INTRODUCTION — Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. In the United States, breast cancer is second to lung cancer as the most common cause of cancer death in women [1]. However, there has been a decline in breast cancer mortality rates in the United States and elsewhere in the Western world, attributable to the increased use of screening mammography and advances in adjuvant therapies. As a result of improved survival and the aging of the population, there are over three million women living with a history of breast cancer in the United States alone, accounting for 41 percent of all female cancer survivors [2]. Breast cancer survivors are the largest constituent of all cancer survivors, representing 3.6 percent of the United States population [3,4].

The majority of breast cancer recurrences occur within the first five years of diagnosis, particularly with hormone receptor-negative or human epidermal growth factor receptor 2 (HER2)-positive disease. However, some recurrences occur much later, particularly in the setting of hormone receptor-positive, HER2-negative tumors, which tend to behave more indolently [5]. These data are discussed elsewhere. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.).

Relapse patterns and long-term complications of therapy for invasive breast cancer in women who are at least five years out from their initial diagnosis will be reviewed here. Recommendations for surveillance strategies in breast cancer survivors and an overview of the approach to breast cancer survivors are discussed separately. (See "Approach to the patient following treatment for breast cancer".)

OVERVIEW OF BREAST CANCER

Treatment overview — Patients with early-stage and locally advanced breast cancer benefit from a multidisciplinary approach to treatment planning that may include surgery, radiation therapy (RT), and systemic therapy. The following provides a broad overview of contemporary breast cancer treatment (see "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer" and "Breast cancer in men"):

Surgery — For women with newly diagnosed breast cancer, the surgical approach depends on the extent of disease and patient preferences, with additional considerations when the patient has a known predisposing germline mutation (eg, in breast cancer susceptibility gene 1 or 2 [BRCA1 or BRCA2]).

●DCIS – In general, women with limited breast ductal carcinoma in situ (DCIS) undergo breast-conserving surgery. Axillary node evaluation is not routinely indicated for these women as long as an invasive component is not present in the excised breast tissue. However, for more extensive disease (ie, tumor extent >3 cm) or if there was evidence of microinvasive disease, a sentinel node biopsy is generally performed. (See "Ductal carcinoma in situ: Treatment and prognosis".)

●Invasive disease – Most women with early invasive breast cancer require surgery to remove the primary breast tumor and evaluate the ipsilateral axillary nodes. However, some women with early-stage disease and most women with locally advanced disease do not undergo initial surgery. Instead, these women are often treated with neoadjuvant systemic therapy prior to definitive surgery. (See "Breast-conserving therapy", section on 'Patient selection for BCT' and 'Chemotherapy' below and "General principles of neoadjuvant management of breast cancer" and "Mastectomy", section on 'Indications for mastectomy'.)

The removal of lymph nodes for women with invasive breast cancer gives important staging information and is used to make further treatment decisions. Sentinel lymph node biopsy is less morbid than axillary lymph node dissection and results in similar survival outcomes. Therefore, women with early-stage breast cancer without evidence of clinical axillary node involvement typically undergo a sentinel node procedure. Patients who are found to have three or more positive nodes typically undergo a completion axillary dissection. Women who are recommended for neoadjuvant chemotherapy will often undergo a work-up to evaluate the nodal status prior to the initiation of chemotherapy. This is discussed more extensively separately, as is axillary radiotherapy. (See "Management of the regional lymph nodes in breast cancer" and "Overview of sentinel lymph node biopsy in breast cancer" and "General principles of neoadjuvant management of breast cancer", section on 'Node evaluation'.)

●Metastatic at presentation – For women who present with metastatic disease (outside the breast and the axilla), systemic therapy is usually administered. However, surgery may play a role in disease management (eg, removal of limited central nervous system metastases, alleviation of spinal cord compression, stabilization of fractures, or control of ulcerated breast lesions). In these cases, decisions regarding surgery are based on individual consideration of disease status, alternative treatment options, as well as overall prognosis. (See "The role of local therapies in metastatic breast cancer" and "Systemic treatment for metastatic breast cancer: General principles" and "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer".)

Radiation therapy — Breast RT is an important component of breast-conserving therapy (BCT) for both in situ and invasive breast cancer. RT may also be administered to some women following a mastectomy, particularly those with large tumors (ie, >5 cm), positive margins, and nodal involvement. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)

Endocrine therapy — Endocrine (antiestrogen) therapy is an important component of treatment for a high proportion of patients with estrogen (ER) or progesterone (PR) receptor-positive tumors.

●For women with ER-positive DCIS, the risk of distant spread is low (1 to 2 percent in most large series), and the goal of endocrine therapy is to lessen the ipsilateral breast recurrence risk. An added benefit is a chemoprevention effect on the contralateral breast. For women who have undergone breast-conserving surgery for DCIS, five years of antiestrogen therapy is the standard duration of treatment, with both tamoxifen and aromatase inhibitors (AIs) demonstrating efficacy. (See "Ductal carcinoma in situ: Treatment and prognosis", section on 'Tamoxifen' and "Ductal carcinoma in situ: Treatment and prognosis", section on 'Aromatase inhibitors'.)

There is a weaker rationale for antiestrogens in women who have undergone full mastectomy for DCIS since the risk of ipsilateral recurrence has been effectively removed by surgery. (See "Ductal carcinoma in situ: Treatment and prognosis", section on 'Tamoxifen'.)

●For ER-positive invasive breast cancer, antiestrogens have been and are increasingly important in the adjuvant setting for both pre- and postmenopausal women. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications'.)

For premenopausal women, there are several options available, including tamoxifen or ovarian function suppression (OFS) or ablation (OA) with an AI or tamoxifen. For patients determined to be at highest risk for recurrence, the option of OFS or OA plus an AI is preferred. However, AIs without OFS or OA are not indicated for premenopausal women. (See "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Ovarian suppression plus endocrine therapy'.)

For postmenopausal women, standard treatment in the adjuvant setting includes the following options, with a choice driven by individual tumor risk factors, as well as patient tolerability [6]. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Efficacy' and "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment' and "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Approach to treatment'.):

•Treatment with an AI (eg, anastrozole, exemestane, or letrozole) for five years, and up to ten, for certain high-risk tumors.

•Sequential treatment with tamoxifen or an AI for two to three years followed by the alternative agent for three to two years (for a five-year total treatment course).

•Treatment with tamoxifen for up to 10 years.

•Treatment with tamoxifen for five years followed by an AI for an additional five years.

Endocrine therapy may be used as neoadjuvant treatment of locally advanced hormone-positive breast cancer or as primary treatment for older women who are medically unsuited for chemotherapy. (See "Overview of the approach to early breast cancer in older women", section on 'Hormone receptor-positive breast cancer' and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Neoadjuvant endocrine therapy'.)

Endocrine therapy is also preferred treatment as initial therapy for most women with metastatic, hormone receptor-positive disease. The choice of treatment is based on the menstrual status of the woman at the time of diagnosis of metastatic disease, whether and which kind of prior endocrine treatment was administered (ie, as adjuvant treatment), and the temporal relationship of the diagnosis of metastases to adjuvant endocrine therapy. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents".)

Chemotherapy — Adjuvant chemotherapy is generally recommended for women with invasive breast cancers that are either hormone receptor negative or who have higher-risk, hormone receptor-positive tumors including those that are also human epidermal growth factor receptor 2 (HER2) positive. For women with hormone receptor-positive tumors, molecular assays are available to identify patients at high risk. (See "Prognostic and predictive factors in early, non-metastatic breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

Multiple adjuvant options are used, although a regimen containing a taxane and an anthracycline is commonly used for patients with node-positive tumors. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

Chemotherapy is also administered prior to surgery (ie, neoadjuvant therapy) for women who present with locally advanced breast cancer, including inflammatory breast cancer, and in those women who are not candidates for breast-conserving surgery at the time of presentation. In the latter group, a proportion of patients are able to undergo breast conservation following neoadjuvant treatment. Women with smaller tumors at diagnosis may also receive neoadjuvant chemotherapy as well. There is no evidence that neoadjuvant chemotherapy improves survival outcomes (compared with surgery followed by adjuvant treatment).

Finally, neoadjuvant systemic therapy is also increasingly used in clinical trials, since tumor tissue is available at diagnosis and again after medical therapy at the time of definitive surgery. This affords clinicobiologic correlations that are essential in understanding cancer response and resistance. (See "General principles of neoadjuvant management of breast cancer".)

For women with advanced or metastatic breast cancer, chemotherapy is indicated for women whose tumors are hormone receptor-positive but who have exhausted antiestrogen strategies, women whose tumors are hormone receptor-negative, and women with hormone receptor-positive cancers who present in a visceral crisis (eg, liver or lung) as a result of metastatic disease. Incorporation of palliative care is also important [7]. (See "Systemic treatment for metastatic breast cancer: General principles".)

Anti-HER2-directed treatment — For patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancers that are treated with chemotherapy, the addition of trastuzumab is recommended. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)

Pertuzumab may be added to trastuzumab in select patients with high-risk disease. Modest additional benefit has been demonstrated in the APHINITY trial. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Option of adjuvant dual anti-HER2 therapy'.)

Anti-HER2-directed treatment is also administered in the neoadjuvant setting and in the treatment of HER2-positive metastatic breast cancer. Discussion of the use of trastuzumab emtansine (an antibody-drug conjugate consisting of trastuzumab covalently linked to the cytotoxic agent DM1) for those with residual disease after neoadjuvant treatment is found elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Treatment overview'.)

Multiple additional agents have been approved based on efficacy demonstrated in trastuzumab-resistant tumors. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Timing of HER2-directed agents'.)

RELAPSE PATTERNS — While the outcome is increasingly favorable, women treated for invasive breast cancer remain at risk of both a locoregional recurrence and the evolution of metastatic disease [8]. Breast cancer is no longer recognized as a homogeneous entity, but rather a family of malignancies that can be distinguished by gene expression profiling as intrinsic subtypes. Clinical patterns of recurrence are associated with these genomic subtypes. In general, luminal A and B cancers exhibit a tendency to recur that is continuous over a long period of time (20 years or more), with the majority of these events identified beyond five years from diagnosis. Skeletal involvement is common. Human epidermal growth factor receptor 2 (HER2)-enriched and basal subtypes are most often associated with early recurrence events (most within five years from diagnosis), a higher incidence of visceral involvement, and a lower likelihood of skeletal metastases.

Locoregional recurrence — Women who have undergone either mastectomy or breast-conserving surgery and radiation therapy (RT), which we will refer to as breast-conserving therapy (BCT), are at risk for locoregional recurrence (recurrence that occurs in the breast or lymph nodes). For women treated for early breast cancer, the recurrence rate ranges from 4 to 7 percent with mastectomy or BCT, respectively [9]. If relapse occurs within two years of primary treatment, distant metastatic disease is already present in 25 to 30 percent of cases [10]. (See 'Metastatic disease' below.)

For women treated with BCT, locoregional recurrences tend to occur later compared with those who underwent a mastectomy. In either case, potentially curative surgery may be an option. The surgical approach depends on whether or not RT (and the type of RT) was previously administered. In general, for women who were previously treated with BCT and experience an isolated operable locoregional recurrence, a mastectomy should be performed because further radiation treatment is not generally an option to reduce the risk of another local recurrence. However, for women who did not previously receive RT and for those treated with partial breast irradiation, re-excision may be appropriate because the women may be candidates for RT.

By contrast, a local recurrence following mastectomy is usually manifest as a mass in the chest wall, regional nodal basins (ie, infraclavicular, supraclavicular, or axillary regions), or overlying skin. Treatment generally involves excision of the recurrence (if surgically resectable), as well as possibly RT (if not previously administered), and systemic therapy. Management of locoregional recurrence, including indications for surgery, radiation, and systemic therapy (including chemotherapy and endocrine therapy), is discussed elsewhere. (See "Surgery and radiation for locoregional recurrences of breast cancer" and "Systemic therapy for locoregionally recurrent breast cancer".)

Metastatic disease — Although approximately 15 to 40 percent of recurrences involve the chest wall and axillary or supraclavicular lymph nodes, breast cancer has the potential to metastasize to almost every organ in the body (table 1). The most common sites of metastases are bone, liver, and lung. Approximately 50 to 75 percent of patients who relapse distantly do so in a single organ; the remainder will develop diffuse metastatic disease. Less than 5 percent of patients overall will manifest central nervous system (CNS) involvement as the first site of metastatic disease, but the frequency is significantly higher in HER2-enriched and basal intrinsic subtypes. The treatment approach to women presenting with metastatic breast cancer is discussed separately. (See "Systemic treatment for metastatic breast cancer: General principles" and "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "The role of local therapies in metastatic breast cancer".)

SECOND PRIMARY BREAST TUMORS — For women without an inherited predisposition to breast cancer (ie, a breast cancer susceptibility gene 1 or 2 [BRCA1 or BRCA2] mutation), the risk of a second breast cancer is between 0.5 and 1.0 percent per year [11,12]. For women with a known genetic predisposition, the risk is much higher. The lifetime risk of second primary breast cancers may be as high as 65 percent for BRCA1 mutation carriers and 50 percent for BRCA2 carriers [13]. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes" and "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2".)

Limited data suggest a slight excess of contralateral breast cancers following breast or chest wall radiation therapy (RT) [14-16]. As an example, in data from an Early Breast Cancer Trialists' Collaborative Group meta-analysis, the annual odds ratio for contralateral breast cancer for irradiated compared with nonirradiated women was 1.18 (p = 0.002) [14]. This result was statistically significant for women 50 years of age and older (1.25, p = 0.002) but not for younger women (1.09, p = 0.30). On the other hand, other data suggest that the risk may be higher with younger age at treatment [15-17]. A Dutch report suggests that postmastectomy radiotherapy using direct electron fields leads to a significantly lower radiation exposure to the contralateral breast than postlumpectomy RT using photons with tangential fields [16]. The joint effects of postlumpectomy RT and strong family history for breast cancer in this series were associated with a higher risk for a secondary breast tumor than expected when individual risks were summed (hazard ratio 3.52). However, a nested case-control study by the investigators from the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study Collaborative group, which included patients with known BRCA1/BRCA2 mutations, did not find a significant increase in contralateral breast cancers in carriers irradiated for breast cancer [18]. A similar finding was reported in a separate study of breast cancer patients who were carriers of deleterious BRCA mutations despite the use of tangential fields in the majority of patients [19]. Clearly, data are conflicting and further study is needed.

A substantial number of second primary breast cancers occur after five years, necessitating long-term surveillance for all women with a history of breast cancer [20,21]. This is especially true for hormone receptor-positive breast cancers. As an example, in NSABP trial B-04, which evaluated mastectomy with and without RT, 50 percent of all contralateral breast cancers were detected after five years of follow-up [22]. (See "Approach to the patient following treatment for breast cancer", section on 'Breast imaging'.)

LONG-TERM ADVERSE EFFECTS OF PRIMARY THERAPY — Most breast cancer survivors report good quality of life, but some patients may have chronic difficulties associated with emotional, cognitive, and social functioning [23-25]. Fatigue, cognitive dysfunction, difficulties with sleep, pain, and menopausal symptoms can be chronic and debilitating. The various long-term physical and psychological sequelae due to specific breast cancer treatments are summarized in the following (table 2).

Chest wall and breast complications — Breast surgery, breast reconstruction, and radiation therapy (RT) may result in long-term complications in the breast and chest wall. These include formation of seromas, fat necrosis, chronic pain, and recurrent skin infections (cellulitis). (See "Complications of reconstructive and aesthetic breast surgery" and "Clinical manifestations and diagnosis of postmastectomy pain syndrome" and "Postmastectomy pain syndrome: Risk reduction and management".)

In addition to surgical complications, RT may result in long-term issues, including skin and soft tissue fibrosis or necrosis. Radiation-induced fibrosis of the skin and subcutaneous tissue is seen most commonly in breast cancer patients in areas with overlapping treatment fields following breast-conserving surgery with postoperative RT or after mastectomy and RT. The risk of radiation fibrosis after conventional RT for breast cancer is low, particularly with the use of modern skin-sparing megavoltage equipment. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis", section on 'Skin and subcutaneous tissue'.)

Soft tissue necrosis in long-term survivors is exceedingly rare, with an estimated incidence of 0.2 percent of patients undergoing RT for early-stage breast cancer in one series [26].

Musculoskeletal — Breast and axillary surgery also can result in musculoskeletal issues including reduced arm mobility. RT may compound surgery-related pain and motor restriction, both in the short and long term [27]. Rib fractures from RT are uncommon. In one report, the incidence of a rib fracture was less than 3 percent, and the median time to develop a fracture was about one year [26]. The incidence appears to be higher with RT doses that exceed 50 Gy.

Women treated with an aromatase inhibitor (AI) frequently experience muscle and joint pains, resulting in treatment discontinuation in up to 20 percent of patients. In addition to these complaints, treatment with an AI increases the risk for osteoporosis and subsequent fractures. In one study, patients taking an AI had a 35 percent higher rate of fracture compared with those not on an AI (rate of 8.6 versus 6.4 events per 100 person-years; relative risk [RR] 1.35, 95% CI 1.16-1.58) [28]. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects'.)

Lymphedema — Both breast surgery and radiation can lead to the development of early- or delayed-onset lymphedema, which can involve the breast, chest, and the ipsilateral extremity. Rates of lymphedema are highest in women who undergo breast-conserving surgery or mastectomy with axillary lymph node dissection followed by breast/chest wall and comprehensive nodal RT including the full axilla. Patients in long-term follow-up who present with new-onset lymphedema should be evaluated for alternate causes of new swelling including tumor recurrence, infection, and thrombosis. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Cancer and cancer treatment'.)

Neurologic — Breast surgery can cause nerve injury, which may result in long-term symptoms of paresthesias and/or persistent pain in the chest wall. In addition, RT can result in a brachial plexopathy, manifesting as paresthesia or weakness in the arm or hand [26]. Permanent brachial plexopathy occurs in less than 1 percent of women receiving ≤50 Gy in 2 Gy fractions administered to a supraclavicular and axillary apex field. The incidence of plexopathy is significantly higher with an axillary dose greater than 50 Gy, concomitant chemotherapy administration [26], and daily RT fractions in excess of 2 Gy [29,30]. (See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy'.)

Neurotoxicity is also a well-recognized side effect of adjuvant chemotherapy, particularly with taxanes. The peripheral neuropathy that develops during and after taxanes is generally limited to distal paresthesias and is usually at least partially reversible after treatment discontinuation. In rare instances, the neuropathy is permanent. Neuropathy may be painful and interfere with activities of daily living. Symptomatic improvement may be seen with the antidepressant duloxetine. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Taxanes'.)

Pulmonary — RT to the breast can result in pneumonitis, which typically presents as a persistent dry cough or shortness of breath [26]. Fortunately, with modern RT techniques, pneumonitis is a rare event [31] (see "Radiation-induced lung injury"). Overlapping exposure to taxanes may increase the risk of acute pneumonitis.

Cardiovascular morbidity — Cardiovascular disease may be a complication of breast RT and specific systemic agents used in the treatment of breast cancer. Symptoms of early congestive heart failure should prompt a cardiac evaluation.

Radiation therapy — At present, there does not appear to be a minimum radiation dose that is entirely safe; however, studies are ongoing to better quantify low radiation doses and the effects on the heart. It appears clear that the effects of radiation on the heart increase with increasing doses of radiation. The increased risk can be seen within the first five years and remains elevated for at least 20 years. Women with significant risk factors for an acute coronary event may be at a particularly increased risk. In addition, RT that involves the internal mammary nodes may be associated with treatment-related cardiovascular toxicity if by treating the nodes, a portion of the heart is placed in the radiation field. For all patients with left-sided breast cancers, careful treatment planning is critical to minimize cardiac exposure to radiation [32]. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies", section on 'Breast cancer'.)

Systemic treatment — Exposure to chemotherapeutic and biologic agents, such as anthracyclines and trastuzumab, can result in cardiac morbidity. In a 2012 study that included 12,500 women with invasive breast cancer, the five-year cumulative incidence of cardiovascular disease (defined as heart failure or cardiomyopathy) was increased in the following groups [33-35]:

●Older women – The incidence was 6 and 11 percent among women aged 65 to 74 and ≥75 years, respectively. By contrast, the cumulative incidence was 1 to 2 percent in younger women.

●Women treated with chemotherapy – Women who received an anthracycline had a cumulative incidence of 4 percent, which when compared with patients who did not receive chemotherapy, represented an increased risk (hazard ratio [HR] 1.4, 95% CI 1.11-1.76). In addition, women treated with other chemotherapy agents were also at an increased risk (incidence 4.5 percent; HR 1.49, 95% CI 1.25-1.77).

●Women treated with trastuzumab – Women treated with an anthracycline plus trastuzumab had a cumulative incidence of 20 percent, which represented an increased risk compared with patients who did not receive chemotherapy (HR 7.19, 95% CI 5.0-10.4). The risk was also increased among patients treated with trastuzumab without an anthracycline (HR 4.12, 95% CI 1.11-1.76).

The incidence of cardiomyopathy and heart failure secondary to doxorubicin is dose dependent, typically occurring at higher doses than those administered in the adjuvant setting. The risk increases substantially at cumulative doses greater than 500 mg/m² [34]. In contrast to cardiotoxicity from anthracyclines, trastuzumab-related cardiotoxicity does not appear to be related to cumulative dose. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Prevention and management of anthracycline cardiotoxicity" and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity".)

Endocrine therapy — The AIs, used in the treatment of hormone-positive postmenopausal breast cancers, may increase the risk of cardiovascular adverse events compared with tamoxifen, although the overall risk appears to be low and remains not fully characterized. In a meta-analysis of seven adjuvant trials (n = 19,818 patients), compared with tamoxifen, AIs were associated with an increased risk of cardiovascular adverse events (relative risk [RR] 1.31, 95% CI 1.07-1.60), which translated into a number needed to harm of 189 patients [36]. As tamoxifen has been associated with a cardioprotective effect in some long-term studies, it is unknown whether AIs are associated with increased cardiac risk relative to placebo, or only relative to tamoxifen.

Second cancers — Although difficult to quantify, there is an increased risk for second cancers associated with breast cancer treatment, whether RT, chemotherapy, or tamoxifen [37-39]. Second cancers that have been associated with breast cancer treatment include esophageal, lung, and uterine cancers, as well as melanoma, soft tissue sarcoma (notably angiosarcoma), acute myeloid leukemia, and myelodysplastic syndromes [37,38].

The development of second malignancies is dependent upon treatment factors (type of treatment, including dose and duration of exposure), lifestyle factors (including a history of smoking or alcohol use), and genetic susceptibility.

Radiation therapy — While patients treated with adjuvant RT are at risk for radiation-induced solid tumors and myeloid neoplasms, these are rare late complications [37,40-42].

Preliminary results of an Early Breast Cancer Trialists' Collaborative Group meta-analysis of trials including over 40,000 women randomly assigned to radiation or not reported that radiation was associated with an increase in overall second cancer incidence (RR 1.23, 95% CI 1.12-1.36), and increased rates, specifically of [43]:

●Contralateral breast cancer (881 versus 673 cases; RR 1.20, 95% CI 1.08-1.33),

●Esophageal cancer (RR 2.42, 95% CI 1.19-4.92), mainly in trials including irradiation of the internal mammary chain nodes and supraclavicular fossa where the esophagus was not shielded from the radiation field,

●Leukemia (RR 1.71, 95% CI 1.05-2.79), and

●Lung cancer incidence in the second decade following RT (RR 2.10, 95% CI 1.48-2.98). The risk was increased primarily in women who smoked prior to and after their diagnosis of breast cancer.

However, the absolute risk of developing a secondary malignancy because of radiation is small. In a cohort study of 58,000 patients treated for invasive breast cancer, although the 10-year risk of a second nonbreast primary cancer relative to the general population was elevated (RR 1.22, 95% CI 1.17-1.27), this translated into approximately 13 cancers per 1000 women [37].

The risk of a secondary malignancy after RT varies on the time that has elapsed since treatment was completed. As an example, secondary leukemias (usually myeloid) tend to occur within five to seven years; solid tumors, including esophageal cancer, usually present at least 10 years after radiation [44-46]. However, radiation-induced angiosarcoma typically presents with a latency period of five to eight years. These issues are discussed in detail elsewhere. (See "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging".)

Women with germline mutations in p53 are at high risk for second malignancies as a result of radiation exposure and should not be treated with this modality. (See "Li-Fraumeni syndrome", section on 'Breast cancer'.)

Chemotherapy — The cumulative incidence of developing treatment-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is generally less than 1 percent, but corresponds to a twofold increased risk of AML/MDS for patients treated with adjuvant therapy as compared with controls (five excess cases per 10,000 treated patients at 10 years) [37-39,46-57]. Two-thirds of these patients are first recognized by evidence of myelodysplasia (usually trilineage dysplasia), marrow failure, and pancytopenia. In general, treatment-related leukemias are more refractory to conventional antileukemic therapy, and they have a very poor prognosis. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Ovarian failure — The ovaries of premenopausal women who received chemotherapy typically have normal to mildly decreased numbers of primordial follicles and a greater decrease in the numbers of maturing follicles, indicating a greater effect on follicular development than on oocytes [58,59]. Consistent with these histologic findings are the clinical observations that many premenopausal women are amenorrheic during chemotherapy, often with high serum gonadotropin concentrations, but that menstrual function and fertility often return several months to years after the cessation of therapy [60,61]. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer", section on 'Chemotherapy-induced amenorrhea'.)

For women who develop long-term, chemotherapy-induced ovarian failure, the adverse effects of premature menopause may be significant (see "Clinical manifestations and diagnosis of menopause"). The approach to management of ovarian failure is discussed separately. (See "Approach to the patient following treatment for breast cancer".)

The impact of changing trends in antiestrogen therapy — As noted in this section and elsewhere, antiestrogen therapy is playing an increasing role in the management of the 65 to 75 percent of women with hormone-receptor-positive malignancies. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer".)

Accumulating data from adjuvant trials examining the impact of genomic signatures on selection of therapy are progressively reducing the proportion of patients who will receive chemotherapy in the future. On the other hand, data supporting improved outcomes for some patients as a result of extended duration and increased intensity of endocrine therapy place a new emphasis on understanding and attempting to mitigate the side effects of these regimens, which are administered over years rather than weeks. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Receptor status' and "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer".)

Cognitive issues and constitutional effects are well described in many of the trials and substudies that have supported the efficacy of these treatments [62].

Cognitive dysfunction — The extent of disability associated with treatment-related cognitive dysfunction (eg, impaired memory and decreased ability to concentrate, also known as "chemo-brain") is not well characterized [63-67]. Data suggest that cognitive dysfunction related to chemotherapy may be an issue for breast cancer survivors. In addition, symptoms appear to stabilize with the passage of time. Patients considering chemotherapy may be counseled that the acute effect of treatment on cognitive functioning stabilizes six months following completion of treatment (the cutoff point used in this study). However, patients may be aware of minor cognitive dysfunction affecting verbal and visuospatial abilities. Strategies to compensate for these difficulties should be discussed with the patient [68]. (See "Cognitive function after cancer and cancer treatment", section on 'Breast cancer'.)

Fatigue — A sense of fatigue may persist in survivors for years after cessation of treatment. In one study, for example, approximately 30 percent of breast cancer survivors had moderate to severe fatigue more than two years after treatment [69-71]. Before assuming that fatigue is related to prior treatment for breast cancer, treatable reasons for low energy should be ruled out, including anemia, thyroid dysfunction, pain, depression, and lack of sleep. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Prevalence and time course' and "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

Psychological effects — Women may experience heightened anxiety after the completion of therapy. This can be attributed to worry about the risk of recurrence and the loss of the security that many feel while they are actively undergoing therapy. Feelings of uncertainty can persist for years. Dealing with this uncertainty is often the most difficult part of the recovery, and fear of recurrence may extend well past the initial five years of cancer survivorship.

An example of the long-term psychological complications comes from a 20-year follow-up study involving 153 patients who participated in a phase III clinical trial conducted by the Cancer and Leukemia Group B [72]. Although the incidence of clinical distress was only 5 percent in this study, 15 percent had two or more symptoms of post-traumatic stress disorder (PTSD). Statistically significant factors associated with PTSD included lower level of education, less social support availability, more negative life events, and a greater sense of dissatisfaction with medical care.

APPROACH TO THE LONG-TERM SURVIVOR — Guidelines from the American Society of Clinical Oncology (ASCO) suggest that if a patient with early-stage breast cancer (tumor <5 cm and fewer than four positive nodes) desires follow-up exclusively with a primary care clinician, care may be transferred approximately one year after diagnosis [73,74]. In such cases, both the patient and the primary care clinician should be advised of the appropriate follow-up and management strategy.

For patients receiving adjuvant hormonal therapy, informed decisions regarding long-term options are best managed with referral for oncology assessment, as endocrine strategies are evolving over time. Additionally, oncologic consultation is indicated if there is suspicion or evidence of disease recurrence, or questions arise regarding the safety of certain interventions (eg, vaginal estrogen in a patient who has severe atrophic vaginitis despite nonhormonal remedies). (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer".)

Breast cancer survivors should receive ongoing age-appropriate screening studies and preventive care, consistent with recommendations for the general population, for conditions other than those related to breast cancer and its treatment. Patients with a history of breast cancer are recommended to undergo regular follow-up to include medical history, physical examination, evaluation and management of treatment-related late effects, and breast imaging to assess for recurrence or new primary disease. Magnetic resonance imaging (MRI) should not be a routine part of surveillance for all women treated for breast cancer. However, for women with a known breast cancer susceptibility gene (BRCA) mutation, or other moderate- to high-risk pathogenic variants, an MRI is often a part of the surveillance following treatment of breast cancer. Women who have had radiation exposure to the chest, particularly before age 30 years (eg, mantle radiation for Hodgkin disease) are at very high risk for development of breast cancer with onset beginning approximately 10 years from treatment exposure and increasing thereafter. These women are also candidates for enhanced imaging surveillance including annual breast MRI.

Data are sparse to inform optimal follow-up of male breast cancer survivors; recommendations for women are usually applied to men, with modification as appropriate.

A more extensive discussion on the follow-up of long-term breast cancer survivors is covered separately. (See "Approach to the patient following treatment for breast cancer".)

SUMMARY

●Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. In the United States, breast cancer is the most common female cancer, the second most common cause of cancer death in women, and the main cause of death in women ages 40 to 49 years. (See 'Introduction' above.)

●Women who have undergone either mastectomy or breast-conserving therapy (BCT) are at risk for locoregional recurrence. Women who undergo BCT without radiation therapy (RT) have a much higher rate of local recurrence compared with those who receive RT, although this has not been found to increase overall or breast cancer-specific mortality in women older than age 65 years. For patients who have received RT after breast-conserving surgery, local recurrences tend to occur later than after mastectomy. (See 'Locoregional recurrence' above.)

●The most common sites of metastases are bone, liver, and lung. Approximately 50 to 75 percent of patients who relapse distantly do so in a single organ; the remainder will go on to develop diffuse metastatic disease. (See 'Second primary breast tumors' above and 'Metastatic disease' above.)

●Breast surgery, breast reconstruction, and RT may result in long-term complications in the breast and chest wall. These include formation of seromas, recurrent skin infections, and rarely, soft tissue necrosis. (See 'Chest wall and breast complications' above.)

●Musculoskeletal complications can also be attributed to several modalities used to treat breast cancer. This includes reduced arm mobility and lymphedema secondary to surgery; pain, motor restriction, and a higher risk of fractures secondary to RT; and muscle and joint pains due to aromatase inhibitors. (See 'Musculoskeletal' above.)

●Both breast surgery and radiation can lead to the development of lymphedema of the breast, chest, arm, and hand. Rates of lymphedema are highest in women who undergo breast-conserving surgery or mastectomy that is accompanied by a full axillary lymph dissection plus breast/chest wall and comprehensive nodal RT. (See 'Lymphedema' above.)

●Breast surgery, RT, and chemotherapy can be associated with nerve injury, which can cause long-term symptoms of paresthesias, weakness, and/or persistent pain. (See 'Neurologic' above.)

●Cardiovascular disease may be a complication of breast RT if a portion of the heart is in-field and specific agents are used in the treatment of breast cancer, especially anthracyclines and the human epidermal growth factor 2 (HER2)-directed agent trastuzumab, especially in combination with left-sided breast irradiation. Symptoms of early congestive heart failure should prompt a cardiac evaluation. (See 'Cardiovascular morbidity' above.)

●There is an increased risk for second cancers associated with breast cancer treatment, whether breast irradiation, chemotherapy, or tamoxifen. (See 'Second cancers' above.)

●The extent of disability associated with treatment-related cognitive dysfunction appears to be small. Cognitive ability stabilizes approximately six months following completion of chemotherapy, but may be ongoing during the long duration of antiestrogen treatment. Patients may be at risk for minor issues related to verbal and visuospatial abilities. (See 'Cognitive dysfunction' above.)

●Women may experience heightened anxiety after the completion of therapy, particularly worry about the risk of recurrence. Fear of recurrence can persist for years. (See 'Psychological effects' above.)

●Fatigue may persist in survivors for years after cessation of treatment. Before assuming that fatigue is related to prior treatment for breast cancer, treatable reasons for low energy should be ruled out, including anemia, thyroid dysfunction, pain, depression, and lack of sleep. (See 'Fatigue' above.)

●Breast cancer survivors should receive ongoing age-appropriate screening and preventive care, consistent with recommendations for the general population, for conditions other than those related to breast cancer and its treatment. (See "Approach to the patient following treatment for breast cancer".)

●Patients with a history of breast cancer should undergo regular follow-up including medical history, physical examination, surveillance mammography, and evaluation and management of treatment-related late effects, including assessment of psychosocial distress. Breast magnetic resonance imaging (MRI) for surveillance should not be performed as part of routine surveillance. (See "Approach to the patient following treatment for breast cancer".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Arti Hurria, MD, now deceased, who contributed to an earlier version of this topic review.