytotoxic effects.

Radiation Therapy

Adjuvant radiation therapy is indicated after a lumpectomy for virtually all patients; this recommendation is based on data from a phase III randomized trial.^89–91 Women older than 70 years with small, low-grade, ER-negative invasive tumors who take tamoxifen have been reported to have sufficiently low risk of recurrence without radiation therapy, indicating that observation may be considered.⁹² Women with early-stage breast cancer who undergo segmental mastectomy now have several adjuvant radiation therapy options, including a shorter course of radiation therapy to the whole breast (more dose per day than the standard 5- to 6-wk regimens)^93,94 and accelerated partial breast irradiation (treats only the tissue adjacent to the lumpectomy cavity with high dose per fraction twice a day for 1 wk). Selection of patients and techniques for the latter approach are still under investigation and should be carefully considered.⁹⁵ Adjuvant radiation therapy in the postmastectomy setting reduces the risk of locoregional recurrence by two thirds and should be offered to all patients with stage III breast cancer and high-risk node-positive patients with stage II breast cancer.⁸⁹ Common toxicities are summarized in Table 27-5. Adjuvant radiation therapy for patients who receive neoadjuvant systemic therapy has not been studied extensively but is routinely given to patients who presented with stage III disease, regardless of response, and to stage II patients with residual disease, particularly in the lymph nodes.^96,97 Adjuvant radiation therapy has been shown to improve survival by preventing locoregional recurrences.⁸⁹ A 21-gene expression signature has recently been shown to predict for locoregional recurrence, and in the future, it may be possible to better select patients who are at the highest risk of locoregional recurrence.³⁸

Table 27-5 Radiation Therapy and Toxicities

Monitoring Tumor Response

Increasingly, neoadjuvant chemotherapy is used in the management of locally advanced breast cancer. Early initiation of systemic therapy can improve overall and disease-free survival for patients with locally advanced breast cancer or inflammatory cancer or for patients at high risk of recurrence. By downstaging the primary tumor, neoadjuvant chemotherapy can make surgery or breast-conservation therapy an option for patients whose cancer was initially considered inoperable. Nodal disease can be eradicated in 40% of patients who have node-positive disease at initial presentation,⁹⁸ and the eradication of nodal disease is likely to increase with the improvement in targeted therapies, such as trastuzumab in combination with chemotherapy.⁹⁹ Therefore, it is important to determine early in the course of the disease which patients are most likely to respond to neoadjuvant chemotherapy.

Physical examination, mammography, and ultrasonography have all been used to assess the response to neoadjuvant chemotherapy. The principal value of these techniques is in measuring the size of the residual lesion based on morphologic changes in the tumor. Unfortunately, treatment-induced fibrosis or inflammation can result in an overestimation or underestimation of the extent of residual disease, meaning the true response to therapy is not reflected in the findings from physical examination, mammography, or ultrasonography. MRI with intravenous contrast and advanced MRI techniques provide new opportunities for assessing tumor morphologic changes, tumor vascularity, tumor cellularity, and tumor metabolic features. MRI has been shown to be more reliable than the conventional methods of physical examination, mammography, and sonography in the assessment of tumor size and vascularity changes during and after chemotherapy.¹⁰⁰ The addition of advanced imaging techniques such as diffusion-weighted imaging or proton MRS to further characterize tumor cellularity and metabolic features appears promising. However, there is still no consensus on the role of MRI for assessing response to neoadjuvant chemotherapy or on standardized MRI studies in patients receiving neoadjuvant chemotherapy. More investigations are needed to determine the potential of MRI in predicting those patients who would respond to neoadjuvant chemotherapy.

Detection of Recurrence

After mastectomy or breast-conserving surgery for breast cancer, disease can reappear locally, regionally, or at distant sites. Locoregional recurrent disease refers to the reappearance of the original breast cancer in the treated breast within the skin flaps, mastectomy scars, or ipsilateral chest wall. Regional recurrent disease refers to the breast cancer recurring in the regional lymphatic system of the treated breast such as the ipsilateral axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. The recurrent disease may present as a small solitary tumor or a palpable lesion or the recurrent disease may be more diffuse, involving the entire chest wall or regional lymph nodes. The majority of recurrences occur in the first decade after the diagnosis of the primary breast cancer with peak incidence at 2 years and a second peak incidence at 5 years after initial diagnosis.¹¹⁵ Therefore, the goal of an intensive surveillance program after treatment is to detect potential curable recurrences or secondary primary tumors.

The modes of surveillance recommended by the American Society for Clinical Oncology 2006 clinical guidelines¹¹⁶ are as follows: a monthly breast self-examination, a complete history and physical examination every 3 to 6 months for the first 3 years followed by every 6 to 12 months for years 4 and 5, and regular screening mammography. A mammogram is recommended 1 year after the initial mammogram that led to the diagnosis of breast cancer or 6 months after definitive radiation therapy. However, diagnostic tests, including serum markers or other imaging studies (such as breast MRI, radionuclide scans, CT scans, or PET scans), are not routinely recommended. When there is a clinical suspicion of locoregional recurrent disease, a biopsy is required to confirm the diagnosis and to rule out common benign processes associated with post-treatment changes such as fat necrosis, granulomas, or foreign body reactions. Locoregional recurrent disease, with or without simultaneous distant metastasis, occurs in up to 49% of cases during 18 years of follow-up.¹¹⁷ At least half of the patients with locoregional recurrent disease develop distant metastases.^118–119 Some prognostic factors associated with an increased likelihood of locoregional recurrence include a tumor greater than 5 cm in diameter, disease-positive lymph nodes, and initial disease involving the skin or fascia. Isolated locoregional recurrent disease detected on imaging or before the manifestation of symptoms has better rates of survival than locoregional recurrences detected late or with symptomatology.¹²⁰ More than half of the patients with locoregional recurrent disease will develop distant metastases within 5 years, and approximately two-thirds of these patients will develop distant metastases within 10 years.¹²¹

New Therapies

The investigation for new diagnostic imaging tools and new therapies is a dynamic process, with promising preliminary results in molecular imaging (positron-emission mammography and scintimammography) and targeted therapy. As the mechanisms of chemotherapy agents are better understood, novel drug designs are being implemented to improve drug delivery, overcome known mechanisms of resistance, and/or reduce toxicity. Response to chemotherapy is also being enhanced with the administration of targeted agents that block known mechanisms of drug resistance or improve delivery of the drug to the tumor bed. In addition, molecular profiling is being used to identify patients who are most likely to benefit from chemotherapy treatments, which will one day allow for a more personalized selection of cancer therapy. New radiation therapies, including the deep inspiration breathhold respiratory technique, intensity-modulated photon therapy, intensity-modulated proton therapy, and partial breast irradiation delivery systems, are under investigation; these therapies may reduce side effects and make treatment more convenient for the patients. At the cellular level, research investigating cancer stem cells is promising. Cancer stem cells are a subset of tumor cells that are responsible for initiating and maintaining the disease. The genetic changes and cellular context determining the characteristics of cancer stem cells and the cell of origin remain unclear. The cancer stem cell models can become powerful tools for basic and clinical research on human cancers, such as breast cancer.