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Inflammatory breast cancer: A race against time

Early recognition of this rapidly spreading disease is essential for the timely initiation of therapy. Unfortunately, patients with IBC continue have a poor prognosis overall.

Adera Kaye Kidwell, MS, PA-C

Kaye Kidwell practices in the Breast Radiation Oncology department at M. D. Anderson Cancer Center, Houston, Texas. She has indicated no relationships to disclose relating to the content of this article.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that has recently received considerable media interest. News programs have aired segments educating the public about IBC. E-mails circulating on the Internet provide links to Web sites with information on IBC. Given the heightened public awareness surrounding this disease, health care providers should be well-informed on the presentation, diagnosis, and treatment of IBC.

Rapid enlargement of the breast, erythema with edema or an orange-peel appearance, and induration or ridging over more than one third of the breast are the hallmarks for a clinical diagnosis of IBC. Multimodality therapy including chemotherapy, mastectomy, radiation, and hormonal therapy has become the preferred regimen for managing patients with this disease. Early diagnosis of IBC enables induction chemotherapy to be initiated in a timely fashion, significantly improving patient outcomes. Unfortunately, IBC recurs in many patients, and the prognosis for long-term survival remains poor. However, new targeted therapies under investigation are promising, and research on the molecular biology of IBC is leading to the development of unique chemotherapeutic agents for combating this very aggressive form of breast cancer.

EPIDEMIOLOGY

IBC represents an estimated 1% to 2% of all new cases of invasive breast cancer diagnosed each year.¹ This low incidence rate means that the majority of clinicians have never seen a patient with IBC.

Two large cancer registries in the United States, the Surveillance, Epidemiology, and End Results Program (SEER) at the National Cancer Institute and the National American Association of Central Cancer Registries (NAACCR), provide population-based analyses of malignancies.^2,3 In the SEER 9 Registries database, 3,648 of 180,224 cases of breast malignancies—or 2% of the total—reported between 1988 and 2000 were confirmed to be IBC.³ Cases reported to the NAACCR registry between 1994 and 1998 revealed that 1% of new breast cancer diagnoses in women were IBC; among men, the rate was 0.59%.² SEER data for 1973 to 2000 reported that 1.4% of all cases of breast cancer in men were IBC.⁴

Patients with IBC tend to be younger than patients with other types of breast cancer (median age, 58.8 years).³ Many women with IBC are in their 30s and 40s. Most of the literature reports that IBC is diagnosed in African-American women at a higher rate than in other racial and ethnic groups;^2-4 however, the rate is increasing in white women, possibly as a result of heightened clinical awareness and earlier detection.³

Additionally, women with IBC are more likely to present with larger tumors that have negative prognostic factors such as a higher nuclear grade, negative hormone-receptor status, and regional lymph node involvement.^2-4 Also, the age-specific incidence rate of IBC in women continues to rise until age 50 years and then levels off, whereas rates of other breast malignancies continue to rise after that age. The premenopausal hormonal milieu may be a factor in the initiation and progression of IBC.^3-5

SIGNS AND SYMPTOMS

The AJCC [American Joint Committee on Cancer] Cancer Staging Manual describes the clinical manifestation of IBC as diffuse erythema and edema of the breast that arises quickly, often without an underlying palpable mass.⁶ Changes in the breast such as erythema, warmth, and edema should make the clinician consider a diagnosis of IBC. Unfortunately, these symptoms are often initially attributed to other causes, such as mastitis or breast abscess, which results in a significant delay in the diagnosis of IBC.

In addition to experiencing breast enlargement and skin changes that seem to occur overnight, some patients may complain of pain or itching that does not resolve with creams or ointments. Swelling of the breast can cause the skin to have an orange peel appearance, called peau d’orange, with exaggerated hair follicle pits because of blockage of the lymphatics in the skin (see Figure 1). The affected breast becomes much larger than the other breast; this significant asymmetry develops over a short period of time. Skin color may become pink, red, or purplish, resembling ecchymosis. Thickening of the skin with induration, wheals, or ridging may occur. The nipple may become inverted, retracted, or flattened and may have a discharge. On palpation, the breast is typically warm to the touch, firm, and tender. In many cases, a discreet mass is not appreciated. Enlarged lymph nodes also may be palpable in the axilla and the supraclavicular fossa on the affected side. Women with IBC typically do not have fever or leukocytosis and will not show significant improvement with antibiotic treatment.^7,8

DIAGNOSIS

Because of its rapid onset, IBC is often initially misdiag-nosed as acute mastitis or breast abscess, and antibiotics are prescribed. A workup to rule out breast carcinoma should be performed if the condition does not significantly improve after a 1-week course of antibiotics. Imaging studies of all patients who present with significant breast symptoms should be obtained. Mammography should be performed, if tolerated. However, IBC is difficult to detect on a mammogram because half of patients with IBC do not present with a mass.^9,10 Skin thickening, increased density, trabecular thickening, and axillary adenopathy are the findings associated with IBC. Architectural distortion or focal asymmetric density, nipple retraction, and malignant-appearing calcifications may also be present.⁹ Ultrasonography (US) is used to evaluate the extent of lymph node involvement, typically revealing axillary adenopathy and skin thickening. MRI is used to determine the extent of disease in the breast and the regional lymphatics (see Figure 2). Positron emission tomography (PET) is being used more frequently to identify areas of hypermetabolic activity. PET provides the clinician with information about the primary tumor, suspicious adenopathy, and distant metastases. After the diagnosis is made, imaging studies also help assess the patient’s response to neoadjuvant chemotherapy.

The classic criteria for a clinical diagnosis of IBC, established by Haagensen in 1956, continues to be utilized today.¹¹ The diagnosis of IBC is most often based on the clinical presentation (see Table 1).

Dermal lymphatic invasion is detected in up to 70% of patients and is the hallmark for a pathologic diagnosis of IBC.^7,12-13 However, dermal lymphatic invasion alone does not warrant a diagnosis of IBC.⁶ The absence of clinical symptoms differentiates IBC from a neglected locally advanced breast cancer. Malignant cells in the lymphatics of the skin can obstruct the flow of lymph, causing erythema and edema. A skin punch biopsy will confirm dermal lymphatic invasion. When a mass, an area of architectural distortion, asymmetric density, or a suspicious calcification is present, core needle biopsy is used to determine the histologic subtype and grade of the tumor cells. Invasive ductal carcinoma is the most common pathologic subtype (see Figure 3). IBC can also be associated with lobular, small cell, medullary, and large cell carcinomas.^8,14,15 Estrogen and progesterone receptors and the amplification of the ERBB2 gene are also evaluated; depending on results, additional therapies may be needed to manage this aggressive disease.

The NAACCR data found that nearly 70% of women had regional lymph node involvement at the time IBC was diagnosed.² Fine needle aspiration determines if lymph nodes in the axillary, infraclavicular, supraclavicular, or low-neck regions contain tumor cells. Staging studies determine the presence of distant metastases. The bone, liver, and lung are the most common sites of metastases. A bone scan, CT of the abdomen or liver US, and a chest radiograph are commonly used to evaluate these areas. In patients with CNS-related symptoms, MRI is used to determine the presence of distant metastases in the brain and the base of the skull.

MANAGEMENT

Treatment of IBC has significantly changed over the past several decades. Historically, patients were treated with mastectomy alone. Survival rates were poor, however, because of systemic spread of the disease.^14-17 When radiation therapy became the primary treatment modality in the 1950s, the local control rate improved; however, no significant change in long-term survival was appreciated.^14,17 The addition of chemotherapy in the 1970s created a new treatment paradigm—bimodality therapy (chemotherapy plus surgery or radiation) or trimodality therapy (chemotherapy plus surgery and radiation)—that significantly improved outcomes for patients with IBC.^{10,14,15,17-19}

Chemotherapy Monomodality therapy (mastectomy or radiation alone) had poor outcomes. Patients died from the systemic spread of the disease caused by distant metastases. When initial induction chemotherapy, known as neoadjuvant chemotherapy, was added to local therapy, long-term survival rates improved significantly.^10,15,18

A subclavian catheter or port is placed for chemotherapy delivery. Presently, the most commonly prescribed combination of neoadjuvant chemotherapeutic drugs consists of an anthracycline, either doxorubicin or epirubicin, and cyclophosphamide, with or without 5-fluorouracil. Some studies have found that adding taxanes to the regimen may also be a benefit.^17,20

Ueno and colleagues reported that 74% of patients with IBC experienced a response from an anthracycline-based regimen, and 12% had a complete response.¹⁰ Most studies reported that the initial response to neoadjuvant chemotherapy was a predictor for long-term survival.^10,12,15 Unfortunately, the risk of relapse remains high; adding adjuvant chemotherapy with an anthracycline or taxane after local therapy is recommended.^14,17 Five years of adjuvant hormonal therapy with an agent such as tamoxifen or anastrozole is also recommended for patients with hormone-receptor positive tumors to lower recurrence risk and improve overall outcomes.¹⁴ More recently, trastuzumab, a targeted therapy, was added to the systemic treatments for patients with tumors that overexpress the HER2/neu protein. Researchers are seeing an excellent tumor response with this drug.

Surgery is used to maintain local control and improve survival. Many of the women in the review by Ueno and colleagues initially presented with inoperable disease. After induction chemotherapy, 95% of these patients were able to have surgery.¹⁰ Neoadjuvant chemotherapy often resulted in negative margins at the tumor edge at the time of surgery, thereby improving local control.^18,21

The surgical procedure of choice is mastectomy with axillary lymph node dissection. Most studies that reviewed patients who had mastectomies after neoadjuvant chemotherapy found improved local control rates and, possibly, an overall survival benefit.^16,19,21 Breast conservation for patients with IBC remains controversial; sentinel lymph node biopsy is not recommended. Even in patients who had a complete pathologic response to their chemotherapy and received radiation treatments, the local control rate without mastectomy was less than optimal.^12,19,21,22

Radiation The sequencing of radiotherapy, either before or after mastectomy, is dependant on the patient’s response to neoadjuvant chemotherapy. Ideally, higher doses of radiation can be administered more safely after mastectomy, improving long-term local control rates.²³ The targets for radiation treatment are the chest wall and the draining lymphatics including the axillary, infraclavicular, supraclavicular, and internal mammary regions. If radiation is administered preoperatively because of a poor response to chemotherapy, the breast and draining lymphatics are the targets.

Initially, radiation for IBC was administered once a day. Because of the highly proliferative nature of IBC cells, a twice-a-day treatment regimen was studied in the 1970s. Local recurrence rates for patients receiving radiation once a day was 46%, whereas those receiving a hyperfractionated schedule with treatments twice a day experienced only a 27% local recurrence rate.²⁴ In the 1980s, Liao and colleagues found that increasing the total dose of radiation from 60 Gray (Gy) to 66 Gy improved local regional control of the disease; the 10% dose increase also improved disease-free survival and overall survival.²³ Patients now typically receive a total dosage of 66 Gy divided over 44 treatments, delivered in two treatments a day for 22 treatment days.

The most recent improvement to radiation therapy is the addition of CT-based planning and three-dimensional dose calculation. This type of treatment planning improves the radiation dose distribution, giving a more even dose across the target area, and aids in minimizing the exposure of healthy structures to radiation.²² Combined-modality therapy has been proven to be effective in the management of IBC and is now the preferred treatment regimen.^14,17,18 However, optimal sequencing of the modalities to achieve the most favorable overall response is still under investigation.

OUTCOMES

IBC is a rare and aggressive disease, with a poor outcome for most patients. In Ueno and colleagues’ review, 15-year disease-free survival was 28% for patients who received chemotherapy plus local therapy. The 5-year and 10-year overall survival rates were 40% and 33%, respectively.¹⁰ Similarly, patients treated at another large institution had an overall survival rate of 42% at 5 years, and 21% were disease-free.¹⁸

The use of induction chemotherapy combined with local therapy has made a positive impact on survival rates. Response to chemotherapy is an important prognostic factor in disease-free survival and overall survival.^10,12,15,21 Forty-four percent of patients with IBC who achieved a complete response from neoadjuvant chemotherapy were disease-free at 15 years.¹⁰ Median survival rates for patients with IBC, however, was only 37 months.^10,18 Panades and colleagues reported that patients who initially presented with an involved supraclavicular lymph node had a worse prognosis, with a median overall survival of only 1.85 years.²¹

OUTLOOK ON NEW THERAPIES

Research into new novel therapies for locally advanced breast cancers, including IBC, is ongoing. The molecular biology of very aggressive breast cancer cells provides pathways for unique, targeted chemotherapy agents. One such drug is trastuzumab, a monoclonal antibody that directly targets the HER2/neu protein in tumor cells.²⁵ Trastuzumab, when combined with other agents such as taxanes, improves survival in patients with locally advanced breast cancers, including IBC.²⁶

Lapatinib is another novel agent that directly targets tumor cells that overexpress the ERBB1 and ERBB2 growth factor receptors and attacks the cancer cells without harming normal cells. In patients whose disease has not responded to trastuzumab, lapatinib appears promising for treatment of metastatic breast cancer.²⁷ Several other genes and markers that may be associated with IBC are presently being evaluated. Further research into the molecular biology of IBC may produce unique targeted therapies that can improve the prognosis for affected patients.

CONCLUSION

IBC is often fatal because it is rare, and thus often missed, and aggressive, and thus difficult to treat. Prompt recognition and early diagnosis are essential for the timely initiation of induction chemotherapy. The era of multimodality therapy has produced improvements in disease-free survival and overall survival, but patients with IBC continue to have a poor prognosis overall. As we understand more about the molecular biology of IBC, the development of new targeted therapies hold promise for the future.

DRUGS MENTIONED

Anastrozole (Arimidex)
Cyclophosphamide (Cytoxan, Neosar)
Doxorubicin (Adriamycin, Doxil, Rubex)
Epirubicin (Ellence)
Fluorouracil (Adrucil)
Lapatinib (Tykerb)
Tamoxifen (Nolvadex)
Trastuzumab (Herceptin)

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