Breast

GENERAL CONSIDERATIONS

Most women will experience a benign breast concern in their lifetime. These patients are often referred to general surgeons for evaluation and management.

Evaluation of any breast complaint begins with a focused history and physical examination. The history should include an assessment of the patient’s presenting problem including onset, symptoms, quality, duration, presence of aggravating/alleviating factors, and any new changes in health. Additionally, personal and familial risk factors should be noted and if available, input into risk prediction models. Patients who are identified as increased risk either by history or diagnosis should be offered enrollment in high-risk screening programs and may benefit from risk-reducing lifestyle modifications or chemoprevention with tamoxifen or raloxifene.

Focused physical examination begins with visual inspection for any asymmetry, retraction, nipple abnormalities, or skin changes such as erythema or peau d’orange. Palpation should systematically cover all areas of both breasts including the axillary tail and should include examination of the axillary, supraclavicular, and cervical nodal basins. If the patient presents with a complaint of nipple discharge, then it is appropriate to attempt to elicit the discharge with palpation. Any nipple discharge should be characterized in terms of color and location as well as whether it arises from a single duct or multiple ducts, and if a trigger point can be identified.

Physical examination should be followed with the appropriate diagnostic imaging. In patients younger than age 30 years, diagnostic ultrasound is the initial study of choice; mammography is not usually helpful because of increased breast density and low likelihood of breast cancer in this patient population. For patients aged 30 to 39 years, diagnostic mammogram is indicated in addition to ultrasound because they often have reasonably interpretable mammograms despite dense breast tissue, and it may be possible to see microcalcifications or other abnormalities not detected by ultrasound. At age 40 years and older, patients should have up-to-date bilateral mammograms annually. Evaluation of any concerns should include diagnostic mammography and targeted ultrasound as needed. In general, for average-risk patients, mammography and ultrasound are sufficient imaging for evaluation of most breast complaints. More costly imaging such as magnetic resonance imaging should be reserved for suspicious clinical or imaging findings that remain indeterminate despite complete mammographic and sonographic evaluation. When a biopsy is indicated, an image-guided core needle biopsy is preferred, and a clip should be left marking the area biopsied.

COMMON BREAST COMPLAINTS

MANAGEMENT OF BENIGN BREAST MASSES AND LESIONS

A palpable breast mass is one of the most common complaints leading women to present to a surgeon. In premenopausal women, most palpable breast masses are caused by benign lesions, with a minority representing cancer. Ruling out cancer is an essential part of the evaluation of a breast mass. In postmenopausal women, a new breast mass should be assumed to be cancer until proven otherwise. Diagnostic imaging can show distinct characteristics of benign masses helpful in distinguishing from a cancer. In most cases, solid masses are definitively diagnosed with image-guided core needle biopsy.

SPECIAL POPULATIONS

INTRODUCTION

The American Cancer Society (ACS) estimates that in the United States in 2021 there will be about 284,200 new cases of invasive breast cancer and about 49,290 new cases of ductal carcinoma in situ. They estimate that approximately 44,130 deaths will be attributable to breast cancer in the United States. In the United States, breast cancer is the most commonly diagnosed cancer in women and the second most common cause of cancer death. Since the late 1980s, based on accumulated evidence from long-term follow-up of randomized controlled trials and observational studies of population-based screening, several organizations have published guidelines for breast cancer screening. Published guidelines have changed over time and have not always been in agreement across different organizations. In the past decade, there has been a greater emphasis on estimating harm from screening and recognizing the interplay between published recommendations and an individual woman’s values, preferences, and informed decision making. This chapter considers screening modalities and guidelines used to identify early breast cancer in asymptomatic women, including women considered to be at average risk of breast cancer and in those considered to be at increased risk.

Potential improvement in outcomes with screening includes the possibility of improved breast cancer–related survival, but also lower morbidity of treatment. Early detection may be associated with the ability to provide disease control with a lumpectomy rather than a mastectomy, and with less toxic systemic treatments. Potential harms of screening must be considered. Potential harms include exposure to radiation and false-positive imaging findings, which can lead to additional imaging evaluation, potential biopsy, increased cost, and anxiety. As with all cancers, screening practices for breast cancer should be based on evidence regarding the prevalence of disease in the screened population, the effectiveness of the screening procedure, and any attendant harm, including the risks and costs associated with the screening test and any additional tests and procedures that follow a positive screening test. There have been debates about who should be screened, at what age, and with what method. As more data have emerged regarding the frequency and consequences of false-positive test results and overdiagnosis (i.e., diagnosis of low-grade, nonaggressive tumors that likely would not have an impact on a person’s life) and as breast cancer treatment becomes more effective, the trade-off between benefits and harms of screening have evolved.

SCREENING MODALITIES

SCREENING RECOMMENDATIONS

Screening guidelines have existed for decades and have been published by many organizations including the ACS, the NCCN, the United States Preventative Services Task Force (USPSTF), the American College of Radiology, the American College of Obstetrics and Gynecology, the Society for Breast Imaging, the Canadian Task Force on Preventative Health Care, and the American College of Physicians. Published guidelines have changed over the years as new data and viewpoints are considered, and the recommendations vary somewhat from one guideline set to another. Although many unanswered questions remain, it is clear that screening for breast cancer remains a valuable part of breast cancer detection.

SUMMARY

Breast cancer remains a common cancer for which early detection can improve outcomes, including both lower morbidity of treatment and improved survival. Mammography remains the dominant screening strategy for most women. Enhanced screening with annual MRI can be appropriate and valuable for women who are at very high risk of breast cancer. The majority of breast cancers in the United States are diagnosed as a result of an abnormal screening study, and death rates from breast cancer in the United States have decreased 30% since the 1990s. It is estimated that approximately one-third of this effect is a result of screening, with the rest attributable to treatment advances. Challenges remain in providing appropriate screening for all who may benefit. There is great interest in developing newer screening methods that may provide screening at lower cost, with greater accuracy, and in areas currently without screening.

TECHNIQUES

Ultrasound-guided biopsy is usually the most straightforward approach, but lesions better seen on mammography images, particularly microcalcifications, require stereotactic localization. The principles of localization involve mapping the distance between the geometric center of the breast with the target lesion in two different planes and then projecting the coordinates onto the patient’s breast ( Fig. 1 ).

Earlier techniques in stereotactic biopsy used mammographic projections to localize the target lesion within the breast and manual localization through the use of grids and two-dimensional (2D) images from two views (central with compression from superior/inferior and medial/lateral oblique compression of the breast). Advances in digital mammography have since superseded manual computations. Localization are performed with dedicated stereotactic equipment that fixes the breast in place. Stereotactic techniques have also been developed within other imaging modalities, including ultrasonography and MRI. These techniques offer more options and greater flexibility in performing stereotactic biopsy. Digital tomosynthesis creates a three-dimensional (3D) image of the breast using x-rays. It has been approved by the US Food and Drug Administration (FDA), but it is not available in all hospitals. This technique is called mammography with tomosynthesis and involves taking multiple x-ray images at 1-mm slices of each breast from many angles ( Fig. 2 ). The breast is positioned in the same way as conventional mammography but with limited pressure. The x-ray tube moves in an arc around the breast while numerous images are taken within a few seconds. The information is then relayed to a computer that generates a highly focused 3D image throughout the breast. Performing a biopsy using 3D images can be beneficial when the mass is not easily seen on 2D imaging, and it is especially helpful in dense breast tissue, where 3D images can differentiate a true distortion or asymmetry seen on mammography from overlapping breast tissue.

INDICATIONS

There are six Breast Imaging-Reporting and Data System (BI-RADS) categories: (1) negative, (2) benign finding, (3) probably benign finding, (4) suspicious, (5) highly suggestive of malignancy, and (6) known biopsy proven malignancy. Indications for stereotactic biopsy include the following ( Box 1 ):

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  Highly suspicious microcalcifications or densities (BI-RADS 5) to confirm the diagnosis and facilitate treatment planning

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  Suspicious microcalcifications or densities (BI-RADS 4)

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  Probably benign microcalcifications or densities (BI-RADS 3) when there are valid clinical indications

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  Multifocal or multicentric lesions to facilitate treatment planning

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  Repeat biopsy in the setting of discordant imaging assessment with initial biopsy

CONTRAINDICATIONS

Lesion location can affect accurate targeting by image guidance. Contraindications include lesions immediately juxtaposed to an implant, lesions that are too posterior to the chest wall, or those that are too superficial to the skin or nipple ( Box 2 ).

Multiple patient factors can preclude a stereotactic biopsy, such as inability to lay prone for stereotactic or MRI guided biopsy, mental disability that limits patient cooperation, body habitus (obesity, pregnancy, or kyphosis). Weight >300 lb exceeds the weight limit on a prone biopsy table. If a patient has thin or small breasts, adequate breast tissue thickness may not be available while in compression to allow access for the computerized biopsy equipment. There may not be enough breast tissue to compress to safely biopsy without the needle penetrating through to the other side of the breast. Further, if the breast is too large and the lesion is deep, stereotactic biopsy may not be technically feasible. Stereotactic core biopsy is also not indicated in pregnant women. Patients who are unable to undergo stereotactic biopsy should be referred for surgical excisional biopsy. It is unclear how to manage patients who receive antiplatelets and anticoagulants, and the risk of bleeding must be balanced against the risk of stopping the anticoagulant.

EQUIPMENT

The first choice for diagnosis of most breast lesions is through core biopsy under ultrasound guidance. The potential for sampling error has led to more invasive and larger-volume percutaneous biopsy devices such as vacuum-assisted biopsy devices. The vacuum-assisted devices have the ability to sample larger tissue volumes. These devices consist of an outer shell with an aperture at its end for collecting tissue. It is a single-insertion device that uses vacuum suction to pull the target tissue into the collecting aperture. The tissue is then excised by a rotating cutter. Multiple harvests can be performed in 360 degrees around the lesion while the probe remains in the lesion during the whole procedure, allowing for up to 12 biopsies with a single insertion of the device. The vacuum device can be used under ultrasound guidance or stereotactic guidance, particularly for microcalcifications; the patient is prone or upright with the use of certain units, with adequate room to accommodate the device. The vacuum devices are available 7- to 12-gauge sizes; the 9-gauge device is most popular as it can remove up to 1 cm of tissue. The vacuum-assisted device has been demonstrated to be superior in the diagnosis of ductal carcinoma in situ (DCIS) compared with a 14-gauge core biopsy, with 6% found to be invasive carcinoma after vacuum-assisted biopsy at surgery compared with 21% with 14-gauge core biopsy. Repeat biopsy rates for inadequate sampling of microcalcifications is also significantly lower when using vacuum-assisted biopsy (11.6% vs. 23.7% for core biopsy), although an equal proportion of malignancy is diagnosed following re-biopsy. Although vacuum-assisted biopsy appears to be nearly three times more accurate than core biopsy in the diagnosis of atypical ductal hyperplasia (ADH), underestimation still occurs in 18% to 25% of cases. Vacuum-assisted biopsy removes more tissue than core biopsy, and it is possible to remove the entire lesion through this technique. For patients with microcalcifications, stereotactic vacuum-assisted biopsy is the standard approach; however, if calcifications are associated with a solid mass, then ultrasound-guided biopsy may be used.

PROCEDURE

Before performing a stereotactic biopsy on the breast, a complete mammographic examination should be performed and reviewed before the procedure, to confirm the location to be sampled. There should also be documentation of a clinical breast examination and radioopaque markers placed on the skin over areas of palpable concern and pain. The possibility of a nondiagnostic result along with the risks, benefits, and alternatives to the procedure should be discussed with the patient. The procedure can be performed with a traditional prone stereotactic biopsy table or upright with an add-on stereotactic biopsy unit that attaches to the standard mammography equipment. The breast is compressed and held in position throughout the procedure between the image receptor and the compression plate. Imaging is performed to confirm that the targeted lesion lies within the area of accessibility. The computer-generated coordinates are then transferred to the stereotactic targeting device. Using sterile technique, local anesthetic is injected into the breast, and accurate needle positioning is determined through scout films. The ideal approach is the shortest distance from the skin to a targeted lesion. A scout view is obtained, and after the target is identified, two additional images are obtained 30 degrees apart, at +15 degrees and −15 degrees. The basis of stereotactic localization is the principle of parallax, which is used to locate the lesion in the 3D breast from a pair of 2D images. Scout view provides the x (horizontal) and y (vertical) coordinates of the lesion to be targeted in the breast. Two additional images are then used to determine depth ( z coordinate). A small nick is made in the skin, and the vacuum-assisted device is inserted into the breast under image guidance and placed either in the suspicious lesion or adjacent to it. The device is typically rotated, and multiple biopsies are taken from the suspicious lesion. The distance from post-fire needle tip to image receptor plate should be 5 mm or more to avoid penetration of the opposite side of the patient’s skin and penetration of the image receptor plate. Once the needle device is introduced into the breast and preimages are obtained to confirm the position, the needle is fixed and then post-fire images are obtained to confirm position. When the vacuum-assisted biopsy device is used, tissue sampling is performed in a 360-degree fashion. Typically, 6 to 12 samples are obtained. After the procedure, a radiopaque tissue marker (clip) is placed at the biopsy site. Sonographically visible markers are preferable. Specimen radiographs must be obtained to document appropriate sampling in all cases in which microcalcifications were targeted. Effort should be made to select an approach that will avoid puncturing blood vessels adjacent to the target and minimize hematoma by compressing the breast and skin entry site at the conclusion of the procedure. Post-procedure two-view mammography or stereotactic views should be performed to document clip position in relation to the biopsy site.

COMPLICATIONS

Complications include vasovagal reaction (less common prone), pneumothorax, hemorrhage, infection, or other wound complications. The overall incidence of severe complications from core or vacuum-assisted biopsy is less than 0.2%.

CONCORDANCE

For any combination of guidance methods and needle types, concordance between the cytologic or pathologic result and the radiologic appearance of the targeted lesion must be verified. This mandatory task must be performed by the professional who performed the image-guided sampling, usually a breast radiologist, in collaboration with the reporting pathologist. In most cases, the radiologist will consider the cytology or pathology result as concordant with imaging findings, especially when core needle or vacuum-assisted biopsy has been performed. However, in the case of inadequate sampling (more frequent in the case of FNA) or discordance between cytology/pathology and imaging findings, a repeat biopsy using the same or a different biopsy method can be considered. This is done after discussion in a multidisciplinary meeting. In the case of findings highly suspicious for malignancy on ultrasound, mammography/tomosynthesis, or MRI with discordant benign findings on FNA, core needle biopsy, and/or vacuum-assisted biopsy, surgical removal is indicated after preoperative image-guided localization if the lesion is nonpalpable ( Box 3 ).

FOLLOW-UP

For most patients with concordant radiologic-pathologic findings after biopsy, a follow-up mammogram is suggested at approximately 6 to 12 months. Following excision of DCIS associated with larger areas of malignant calcifications, a postoperative mammogram is suggested to ensure completeness of resection beyond specimen radiography and pathologic margin assessment. A shorter imaging period may be indicated in certain situations. If the patient is older than 35 years of age, a unilateral diagnostic mammogram is generally obtained as a new baseline study within 4 to 6 months of the procedure.

INTRODUCTION

Breast cancer is the most frequently diagnosed non-skin cancer in women and the second leading cause of cancer-related death. Breast cancer is a heterogenous disease composed of distinct subtypes with varied molecular pathogenesis. Better understanding of tumor biology is critical to improving breast cancer therapies and survival. This chapter focuses on molecular targets and available therapies within breast cancer subtypes.

BREAST CANCER SUBTYPES

In 2000, Perou and colleagues first identified the five intrinsic subtypes of breast cancer based on gene expression analysis: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, and normal-like. Each of these intrinsic subtypes reflects fundamental differences of the tumors at the molecular level. However, because of the limited applicability of gene expression profiling in the clinic, classification of breast cancer subtypes through use of immunohistochemistry (IHC) remains the cornerstone of breast cancer clinical management. Table 1 broadly maps the IHC profile and clinical classification of each of the intrinsic subtypes. Classification of IHC subtype guides clinical therapy, and the development of distinct molecularly targeted therapies for each of these subtypes has cumulatively improved breast cancer outcomes dramatically. Here, we review the currently approved molecularly targeted therapies across each of these breast cancer subtypes ( Table 2 ).

HORMONE RECEPTOR–POSITIVE BREAST CANCER

The estrogen receptor (ER) was the first recognized molecular marker for therapy in breast cancer. ER expression has been shown to have significant predictive value on tumor response to hormone therapy in curative and metastatic disease. The role of progesterone receptor (PR) expression in predicting tumor response to therapy is less clear, although tumors that are positive for both ER and PR expression have improved response to hormonal therapy. The prognostic value of ER/PR expression in addition to predictive value remains controversial. HR-positive (ER and/or PR-positive) tumors, defined technically by expression level of either or both receptors ≥1%, comprise approximately 70% of all breast cancers.

HER2-POSITIVE BREAST CANCER

Approximately 20% of breast cancers are HER2-positive. Assessment of HER2 status is conducted by evaluating samples of either the primary tumor or metastatic tissue with immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). HER2-positive disease is defined as: (1) IHC score of 3+ characterized by strong staining of the entire membrane circumference of more than 10% of cells or (2) IHC score of 2+ defined as weak to moderate complete membrane staining in more than 10% of cells with subsequent FISH testing resulting positive. HER2-directed therapy has dramatically altered the natural history of HER2-positive breast cancer. Before HER2-targeted therapy, HER2-positive breast cancer was associated with a poor prognosis with a short time to relapse and decreased OS. However, with the successful development of HER2-directed therapies—first for palliation and then for cure—breast cancer–specific outcomes are now dramatically improved. Central nervous system (CNS) metastases remain a challenge in the management of HER2-positive metastatic breast cancer, however. Approximately 50% of patients with metastatic disease develop CNS metastases in the course of their disease. Although significant progress has been made in the management of CNS metastases, this remains an area of unmet need.

TRIPLE-NEGATIVE BREAST CANCER

Approximately 10% of breast cancers are classified as triple-negative breast cancer (TNBC), defined by the lack of expression of ER/PR and HER2. As a result, TNBC comprises a heterogenous group of tumors with significant variability in disease response to therapy and clinical outcomes. Because of the lack of clinically identifiable targets, chemotherapy has historically been the backbone of therapy for patients with TNBC. However, recent gene expression analysis studies have helped identify subtypes of TNBC with increasing roles of targeted approaches. For example, PARP inhibitors are an available targeted therapy for patients with TNBC with germline BRCA1/2 mutation (see earlier). Ongoing studies are evaluating PARP inhibition beyond germline BRCA1/2 mutation in patients with other abnormalities of the DNA damage response pathway. Other agents that target the DNA damage repair pathway are also in development. In addition to PARP inhibition, several other targeted approaches have a role in the management of TNBC.

HER2-LOW BREAST CANCER

Approximately 50% of patients with breast cancer who are classified as HER2-negative still express HER2 at low levels (IHC 1+ or 2+ and FISH negative). These HER2-low patients are initially treated as HR+ or TNBC disease as above. Recent studies, however, have explored HER2 ADCs in these patients on relapse. The DESTINY-Breast04 study evaluated T-DXd versus physician’s choice chemotherapy in patients with HER2-low disease after prior endocrine therapy, if indicated, and at least one prior line of chemotherapy in the metastatic setting. The majority of patients enrolled (89%) had HR+ disease. The primary endpoint was PFS in the HR+ cohort. The study reported significant improvement in median PFS and OS in both the HR+ cohort and overall study population, resulting in FDA approval of T-DXd for HER2-low disease. Drug-related interstitial lung disease was seen in 12.1% of patients treated with T-DXd. Although the majority of these events were grade 1/2, three patients did experience grade 5 events. Other novel ADCs including disitamab vendotin and ARX788 are also being explored in the management of HER2-low disease. The efficacy of sequencing ADCS, either with a change in antibody target or change in payload, remains unclear at this time.

CONCLUSION

Significant advances have been made in breast cancer management. Through the identification of clinically relevant breast cancer subtypes, targeted approaches have been identified that provide benefit for many patients with breast cancer. However, with continued understanding of tumor pathogenesis and molecular targets, there is a growing need to better define the biology of each individual cancer in order to realize the potential of personalized cancer therapy.

SCREENING FOR BREAST CANCER

A woman in the United States has a 12.3% risk of developing breast cancer in her lifetime (i.e., 1 in 8 women). The majority of new breast cancers are diagnosed after an abnormal screening mammography. Imaging abnormalities, such as suspicious calcifications or a spiculated mass, warrant further characterization with supplemental mammographic views and/or sonography. The American College of Radiology uses the BI-RADS (Breast Imaging Reporting and Data System) assessment categories to designate the relative likelihood of a normal, benign, or malignant diagnosis, and standardize recommendations for further management. Breast cancer screening has led to a greater detection of breast cancer at an earlier stage, facilitating the use of early treatment.

The National Comprehensive Cancer Network (NCCN) guidelines recommend annual screening mammogram in asymptomatic women 40 years of age and older who have an average risk of breast cancer (less than 15% lifetime risk). Tomosynthesis—a 3D-mammogram constructed by a moving x-ray and digital detector—has an improved cancer detection rate and decreased call-back rate, and can be used as an alternative screening modality. Women with an increased risk for developing breast cancer are candidates for supplemental screening. In women with ≥ 20% lifetime risk as determined by risk models that are largely influenced by family history, annual breast MRI and mammogram should begin 10 years before the youngest family member’s historical diagnosis with breast cancer. In women who received thoracic radiotherapy between the ages of 10 and 30 years, annual breast MRI and mammogram should begin 8 years after radiotherapy. Breast MRI screening as an adjunct to mammography may also be used in women with lobular neoplasia (lobular carcinoma in situ/atypical lobular hyperplasia) or atypical ductal hyperplasia and ≥ 20% lifetime risk. Contrast-enhanced mammography or whole-breast ultrasound should be considered for those who qualify but cannot undergo breast MRI. MRI screening is not recommended in women with an average-to-moderate risk of breast cancer. There is no clear age to stop screening in elderly women, and this should be individualized based on the individual’s overall health and estimated longevity.

DIAGNOSIS OF BREAST CANCER

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in women. For 2021, the American Cancer Society estimated there will be 284,200 new invasive breast cancers (male and female) diagnosed in the United States, and approximately 44,130 deaths. Breast cancer mortality has decreased in the past two decades, largely attributed to mammographic screening and treatment advances.

For women who present with a palpable mass, imaging is warranted. Those with suspicious radiologic or clinical findings should undergo core needle biopsy for tissue diagnosis. Additionally, if clinically suspicious without imaging correlate, a biopsy should also be performed. The breast tissue biopsy allows histopathologic examination and provides information regarding in situ versus invasive cancer, histologic variant (e.g., ductal, lobular, mixed), hormone receptor status (estrogen, progesterone, and human epidermal growth factor receptor 2 [HER2]), and grade of the cancer. These findings guide therapeutic decisions.

In women with a new breast cancer diagnosis, further imaging may be necessary to evaluate the extent of disease. Axillary ultrasound can be used to evaluate for nodal involvement in women with a suspicious clinical examination. Routine breast MRI is not recommended but can be considered when disease extent is difficult to define by mammography and ultrasound.

A clinical stage is assigned based on the size of the largest tumor in the breast and the clinical axillary nodal status. Extent of disease evaluation may include positron emission tomography (PET) or computed tomography (CT) of the chest, abdomen, and pelvis, plus a bone scan; these are usually reserved for patients who have a high risk for distant disease, usually clinical stage III at presentation. However, NCCN guidelines (Breast Cancer Version 8.2021) state that the use of PET or PET/CT is not indicated in the staging of clinical stage I or II breast cancer, or for those with operable stage IIIA (T3 N1) breast cancer. Further imaging can also be used for patients who present with signs/symptoms concerning for metastatic disease (i.e., bone scan for patients with localized bone pain or elevated alkaline phosphatase, CT of the abdomen and pelvis for patients with abdominal pain or abnormal liver function tests, and CT of the chest for patients with pulmonary complaints).

DISCUSSION OF SURGICAL OPTIONS

The majority of women who are diagnosed with a new breast cancer in developed countries have no evidence of metastatic disease. Broadly, non-metastatic breast cancer is defined in two categories: (1) early-stage or (2) locally advanced. Women with early-stage breast cancer (stage I or II) are usually treated with primary surgery (breast-conserving surgery or mastectomy). Neoadjuvant therapy has become increasingly accepted in women with HER2-positive or triple-negative operable breast cancer and in situations in which downstaging of disease in the breast and/or axilla is desired. Women with estrogen receptor–positive tumors undergo primary surgery unless contraindicated because of comorbidities or unless categorized as those who desire downstaging to breast-conservation surgery, for whom primary endocrine therapy may be considered.

During initial evaluation, the patient’s clinical prognostic stage, fitness for general anesthesia and surgery, contraindications to radiotherapy, life goals, including fertility and quality-of-life concerns, and estimation of contralateral breast cancer must be carefully assessed to accurately weigh surgical options. A personal history of breast cancer or high-risk pathologic factors (i.e., lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia), a history of irradiation to the chest, and a strong family history of breast cancer may affect surgical decision making. A thorough family history dating back three generations on both the maternal and paternal sides should be obtained to determine eligibility for genetic testing. Approximately 10% of newly diagnosed breast cancers are caused by a strong family history or genetic predisposition. Genetic counseling and panel testing to include breast cancer susceptibility genes such as BRCA1, BRCA2, p53, PALB2, CHEK2, and RAD51C may help in counseling women on surgical options that include risk-reducing surgical approaches, such as bilateral mastectomy. The decision between lumpectomy and mastectomy is often a very difficult choice for women. Previous randomized prospective trials have demonstrated similar breast cancer–specific and overall survival when comparing lumpectomy plus radiation versus mastectomy. Several studies in more recent years have found that women treated with lumpectomy plus radiation have better outcomes than those treated with mastectomy, as this is thought to be secondary to advancements in systemic and radiation treatment. For women with estrogen receptor–positive and HER2-positive breast cancer undergoing lumpectomy plus radiation, the 10-year rates of locoregional recurrence are approximately 2% to 3%, and 5% for those with triple-negative tumors, and do not significantly differ compared with mastectomy. The decisions regarding systemic therapy, including chemotherapy, HER2-targeted therapy, and endocrine therapy, are based on the characteristics of the tumor and are independent of the type of surgery performed. Conversely, adjuvant radiotherapy is recommended following lumpectomy for the majority of patients, but factors such as older age may play a role in decision making. Based on evidence from the Cancer and Leukemia Group B (CALGB) 9343 trial showing no survival benefit with the addition of radiotherapy in women ≥ 70 years of age with early-stage, hormone receptor–positive breast cancers, undergoing lumpectomy now allows for omission of radiotherapy in this subset of women. Decisions for postmastectomy radiation therapy are more complex and are based on clinical and tumor characteristics, including the presence of axillary nodal involvement.

The rate of contralateral prophylactic mastectomy in women with unilateral breast cancer has been steadily increasing in the United States, especially among young women. The majority of women opting for contralateral prophylactic mastectomy will derive no survival benefit, and many are even candidates for breast-conserving therapy. Most women overestimate their risk for contralateral second primary breast cancer, and education to address the possible misconceptions surrounding it is crucial to the shared decision-making process.

LUMPECTOMY

Breast-conserving surgery (i.e., lumpectomy) preserves the cosmetic outcome of the breast and minimizes the extent of surgery without sacrificing oncologic outcomes. Whole-breast radiation therapy, an essential component of breast-conserving therapy, has been shown to decrease the risk of breast cancer recurrence. Contraindications and relative contraindications to breast-conservation therapy (lumpectomy plus radiation) include current pregnancy, prior radiation therapy including chest radiation, multicentric or widespread disease that cannot be incorporated by local excision, large tumor size in relation to the breast that compromises cosmetic results (although the emergence of advanced oncoplastic techniques may allow for breast conservation), diffuse malignant-appearing calcifications on imaging, or persistently positive pathologic margins despite reexcision attempts.

An intraoperative radiograph of the lumpectomy specimen can be used to assess successful retrieval of the lesion with radiographically negative margins. For nonpalpable lesions, image-guided localization utilizing wire localization, radioactive seed localization, and other alternatives are now available ( Fig. 1 ). Each method has its own advantages and disadvantages, and studies have not been able to prove one method to be superior.

Incision placement can vary according to the location of the lesion, but incisions should generally be placed over the tumor to avoid excessive tunneling. Because some women who undergo lumpectomy may ultimately require a mastectomy, consideration for the lumpectomy incision should consider the possibility of needing a mastectomy incision. Excision of the skin or underlying fascia is not required with the specimen as long as the tumor is not close to or involving the skin or fascia. To improve cosmetic outcome and hide the scar, a periareolar incision may be placed in select patients. Otherwise, incisions should follow natural skin creases (Langer’s lines) in the upper inner or upper outer quadrants of the breast in a curvilinear or horizontal fashion. In the lower inner or lower outer quadrants of the breast, a curvilinear or radial incision can be used following the contour of the breast.

Some surgeons routinely perform circumferential cavity shave margins after the lumpectomy, as there is evidence that this practice decreases the rate of positive margins and reexcision by one-half. Shave margins should include the superior, inferior, medial, and lateral aspect of the cavity along with the anterior and posterior margins if the resection did not extend to the dermis or pectoralis fascia. The new cut surface represents the final margins and should be marked for the pathologist. The Society of Surgical Oncology (SSO)/American Society for Radiation Oncology (ASTRO) consensus guidelines for appropriate margins in the setting of lumpectomy are no tumor at the inked surface of the lumpectomy specimen for invasive cancer and a 2 mm margin for ductal carcinoma in situ. Requirements for optimal margin evaluation include orientation of the surgical specimens, descriptions of the gross and microscopic margin status, and reporting of the distance, orientation, and type of tumor (invasive or ductal carcinoma in situ) in relation to the closest margin. The number of reexcisions that can be attempted for persistently positive margins depend on the volume of breast tissue already resected in relation to the size of the breast. Failure to achieve clear or negative margins warrants a conversion to completion mastectomy. Wider margins have not been shown to reduce the risk of local recurrence, assuming appropriate adjuvant radiation and systemic therapies are delivered.

Oncoplastic surgery incorporates reconstructive surgery principles without compromising oncologic management to offer breast-conserving options in situations in which the resection itself would likely yield an unacceptable cosmetic outcome. Oncoplastic techniques are valuable for patients with a large tumor size relative to their breast size, when the nipple-areolar complex needs repositioning, or in women with preexisting aesthetic concerns (e.g., desire for contralateral breast reduction for macromastia). For boost cavity localization for radiotherapy treatment planning, close communication between the radiation oncologist and surgeon is necessary. Retrospective studies suggest that oncologic outcomes are similar in women undergoing surgery compared with those undergoing mastectomy. Additionally, patient-reported outcomes in women undergoing oncoplastic breast-conserving surgery were higher than those undergoing mastectomy with immediate reconstruction when comparatively measured using the BREAST-Q questionnaire and self-rated breast appearance scores.

MASTECTOMY

Removal of the totality of glandular breast tissue (mastectomy) is a surgical option for the treatment of breast cancer or for breast cancer risk reduction. Glandular breast tissue extends to the clavicle superiorly, to the inframammary fold inferiorly, to the sternum medially, and to the latissimus dorsi muscle laterally. Mastectomy is performed in women with a contraindication for breast-conserving surgery, women with inflammatory breast cancer, and those who prefer mastectomy for various reasons, including patient preference. Bilateral prophylactic mastectomy reduces the risk of developing a breast cancer by over 90% in women with a BRCA mutation. The types of mastectomies used in modern breast surgery include simple mastectomy, modified radical mastectomy, skin-sparing mastectomy, and nipple-sparing mastectomy.

For a simple mastectomy performed without reconstruction, a large elliptical incision is made encompassing the nipple-areolar complex. When marking the incision preoperatively, the operating surgeon should take into account the vertical laxity of the breast to achieve a resection with minimal redundant skin. For example, a large ptotic breast will require a wider elliptical incision than a small, firm breast. Enough skin should be resected to achieve a resection so the skin lies flat against the chest; avoiding redundant skin in the axillary region deserves special attention, as it can be uncomfortable to patients otherwise. No axillary surgery is performed in a simple mastectomy. When a woman has clinically and biopsy-proven positive lymph node involvement, a modified radical mastectomy is performed, which includes a concurrent level I to II axillary lymph node dissection. A mastectomy dissection is performed along the plane defined by suspensory ligaments of Cooper, which serve as the connective tissue between the glandular breast tissue and subcutaneous fat. The thickness of the mastectomy flaps varies according to the thickness of the subcutaneous tissue in the individual woman.

For women planning for mastectomy with reconstruction, a skin-sparing mastectomy or nipple-sparing mastectomy can be performed. A skin-sparing mastectomy involves removal of the entire glandular breast tissue and nipple-areolar complex, but preserves as much of the skin envelope to allow for reconstruction. An elliptical incision is made incorporating the nipple-areolar complex and, if possible, any previous breast-conserving surgery scar. Incision planning with the plastic surgeon who will be performing the immediate reconstruction is ideal. Evidence suggests that the risk of locoregional recurrence in women undergoing skin-sparing mastectomy with immediate reconstruction is comparable to those undergoing a standard mastectomy without reconstruction.

Nipple-sparing mastectomy is appropriate in some patients and preserves the entire skin envelope of the breast, including the nipple and areola. Because of concern for occult tumor cells being harbored in the nipple-areolar complex, nipple-sparing mastectomy was historically reserved for prophylactic risk-reduction purposes. Growing evidence has demonstrated that nipple-sparing mastectomy provides safe oncologic outcomes, leading to its increasing use in recent years, particularly for therapeutic treatment for invasive breast cancer. However, appropriate selection of women for a nipple-sparing technique is controversial because of lack of level 1 evidence. Women ineligible for nipple-sparing mastectomy include those with locally advanced breast cancer, extensive disease in the periphery of the breast, direct invasion of the nipple with cancer, and tumors ≤ 1 cm from the nipple. The majority of nipple-sparing mastectomy incisions are placed along the inframammary fold. An inferolateral breast incision allows for access to the axillary tail if lymph node sampling or dissection is necessary. Alternative locations for incision placement include radially or as a periareolar incision ( Fig. 2 ). Because nipple-sparing mastectomy results in long skin flaps, which confer an increased risk of flap and nipple necrosis, this technique is avoided in women with a prior history of radiation, smoking history, and larger or ptotic breasts. To minimize thermal damage to the nipple-areolar complex subdermal plexus, sharp dissection is of benefit. The retroareolar tissue margin is sent separately from the main mastectomy specimen for pathologic examination. If there is evidence of malignancy in the retroareolar margin, then resection of the nipple is indicated.

The complications of mastectomy include hematoma, seroma, wound infection, skin flap necrosis, chronic pain, phantom breast syndrome, and arm morbidity. Postmastectomy bleeding occurs approximately 3% of the time. It is standard practice to place closed suction drains beneath the mastectomy flaps and the axilla for seroma prevention. Women are encouraged to resume activities of daily living postoperatively, but they should be counseled to avoid rigorous shoulder exercises to reduce the risk of seroma formation. Clinically significant seromas should be aspirated to prevent wound infection, delayed wound healing, and poor cosmetic outcomes. Risk factors for a wound infection include obesity, smoking, diabetes, and older age. Most postmastectomy cellulitis can be managed with oral antibiotics. If skin flap or nipple necrosis is extensive or unable to be managed conservatively, surgical debridement or skin resection may be required.

MANAGEMENT OF THE AXILLA

The axillary lymph nodes receive 85% of the lymphatic drainage from the breast and are the regional nodal basin where metastatic breast cancer cells are most likely to be found. The remainder drain to the internal mammary, supraclavicular, and infraclavicular lymph nodes. Axillary lymph node dissection, which continues to be the standard of care for clinically node-positive disease, was historically the initial approach to breast cancer axillary staging and management. The development of sentinel lymph node biopsy in 1994 has been groundbreaking to the management of the axilla. It has allowed for safe omission of axillary lymph node dissection in most patients with clinically node-negative disease, saving them from unnecessary morbidity. Determining the axillary nodal status provides prognostic information and is used for decision making regarding adjuvant treatment. A sentinel lymph node biopsy can be performed in conjunction with a lumpectomy or mastectomy, and sentinel node mapping can be accomplished using blue dye, technetium sulfur colloid radiotracer, or both.

For women with clinically node-negative breast cancer, sentinel lymph node biopsy is the standard of care. Several landmark trials have shown that some women with positive sentinel lymph nodes may not need to undergo a completion axillary lymph node dissection. According to the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, patients with T1 to T2 tumors who are clinically node negative and undergoing lumpectomy with sentinel lymph node biopsy do not require a completion axillary lymph node dissection if they are found to have one or two positive sentinel lymph nodes. There is no difference in overall survival or locoregional recurrence in this subset of patients if they undergo a completion axillary dissection versus no further axillary surgery. This suggests that adjuvant radiation and systemic therapies have a significant effect on any potential remaining positive nodes and contribute to effective local control without a completion axillary lymph node dissection.

The AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery) trial followed a similar design but included a subset of patients undergoing mastectomy and randomized patients with positive sentinel lymph nodes to axillary lymph node dissection or axillary radiation. There was no statistically significant difference in overall survival or axillary recurrence, but the patients who underwent completion axillary dissection had a 2-fold increased risk of lymphedema compared with those who underwent axillary radiation (40% vs. 22% at 1 year, and 28% vs. 14% at 5 years). The majority of patients in the AMAROS trial (82%) underwent lumpectomy, but 18% did undergo mastectomy; therefore, postmastectomy radiation can be considered in place of completion axillary dissection for patients undergoing mastectomy with a limited number of positive sentinel lymph nodes.

For women who present with clinically positive axillary lymph nodes confirmed by fine-needle aspiration or core needle biopsy, locally advanced breast cancer, or inflammatory breast cancer, axillary lymph node dissection may be performed. In general, level I and II anatomic lymph node dissection is preferred unless there are grossly positive axillary lymph nodes identified intraoperatively, in which case, level III lymph nodes should be removed as well. Women who present with clinically positive lymph nodes warrant consideration of neoadjuvant therapy for possible downstaging of the axilla. Subsequent surgical management of the axilla will then depend on the response to neoadjuvant therapy, which is dependent on molecular subtype, and greatest in triple-negative and HER2-positive tumors.

Lymphedema, caused by a disruption of the lymphatic system resulting in the accumulation of lymph fluid in the interstitial tissue, is a potential side effect of axillary surgery. The key to optimal management of lymphedema is early detection and diagnosis, as the early stages of lymphedema are reversible according to NCCN guidelines. Treatments for lymphedema include compression garments, physical therapy, and manual lymphatic drainage.

INFLAMMATORY BREAST CANCER

Inflammatory breast cancer is an aggressive subtype and represents approximately 2% of breast cancers in the United States. Patients with this clinical syndrome present with acute onset of erythema and edema (peau d’orange) of a third or more of the skin of their breast. The differential diagnosis includes mastitis or cellulitis, especially for a pregnant or lactating woman. Failure to improve with antibiotics should prompt diagnostic breast imaging and a punch biopsy of the affected skin. Finding adenocarcinoma in the dermal lymphatics is diagnostic of inflammatory breast cancer in this setting, but a negative skin biopsy does not exclude the diagnosis. The workup of a newly diagnosed inflammatory breast cancer should include CT of the chest, abdomen, and pelvis along with a bone scan and/or PET scan. For women with non-metastatic inflammatory breast cancer, neoadjuvant chemotherapy is recommended followed by a modified radical mastectomy with axillary lymph node dissection. Because postmastectomy radiation is indicated, women who desire reconstruction should consider reconstruction in a delayed fashion.

LOCALLY ADVANCED BREAST CANCER

Women with locally advanced breast cancer include a subset of women with invasive breast cancer in whom clinical staging confines disease to the breast and regional lymph nodes (stage III). These patients have an increased risk of local recurrence and distant metastases, and thus are preferred to receive neoadjuvant chemotherapy. Women with stage IIIA locally advanced breast cancer who are eligible for primary surgery should receive postsurgical systemic treatment similar to that received by patients with stage II disease. Otherwise, among those for whom an initial surgical approach is unlikely to remove all disease or achieve long-term disease control, neoadjuvant chemotherapy is used to downstage the breast as well as the axilla. A woman’s tumor response to neoadjuvant chemotherapy also provides foresight of escalation/de-escalation strategies if treatment is required in the adjuvant setting. Standard therapy for women in inoperable, noninflammatory, locally advanced breast cancer is anthracycline-based chemotherapy with or without taxanes. Women with HER2-positive tumors should include trastuzumab with possible use of pertuzumab in the chemotherapy regimen.

Repeating imaging with mammography, ultrasound, and breast MRI following neoadjuvant therapy can assess response to treatment and determine eligibility for certain surgical options. MRI is typically the most sensitive imaging modality for evaluating response to neoadjuvant therapy. All women should undergo surgery following their course of neoadjuvant chemotherapy, whether there was a complete clinical and/or radiologic response or if there was evidence of disease progression. The choice between lumpectomy or mastectomy should follow the same criteria used for the treatment of early-stage breast cancer.

Management of the axilla following neoadjuvant therapy is dependent on the nodal status at diagnosis and the response to treatment in the axilla ( Fig. 3 ). Studies show equivalent sentinel lymph node identification and false-negative rates compared with those seen with initial sentinel lymph node surgery and a low risk of nodal recurrence after a negative sentinel lymph node biopsy result; therefore, patients who are clinically node negative before and during neoadjuvant treatment should undergo sentinel lymph node biopsy post-systemic treatment. As demonstrated in the SENTINA (Sentinel Neoadjuvant) trial, the false-negative rate of a repeat sentinel lymph node biopsy (e.g., a sentinel lymph node biopsy performed before neoadjuvant therapy and then repeated again after neoadjuvant therapy) is unacceptably high. Thus, the preferred approach is to perform a sentinel lymph node biopsy following neoadjuvant therapy in patients who are clinically node negative at diagnosis.

For patients who present with clinically positive axillary lymph nodes at diagnosis (either identified by physical examination or axillary ultrasound), an image-guided tissue biopsy either by fine-needle aspiration or core needle biopsy is indicated. Marking of the biopsy-proven involved node with either a radiopaque clip or other marker is favored, as it enables identification of the metastatic node following neoadjuvant chemotherapy. Following neoadjuvant therapy, the axilla should be reassessed for treatment response. If the axilla has converted from clinical N1 to posttreatment clinical node-negative (ypcN0), then a sentinel lymph node biopsy may be appropriate in select patients. The surgical technique used during the sentinel lymph node biopsy procedure is also critical to minimize the false-negative rate to an acceptable level. As demonstrated by the ACOSOG Z1071 and SENTINA trials, using dual tracer (isosulfan blue dye and technetium sulfur colloid radiotracer), attempting to remove at least three sentinel lymph nodes, and successfully retrieving the previously biopsied clipped lymph node all contribute to a lower false-negative rate. The clipped lymph node is not one of the sentinel lymph nodes in 9% to 24% of cases. The term targeted axillary dissection has been coined to refer to retrieval of the clipped lymph node in addition to the sentinel lymph nodes. Techniques to aid in successful retrieval of the clipped lymph node include use of intraoperative ultrasound to identify a sonographically visible biopsy clip, preoperative wire or radioactive seed localization of the clipped lymph node, and injection of tattoo ink into the clipped lymph node to assist in intraoperative visualization. The breast and nodal specimens are pathologically examined to determine neoadjuvant treatment effect by assessing the presence and extent of residual disease. Achieving pathologic complete response (pCR) of the breast and axilla (ypT0 and ypN0) is associated with improved survival in triple-negative and HER2-positive breast cancers.

In the event of persistently clinically positive nodes (ypN+) or evidence of extensive nodal involvement (cN2 or cN3) before treatment, an axillary lymph node dissection is recommended. The possibility of omitting axillary lymph node dissection in women with residual nodal disease after neoadjuvant chemotherapy awaits results from the ALLIANCE A011202 trial that randomizes patients to axillary lymph node dissection or axillary radiation alone in patients with a positive sentinel node.

BREAST CANCER STAGING: AMERICAN JOINT COMMITTEE ON CANCER

The tumor, node, metastasis (TNM) staging system for breast cancer is an internationally accepted system used to assess disease prognosis and guide management. The eighth edition of the American Joint Committee on Cancer (AJCC) staging guidelines, released in late 2017, is the most recent system approved. Prognosis can vary widely for cancers with the same T and N status; thus, the latest staging system incorporated underlying tumor biology to improve the prognostic value. The staging groups in the AJCC staging system are now divided into anatomic and prognostic staging groups. The anatomic staging groups are based purely on TNM criteria and are used when biomarker information is unavailable. The standard anatomic TNM staging system classified tumors based on the size of the tumor (T), the number of lymph nodes involved (N), and the presence or absence of distant metastatic disease (M). Women are staged clinically, using physical examination with or without imaging and data from biopsy results, and pathologically, incorporating all information from clinical stage and surgical resection. The TNM status combination defines the anatomic stage of the tumor (stages I–IV).

The prognostic staging groups are based on TNM criteria and biomarker information, including the grade of the tumor and the estrogen receptor, progesterone receptor, and HER2 receptor status. The Oncotype DX Breast Recurrence Score (Exact Sciences, Redwood City, CA), if applicable, is also included. Oncotype DX is currently the only multigene panel included in the staging system, but others may be added in the future. The assigned stage based on clinical/pathologic prognostic staging groups reflects the biology of the tumor and expected prognosis based on treatment with appropriate therapies.

ADJUVANT THERAPY

Adjuvant therapy can be provided in the form of systemic therapy and/or radiotherapy. Systemic therapy, which encompasses antihormonal therapy, chemotherapy, and biologic agents, has been associated with significant reductions in locoregional and distant recurrence risk. In women with estrogen receptor–positive tumors, antihormonal therapy with an aromatase inhibitor or selective estrogen receptor modulator for 5 to 10 years is standard treatment. Some estrogen receptor–positive tumors are higher risk than others and may benefit from adjuvant chemotherapy in addition. High-risk features include a high tumor grade, large tumor size, pathologically involved nodes, low expression of estrogen receptor and/or progesterone receptor, and presence of lymphovascular invasion. Multigene assays (i.e., Oncotype DX) can also be used to stratify patients with estrogen receptor–positive, HER2-negative disease at high risk for whom chemotherapy is beneficial. The RxPONDER trial found that postmenopausal women with early-stage estrogen receptor–positive, HER2-negative breast cancer and one to three positive nodes derive no invasive disease–free survival benefit with the addition of chemotherapy to adjuvant endocrine therapy if the Oncotype DX Recurrence Score was ≤ 25, allowing for the safe omission of adjuvant chemotherapy. In most patients with triple-negative breast cancers, chemotherapy is the mainstay of treatment. Anti-HER2 therapies with trastuzumab and the possible addition of pertuzumab have dramatically improved outcomes in women with HER2-positive tumors, and are recommended for early-stage and advanced breast cancers.

Radiation therapy can be delivered to a portion or to the whole breast postlumpectomy, the chest wall postmastectomy, and/or the regional lymph nodes, including the axillary and supraclavicular nodes. Whole-breast radiation therapy following lumpectomy reduces the risk of recurrence, with a subsequent reduction in mortality rates after 15 years of follow-up in women with both positive and negative axillary nodes. Postmastectomy radiation therapy provides a long-term survival benefit for women with node-positive disease, regardless of the number of nodes involved. Deescalation of radiotherapy has been of more interest recently, given the reductions in local recurrence rate that have been noted. Rather than conventional radiotherapy, radiation to an anatomically defined, volume-based target (partial-breast irradiation) is an option in women with low-risk breast cancer. Outcomes of partial breast irradiation are equal to whole-breast radiotherapy so long as the patients selected for this treatment are at low risk and an adequate tumoricidal dose is delivered to the target volume. Potential candidates for partial-breast irradiation include women ≥ 50 years of age with small (<2 cm), node-negative breast cancers that have been excised with negative surgical margins, and it should be cautioned in those with multicentric disease, lymphovascular invasion, extensive intraductal component, or close margins (<2 mm).

SURGERY FOR STAGE IV BREAST CANCER

For patients who present with stage IV breast cancer, a prompt referral to medical oncology to discuss systemic therapy is indicated. Primary tumor resection may or may not be performed, depending on the extent of metastatic disease and the response to systemic therapy. Recent randomized trials have not shown a consistent and clear benefit with surgery, and surgery’s impact on survival remains controversial. In general, surgery to address the breast primary site is reserved for patients with stable oligometastatic disease and a reduction in breast tumor size in response to chemotherapy; locoregional lymph node surgery may be contemplated in the setting of a multidisciplinary discussion with surgery, medical oncology, and radiation oncology. For patients with widespread metastatic disease and/or a poor response to systemic therapy, surgery is considered for palliative purposes.

CONCLUSION

Surgery is a key facet in the multidisciplinary treatment of patients diagnosed with breast cancer. Over time, the integration of surgical techniques with advances in radiation and systemic therapies has allowed for less-invasive surgical procedures. This has resulted in decreased surgical morbidity for patients without a detrimental effect on outcomes and survival.

EPIDEMIOLOGY OF BREAST CANCER IN PREGNANCY

Breast cancer is one of the most common cancers in pregnant and nonpregnant women. Gestational or pregnancy-associated breast cancer is defined as breast cancer that is diagnosed during pregnancy, in the first postpartum year, or any time during lactation.

Unfortunately, in recent years, we are faced with increasing numbers of pregnancy-associated breast cancers caused by both the decreasing age of breast cancer diagnosis and the globally increasing age of childbearing. The diagnosis and management of malignancy in the prenatal and postnatal settings is associated with several challenges.

Currently in the United States, 1 in 1000 pregnancies are complicated by breast cancer. Worldwide, there are 10,000 cases of breast cancer in pregnancy diagnosed per year. The incidence rate has been reported to range from 17.5 to 39.9 per 100,000 births, but the rate is substantially lower during pregnancy (ranging from 3.0 to 7.7) than during the postpartum period (ranging from 13.8 to 32.2).

Pregnancy has direct effects on the metabolism, gene expression profile, and proliferation of the mammary epithelial cells in response to hormones. These alterations can significantly affect a woman’s risk of developing breast cancer. Women who become pregnant before 20 years of age have a 50% reduced risk of developing breast cancer compared with nulliparous women. This protective effect is extended to subsequent pregnancies, with a 10% reduction in risk for subsequent pregnancies. This protective effect is not present for women whose first pregnancy is between 30 and 34 years of age, and the risk of developing breast cancer is actually increased for those whose first pregnancy is after 35 years of age. The overall risk of developing breast cancer increases immediately after giving birth independent of race, age, or number of pregnancies. Interestingly, studies have shown a 2.8-fold increase in metastasis and a 2.7-fold increase in mortality in breast cancer patients diagnosed with breast cancer at age less than or equal to 40 years, within 5 years postpartum. Breast cancer in pregnancy tends to be more advanced at diagnosis, but when matched for tumor characteristics and stage, outcomes are similar to nonpregnant patients.

Studies have demonstrated that disease-free survival (DFS) and overall survival (OS) were the same when comparing breast cancer in pregnant patients versus nonpregnant patients when they receive standard-of-care therapy. It is important to note that management of the pregnant breast cancer patient involves a unique set of considerations that are important for surgeons to be familiar with in their practice as giving these patients the appropriate levels of care can ensure that their outcomes are similar to those of the general population.

PREGNANCY CHANGES TO THE BREAST

The mature breast is located on the anterior thoracic wall and lies on top of the pectoralis major muscle. When a woman undergoes puberty, this leads to changes in the breast that remain incomplete until pregnancy. The breast after puberty consists of adipose tissue and lactiferous units called lobes . These eventually drain into the lactiferous ducts and then into the lactiferous sinus to the nipple-areolar complex ( Fig. 1 ). During pregnancy, the breast undergoes both anatomic and physiologic changes to prepare for lactation. During the first trimester, the ductal system expands and branches out into the adipose tissue in response to the increase of estrogen and progesterone produced by the corpus luteum, which occurs during the second week of pregnancy. At about 8 weeks after fertilization, trophoblasts, the cells that eventually become the placenta, produce the human chorionic gonadotropin (hCG) hormone. HCG works to prevent degradation of the corpus luteum and stimulate the corpus luteum to continue the production of progesterone and estrogen. HCG peaks and then declines at 9 weeks ( Fig. 2 ). Elevated levels of estrogen cause an involution of adipose tissue as well as ductal proliferation and elongation, and progesterone stimulates the development of lobules. Mononuclear inflammatory cells also infiltrate the breast tissue. During this time, estrogen stimulates the pituitary gland producing elevated levels of prolactin. By the 20th week of gestation, the proliferative process is most pronounced and the mammary glands are sufficiently developed to produce components of milk as a result of prolactin stimulation. Lobule growth continues during the second and third trimesters via cellular proliferation and increased cell size. Myoepithelial cells become flattened and less prominent, whereas epithelial cells are enlarged. During the second trimester, secretory substances accumulate in the epithelial cells of lobule acini, and during the third trimester, increased levels of prolactin promote alveolar cell differentiation and initiate lactogenesis. Milk production is inhibited by high estrogen and progesterone levels, and colostrum is produced during this time. In the third trimester, and then rapidly after birth, these levels decrease, allowing for milk production and eventual let-down to allow for breastfeeding. Most pregnancies cause the areola to darken, the breast to increase in size, and the areolar glands to become more prominent. Postlactational involution occurs at the cessation of milk production caused by a decline in prolactin. Massive apoptosis and cell death occur in the mammary gland, and the tissue in the breast is remodeled. The connective tissue of the lobules goes from a loose to a dense structure. Acini lose lining cells, and the basement membrane of the acini becomes thickened. Preclinical studies have shown that postpartum mammary gland involution promotes tumor growth. Using xenograft and isogenic tumor transplant models, the normal tissue microenvironment of the actively involuting mammary gland has been demonstrated to increase breast cancer tumor take and metastasis compared with the mammary microenvironment of the nulliparous or parous host, which can explain the increased incidence in the postpartum period.

PRESENTATION AND DIAGNOSTIC WORKUP

Breast cancer diagnosis and staging are more difficult in the pregnant patient because of the physiologic changes in the breast. Physical examination may be more challenging as some masses detected on examination are physiologic and unique to this time, including galactoceles, lactating adenomas, or infarctions. Further on examination, the patient may have findings of bilateral edema and erythema in dependent portions of the engorged breast as well as swelling in the axilla if there is axillary breast tissue. Nipple discharge bilaterally is physiologic, and bloody nipple discharge bilaterally can occur in up to 15% of nursing mothers.

When obtaining imaging studies, limiting radiation exposure to the fetus is of utmost importance. Breast cancer in pregnancy most commonly presents as a painless mass. Ultrasound is the first imaging modality used to assess these patients. Breast ultrasonography can determine whether a breast mass is a simple or complex cyst or a solid tumor without the risk of fetal radiation exposure and may be used to guide the diagnostic biopsy. During pregnancy, duct ectasia is frequent, and breasts are more hypoechoic on ultrasound imaging because of lobular hyperplasia and duct dilation. During lactation, there is diffuse hyperechogenicity, a prominent ductal system, and increased vascularity.

A bilateral mammogram with abdominal shielding is recommended and may help determine the extent of disease, especially by visualizing calcification, which would normally not be seen with ultrasound. Mammogram is also useful for evaluating the contralateral breast. The ionizing radiation to the fetus from the mammogram is <0.03 µGy, which is significantly lower than the threshold of acceptable fetal exposure of <50,000 µGy, and therefore is considered safe in pregnancy with shielding. Abdominal shielding is recommended, although there are no data regarding fetal outcomes when mammography has been performed with or without shielding. Mammographic sensitivity is altered by the increased water content, higher density, and loss of contrasting fat in the pregnant or lactating breast. Nevertheless, data suggest that mammography is sufficiently sensitive to diagnose breast cancer during pregnancy and lactation. It is recommended to perform mammography immediately after breastfeeding as breast density will be lower. Figure 3 shows the mammogram and sonogram of a 10-week-pregnant patient with inflammatory breast cancer. Multifocal lesions are noted in the left breast, but a hyperechoic background is also notable bilaterally.

Magnetic resonance imaging (MRI) with contrast is contraindicated throughout the entire pregnancy as gadolinium is considered teratogenic. MRI without contrast can be considered but is unlikely to be helpful as MRI is a dynamic study assessing uptake and release of gadolinium over short time intervals.

Gadolinium-enhanced breast MRI may be considered in women who are postpartum and lactating at the time of diagnosis if the mammogram and/or ultrasound images are equivocal.

The American College of Radiology guidelines do not require that patients discontinue breastfeeding. MRI may be difficult to interpret in the lactating state because the increased enhancement from physiologic hypervascularity increases the background enhancement, where diffuse high-signal intensity on T2-weighted images can decrease efficacy. Prudence must be exercised in this setting to avoid unnecessary interventions to the lactating breast.

HISTOLOGY OF BREAST CANCER IN PREGNANCY

There are no obvious differences in histologic types of breast cancer among those associated and not associated with pregnancy. Invasive ductal carcinoma, not otherwise specified (NOS) is the most prevalent type of tumor in pregnancy; representing 78% to 88% of cases. Invasive lobular carcinoma is reported with a very low frequency in some studies. Mucinous, medullary, and other types of carcinoma are also reported. Ductal carcinoma in pregnancy has a higher histologic grade, a more aggressive profile, and a more advanced stage at diagnosis: a larger tumor size, a higher frequency of nodal involvement, less frequent expression of estrogen receptors (ERs) and progesterone receptors (PRs), and a higher proportion of inflammatory breast cancer.

TREATMENT: BREAST CANCER IN PREGNANCY

There are still certain cultures and countries that recommend abortion when a woman is diagnosed with breast cancer during her pregnancy. Termination of pregnancy does not improve maternal prognosis or outcome. The conversation with these patients should focus on balancing the risks to the fetus from the cancer treatment with the risks to the mother from the cancer, which leads to alterations to standard treatment options and sequences that have not been shown to change the prognosis of these women.

The treatment of their cancer should adhere as much as possible to standard treatments for breast cancer in the nonpregnant patient. Surgery and chemotherapy are possible and safe during pregnancy and should be tailored based on anatomic stage, tumor biology, and the gestational age of the fetus to guide choices of treatment and sequence of treatment.

Managing the pregnant breast cancer patient should involve a multidisciplinary team including the breast surgeon, medical oncologist, radiation oncologist, radiologist, maternal fetal medicine specialist, anesthesiologist, obstetrician, neonatologist, and genetic counselor.

Genetic testing is indicated when a pregnant patient is diagnosed with breast cancer. Special surveillance tests, chemoprevention, and risk-reducing surgery would not be recommended for pregnant women found to carry pathogenic variants. These interventions can be considered postpartum. The probability of detecting a pathogenic BRCA variant in a young patient with a triple-negative breast cancer is approximately 20%.

SURGICAL CONSIDERATIONS

Surgery may be performed at any time during pregnancy in all trimesters, but the safest time to operate on a pregnant patient is in the second trimester (weeks 12–24). General anesthetics all cross the placenta but have not been reported to increase the risk of congenital anomalies. Spontaneous abortion has been reported in women undergoing surgery in the first and early second trimesters of pregnancy. Key tenets for a successful operation are avoiding maternal hypoxia or hypotension. The goal should be to maintain the mean arterial pressure (MAP) at 60 mm Hg, as this is the optimal MAP for uterine perfusion during surgery.

After 20 weeks’ gestational age, the position of the patient should be in the left lateral tilt position for uterine displacement off the inferior vena cava. After 24 weeks, which is when the fetus is considered viable, intraoperative fetal monitoring is necessary. Maternal fetal medicine specialists should also be available and the neonatologist on standby should the patient start to labor during the operation. Figure 4 shows a pregnant patient positioned in the operating room with fetal monitoring after undergoing a mastectomy.

Mastectomy versus Breast Conservation

In the past, mastectomy was considered the standard surgical procedure for the local management of all pregnant patients with breast cancer. However, mastectomy is not mandatory at all stages of pregnancy. Breast conservation and mastectomy are options for these patients depending on the gestational age at diagnosis. Mastectomy can be performed in all trimesters. When considering breast-conserving surgery, timing for radiation therapy must be considered as radiation cannot be given during pregnancy. Therefore, mastectomy is the standard for local control in the first trimester. Suitability for breast-conserving surgery in the second and third trimesters is determined in the same way as for nonpregnant patients and considers tumor size, tumor location, and tumor–to–breast size ratio as well as adjuvant therapy.

Breast-conserving surgery is not recommended in the first trimester or early second trimester as this would cause a significant delay in the receipt of radiation and increase the risk of local recurrence. Breast conservation is an option in the second trimester if followed by adjuvant chemotherapy during the remainder of the pregnancy and then radiation therapy soon after delivery. In the third trimester, breast-conserving surgery can be performed and followed with postpartum radiation. Further, breast conservation can be performed preceding neoadjuvant chemotherapy, which would start during week 14. The patient can then receive adjuvant chemotherapy until the end of the pregnancy and postpartum radiation thereafter. This decision should be made in the context of a multidisciplinary team discussion. Figure 5 outlines the breast and axillary surgeries allowable by trimester of pregnancy.

CHEMOTHERAPY IN PREGNANCY

The decision to administer chemotherapy to the pregnant breast cancer patient should follow the same guidelines as in nonpregnant patients, taking into account the gestational age and the overall treatment plan such as the timing of surgery and the need for radiotherapy. Chemotherapy can be administered in the adjuvant or neoadjuvant setting and should be administered after the first trimester. Chemotherapy is contraindicated in the first trimester because of the risk of fetal teratogenesis during weeks 4 to 12 but can be started as early as week 14. Chemotherapy has been shown to be safe in the second and third trimesters. Fluorouracil, cyclophosphamide, doxorubicin, and taxanes are all safe in pregnancy. Clinicians can use standard regimens used for nonpregnant patients. One of the most common regimens is doxorubicin-based (doxorubicin plus cyclophosphamide or doxorubicin plus cyclophosphamide and taxanes [paclitaxel weekly to every 3 weeks or docetaxel every 3 weeks]. There are other regimens described such as fluorouracil, epirubicin, and cyclophosphamide. Some investigators recommend weekly epirubicin treatment on the basis of fetal safety data, but this is not the standard treatment for breast cancer, and clinicians should not put maternal prognosis at risk to limit or reduce unproven fetal damage. The main advantage of weekly regimens during pregnancy is shorter nadir periods that might reduce the risk of complications when unexpected delivery occurs. Dose-dense regimens of doxorubicin with cyclophosphamide and taxane result in improved DFS and OS in hormone receptor–negative nonpregnant breast cancer patients. Hormone receptor–negative disease is more common in pregnancy, but the data on dose-dense chemotherapeutic regimens during pregnancy are scarce. Small studies have shown that there is no increased risk of maternal or fetal complications with the use of dose-dense regimens.

In regard to supporting the pregnant patient on chemotherapy, antiemetics (i.e., metoclopramide, ondansetron, granisetron, and prochlorperazine) are considered safe. Steroids are used before induction of chemotherapy and are safe in pregnancy, specifically methylprednisolone and hydrocortisone, which are extensively metabolized in the placenta and are therefore preferred. Further, growth factors used for white blood cells and red blood cells during chemotherapy are considered safe in pregnancy, specifically in the second and third trimesters.

Chemotherapy doses are similar to those in the nonpregnant patient and are based on body surface area and creatinine clearance. Doses should be adapted throughout the pregnancy, taking into account the weight changes. Gestational changes include an increase in heart rate and blood pressure, an increase in plasma volume and glomerular filtration rate, and hormonal changes in hepatic function. For doxorubicin, epirubicin, paclitaxel, and carboplatin, these changes result in a decrease in plasma drug exposure and peak plasma concentration. There is also an increase in distribution volume and drug clearance secondary to the physiologic changes during pregnancy. This raises doubt about the effectiveness of such regimens in this setting, but no direct relation exists between toxic tissue effects and prognosis. Further, studies have shown similar outcomes to nonpregnant women when controlling for stage and tumor characteristics and regimens received.

Chemotherapy is avoided after 35 weeks’ gestational age or within 3 weeks of planned delivery. A 3-week interval should be left between the last cycle of chemotherapy and the delivery to avoid problems associated with myelosuppression (bleeding, infection, anemia) in the mother and baby and to avoid drug accumulation in the fetus. Further, the myelosuppression (i.e., pancytopenia, neutropenia) caused by the chemotherapeutic agents may increase the risk of sepsis complications at delivery. The placenta of these patients should be sent for evaluation as there are reports of placental metastasis, but none of fetal metastasis.

Treatments that are contraindicated during pregnancy are HER2-targeted therapy (risk of oligohydramnios resulting in pulmonary and renal insufficiency); methotrexate (teratogenic); tamoxifen (teratogenic causing craniofacial malformations, ambiguous genitalia, and fetal death); bisphosphonates (category C risk of maternal toxicity, fetal underdevelopment, embryolethality, hypocalcemia, and skeletal retardation); and radiation therapy.

If neoadjuvant chemotherapy is to be administered during pregnancy, the regimen is started at 14 weeks’ gestation and is continued for a standard cycle as tolerated. At this point, the patient can decide between mastectomy or breast conservation, which is followed by postpartum radiation therapy.

Further, there have been several cases reporting radiation administered for breast cancer in pregnancy with low fetal doses and resulting in the delivery of healthy babies. Therefore, radiation might be considered in the first or early second trimester if the risk of delay or omission is believed to outweigh that of harming the fetus, but this is not the standard and should be discussed with the multidisciplinary team.

PEDIATRIC OUTCOMES AFTER MATERNAL CANCER DIAGNOSIS

The rate of congenital abnormalities in children exposed to chemotherapy is 3%, which is similar to the national average. Overall, the outcomes of the babies born to women with breast cancer during their pregnancy are favorable and comparable to those of women without breast cancer. But it is important to note that pregnant patients have a higher rate of preterm delivery (61.2% compared with 8% in the general population). Women treated for breast cancer during pregnancy also tend to have children of lower birth weight, but this normalizes over time. There have been no long-term health problems or cognitive developmental issues in children born to mothers that had breast cancer treatment during their pregnancy. If oncologically safe, the patient should be encouraged to carry the pregnancy to as close to term as possible.

KEY POINTS

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  Ultrasound is the first-line imaging modality used.

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  Surgery can safely be performed at any time during the pregnancy.

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  The recommended method of sentinel node localization is with technetium-99 (99m-Tc sulfur colloid) alone.

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  Radiation, trastuzumab, and tamoxifen are contraindicated and given only in the postpartum period.

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  Chemotherapy is contraindicated in the first trimester. Anthracycline-based chemotherapy can be safely given in the second and third trimesters and should be stopped 3 to 4 weeks before delivery.

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  Dosing of chemotherapy should be similar to that in the nonpregnant patient, based on body surface area.

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  Prognosis in the pregnant breast cancer patient appears to be the same as in nonpregnant patients if standard therapy is given.

RADIOFREQUENCY ABLATION

RFA is a widely used ablative technique for various solid tumors at different sites, including liver, lung, kidney, and bone. RFA uses low-frequency electromagnetic waves to generate heat and ablate these tumors. To perform RFA, a needle is inserted percutaneously within the tumor, usually with ultrasound guidance, but CT or MRI guidance may be used. A generator creates a high-frequency alternating current; in response, ions attempt to follow the changing direction, causing agitation and frictional heating. This results in destruction of the tumor tissue through thermal coagulation and protein denaturation ( Fig. 1 ).

In most studies, RFA is followed by immediate or delayed surgical excision of the tumor. Izzo et al. performed one of the first feasibility studies that included 26 breast cancer patients with a mean tumor size of 1.8 cm (range, 0.7–3.0 cm). Complete tumor ablation was obtained in 96% (25 of 26) of the patients. Since then, multiple RFA studies have been performed with success rates varying from 77% to 100%. Only a few studies performed RFA without surgical excision. Oura et al. included 52 patients with a tumor size of 2 cm or less who underwent RFA alone. MRI after 1 to 3 months showed no evidence of residual disease. After a follow-up of 15 months, none of the patients developed locoregional or distant recurrences. Cosmetic outcome was reported excellent in 83%, good in 11%, and fair in 6% of the patients.

Excision RFA (eRFA) consists of surgical excision of the tumor followed by RFA. The aim is to decrease the rate of reexcisions after breast-conserving surgery, to improve locoregional recurrence rates by extending the margins, and ablating possible residual disease. Klimberg et al. performed a study in 100 patients undergoing breast-conserving surgery followed by eRFA in which biopsy showed at least 1 cm circumferential ablation around the resection cavity. Of these 100 patients, 78 had negative margins (>2 mm) and 22 had margins 2 mm or less, of which 3 were focally positive. Recurrence after 5 years of follow-up was seen in 3% of the patients treated with systemic hormonal therapy and in 10% without systemic hormonal therapy. Recently, results of the multicenter Radiofrequency Ablation After Breast Lumpectomy study were presented. A total of 267 T0 to T2 breast cancer patients treated with breast-conserving surgery followed by eRFA were included. Results showed a reexcision rate for positive margins of <5%. The rate of breast recurrence was 2.5% after 3 years of follow-up.

RFA appears to be limited to tumors with a maximum size of 2 cm. RFA treatment is not suitable for infiltrating lobular breast tumors, tumors with an extensive in situ component, and in patients treated with neoadjuvant systemic therapy. Complications from RFA are rare and generally mild, including skin or muscle burns and ecchymosis.

MICROWAVE ABLATION

Thermal ablation can also be performed with the use of microwaves. Microwave ablation (MWA) uses electromagnetic waves at frequencies of at least 900 mHz. Localized heat caused by water molecules moving within tissues results in tissue destruction. Tissues with high water content, such as breast tumors, are heated and damaged more rapidly compared with tissues with lower water content, such as normal breast tissue with surrounding fat, which may remain unharmed. To perform MWA, the breast must be compressed between two plates. The electric-field probe is inserted into the central portion of the tumor under ultrasound or CT guidance. A fiber-optic temperature probe is placed in the tumor to guide and adjust the temperature. Skin temperature probes are applied to the skin to monitor the temperature to avoid skin burns. A cooling system can be used to provide air cooling, decreasing the risk of thermal injury to the skin.

The first pilot study of MWA was performed by Gardner et al. to assess the feasibility and safety of this technique. MWA was performed in 10 breast cancer patients with a mean tumor size of 4.3 cm (range, 1.0–8.0 cm). A reduction in tumor size was seen in 60% (6 of 10) of the patients. Dooley et al. performed a small trial that randomized patients to breast-conserving surgery followed by MWA versus breast-conserving surgery alone. This study found that patients with early breast cancer treated with breast-conserving surgery and MWA had 0% (0 of 34) positive tumor margins compared with 9.8% (4 of 41) for those with breast-conserving surgery only. More recently, Zhou et al. showed that complete tumor ablation using contrasted enhanced ultrasound was seen in 90% (37 of 41) of patients treated with MWA.

CRYOABLATION

Cryoablation is the only ablative technique using cold instead of heat to create tissue necrosis. It is accomplished percutaneously guided by ultrasound, MRI, or CT. Cryoablation involves two phases: freezing and thawing. Liquid nitrogen is inserted into the probe and results in a local freezing reaction; thereafter, a second gas (i.e., helium) is released through the probe to arrest the freezing process, allowing thawing to occur ( Fig. 2A ). Tumor cells are destroyed through direct intracellular and indirect vasculature injury. Intracellular ice formation results in shearing and irreversible rupture of cell membranes. Extracellular formation occurs, creating a hypertonic environment. Water flows out of the cells resulting from osmosis, causing cellular dehydration and damage. When thawing occurs, water flows back into the cell, increasing intracellular volume and lysis occurs. Freezing and thawing is repeated. After at least two freeze-thaw cycles, an ice ball is created, which can be visualized with imaging. The tumor-ice ball remains in situ and is reabsorbed by the body ( Fig. 2B ).

Several studies have investigated the efficacy of cryotherapy in the treatment of fibroadenomas. The prospective Fibroadenoma Cryoablation Treatment Registry included 444 patients with fibroadenomas treated with cryotherapy. Two freeze-thaw cycles were used with a temperature of −160°C for the treatment of lesions with a median size of 1.8 cm. A reduction in size of 51% was seen after a follow-up of 6 months. Furthermore, palpability of the fibroadenomas reduced from 75% at pretreatment to 46% after 6 months and 35% after 12 months of follow-up. Recently, the role of cryoablation in the treatment for malignant breast tumors has been evaluated. The systematic review of Lanza et al. showed complete tumor ablation in 73% of included patients after a mean follow-up of 8 months. Cosmetic satisfaction was reached in 99% of the patients. In 2016, the American College of Surgeons Oncology Group undertook Z1072, a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers, and published their results. Patients with a malignant tumor size less than 2 cm with less than 5% intraductal component were included. There was a complete tumor ablation in 76% (66/87) of patients. If multifocal tumors were excluded, the success rate increased up to 92% (80/87). The Freezing Instead of Resection of Small Breast Tumors trial is currently recruiting women with early-stage invasive breast cancer to investigate whether cryoablation can achieve complete tumor ablation and adequate local control without surgical excision.

Criteria for cryoablation include tumor size smaller than 2 cm, location at least 1 cm from the skin surface, and lack of an extensive in situ component (<25% of carcinoma in situ). Advantages of cryoablation are patients’ comfort and treatment of larger lesions with sparing of normal breast tissue. Disadvantages are potential risk of thermal injury to the skin, losing staging information (e.g., tumor size and margin status), and timing of the sentinel lymph node biopsy.

HIGH-INTENSITY FOCUSED ULTRASOUND

HIFU is a complete noninvasive thermal-based ablative technique using transcutaneously focused ultrasonic waves ( Fig. 3 ). The focused ultrasound waves cause rapid (1–2 seconds) temperature elevation within the targeted tissue up to 50°C to 95°C. This causes melting of the lipid bilayer of the cellular membrane and protein denaturation, leading to tissue necrosis, whereas tissues outside the targeted area are spared. Because of the small (0.8 × 0.2 × 0.2 mm ³ ) ablation zone, multiple overlapping sonifications are required to treat an entire lesion. Complete ablation can take up to 2 to 3 hours.

Peek et al. published a systematic review, including 9 HIFU studies and 167 breast cancer patients. No residual tumor after HIFU treatment was found in 46.2% (55 of 119) of the patients. The most reported complication was pain (40.1%), followed by edema (16.8%), skin burn (4.2%), and pectoralis major injury (3.6%). Symptomatic palpable fibroadenoma patients were included in a separate HIFU-fibroadenoma trial. Twenty of the included patients were treated with HIFU, whereas the other 20 underwent an ultrasound after 6 months (control group). Primary outcome was reduction in treatment time; secondary outcomes were reduction in volume on ultrasound after 12 months and the complication rate. Treatment time was reduced with 29.4% in circumferential ablation compared with whole lesion ablation. Reduction in volume was reported in 43.2% of the patients after 12 months of follow-up.

HIFU is a completely noninvasive ablative technique. Cosmetic outcome is very good because there is no scarring at skin entry site. Disadvantages are patient discomfort, general or spinal anesthesia, and prolonged treatment times.

INTERSTITIAL LASER

Laser interstitial thermotherapy (LITT) is a hyperthermic ablative technique. Laser fibers are percutaneously inserted into the tumor, whereas a second probe is placed to measure the temperature ( Fig. 4 ). A refraction of laser light is produced at the tumor, producing heat and causing coagulation necrosis and protein denaturation, resulting in irreversible tissue destruction. The level of necrosis depends on the temperature and ablation time. Three types of lasers are available: carbon-dioxide, argon, and neodymium-doped yttrium aluminum garnet laser. The two latter lasers have the benefit of being able to treat larger volumes. Only a few studies have evaluated LITT followed by surgical excision. Dowlatshahi et al. performed a study in 54 breast cancer patients and showed complete tumor ablation of 70% in tumors with a mean diameter of 12 mm (range, 5–23 mm). Incomplete tumor ablation was attributed to technical issues, such as inadequate laser energy, patient motion, malfunctioning thermal probes and fluid pump, and suboptimal target visualization. LITT under MRI guidance showed a complete ablation in 76% of the tumors ranging from 1.8 to 4.0 cm. LITT performed in patients with fibroadenomas (n = 24) showed a reduction of 60% after 6 months of follow-up.

The advantage of LITT is that it has a photocoagulation effect that reduces bleeding during the procedure. Disadvantage is that tumors larger than 2 cm or tumor with extensive in situ component are not good candidates for laser therapy.

IRREVERSIBLE ELECTROPORATION

Irreversible electroporation is a nonthermal ablative technique that uses electrical fields to create permeable cell membranes and cause cell death. Electroporation occurs when short electric pulses (1000 V/cm field) are passed across the cell membranes, resulting in membrane permeabilization. This ablative technique only affects the cell membrane while sparing the extracellular matrix and other tissues (i.e., blood vessels). Permeabilization can be reversible or irreversible, depending on the number, duration, and time between electric pulses and electric field strength. Irreversible electroporation has been investigated for a short period and much of in vivo research involves animal models only. Disadvantages of this technique are the potential occurrence of cardiac arrhythmias and general anesthesia because the electric pulses cause muscle contractions.

SUMMARY

A meta-analysis showed that complete ablation rates of ablative techniques such as RFA, MWA, cryoablation, LITT, and HIFU vary and have been highest in patients undergoing RFA (87.1%), followed by MWA (83.2%), cryoablation (74.1%), laser ablation (52.2%), and HIFU (47.6%). Other important but less investigated outcomes are recurrence and complication rates. No local recurrences have been reported using MWA (0%). Other ablative techniques have small but measurable recurrence rates: cryoablation (1.4%), HIFU (2.9%), RFA (3.1%), and laser ablation (10.7%). Complications occur in about 10% of patients. Most commonly seen were skin burns followed by pectoralis major muscle damage. MWA is associated with the highest posttreatment complication rate of 14.6%, followed by cryoablation (10.9%), RFA (10.5%), HIFU (6.5%), and laser ablation (6.3%). Excellent cosmetic outcome has been reported in patients treated with ablation. Cryoablation results in greater than 90% excellent cosmesis compared with 85.3% in patients treated with RFA and 59.3% in patients treated with HIFU. HIFU may ultimately have the best cosmetic outcome because this technique is completely noninvasive.

All ablative techniques show several benefits compared with breast-conserving surgery; however, larger multicenter randomized controlled trials are required to confirm the efficacy of ablation compared with resection. Current problems are the lack of a predictive tool for assessing complete tumor ablation, determination of accurate tumor size, information on the timing of axillary surgery, and adequate patient and tumor inclusion criteria. Ablative treatment techniques may be most suitable for patients with contraindications to operation or patients with a preference to avoid breast-conserving therapy. Furthermore, ablative treatment can only be used for small (T1) breast tumors (≤2 cm) 1 cm from the skin and pectoralis major, less than 25% carcinoma in situ component, and, most important, tumors must be visible using imaging modalities. In addition, many techniques result in a palpable mass, disturbing to patient and surgeon. Intraoperative RFA after surgical excision may become a means to avoid radiation after breast-conserving surgery for patients with favorable tumors.