gynecology and obstetrics
Breast Cancer
Treatment of Breast Cancer
Surgery Radiation therapy Systemic chemotherapy Adjuvant endocrine therapy For more detailed information about treatment, seeNational Comprehensive Cancer Network (NCCN) Clinical Practice Guideline: Breast Cancer. For most types of breast cancer, treatment involves surgery and radiation therapy; systemic therapy is given for lymph node involvement or metastatic disease. Choice of treatment depends on tumor and patient characteristics (see table). Recommendations for surgery are evolving and include early referral to a plastic or reconstruction surgeon for oncoplastic surgery (which combines cancer removal with reconstruction of the breast). Surgery involves mastectomy or breast-conserving surgery. Mastectomyis removal of the entire breast and includes the following types: Skin-sparing mastectomy:Spares the pectoral muscles and enough skin to cover the wound, making breast reconstruction much easier, and spares axillary lymph nodes Nipple-sparing mastectomy:Same as skin-sparing mastectomy plus spares the nipple and areola Simple mastectomy:Spares the pectoral muscles and axillary lymph nodes Modified radical mastectomy:Spares the pectoral muscles and removes some axillary lymph nodes Radical mastectomy:Removes axillary lymph nodes and the pectoral muscles Radical mastectomy is rarely done unless the cancer has invaded the pectoral muscle. Breast-conserving surgeryinvolves determining the size of the tumor and the required margins (based on the tumor's size relative to the volume of the breast), then surgically removing the tumor with its margins. Various terms (eg,lumpectomy,wide excision, quadrantectomy) are used to describe how much breast tissue is removed. For patients with invasive cancer, survival and recurrence rates with mastectomy do not differ significantly from those with breast-conserving surgery plus radiation therapy as long as the entire tumor can be removed ( Treatment references ). Thus, patient preference is part of shared decision-making. The main advantage of breast-conserving surgery plus radiation therapy is less extensive surgery and opportunity to keep the breasts. The need for total removal of the tumor with a tumor-free margin overrides any cosmetic considerations. Consulting a plastic surgeon about oncoplastic surgery may help if patients have ptotic (sagging) breasts, while also achieving good resection margins. Some oncologists treat with neoadjuvant chemotherapy to shrink the tumor before removing it and applying radiation therapy; thus, some patients who might otherwise have required mastectomy can have breast-conserving surgery. During both mastectomy and breast-conserving surgery, axillary lymph nodes are typically evaluated. Methods include Axillary lymph node dissection (ALND) Sentinel lymph node biopsy (SLNB) ALND is a fairly extensive procedure that involves removal of as many axillary nodes as possible; adverse effects, particularly lymphedema, are common. Risk of lymphedema is increased for patients with a high preoperative body mass index (BMI ≥ 30) and for those with significant weight gain during and after breast cancer treatment ( Treatment references ). Most surgeons now first do SLNB unless biopsy of clinically suspect nodes detected cancer; risk of lymphedema is less with SLNB. Routine use of ALND is not justified because the main value of lymph node removal is diagnostic, not therapeutic, and SLNB has≥95% sensitivity for axillary node involvement. For SLNB, blue dye and/or radioactive colloid is injected around the breast, and a gamma probe (and when dye is used, direct inspection) is used to locate the nodes the tracer drains into. Because these nodes are the first to receive the tracers, they are considered the most likely to receive any metastatic cells and are thus called sentinel nodes. If any of the sentinel nodes contain cancer cells, ALND may be necessary, based on numerous factors such as Tumor stage Hormone receptor status Number of involved nodes Extranodal extension Patient characteristics ( Treatment references ) Some surgeons do frozen section analysis during mastectomy with SLNB and get prior agreement for ALND in case nodes are positive; others await standard pathology results and do ALND as a 2nd procedure if needed. Frozen section analysis is not routinely done with lumpectomy. of the ipsilateral arm often occurs after axillary node removal (ALND or SLNB) or radiation therapy, sometimes resulting in substantial swelling due to lymphedema. Magnitude of the effect is roughly proportional to the number of nodes removed; thus, SLNB causes less lymphedema than ALND. The lifetime risk of lymphedema after ALND is about 25%. However, even with SLNB, there is a 6% lifetime risk of lymphedema ( Treatment references ). To reduce risk of lymphedema, clinicians usually avoid giving IV infusions on the affected side. Wearing compression garments and preventing infection in the affected limbs (eg, by wearing gloves during yard work) are important. Avoiding ipsilateral blood pressure measurement and venipuncture is sometimes also recommended, even though supporting evidence is minimal ( If lymphedema develops, a specially trained therapist must treat it. Special massage techniques used once or twice a day may help drain fluid from congested areas toward functioning lymph basins; low-stretch bandaging is applied immediately after manual drainage, and patients should exercise daily as prescribed. After the lymphedema lessens, typically in 1 to 4 weeks, patients continue daily exercise and overnight bandaging of the affected limb indefinitely. Reconstructive procedures include the following: Prosthetic reconstruction:Placement of a silicone or saline implant, sometimes after a tissue expander is used Autologous reconstruction:Muscle flap transfer (using the latissimus dorsi, gluteus maximus, or the lower rectus abdominis) or muscle-free flap transfer Breast reconstruction can be done during the initial mastectomy or breast-conserving surgery or later as a separate procedure. Timing of surgery depends on patient preference as well as the need for adjuvant therapy such as radiation therapy. However, doing radiation therapy first limits the types of reconstructive surgery that can be done. Thus, consulting a plastic surgeon early during treatment planning is recommended. Advantages of breast reconstruction include improved mental health in patients who have a mastectomy. Disadvantages include surgical complications and possible long-term adverse effects of implants. Contralateral prophylactic mastectomy is an option for some women with breast cancer (eg, those with a genetic mutation conferring a high risk of breast cancer). In women with lobular carcinoma in situ in one breast, invasive cancer is equally likely to develop in either breast. Thus, the only way to eliminate the risk of breast cancer for these women is bilateral mastectomy. Some women, particularly those who are at high risk of developing invasive breast cancer, choose this option. Advantages of contralateral prophylactic mastectomy include Decreased risk of contralateral breast cancer (especially in women in a family history of breast or ovarian cancer) Improvement in survival in breast cancer patients with an inherited genetic mutation (eg,BRCA1orBRCA2mutation) and possibly in women diagnosed at age < 50 years Decreased anxiety in some patients Decreased need for cumbersome follow-up imaging Disadvantages of contralateral prophylactic mastectomy include An almost two-fold increase in surgical complication rates Contralateral prophylactic mastectomy is not mandatory for patients with the highest risk of developing cancer in the contralateral breast. Close surveillance is a reasonable alternative. may not be necessary; adding radiation therapy does not significantly decrease the rate of mastectomy for local recurrence or the occurrence of distant metastases nor increase the survival rate ( Treatment references ). Radiation therapy is indicated after mastectomy if any of the following is present: The primary tumor is ≥ 5 cm. Axillary nodes are involved. Margins are positive for cancer in resected tissue. In such cases, radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and improves overall survival. Adverse effects of radiation therapy (eg, fatigue, skin changes) are usually transient and mild. Late adverse effects (eg, lymphedema, brachial plexopathy, radiation pneumonitis, rib damage, secondary cancers, cardiac toxicity) are less common. To improve radiation therapy, researchers are studying several new procedures. Many of these procedures aim to target radiation to the cancer more precisely and spare the rest of the breast from the effects of radiation. (See alsoNational Comprehensive Cancer Network (NCCN) Clinical Practice Guideline: Breast Cancer.) Endocrine therapy, chemotherapy, or HER2-directed therapy delays or prevents recurrence in almost all patients and prolongs survival in some. Hormone positive cancer can be evaluated with Oncotype Dx, which allows targeting chemotherapy and endocrine therapy to the populations most likely to benefit. Hormone negative cancer and HER2 positive cancer are treated with chemotherapy and targeted therapy. Decisions about the type of adjuvant therapy are made based on tumor characteristics, includingestrogenreceptor (ER) andprogesteronereceptor (PR) status, presence of human epidermal growth factor 2 (HER2) protein, grade and stage (including lymph node involvement), and genomic risk stratification. Some patients are treated with a combination of endocrine therapy and chemotherapy. Chemotherapy is usually begun soon after surgery. If systemic chemotherapy is not required, endocrine therapy is usually begun soon after surgery and is continued for 5 to 10 years. In higher stage disease, neoadjuvant chemotherapy may be started before surgery. In patients with ER+tumors, particularly low-risk tumors, endocrine therapy is typically given. Predictive genomic testing of the primary breast cancer is used to stratify risk in patients and to determine whether combination chemotherapy or endocrine therapy alone is indicated. Common prognostic tests include The 21-gene recurrence score assay (based on Oncotype Dx) The Amsterdam 70-gene profile (MammaPrint) The 50-gene risk of recurrence score (PAM50 assay) In the United States, most women with breast cancer have ER+/PR+/HER2- breast cancer with negative axillary nodes. In these women, a low or intermediate score on the 21-gene recurrence score assay predicts similar survival rates with chemotherapy plus endocrine therapy and with endocrine therapy alone. Therefore, in this subset of women with breast cancer, chemotherapy may not be necessary. receptor expression; benefit is greatest with the strongest level of hormone receptor expression ( Treatment references ). Medications used for endocrine therapy include therapy for 5 years reduces annual odds of death by about 25% in premenopausal and postmenopausal women regardless of axillary lymph node involvement ( Treatment references ). Treatment for 10 years appears to be even more effective; it prolongs survival and reduces recurrence risk compared with 5 years of treatment (15-year recurrence reduced to 21% from 25%) ( Aromatase inhibitors(anastrozole,exemestane,letrozole) block peripheral production ofestrogenin postmenopausal women. More effective thantamoxifen, these medications are becoming the preferred treatment for early-stage hormone receptor–positive cancer in postmenopausal patients.Letrozolemay be used in postmenopausal women who have completedtamoxifentreatment. Optimal duration of aromatase inhibitor therapy is uncertain. A recent trial showed that extending treatment to 10 years resulted in a lower rate of breast cancer recurrence and higher rate of disease-free survival. There was no change in overall survival and a higher rate of fractures and osteoporosis in patients treated for an extended time. Patients with DCIS are often treated with daily oraltamoxifen. Preferred therapy for premenopausal women with ER+ breast cancer is typicallytamoxifenor ovarian suppression (usually withleuprolide, a GnRH agonist) combined with an aromatase inhibitor. For postmenopausal women, an aromatase inhibitor is preferred. CDK 4/6 inhibitors, such aspalbociclib,ribociclibandabemaciclib, are also used for patients with hormone receptor-positive, HER2-negative cancer.Olaparibis used in patients with germline BRCA1 and 2 mutations with HER2-negative breast cancer. Usual indications for chemotherapy are one or more of the following: Estrogenreceptor (ER) andprogesteronereceptor (PR)-negative Human epidermal growth factor 2 (HER2) oncogene-positive (chemotherapy and HER2-directed therapy is given) ER/PR+ and positive lymph nodes in a premenopausal patient ER/PR+ and HER2- with high Oncotype Dx score However, studies have shown that chemotherapy is not necessary for many small (< 0.5 to 1 cm) tumors with no lymph node involvement (particularly in postmenopausal patients) because the prognosis is already excellent ( Treatment references ). Postmenopausal patients with ER− tumors benefit the most from adjuvant chemotherapy (see table). Combination chemotherapy regimens are more effective than a single medication. Dose-dense regimens given for 4 to 6 months are preferred; in dose-dense regimens, the time between doses is shorter than that in standard-dose regimens. There are many regimens; a commonly used one is ACT (doxorubicinpluscyclophosphamidefollowed bypaclitaxel). Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, cardiotoxicity, and thrombocytopenia. Growth factors that stimulate bone marrow (eg,filgrastim,pegfilgrastim) are commonly used to reduce risk of fever and infection due to chemotherapy. Long-term adverse effects are infrequent with most regimens; death due to infection or bleeding is rare (<0.2%). If the tumor overexpresses HER2 (HER2+), anti-HER2 monoclonal antibodies (trastuzumab,pertuzumab) may be used. Adding the humanized monoclonal antibodytrastuzumabto chemotherapy provides substantial benefit.Trastuzumabis usually continued for a year, although the optimal duration of therapy is unknown. If lymph nodes are involved, addingpertuzumabtotrastuzumabimproves disease-free survival. A serious potential adverse effect of both these anti-HER2 medications is a decreased cardiac ejection fraction. Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by 6 months or longer. These treatments (eg, chemotherapy), although relatively toxic, may palliate symptoms and improve quality of life. Thus, the decision to be treated may be highly personal. Choice of therapy depends on the following: Hormone-receptor status of the tumor Length of the disease-free interval (from remission to manifestation of metastases) Number of metastatic sites and organs affected Patient’s menopausal status Systemic endocrine therapy or chemotherapy is usually used to treat symptomatic metastatic disease. Initially, patients with multiple metastatic sites outside the central nervous system (CNS) should be given systemic therapy. If metastases are asymptomatic, there is no proof that treatment substantially increases survival, and it may reduce quality of life. Endocrine therapyis preferred over chemotherapy for patients with any of the following: ER+ tumors A disease-free interval of > 2 years Disease that is not immediately life threatening In premenopausal women,tamoxifenis often used first. Reasonable alternatives include ovarian ablation by surgery, radiation therapy, and use of a luteinizing-releasing hormone agonist (eg, buserelin,goserelin,leuprolide). Some experts combine ovarian ablation withtamoxifenor an aromatase inhibitor. In postmenopausal women, aromatase inhibitors are being increasingly used as primary endocrine therapy. If the cancer initially responds to endocrine therapy but progresses months or years later, additional forms of endocrine therapy (eg, progestins, the antiestrogenfulvestrant) may be used sequentially until no further response occurs. The most effectivechemotherapy agentsarecapecitabine,doxorubicin(including its liposomal formulation),gemcitabine, the taxanespaclitaxelanddocetaxel, andvinorelbine. Response rate to a combination of agents is higher than that to a single agent, but survival is not improved and toxicity is increased. Thus, some oncologists use single agents sequentially. plus chemotherapy ( Treatment references ). Tyrosine kinase inhibitors(eg,lapatinib,neratinib) are being increasingly used in women with HER2+ tumors. Radiation therapyalone may be used to treat isolated, symptomatic bone lesions or local skin recurrences not amenable to surgical resection. Radiation therapy is the most effective treatment for brain metastases, occasionally providing long-term control. Palliative mastectomyis sometimes an option for patients with stable metastatic breast cancer. IV bisphosphonates(eg,pamidronate, zoledronate) decrease bone pain and bone loss and prevent or delay skeletal complications due to bone metastases. About 10% of patients with bone metastases eventually develop hypercalcemia, which can also be treated with IV bisphosphonates. 1.Fisher B, Anderson S, Bryant J, et al. 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