Inflammatory Breast Cancer

Authors: Holly Dushkin MD1 and Massimo Cristofanilli MD1
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  • 1 From the Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Inflammatory breast cancer (IBC) represents the most virulent form of breast cancer, characterized by involvement of the skin and rapid progression of the disease. Management involves careful coordination of multidisciplinary modalities, including imaging, systemic chemotherapy, surgery, and radiation therapy. The use of neoadjuvant chemotherapy has contributed significantly to improvement in overall survival since the first descriptions of this entity, and has made the role of locoregional therapy, including surgery and radiation, critical to continued improvements in this disease. This article examines the unique epidemiology and pathology of IBC, and reviews the various treatment modalities, noting the significance of a multimodality approach and delineating each of the specific components. Moreover, the current research in IBC is briefly described, which experts hope will further improve systemic therapies.

Medscape: Continuing Medical Education Online

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This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and JNCCN – The Journal of the National Comprehensive Cancer Network. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscapecme.com/journal/jnccn; (4) view/print certificate.

Release date: February 7, 2011; Expiration date: February 7, 2012

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Evaluate the epidemiology and clinical presentation of IBC
  • Distinguish effective imaging modalities in cases of suspected IBC
  • Analyze effective management strategies for cases of IBC

Overview/Epidemiology

Inflammatory breast cancer (IBC) is an aggressive form of disease accounting for 1% to 5% of all breast cancers diagnosed in the United States.1 Lee and Tannenbaum2 first used the term inflammatory breast cancer in 1924 to describe this clinical presentation. Subsequently, Haagensen3 described diagnostic criteria for IBC, including a rapidly enlarging breast, erythema involving at least one third of the breast, generalized induration, and biopsy-proven carcinoma.

IBC is a clinicopathologic entity characterized by distinct skin changes, including diffuse erythema and edema (peau d'orange), often without a clinically evident underlying mass.4 It is associated with abrupt onset and rapid progression, with a high risk of axillary lymph node involvement, and distant metastases at initial diagnosis.5 Despite multimodality therapy, survival rates are lower than those for other breast cancers. Its aggressive course, together with accumulating molecular and epidemiologic data, also supports the concept that IBC may be a distinct biologic entity rather than a subtype on the spectrum of locally advanced breast cancer. In fact, several important epidemiologic aspects of IBC are known and support this notion, such as the higher incidence in African-Americans, the younger age at onset, the association with high body mass index, and the relatively poor prognosis compared with breast cancer overall.6

Other aspects, such as the incidence of disease, the identification of risk factors, the consistency of biomarker assays, and even the effectiveness of different therapeutic modalities, are difficult to interpret largely because of the differences in the definition of this entity. Currently, the most widely referenced case definition is that of the American Joint Committee on Cancer (AJCC),7 which states in part that

“inflammatory carcinoma is a clinicopathologic entity characterized by diffuse erythema and edema (peau d'orange) of the breast, often without an underlying mass. These clinical findings should involve the majority of the breast...It is important to remember that inflammatory carcinoma is primarily a clinical diagnosis. Involvement of the dermal lymphatics alone does not indicate inflammatory carcinoma in the absence of clinical findings.”

Clinical and Biologic Characteristics

IBC is primarily a clinical diagnosis. One of the commonly described changes associated with IBC is erythema, with the skin overlying the breast showing a pink or mottled pink hue (Figure 1A). The erythema may be associated with a sensation of heat in the affected breast. Concurrently or soon after, the breast begins to enlarge rapidly, sometimes increasing in size 2- to 3-fold within a few weeks (Figure 1B). This rapid rate of progress, along with diffuse erythema of more than one third of the skin overlying the breast, distinguishes IBC from neglected locally advanced breast cancer with skin involvement. In more advanced and aggressive cases, the area can change color dramatically within a few days, turning from pinkish to dark red or purple, spreading diffusely over the entire breast. The increased size of the breast is the result of edema caused by tumor blockage of the lymphatic channels. Although nipple involvement is not a principal feature of IBC, flattening, retraction, crusting, or blistering may be apparent on examination. These nonspecific characteristics can ultimately result in delayed diagnosis, and other disease states can be confused with IBC. Infectious mastitis and abscess typically occur only in lactating women. The inflammation associated with ductal ectasia is more localized and responds quickly to supportive measures. Sarcomatous, lymphomatous, or leukemic involvement of the breast requires histologic examination for accurate diagnosis.8

Figure 1
Figure 1Figure 1

Clinical signs of inflammatory breast cancer. A) Patient presenting with erythema and increased breast size. B) Detailed view of involved breast.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 2; 10.6004/jnccn.2011.0018

It is important to distinguish 2 distinct clinical varieties of IBC that are commonly cited in the literature. Primary IBC is used to describe the de novo development of IBC in a previously normal breast. Unlike primary IBC, secondary IBC describes the development of inflammatory skin changes that mimic IBC in either a breast that already has cancer or on the chest wall after a mastectomy for a noninflammatory breast cancer. (Figure 2). The breasts are usually photographed during the examination, because response to treatment can be monitored by reduction of the erythema and edema.

IBC is not a specific histologic subtype and can occur with invasive ductal and lobular, small cell, medullary, and large cell carcinomas. Although skin changes in IBC resemble an acute inflammatory process, these changes in fact result from dermal lymphatic invasion by tumor emboli, leading to obstruction of lymphatic drainage.9 Although dermal lymphatic invasion is not a prerequisite for diagnosis, because it can also be found in locally advanced or neglected breast cancers, the presence of tumor emboli is a more distinct pathologic feature of IBC. Therefore, in addition to diagnostic core biopsy, a full-thickness skin biopsy is often obtained if IBC is suspected.

Distinct biologic characteristics typical of IBC are associated with poor outcome, including high S-phase fraction, high grade, aneuploidy, lack of estrogen and progesterone receptor expression, and overexpression of human epidermal growth factor receptor 2 (HER2).1012 Inflammatory breast tumors are more likely to have mutations in p53, associated with decreased response to chemotherapy and decreased survival outcomes.13 Several genes have been identified that are believed to contribute to the aggressive nature of IBC. Expression of nuclear factor kappa β–related genes, which mediate cell migration, invasion, and metastasis, was reported to be higher in IBC.14 Overexpression of RhoC GTPase, a member of the Ras family of guanosine-5'-triphosphate (GTP)–binding proteins, upregulate angiogenic factors (e.g., vascular endothelial growth factor [VEGF], basic fibroblast growth factor), promoting cell motility and invasion.15 IBC is associated with loss of expression of Wisp-3, a tumor suppressor gene coding for insulin-like growth factor binding protein–related protein (IGFBP-rP9) regulates tumor cell growth and invasion.16 Currently, except for HER2 status, these features are rarely used for treatment decisions in IBC.

Figure 2
Figure 2

Clinical presentation of diffuse recurrent inflammatory breast cancer. The patient presented with skin rash and skin nodules.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 2; 10.6004/jnccn.2011.0018

Diagnostic Modalities

In most cases of IBC no discrete mass is palpable on clinical examination, but imaging studies may show an underlying mass and characteristic thickening of the skin (Figure 3).17 Although IBC is a clinicopathologic entity, the key role of imaging studies is to identify a primary breast tumor, facilitate biopsy for evaluation of biomarkers, stage locoregional and metastatic disease, and evaluate tumor response to neoadjuvant therapy.

Figure 3
Figure 3

A 33-year-old woman with right inflammatory breast cancer. An axial postcontrast T1-weighted VIBRANT MR image shows diffuse skin thickening in the right breast, with large multifocal disease mostly localized in the right lower quadrant.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 2; 10.6004/jnccn.2011.0018

Although mammography is believed to be the gold standard in breast imaging, findings in IBC are less sensitive, detecting only 43% of primary lesions.18 The most common mammographic finding is skin thickening, and this may be missed without clinical correlation. The advent of digital mammography with improved contrast resolution, however, has increased detection of skin thickening and diffuse increased breast density often associated with IBC. Ultrasonography can identify an area of heterogeneous infiltration and may be used in conjunction with mammography. The greatest benefit of ultrasound, however, may be detection of nodal involvement, both for locoregional therapeutic planning and for evaluating response to induction therapy. Ultrasonography has been reported to detect up to 93% of ipsilateral axillary nodal involvement and up to 50% of infraclavicular, internal mammary, or supraclavicular nodal involvement.19

The use of MRI has been found to be the most accurate test for detecting a primary breast lesion in IBC.20 MRI findings frequently observed in IBC include diffuse skin thickening, breast enlargement, edema, and a mass or parenchymal enhancement. Other findings can include dilated lymphatic ducts or chest wall edema. MRI has also been used to monitor response to chemotherapy, correlating better with actual residual disease than measurements determined through clinical examination, mammography, or ultrasonography.21

FDG-PET/CT is an emerging imaging method that is widely gaining clinical acceptance because of its ability to co-register both anatomic and functional information on one image. Although prospective studies on the current use of FDG-PET/CT in primary breast cancer have suggested limited value in evaluating local lymph nodal disease,22 they have focused primarily on patients with early or small volume disease who have a low probability of lymph node involvement. These findings do not necessarily apply to patients with IBC who frequently have extensive locoregional disease and in whom appropriate delineation of disease extent is helpful for planning treatment, including radiotherapy and chemotherapy (Figure 4). A single study of 7 patients described increased uptake in enlarged breasts, with associated prominent skin uptake, and intense scattered foci.23 Associated ipsilateral axillary adenopathy was seen in 86% of patients, infraclavicular and supraclavicular adenopathy in 1 patient, and bone metastases in another.

A preliminary study on the role of PET/CT in 24 patients with IBC showed that PET/CT is accurate at demonstrating locoregional disease and distant metastases. Multicentric disease was documented in 63% of patients, regional nodal disease in 88%, and distant metastases in 38% of patients and primarily involved the liver, skeleton, and contralateral supraclavicular node in this study.19 Furthermore, the test was useful in detecting internal mammary lymph node involvement, predictive of recurrence risk and distant disease.24

Multimodality Approach to Treatment

Although IBC was once considered a uniformly fatal disease with fewer than 5% of patients alive at 5 years, management has evolved significantly over the past 40 years. A multimodality approach, including primary systemic chemotherapy followed by mastectomy and radiation therapy, has led to improved survival outcomes.25 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer (in this issue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) list the standard approach to treating IBC as neoadjuvant chemotherapy with an anthracycline-based regimen and a taxane. If HER2 is overexpressed, trastuzumab for a total of 1 year is indicated as part of the systemic chemotherapy regimen. Mastectomy with axillary lymph node dissection is standard in patients with IBC who respond to preoperative chemotherapy. After surgery, postmastectomy radiation is recommended with adjuvant endocrine therapy if indicated. A retrospective analysis of 179 patients with IBC by Perez et al.26 showed an improvement in 5- and 10-year disease-free survival in those who underwent multimodality therapy, including chemotherapy, surgery, and radiation (40% and 35%), compared with those who underwent radiation and surgery (24% and 24%) or radiation alone or with chemotherapy but without surgery (6% and 0%).

Neoadjuvant Chemotherapy

Because of its relative rarity and poor prognosis, most clinical trials of neoadjuvant chemotherapy have excluded IBC, and therefore most studies reported are based on small numbers of patients. The response to neoadjuvant chemotherapy has been found to be the most important prognostic factor in patients, including those with IBC (Table 1).27 These results extended the prognostic significance of response to treatment in patients with IBC. In 1997, Ueno et al.28 updated the 20-year experience of 178 patients with IBC treated in 4 prospective trials at MD Anderson Cancer Center. All patients underwent doxorubicin-based primary systemic chemotherapy, radiation therapy with or without mastectomy, followed by adjuvant chemotherapy. The overall response rate was 71%, with 5- and 10-year overall survival rates of 40% and 33%, respectively. An estimated 28% of patients were reported alive and without disease at 15 years.28 Other studies have also reported similar survival advantages for the addition of preoperative anthracycline-based chemotherapy to locoregional therapy, with higher disease-free and overall survival rates in those experiencing a pathologic complete response.2932

Table 1

Neoadjuvant Chemotherapy and Response Rates for Inflammatory Breast Cancer

Table 1
Figure 4
Figure 4

Three-dimensional (coronal, sagittal, and transaxial) display of the PET/CT images for a 47-year-old white female with newly diagnosed inflammatory breast cancer. Extensive active lesions are shown for this patient: 1) primary lesions of inflammatory breast cancer in the left breast (white arrow), 2) extensive left axillary lymph node involvement (blue arrow), and 3) an additional lesion in the left internal mammary node (green arrow); this lesion will likely change the radiation field.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 2; 10.6004/jnccn.2011.0018

The addition of taxanes to systemic chemotherapy in IBC has also been investigated. A retrospective analysis by Cristofanilli et al.33 reviewed 240 patients treated in 6 trials from 1973 to 2000. A total of 178 patients with IBC were treated with FAC alone (fluorouracil, doxorubicin, and cyclophosphamide) and 62 with FAC followed by paclitaxel. The pathologic complete response rate was significantly higher in those treated with FAC and paclitaxel (25% vs. 10%). The addition of paclitaxel led to improvement in progression-free (27 vs. 18 months) and median overall survival (54 vs. 32 months). In summary, the incorporation of primary systemic therapy into the combined modality approach has improved outcomes in the treatment of IBC; however, the outcome remains poor, and additional therapeutic interventions should consider the peculiar phenotype of the disease.

Several studies have documented increased frequency of HER2 overexpression in IBC.3439 Trastuzumab has been studied in combination with chemotherapy in IBC patients with pathologic complete response rates ranging from 17% to 40%.4042 Gianni et al.43 reported on a phase III prospective randomized trial evaluating the addition of trastuzumab to anthracycline- and taxane-based induction chemotherapy. Of 327 patients with locally advanced HER2-positive disease, 27% had IBC. The addition of trastuzumab to neoadjuvant chemotherapy led to a significantly increased 3-year event-free survival (70% vs. 53%). Lapatinib, a reversible inhibitor of the HER1 (ErbB1) and HER2 (ErbB2) tyrosine kinases, is also under evaluation in patients with IBC. In a phase II study of 21 patients with HER2-positive IBC who received induction lapatinib and paclitaxel, Boussen et al.44 reported that the combination was associated with a clinical response rate of 80%.

Several other novel agents are currently being studied for the treatment of IBC. IBC tumors are highly vascular tumors that express angiogenic factors such as VEGF.45 Gene expression patterns of human IBC xenografts have identified several angiogenesis-mediated genes, including VEGF, interleukin-8, bFGF, angiopoietin-13, Flt-1, Tie-2, and CD31.46 Based on studies indicating the importance of angiogenesis in IBC and the results observed with the use of antiangiogenic agents in other types of breast cancer, several studies evaluated the role of anti-VEGF agents (bevacizumab) and SU5416 in combination with chemotherapy in the treatment of IBC, but achieved no promising results.47,48 Multitargeted tyrosine kinases inhibitors directed at inhibition of the various members of the family of VEGF receptors may represent more active agents for the management of IBC and are currently being tested.49

Several members of the Ras pathway have also been proposed as potential molecular targets for treatment of IBC. Farnesyl transferase inhibitors, known to block the farnesylation of prenylated proteins (including the Rho subfamily of GTPases that is highly expressed in IBC) are currently also being studied in combination with chemotherapy in patients with breast cancer, including IBC.50

Locoregional Treatment

After neoadjuvant chemotherapy, standard locoregional treatment includes mastectomy with axillary lymph node dissection and radiation therapy. Patients who experience a pathologic complete remission after neoadjuvant chemotherapy have a significantly higher disease-free and overall survival compared with those who have extensive residual disease. Patients whose disease does not respond to induction chemotherapy may be considered for radiation therapy and then reevaluated.

Mastectomy with axillary lymph node dissection is the optimal surgical procedure for IBC. Axillary lymph node involvement at presentation is noted in 55% to 85% of patients with IBC and this remains an important prognostic factor. Case series have shown that mastectomy improves local control, disease-free survival, and cancer-specific survival.50 Removal of all gross disease is important, as skin lymphatic involvement may extend beyond the area of visible skin change. Clinical response by physical examination or imaging studies may underestimate the extent of residual disease.51 In a review of outcome data for patients with IBC after surgery, Curcio et al.52 found that negative margin status was associated with improved 3-year local control, disease-free survival, and overall survival (60% vs. 31%, 37% vs. 17%, and 47% vs. 0%, respectively). In a series of 192 patients with IBC treated at MD Anderson Cancer Center, the 5-year local control rate was 91% for patients with negative margins and 68% for those with positive margins.29

Postmastectomy chest wall radiation therapy is standard for patients with IBC after neoadjuvant chemotherapy followed by mastectomy. The chest wall and lymph nodes within the axillary, infraclavicular, supraclavicular, and internal mammary regions are targeted with standard fractionation to 50 Gy to locoregional sites followed by a 10-Gy boost to the scar. Given poor locoregional control rates for IBC, an interest has been shown in dose escalation with hyperfractionation. Liao et al.53 reported on 115 patients with IBC and found that escalating the dose from 60 to 66 Gy delivered with twice-daily fractionation significantly improved 5-year locoregional control rates (84% vs. 58%). Experience at MD Anderson has shown that treatment to a chest wall with a cumulative dose of 66 Gy was of clinical value for patients with a poor response to induction chemotherapy, positive surgical margins, and 4 or more positive lymph nodes after induction chemotherapy.54

Conclusions

IBC is an aggressive and often lethal form of breast cancer that can be misdiagnosed and therefore requires clinical suspicion and appropriate workup. Early and accurate diagnosis is essential. Diagnostic biopsies are extremely important; skin biopsy may provide information regarding dermal lymphatic involvement and is recommended. Although IBC is a clinicopathologic entity, imaging modalities such as mammography, ultrasound, MRI, CT, and PET/CT have been useful in diagnosing and staging this disease. Mammography typically shows nonspecific findings, and therefore MRI is also recommended. Such an aggressive disease with high incidence of metastasis at presentation suggests the indication for PET/CT in staging evaluation.

Although primary systemic chemotherapy with anthracycline- and taxane-based regimens are the mainstay of therapy, a multidisciplinary approach using adjuvant chemotherapy, radiation, and/or surgery is utmost importance. The use of this multidisciplinary approach in the treatment of IBC has resulted in significant increases in survival over the past 4 decades, from less than 5% to 44% at 15 years in patients who experience a pathologic complete response. The use of HER2 targeted therapy in the appropriate setting has improved pathologic complete response and outcomes and is considered standard of care. As knowledge of the biologic basis of IBC continues to expand, further improvement in survival can be expected as targeted therapies are added to these regimens.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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Correspondence: Holly Dushkin, MD, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail: holly.dushkin@fccc.edu

Disclosure: Holly Dushkin, MD, has disclosed no relevant financial relationships.

Disclosure: Massimo Cristofanilli, MD, has disclosed no relevant financial relationships.

Supplementary Materials

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    Clinical signs of inflammatory breast cancer. A) Patient presenting with erythema and increased breast size. B) Detailed view of involved breast.

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    Clinical presentation of diffuse recurrent inflammatory breast cancer. The patient presented with skin rash and skin nodules.

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    A 33-year-old woman with right inflammatory breast cancer. An axial postcontrast T1-weighted VIBRANT MR image shows diffuse skin thickening in the right breast, with large multifocal disease mostly localized in the right lower quadrant.

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    Three-dimensional (coronal, sagittal, and transaxial) display of the PET/CT images for a 47-year-old white female with newly diagnosed inflammatory breast cancer. Extensive active lesions are shown for this patient: 1) primary lesions of inflammatory breast cancer in the left breast (white arrow), 2) extensive left axillary lymph node involvement (blue arrow), and 3) an additional lesion in the left internal mammary node (green arrow); this lesion will likely change the radiation field.

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