Daniel F Hayes, MD
Lori J Pierce, MD
Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
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INTRODUCTION — Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, characterized by diffuse dermatologic erythema and edema (peau d'orange).
The epidemiology, clinical features, treatment, and prognosis of IBC will be reviewed here. The pathology and molecular pathogenesis of IBC are presented separately. Locally advanced breast cancer is also discussed separately.
EPIDEMIOLOGY — Inflammatory breast cancer (IBC) is rare. It accounts for 0.5 to 2 percent of invasive breast cancers diagnosed in the United States, but may be higher elsewhere [1,2]. In the United States, its incidence appears to be increasing, particularly among white women [1-3]. As compared with locally advanced breast cancer, IBC is diagnosed at an earlier age (a median of 59 versus 66 years of age) . The incidence of IBC is higher in black Americans compared with whites, and black women are diagnosed at a younger age [1,2]. Data on risk factors are limited and inconclusive .
CLINICAL FEATURES — Patients with inflammatory breast cancer (IBC) typically present with breast pain or a rapidly growing, self-diagnosed breast lump . They may also report a tender, firm, or enlarged breast, or itching of the breast. On presentation, almost all women with IBC have lymph node involvement, and approximately one-third have distant metastases [5-7]. Therefore, some women may report swollen lymph nodes or localizing pain and symptoms depending on the location and extent of metastatic disease. IBC tends to have a higher preponderance of visceral metastases compared with other forms of breast cancer due to earlier and more aggressive hematogenous spread.
Typically the onset of symptoms is rapid, on the order of several weeks to months. Prior to diagnosis of IBC, many patients initially will be treated with antibiotics for presumed mastitis without clinical improvement, prompting further evaluation. Abnormal screening mammogram is the event that triggers diagnosis in less than 10 percent of cases .
On physical exam, the skin over the breast in IBC is typically warm and thickened, with a peau d'orange (skin of an orange) appearance (picture 1). The skin color can range from a pink flushed discoloration initially to redness or a purplish hue that seems to represent ecchymosis (picture 2). Nipple involvement may present as flattening, erythema, crusting, blistering, or retraction of the nipple . A discretely palpable lump may or may not be present.
DIAGNOSIS AND EVALUATION — The diagnosis of inflammatory breast cancer (IBC) is based upon the characteristic clinical presentation and the presence of invasive carcinoma on breast core needle biopsy.
Evaluation — IBC may be suspected in a patient who presents with rapidly progressive inflammation of the breast with no improvement with antibiotics. The initial evaluation focuses on establishing a diagnosis of invasive breast cancer, with subsequent evaluations to confirm histology and assess the extent of involvement. All patients with suspected IBC undergo breast imaging and biopsy.
Breast imaging — Suspected IBC should be imaged with diagnostic mammogram on the affected side and screening mammogram on the contralateral side, with accompanying ultrasound of the breast and regional lymph nodes. Mammographic findings of IBC may include an obvious tumor mass, a large area of calcification and/or parenchymal distortion, and skin thickening . Sometimes, mastitis and IBC without an underlying mass may have similar mammographic appearance. In such cases, if there has been no improvement after a short course of antibiotics (a week or less), biopsy is indicated to determine the diagnosis.
A photograph or other imaging of the breast at presentation may be useful in monitoring changes over time.
Biopsy — A core needle biopsy of the breast should be obtained to make the initial diagnosis of invasive carcinoma. For patients in whom IBC is suspected on the basis of history, physical, and core needle biopsy results, full-thickness skin punch biopsy should be obtained (preferably at least two) . This is because a hallmark of this disease is dermal lymphatic invasion by tumor cells, and this will be observed in most cases (though it is not necessary to make the diagnosis of IBC). Further discussion of the pathologic features of IBC is covered elsewhere. (See "Breast biopsy" and "Diagnostic evaluation of women with suspected breast cancer" and "Inflammatory breast cancer: Pathology and molecular pathogenesis".)
As with other invasive breast cancers, all IBC tumors should undergo testing for hormone receptors and human epidermal growth factor receptor 2 (HER2). (See "HER2 and predicting response to therapy in breast cancer", section on 'Testing for HER2 expression' and "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy", section on 'Estrogen and progesterone receptors'.)
Diagnostic criteria — IBC is designated as T4d in the American Joint Committee on Cancer (AJCC) Tumor, Nodes, Metastasis (TNM) staging system . All of the following criteria must be met for diagnosis of IBC :
●Rapid onset of breast erythema, edema and/or peau d’orange, and/or warm breast, with or without an underlying palpable mass. (See 'Clinical features' above.)
●Duration of history no more than six months.
●Erythema occupying at least one-third of the breast.
●Pathologic confirmation of invasive carcinoma. (See 'Biopsy' above and "Inflammatory breast cancer: Pathology and molecular pathogenesis".)
Staging and pretreatment evaluation — Routine laboratory tests, including a complete blood count with platelets, liver function tests, and serum alkaline phosphatase, should be obtained in individuals with suspected or diagnosed IBC. These tests are part of the pretreatment chemotherapy evaluation; abnormalities in these tests may also suggest potential metastatic disease.
For diagnosed cases of IBC, we obtain computed tomography (CT) scans of the chest, abdomen, and pelvis (optimally with intravenous contrast), and a bone scan given that many patients have metastatic disease at presentation. For women with palpable or suspicious axillary lymph nodes, we also perform an ultrasound-guided fine needle aspiration (FNA) and/or a core needle biopsy of the suspicious nodes in order to make a more accurate determination of the tumor stage. There are limited data on the value of additional imaging studies of the breast, including magnetic resonance imaging and positron emission tomography (PET), and we do not routinely obtain these tests unless other imaging modalities provide equivocal results . Routine brain imaging should not be obtained for IBC in the absence of symptoms. Our approach is in line with recommendations from an international expert group on IBC .
The role of imaging studies in monitoring response to therapy is discussed separately. (See "General principles of neoadjuvant therapy for breast cancer", section on 'Clinical assessment and indications for imaging'.)
DIFFERENTIAL DIAGNOSIS — Several conditions may be confused with inflammatory breast cancer (IBC), leading to potentially preventable delays in diagnosis and treatment.
●Non-inflammatory breast cancer – Not all skin changes that occur with breast cancer qualify as IBC. It may be difficult to differentiate IBC from non-inflammatory, locally advanced breast cancer that involves the skin. However, tumor presentation with ulceration, satellite skin nodules, edema, skin dimpling, or nipple retraction alone, without the other diagnostic criteria does not qualify as IBC. (See 'Diagnostic criteria' above.)
●Infectious mastitis and breast abscess – Infections of the breast, which typically occur in lactating women, can have similar clinical and mammographic appearance to IBC. Such infections are generally associated with fever and leukocytosis, whereas IBC is not a true inflammatory process. Mastitis typically improves with antibiotics. (See "Nonlactational mastitis in adults" and "Primary breast abscess".)
●Ductal ectasia – Ductal ectasia is a benign condition of middle age related to collection of debris in and swelling of the ducts. Unlike in IBC, the inflammation that can accompany ductal ectasia is usually localized. Often, this condition improves without treatment.
●Other malignancies – Rarely, other malignancies such as breast lymphoma or leukemia may also mimic the clinical presentation of IBC. These are differentiated from IBC based on pathology. (See "Breast lymphoma".)
TREATMENT OF INFLAMMATORY BREAST CANCER
Approach to treatment — Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer (LABC). In general, women with IBC without distant metastatic disease are approached similarly to those with non-inflammatory LABC. The main exception is that breast conservation therapy (BCT) and sentinel lymph node biopsy (SLNB) are inappropriate for women with IBC, even in the presence of a strong response to neoadjuvant therapy . Given the relative rarity of this disease and the need for more information about the efficacy of drugs against IBC, inflammatory breast cancer patients should be made aware of clinical trials for which they are eligible.
Multimodality therapy is standard for non-metastatic disease and includes neoadjuvant chemotherapy followed by mastectomy and postmastectomy radiation. Our approach to IBC without evidence of distant metastatic disease is summarized below.
●For neoadjuvant therapy, we utilize an anthracycline- and taxane-based chemotherapy regimen (see 'Neoadjuvant chemotherapy' below). Additional therapies depend on tumor receptor status:
•Patients with IBC and human epidermal growth factor receptor 2 (HER2) overexpression should receive HER2-directed therapy (trastuzumab with or without pertuzumab) with neoadjuvant chemotherapy, although we avoid giving trastuzumab and anthracyclines concurrently given the risk for cardiotoxicity. Trastuzumab should be continued postoperatively for a total of one year of treatment. (See 'HER2-positive tumors' below.)
•For women with hormone receptor-positive disease, endocrine therapy should be initiated after completion of neoadjuvant therapy and continued in the adjuvant setting. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer".)
●Subsequent therapy depends on response to neoadjuvant treatment:
•Patients who have an operable tumor following neoadjuvant therapy should proceed with mastectomy with axillary dissection (BCT and SLNB are not recommended). Immediate reconstruction following surgery should be avoided given the high risk for local recurrence. Radiation therapy to a total dose of at least 60 gray (Gy) should follow mastectomy. However, women with poor-risk features may benefit from dose escalation. (See 'Surgery' below and 'Radiation therapy' below.)
•For patients who do not have an operable tumor following neoadjuvant therapy, we typically treat with second- and third-line chemotherapy agents such as carboplatin, vinorelbine, and capecitabine. If the tumor remains unresectable, preoperative RT to attempt to downstage the tumor may be pursued. (See 'Unresectable disease after neoadjuvant therapy' below.)
Metastatic IBC is managed similarly to metastatic non-inflammatory breast cancer and is discussed in detail elsewhere. (See "Systemic treatment for metastatic breast cancer: General principles".)
Neoadjuvant chemotherapy — Neoadjuvant chemotherapy is the standard approach for IBC. We utilize anthracycline- and taxane-based neoadjuvant chemotherapy. A commonly utilized regimen is dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) (table 1). Addition of HER2-directed agents is appropriate for tumors that overexpress HER2 (see 'HER2-positive tumors' below). If a patient has completed standard neoadjuvant chemotherapy, there is no role for additional postoperative chemotherapy.
The rationale for neoadjuvant chemotherapy is to reduce tumor burden, thereby facilitating surgery. The optimal chemotherapy regimen and schedule for IBC in particular is undefined. Our preference for dose-dense AC-T is consistent with recommendations from an international expert panel on IBC . Most evidence supporting this regimen comes from observational studies and extrapolation from LABC [9,13-16]. The details of neoadjuvant chemotherapy selection and administration are discussed separately. (See "General principles of neoadjuvant therapy for breast cancer".)
Monitoring of the response to primary systemic therapy is discussed elsewhere. (See "General principles of neoadjuvant therapy for breast cancer", section on 'Clinical assessment and indications for imaging'.)
High-dose chemotherapy followed by autologous stem cell transplantation has been investigated in patients with IBC. Although high objective and pathologic response rates were achieved, there was no convincing improvement in disease-free or overall survival [17-24]. Moreover, this approach was associated with markedly increased toxicity and worse quality of life compared with standard-dose chemotherapy.
Locoregional treatment — Strategies for locoregional treatment depend on the response to neoadjuvant chemotherapy.
For patients who experience a response to treatment such that the disease is operable, we proceed with mastectomy and axillary dissection followed by radiation therapy. (See 'Surgery' below and 'Radiation therapy' below.)
For patients in whom the response to neoadjuvant chemotherapy is weak, such that they are not operable even after neoadjuvant chemotherapy, we treat with radiation therapy. If subsequent response occurs such that the tumor becomes resectable, surgery should then be pursued. (See 'Radiation therapy' below.)
Surgery — Mastectomy with axillary dissection is an integral part of the multimodality treatment of IBC. Surgery should only be attempted if a macroscopically complete resection can be accomplished . Patients who remain inoperable should receive locoregional RT, followed by surgery, if feasible. (See "General principles of neoadjuvant therapy for breast cancer", section on 'Poor response or progression on neoadjuvant therapy'.)
Case series have demonstrated that mastectomy improves local control, disease-free survival, and cancer-specific survival in IBC compared with radiation and chemotherapy or radiation alone [26,27]. Some have questioned whether mastectomy can be replaced with breast-conservation surgery, especially for patients who achieve a complete clinical response to neoadjuvant chemotherapy [28-30]. However, limited data suggest that the rate of local failure in IBC is higher with BCT compared with mastectomy . In this study including 23 patients who underwent neoadjuvant chemotherapy followed by radiation and either BCT or mastectomy, failure to control local disease was observed in 2 of 10 patients undergoing mastectomy and in 7 of 13 patients undergoing BCT. Skin-sparing mastectomy is contraindicated for women with IBC given high rates of local failure.
Given the aggressive nature of IBC and frequency of involved axillary lymph nodes, as well as the high false-negative rate of SLNB in cases of IBC, axillary dissection is suggested instead of an SLNB. In a study of the efficacy of SLNB after neoadjuvant chemotherapy, among eight women with IBC, the sentinel lymph node was not identified in two cases and was falsely negative in two cases .
Because patients with IBC need postmastectomy radiation, breast reconstruction is preferred to be delayed until after radiation. Although several small studies report reasonable success with immediate as compared with delayed reconstruction in IBC [32,33], the presence of a reconstructed breast can, in some patients, limit radiation coverage, particularly of the internal mammary lymph nodes . (See "Overview of breast reconstruction", section on 'Radiation therapy and timing of breast reconstruction'.)
Radiation therapy — Radiation therapy (RT) should be administered to all patients with IBC. For patients who respond to neoadjuvant chemotherapy, RT is generally given postoperatively rather than preoperatively because higher doses are more readily achieved [35,36]. Although a survival benefit for RT has not been definitively proven in patients with IBC, the improvement in locoregional control makes RT an important part of their management.
Complications may include acute skin changes, including moist desquamation, and uncommonly, late complications such as brachial plexopathies, lymphedema, pneumonitis, rib fractures, and chest wall fibrosis. Patients treated with axillary node dissection and radiation are also at heightened risk for developing lymphedema. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients treated with mastectomy'.)
Our approach is to utilize standard fractionation RT including coverage to the chest wall, axilla, supra- and infraclavicular nodes, and internal mammary nodes. Some experts, however, omit radiation to the axilla for patients who have no evidence of nodal disease at the time of their axillary dissection in order to avoid the additional risk of lymphedema. Generally, patients receive 50.4 or 50 Gy in 1.8 or 2 Gy fractions to locoregional sites followed by a 10 Gy boost to the chest wall (total dose 60 Gy).
However, an accelerated hyperfractionation schedule to a total of 66 Gy is an alternative option for patients with any of the following risk factors, provided that they are willing to accept a potentially increased risk of toxicity [36-38]:
●<45 years of age
●Close or positive margins
●Four or more positive nodes following preoperative systemic treatment
●A poor response to preoperative systemic treatment
Support for dose escalation with accelerated hyperfractionation schedules comes from small observational or retrospective studies that suggest an improvement in locoregional control [36,37,39,40]. Examples are described below:
●In a series of 61 patients with IBC, patients who received twice-daily postmastectomy RT to a total dose of 66 Gy experienced an improved five-year rate of locoregional control compared with those treated twice daily to a total of 60 Gy (84 versus 58 percent) . There was also a trend towards improved disease-free survival in the patients who received the higher dose of radiation.
●In a later review of 192 patients with IBC treated at the same institution with combined modality therapy, escalation of the postmastectomy radiation dose from 60 to 66 Gy improved locoregional control for patients who experienced less than a partial response to chemotherapy; had positive, close, or unknown surgical margins; or were under the age of 45 .
Additional treatment for specific populations — Considerations regarding adjuvant therapy are as follows:
HER2-positive tumors — Trastuzumab should be utilized in the neoadjuvant and adjuvant setting for IBC that overexpresses HER2 to complete a year of treatment. Timing of initiation of HER2-directed agents follows similar principles as for non-inflammatory breast cancer and is discussed in detail elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Timing of HER2-directed agents'.)
Pertuzumab may also be given with chemotherapy and trastuzumab. The rationale and indications for this agent are the same as those for non-inflammatory, HER2-positive disease and are discussed in detail elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Components of therapy'.)
Trastuzumab-associated cardiotoxicity and pretreatment assessment and monitoring of cardiac function are reviewed in detail separately. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Overview of the treatment of newly diagnosed, non-metastatic breast cancer".)
Hormone receptor-positive disease — Adjuvant endocrine therapy is recommended for hormone receptor-positive IBC and should be administered in a similar fashion as in hormone receptor-positive, non-inflammatory breast cancer. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer".)
Unresectable disease after neoadjuvant therapy — For patients with non-metastatic disease for whom surgery is not feasible even after the completion of a course of neoadjuvant chemotherapy, further efforts are directed at downstaging the tumor such that surgery may be performed. While data in this setting are limited, our approach is to utilize single-agent chemotherapies such as carboplatin, vinorelbine, or capecitabine for patients who are candidates for further chemotherapy. If patients are not candidates for further chemotherapy, or if the tumor continues to be chemoresistant after two or three lines of systemic treatment, we next utilize RT in attempts to decrease the extent of the disease. For patients whose tumor becomes resectable with these treatments, mastectomy and axillary node dissection should be pursued.
For patients who develop metastatic disease during the course of these therapies or do not have an adequate response, further treatment is similar to metastatic non-inflammatory breast cancer and is discussed elsewhere. (See "Systemic treatment for metastatic breast cancer: General principles".)
PROGNOSIS — Inflammatory breast cancer (IBC) is associated with a particularly poor prognosis and high risk of early recurrence, although with proper primary and adjuvant therapies, the survival rate is much higher than in the past [3,41]. Poor prognostic features include triple-negative receptor status, hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative status, four or more involved lymph nodes prior to therapy, and lack of response to neoadjuvant chemotherapy [23,42-47]. HER2-positive IBC may have an equivalent or marginally better prognosis compared with HER2-negative IBC, unlike in the case of non-inflammatory breast cancer [48,49].
The adoption of neoadjuvant chemotherapy has improved outcomes for IBC. Historically, single-modality therapy for IBC was associated with five-year overall survival rates of less than 10 percent . However, with neoadjuvant chemotherapy followed by surgery and RT, reported overall five-year survival rates range between 30 and 70 percent [8,26,35,43,44,46,50]. Longer interval follow-up also suggests an improvement in outcomes for IBC. An analysis from the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 20-year cancer-specific survival of 20 versus 9 percent for patients with IBC treated in 1995 compared with 1975 .
However, despite improvements in treatment, the survival rate for patients with IBC remains significantly worse compared with women with non-inflammatory, locally advanced breast cancer (LABC). In a subsequent report from the SEER database, for breast cancer cases diagnosed between 2004 and 2007, the two-year breast cancer-specific survival rate of patients with IBC versus non-inflammatory LABC was 84 versus 91 percent (hazard ratio [HR] for death 1.43, 95% CI 1.10-1.86) .
FOLLOW-UP — The goal of posttreatment surveillance after primary treatment for breast cancer is early recognition and treatment of disease recurrences, second primary breast cancers, and therapy-related complications. The approach is similar to that for non-inflammatory breast cancer and is discussed elsewhere. (See "Approach to the patient following treatment for breast cancer" and "Patterns of relapse and long-term complications of therapy in breast cancer survivors".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Inflammatory breast cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Locally advanced and inflammatory breast cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Inflammatory breast cancer (IBC) is characterized by diffuse erythema and edema (peau d'orange) involving a third or more of the skin of the breast.
●The diagnosis of IBC is based upon the presence of all of the following clinical criteria: rapid onset of breast erythema, edema and/or peau d’orange, and/or warm breast; duration of history of no more than six months; erythema occupying at least one-third of the breast; and pathologic confirmation of invasive carcinoma. (See 'Diagnosis and evaluation' above.)
●For diagnosed cases of IBC, we obtain computed tomography (CT) scans of the chest, abdomen, and pelvis (optimally with intravenous contrast), and a bone scan given that many patients have metastatic disease at presentation. For women with palpable or suspicious axillary lymph nodes, we also perform an ultrasound-guided fine needle aspiration (FNA) and/or a core needle biopsy of the suspicious nodes in order to make a more accurate determination of the tumor stage. (See 'Staging and pretreatment evaluation' above.)
●For patients with non-metastatic IBC, we recommend neoadjuvant chemotherapy followed by locoregional treatment (Grade 1B). The optimal neoadjuvant chemotherapy regimen, including the sequence of agents and duration of treatment, is undefined, though anthracycline- and taxane-based chemotherapy regimens are typically recommended. Trastuzumab is indicated for human epidermal growth factor receptor 2 (HER2)-positive disease. (See 'Neoadjuvant chemotherapy' above.)
●Additional treatment considerations are similar to non-inflammatory breast cancer, including the use of endocrine therapy for hormone receptor-positive disease, the use of HER2-directed therapy for HER2-overexpressing disease, and the use of systemic agents for metastatic cancer. These issues are discussed in detail elsewhere. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer" and "Systemic treatment for metastatic breast cancer: General principles".)
●For patients with IBC (including patients who achieve pathologic complete response to neoadjuvant chemotherapy), we recommend postmastectomy radiation therapy (Grade 1B). (See 'Radiation therapy' above.)
●Although IBC is associated with a particularly poor prognosis and high risk of early recurrence, there is evidence that outcomes have improved with neoadjuvant chemotherapy followed by locoregional treatment. (See 'Prognosis' above.)
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