Systemic Treatment

Systemic therapy refers to the medical treatment of breast cancer using endocrine therapy, chemotherapy, and/or biologic therapy prior to or following definitive local treatment. To determine the risk of recurrence and the effectiveness of systemic therapy, one must assess factors, such as age, life expectancy, comorbidities, pathologic findings in the breast and axilla, and biological behavior of the tumor. Systemic therapy may be offered based on primary tumor characteristics, such as tumor size, grade, number of involved lymph nodes, status of ER and PR receptors, and expression of HER2 receptor.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is utilized in cases of locally advanced and potentially inoperable breast cancer to render the disease amenable to resection. Clinical criteria for inoperability include inflammatory carcinoma, tumors that are fixed to the bony chest wall (e.g., ribs and sternum), extensive skin involvement with ulceration or satellite skin nodules, fixed or matted axillary lymphadenopathy, involvement of neurovascular structures of the axilla, or lymphedema of the ipsilateral arm. In these cases, systemic therapy may be administered as an initial treatment to reduce tumor burden and will subsequently improve the rate of operability to 80%. Neoadjuvant chemotherapy is also used in cases of operable tumors to downstage disease in the breast and axilla. This may facilitate breast conservation surgery (BCS), improve cosmetic outcome, and in some instances allow patients to avoid axillary lymph node dissection (ALND) and the associated morbidity with this procedure. Last, neoadjuvant therapy may be utilized in women who may have a temporary contraindication to surgery such as women diagnosed with breast cancer during pregnancy.

Chemotherapy remains the standard neoadjuvant approach in most patients, including those with hormone receptor-positive disease; however, endocrine therapy may be used in a certain subset of these patients. For patients with HER2-positive breast cancer, a HER2-directed agent (i.e., trastuzumab with or without pertuzumab) is typically administered in addition to the chemotherapy regimen. For patients with hormone receptor-negative and HER2-negative disease, neoadjuvant therapy consists of chemotherapy alone. Overall, in selected patients, neoadjuvant therapy reduces the rate of axillary lymph node metastases, increases the rate of breast conservation, and has comparable long-term disease-free survival and overall survival compared to patients undergoing primary surgery followed by adjuvant systemic therapy. ^,

Adjuvant Chemotherapy

Generally, adjuvant chemotherapy is indicated for patients with triple-negative breast cancer and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size). Common regimens utilized for HER2-negative disease include anthracycline-based regimens such as doxorubicin and cyclophosphamide. These are typically administered for four cycles of dose-dense treatment (every 2 weeks) followed by paclitaxel administered either weekly for 12 weeks or every 2 weeks for four cycles. With the use of an anthracycline-containing regimen compared with no treatment, there is a reduction in the risk of recurrence from 47% to 39%. Furthermore, breast cancer mortality also decreases from 36% to 29% and overall mortality from 40% to 35%, respectively.

Meta-analyses have demonstrated the benefits of adjuvant chemotherapy in reducing recurrence and breast cancer mortality. There is a greater magnitude of benefit in those with HR-negative disease (21%–25% relative risk reduction) compared to those with HR-positive disease (8%–12%). ^, For patients with HR-positive and node-negative breast cancer, Oncotype DX provides an estimate of chemotherapy benefit. Patients with high Oncotype recurrence scores (≥31) have a large reduction in risk of recurrence with chemotherapy, while those with low scores derive minimal if any benefit from chemotherapy. Chemotherapy for patients in this group may consist of either anthracycline-containing or anthracycline-sparing regimens. In patients with low Oncotype recurrence scores, endocrine therapy alone is sufficient, as these patients have a favorable outcome with a 5-year overall survival of 98% with endocrine therapy alone.

HER2-Directed Therapy

Approximately 20% of patients with early breast cancer have tumors that exhibit overexpression, amplification, or a combination of these characteristics of the HER2 receptor or oncogene. Adjuvant HER2-targeted therapy (trastuzumab and/or pertuzumab) is now the standard of care for these patients. Several large trials have demonstrated that a year of adjuvant trastuzumab after chemotherapy reduces recurrence (about 50%) and increases 10-year disease-free survival (9%) in patients with this type of early breast cancer.

Endocrine Therapy

Hormone receptor-positive breast cancer represents the vast majority of breast cancers around the world; approximately 60%–75% of women with invasive breast cancer are ER-positive and 65% are PR-positive. Endocrine therapy is recommended for most patients with hormone-positive disease. Patients may be treated with endocrine therapy for 5–10 years and possibly longer, as a longer duration of therapy may confer additional benefits. If women are pre- or perimenopausal or if menopausal status is unknown, they should be offered tamoxifen for a total duration of 10 years. Aromatase inhibitors (anastrozole, letrozole, and exemestane) are used in postmenopausal women but may also be prescribed sequentially with tamoxifen. Adjuvant tamoxifen reduces the risk of recurrence by nearly 50% during years 0–4 with continued risk reduction of over 30% in years 5–9. ^, Furthermore, after 5 years of tamoxifen treatment, an additional 5 years of aromatase inhibitors provides an additional 40% relative risk reduction in recurrence.

Breast-conserving Therapy

Successful breast-conserving therapy (BCT) entails complete, cosmetically acceptable surgical removal of the tumor (lumpectomy with negative surgical margins defined as no ink on tumor) followed by radiotherapy (RT) to eradicate any residual disease. Among women with operable breast cancer, randomized trials have demonstrated equivalent disease-free and overall survival between mastectomy and BCT. Advances in neoadjuvant therapy, surgical and radiation therapy techniques, and pathologic assessment of the tumor have increased patient eligibility for this approach. Inability to obtain adequate surgical margins or patient intolerance of adjuvant RT may preclude BCT. Additional contraindications include inflammatory breast cancer, multicentric disease, diffuse malignant microcalcifications on mammography, prior history of chest RT, pregnancy, and connective tissue disease (i.e., scleroderma or lupus erythematosus). ^,

Radiotherapy in Breast-Conserving Therapy

In patients opting for BCT, it is important to determine preoperatively whether the patient is a candidate for adjuvant radiation. For the majority of women treated with lumpectomy, including those who have received neoadjuvant therapy with a complete response to treatment, whole-breast radiation therapy (WBRT) is recommended.

WBRT following BCT reduces the locoregional recurrence rate and risk of breast cancer death. The benefits were demonstrated in a meta-analysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women (known to be either pathologically node-negative or -positive) in 17 trials. Lumpectomy followed by WBRT resulted in a nearly 50% reduction in the 10-year risk of any first recurrence compared with lumpectomy alone and showed an absolute reduction in the 15-year risk of breast cancer death by 3.8%. The conventional dose of WBRT delivered to the entire breast is 1.8–2 Gy in daily fractions over 5 to 7 weeks for a total dose of 45–50 Gy, with a 10–14 Gy boost for most patients. A more current, patient-preferred method of delivery is hypofractionated WBRT. A greater amount of RT is delivered per dose, but the overall treatment duration is shorter, with 40–42.5 Gy administered in approximately 3–5 weeks with or without a boost. This newer approach has been associated with equivalent tumor control, has fewer toxicities, has comparable overall survival, and improved cosmetic outcomes compared to traditional WBRT.

Accelerated partial breast irradiation (APBI) refers to the use of focused RT centered around the tumor cavity. Options for the delivery of APBI include brachytherapy, intraoperative RT, or external beam radiation. Compared with WBRT, APBI delivers a higher dose of RT per day over a shorter period of time (i.e., 5 days) and potentially fewer breast symptoms and late skin side effects. This approach may be reasonable in patients >50 years of age with small (<2 cm) node-negative breast cancer. However, in preliminary trials, it is still unclear if APBI is as effective as traditional or hypofractionated WBI in terms of local control, survival, and cosmesis. ^,

Last, in a subgroup of women aged >65 years with node-negative, early stage, and hormone receptor-positive breast cancer who are treated with endocrine therapy, omission of RT may be a reasonable option depending on the preferences of the patient as the risk of in-breast recurrence is low. ^,

Mastectomy

Mastectomy is an option for breast cancer patients with contraindications to BCT, as well as prophylaxis, to reduce the risk of breast cancer in high-risk women. The rate of mastectomy has been increasing in the United States over the past decades as patients may choose to undergo mastectomy, rather than BCT. This is due to various reasons, including fear of recurrence and a desire to avoid the need for postoperative radiation or future biopsies. Mastectomy options include modified radical mastectomy, total mastectomy (simple mastectomy), skin-sparing mastectomy, and nipple-areolar- sparing mastectomy (NSM). A modified radical mastectomy involves complete removal of the breast and the underlying fascia of the pectoralis major muscle along with the removal of level I and II axillary lymph nodes. With the adoption of sentinel lymph node biopsy (SLNB) for axillary staging in patients with clinically negative axillary lymph nodes, modified radical mastectomy is performed less frequently. Total mastectomy removes most of the overlying skin and the entire breast parenchyma, with preservation of the pectoral muscles and axillary contents. Total mastectomy is generally performed when the patient does not undergo immediate reconstruction.

For skin-sparing mastectomy, the majority of the natural breast skin envelope is preserved, which facilitates immediate reconstructive procedures such as preservation of the skin, and the inframammary fold provides the reconstructed breast with a more natural shape and contour. Multiple studies have demonstrated this procedure to be oncologically safe with comparable local recurrence rates to total mastectomy ranging from 0% to 7%. NSM preserves the nipple-areolar complex and skin envelope but removes the major ducts from within the nipple lumen. This approach was initially used as an option for patients having prophylactic mastectomy with immediate reconstruction; however, this approach is increasingly used in the therapeutic setting as well. There are no randomized trials comparing NSM to other mastectomy techniques, and long-term follow up in clinical series is limited, reporting local recurrence rates of 2%–5%, with a median follow up ranging from 2 to 5 years. As such, patients undergoing therapeutic mastectomy should be carefully selected for a nipple-sparing procedure. Indications for NSM in patients with invasive carcinoma vary by institution. At a large, tertiary, designated cancer institute, the current criteria include patients with tumors <3 cm and at a distance of at least 1 cm from the nipple with no extensive calcifications.

Role of Postmastectomy Radiotherapy

Postmastectomy radiotherapy (PMRT) has been shown to decrease rates of locoregional recurrence and increase long-term breast cancer-specific and overall survival for certain patient populations. ^, Indications for PMRT include patients with four or more involved lymph nodes and a tumor greater than 5 cm. PMRT in women with between one and three positive lymph nodes and T1-2 breast cancers is an area of ongoing debate. ^, In this subset of patients, the decision to administer PMRT should be approached in a multidisciplinary setting.

Axillary Staging

The status of the axillary lymph nodes is one of the most important prognostic factors as it is usually the initial site of metastasis. Preoperative evaluation of axillary lymph nodes separates patients into two categories: patients with clinically positive nodes and patients with clinically negative nodes. SLNB has replaced ALND as the initial assessment of axillary lymph nodes in patients with clinically negative axillary lymph nodes. ^, ALND is indicated for most patients with clinically positive ipsilateral axillary lymph nodes either by fine needle aspirate or SLNB. Based on the pathologic results obtained by SLNB, no further axillary treatment is indicated for patients who meet all of the following criteria: clinically negative nodes based on clinical evaluation, T1 or T2 (≤5 cm) primary breast cancer, less than three metastatic sentinel lymph nodes (SLNs), and plan for lumpectomy procedure followed by WBRT. A completion ALND is indicated for patients who have three or more metastatic nodes on SLNB, matted nodes found intraoperatively, or those with one or two metastatic SLNs who do not desire WBRT. ^,

The next section will describe plastic surgery reconstructive approaches for breast cancer surgery.

Immediate, Single-stage Implant Reconstruction

Single-stage immediate breast reconstruction creates a definitive breast mound at the time of oncologic resection. In general, single-stage implant reconstruction is appropriate for women with small, non-ptotic breasts whose mastectomy preserves an adequate amount of skin envelope and pectoralis muscle. In this case, the implant is placed at the time of the mastectomy. A remote, removable port may be left in place to allow for the subsequent addition of volume. The port is removed at a later date, leaving the initial implant in situ as the final product. Another option for single-stage reconstruction is to incorporate an acellular dermal matrix (ADM) with an implant. ^, In this method, the ADM offers additional support and implant soft-tissue coverage to allow for appropriate healing. The disadvantages of the single-stage approach include the view that esthetic outcomes tend to be inferior compared to two-stage reconstruction, and in many cases, the need for a second, revisionary procedure. Consequently, this approach is not used for the majority of implant-based reconstruction, although it may be successful in select patients.

Immediate or Delayed Two-staged Implant Reconstruction

The most common technique for implant breast reconstruction is two-stage reconstruction. Traditionally, total submuscular coverage has been used in which a tissue expander is placed in a plane under the pectoralis muscle medially with lateral coverage with a portion of the serratus anterior muscle. Although cosmetic results have been described to be excellent, total submuscular reconstruction can be associated with significant postoperative pain, potential for breast animation deformity, lateral deviation of the breast mound, and insufficient lower pole fullness. ^, To reduce manipulation of the pectoralis muscle and associated morbidity, partial subpectoral or partial sub-ADM reconstruction was popularized. This dual-plane reconstruction is performed by release of the inferior and medial inferior insertions of the pectoralis with placement of a tissue expander under the muscle with the inferior portion of the implant supported by an ADM sling. This obviates the need for elevation of the serratus anterior, which may make subsequent expansion less painful and has been shown to have comparable cosmetic outcomes, similar safety profiles, better early fill volumes, and less postoperative pain compared with total submuscular coverage. ^,

In properly selected patients, a tissue expander may be placed in a prepectoral position. This method avoids the morbidity associated with muscle elevation and muscular distortion of the implant in the final reconstruction and has gained increasing popularity in the past decade. Furthermore, patients may experience less pain due to the avoidance of pectoral muscle disruption, there is minimal breast animation deformity with pectoral muscle contraction, and a natural breast contour can be maintained. ^, Comparative studies between prepectoral and total muscle coverage breast reconstruction have demonstrated similar complication profiles with regard to infection, superficial skin necrosis, and seroma. There is also the potential benefit of decreased rate of capsular contracture. ^, Prepectoral tissue expander potentially presents an opportunity to improve upon current reconstructive methods; however, currently available studies are retrospective in nature with limited cohort size and lack of long-term follow up in patients. As such, the associated risks have yet to be fully described, warranting a large multicenter prospective trial to provide better guidance.

Mixed Implant and Autologous Reconstruction

Many patients who are candidates for implant reconstruction have a skin-muscle envelope that is inadequate for expansion. Contributing factors include large skin resection at the time of mastectomy and/or multiple scars and radiation injury to the skin or muscle, resulting in a nonexpandable pocket. In such cases, the addition of autologous tissue (most commonly a latissimus dorsi myocutaneous flap) may be required for adequate coverage of the expander and implant. The addition of autologous tissue to implant reconstruction increases the length and complexity of the procedure, as well as the risk of potential morbidity at the donor site (i.e., on the back). Thus the combination of both reconstruction modalities is generally reserved for select patients.

Tissue Expander Expansion

The expansion process begins at approximately 2 weeks postoperatively. Saline is injected into the integrated port of the expander on a weekly or biweekly basis, depending on patient tolerance, until the expander reaches its final volume (usually after 6 to 8 weeks). The main drawbacks of skin expansion are frequent outpatient visits to gradually fill the expander, the need for an additional procedure (i.e., expander removal for permanent implant or flap), and the relatively high rate of complications, including infection, capsular contracture, and skin perforation. The exchange of the tissue expander to the final implant is then performed as an outpatient procedure and should occur no earlier than 4 to 6 weeks after the final expansion or completion of adjuvant therapy.

Types of Implants

Implant selection is based on dimensional planning and should involve the patient’s input. The patient’s skin laxity and desired shape are considered when deciding on the type of implant, as well as details of height, width, and projection. In the United States, saline-filled and silicone gel-filled breast implants with a silicone shell are predominantly used. The major difference between the implants is the fill material, and the need for subsequent monitoring for rupture. If a saline implant ruptures, the implant deflates and physical exam can diagnose the defect. Silicone implants, on the other hand, maintain their shape for the most part, should a rupture occur. Radiologic imaging, typically with MRI, is required to detect rupture. Silicone implants generally provide a more natural feel, and appearance, while saline implants tend to be firmer, provide less natural fullness in the upper portion of the breast, and are more likely to lead to visible rippling. Overall, patient satisfaction appears to be higher when silicone implants are used for reconstruction, as opposed to saline. In addition, the surface of the breast implants is either smooth or textured. Regardless of the implant chosen, the exchange usually requires capsulectomy for adequate symmetry and cosmesis.

Techniques

Over the last few decades, autologous breast reconstruction techniques have evolved to achieve acceptable morbidity and superior esthetic outcomes. The most commonly considered gold standard donor site is the abdomen. The benefits of using abdominal tissue are the availability of ample tissue to form and shape the tissues to recreate the breast and contouring the abdomen for an abdominoplasty-type effect. Current modalities include a pedicled transverse rectus abdominis myocutaneous (pTRAM) flap, free TRAM flap, deep inferior epigastric artery perforator (DIEP) flap, and superficial inferior epigastric artery (SIEA) flap.

The most common pedicled myocutaneous flap is the pTRAM flap. This flap consists of excising excess skin and soft tissue in the infraumbilical area overlying the rectus abdominis muscle together with the rectus muscle itself along with its supply of superior epigastric vessels. However, this procedure has significant disadvantages, including a high tissue-to-blood supply ratio of the flap; protracted recovery time; and abdominal wall morbidity, including weakness, bulging, and herniation. To overcome the drawbacks and associated morbidity of the pTRAM flap, further refinements led to techniques, including the muscle-sparing free TRAM flap and perforator flaps (DIEP and SIEA). The free TRAM flap technique requires a more limited harvest of the rectus abdominis muscle, safer transfer due to improved perfusion originating from the larger caudal pedicle (deep inferior epigastric artery instead of deep superior epigastric artery), and an improved medial breast contour due to the lack of tunneling of the flap’s cranial pedicle compared to pedicle TRAM flap. ^, The DIEP flap is based on perforating vessels that pass from the inferior epigastric vessels through the rectus muscle into the fat and skin. The DIEP flap has become the gold standard for autologous breast reconstruction because it maximizes the amount of tissue transfer without sacrificing the rectus muscle. Furthermore, it results in less donor site morbidity and excellent esthetic results compared to the traditional TRAM flap. Other advantages include decreased pain, quicker recovery, preservation of abdominal wall function, lower incidence of hernia, shorter hospital stay, and decreased cost.

Given that not every woman is suitable for breast reconstruction using abdominal skin and fat, several more donor sites have been recently described to harvest the most suitable microvascular flap to best personalize breast reconstruction. These flaps include the superior gluteal artery perforator flap, the inferior gluteal artery perforator flap from the gluteal region, fasciocutaneous infragluteal flap, profunda femoral artery perforator flap from the infragluteal region, and the transverse myocutaneous gracilis flap from the inner thigh region. The latissimus dorsi myocutaneous flap also remains an option for autologous breast reconstruction. It is typically not used for initial reconstruction because of the lack of appropriate volume; however, it may serve as a salvage flap or a combined prosthetic approach, as previously discussed.

Radiation Therapy

Radiation is an essential component of breast cancer treatment, but it often has a detrimental effect on reconstructive results. Women who require postmastectomy radiation therapy present a unique reconstructive challenge. Radiation therapy leads to fibrosis, which compromises the quality of the skin and underlying tissue, resulting in a higher incidence of complications from the reconstructive procedure, and ultimately may produce a less esthetically pleasing result. Patients who undergo radiation prior to reconstruction experience high rates of prosthetic device loss. Postmastectomy radiation therapy can also cause prosthetic device loss, capsular contracture, and higher rates of infection. Although autologous reconstruction may be better able to withstand radiation-induced damage, these patients still have high rates of intraoperative microvascular issues ^, and related complications including fat necrosis, flap shrinkage, and contour deformities. Revision rates, however, are unchanged.

Regarding patient-reported outcome measures (PROM), irradiated patients have lower HR-QoL outcomes compared to those who did not receive radiation. However, few differences have been elucidated between or within reconstructive modalities, with studies suggesting higher PROM in autologous patients. To date, the best method of integrating radiation therapy into any reconstruction method remains controversial. ^,

Breast Implant-associated Anaplastic Large Cell Lymphoma

BIA-ALCL is an important public health concern because the use of breast implants has increased over the past two decades in the United States and internationally. It is estimated that as of 2015, more than 3 million textured devices have been used in patients in the United States. The risk of developing BIA-ALCL appears to be associated with prolonged exposure to textured implants, with most case series documenting a median exposure time ranging from 6.4 to 15.5 years, although shorter times of 0.4–2 years have also been reported. However, a recent study estimated the current incidence at 1.79 per 1000 patients and 1.15 per 1000 implants—a higher incidence than previously thought. The US Food and Drug Administration (FDA) has recently recalled certain textured breast implants. Patients who are interested in textured implants should be counseled about these risks prior to surgery.

The FDA does not currently recommend breast implant removal for asymptomatic women who already have this type of implant. The recall does not include smooth surface devices that use either saline or silicone gel as the filler material. Management options for patients with textured devices include continued implant monitoring, exchange for smooth devices, or conversion to autologous tissue reconstruction. It is unknown how the removal of a textured device impacts the likelihood of future BIA-ALCL, although it is reasonable to hypothesize that removal of the implant capsule substantially decreases the risk.

Anesthesia and Type of Breast Cancer Surgery

The preoperative assessment should take into account: (1) patient comorbidities and whether the patient is medically optimized prior to surgery, and (2) type of procedure being performed with an understanding of the incision sites, extent of dissection and tissue trauma, and expected postoperative pain. As described in the previous sections, breast cancer surgeries include a wide range of procedure types from breast-conserving surgery with or without sentinel and/or ALND to mastectomy with or without reconstruction. Breast reconstruction may entail temporary placement of a tissue expander, placement of a permanent implant, or autologous flap reconstruction.

For minimally invasive outpatient procedures such as partial mastectomy or lumpectomy, monitored anesthesia care with a continuous propofol infusion in conjunction with surgeon infiltration of local anesthesia is generally appropriate. ALND involves deeper tissue invasion and typically requires general anesthesia with a laryngeal mask airway. Because of the proximity of the brachial plexus and its branches to the axilla, breast surgeons often prefer avoidance of muscle relaxant medications in order to monitor nerve response during dissection. Consideration should be given to placing the intravenous catheter and blood pressure cuff on the arm opposite to the side of the planned surgery.

Reconstruction after mastectomy may be an immediate or delayed procedure. When immediate reconstruction is planned after mastectomy, general endotracheal anesthesia is generally preferred, particularly if the placement of the tissue expander is subpectoral which may be facilitated by muscle relaxation. Tissue expander reconstruction is a risk factor for worse pain after breast reconstruction compared to autologous flap approaches ; hence an optimal multimodal analgesic regimen should be planned. Patients undergoing exchange of tissue expanders with permanent implants, which typically occurs at least 3 months but not sooner than 6 weeks after initial tissue expander placement, usually require general endotracheal anesthesia due to frequent upright positioning changes to enable surgeons to assess for symmetry, which limits access to the airway.

General endotracheal anesthesia is standard for patients undergoing autologous flap reconstruction. Due to the prolonged nature of these procedures, the anesthesia team should be mindful of noninvasive blood pressure (NIBP) cuff pressure injuries and consider rotating between two separate sites for NIBP measurement, using invasive blood pressure monitoring, or a continuous NIBP monitoring technique. Pressure point checks of the head and extremities at regular intervals throughout the procedure should also be performed.