Inflammatory breast cancer is an aggressive disease that can be difficult to diagnose, progresses rapidly, and has often metastasized to nearby lymph nodes or tissues by the time of diagnosis.¹

Although survival rates have improved in recent years, patients with inflammatory breast cancer tend to have a worse prognosis than patients with other breast cancers.

Estimates suggest that 1% to 5% of breast cancers diagnosed in the United States are inflammatory breast cancers, and anywhere from 7% to 10% of US breast cancer deaths can be attributed to inflammatory breast cancer.^1-4

Risk Factors for Inflammatory Breast Cancer

High body mass index is a known risk factor for inflammatory breast cancer.^2,4 Possible risk factors include viral infections, chronic inflammation, younger age at first live birth, smoking, and breastfeeding.

Black patients tend to develop inflammatory breast cancer more often than White patients, and the cancer tends to occur in patients younger than 40 years of age.¹

There is no known association between inflammatory breast cancer and inherited genetic mutations or family history.^2,4

Prognosis of Inflammatory Breast Cancer

Estimates suggest that 5-year overall survival rates for inflammatory breast cancer range from 30% to 70%.³

According to data from the Surveillance, Epidemiology, and End Results (SEER) program, based on women diagnosed with inflammatory breast cancer between 2012 and 2018, the 5-year relative survival rate for inflammatory breast cancer is 39% overall, 52% for regional disease, and 19% for distant disease.¹

Factors associated with worse prognosis among patients with inflammatory breast cancer include hormone receptor (HR)-negative disease, 4 or more lymph nodes involved at diagnosis, and a lack of response to neoadjuvant chemotherapy.³

Read more: Breast Cancer Survivor

Symptoms and Diagnosis of Inflammatory Breast Cancer

Patients with inflammatory breast cancer may present with pain, a fast-growing breast lump, itching, an enlarged breast, and/or swollen lymph nodes.^1,3 Patients with nipple involvement may have crusting, redness, or blisters as well as flattening or retraction of the nipple.³

These breast cancer symptoms are also seen in patients with other conditions, which can make diagnosing inflammatory breast cancer challenging.³ Conditions that may be confused with inflammatory breast cancer include:

Ductal ectasia, a benign condition in which a milk duct in the breast widens and its walls thicken. The duct can become blocked, leading to fluid build-up. This condition improves without treatment.
Breast infections or inflammation, which not only cause similar symptoms as inflammatory breast cancer but can show similar findings on imaging. Infections typically improve with a short course of antibiotics.
Noninflammatory breast cancer and other cancers such as breast lymphoma. These cancers can be differentiated via biopsy and histologic findings.^3,5

There are several criteria patients must meet for a diagnosis of inflammatory breast cancer, and these include:

Rapid onset of redness, swelling, and/or dimpling of the skin that resembles an orange peel (peau d’orange), and/or a warm breast, with or without an underlying palpable mass
Redness on at least one-third of the breast
A history no longer than 6 months
Pathologic confirmation of invasive carcinoma.³

National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with suspected inflammatory breast cancer have a history and physical exam by a multidisciplinary team.⁶

The guidelines recommend a complete blood count, comprehensive metabolic panel, pathology review, determination of HR and HER2 status, fertility counseling in premenopausal patients, genetic counseling in patients at risk of hereditary breast cancer, and imaging.

Imaging

Imaging should consist of:

Mammography on both breasts, with ultrasound (of both breasts and regional lymph nodes) as necessary
Diagnostic chest computed tomography (CT) scan, with or without contrast
Abdominal (with or without pelvic) diagnostic CT scan with contrast or magnetic resonance imaging (MRI) with contrast
Bone scan or fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT
Optional breast MRI.^3,6

For patients who have inflammatory breast cancer, mammography may show a mass, a sizable area of calcification, or distortion of the breast parenchymal architecture with skin thickening.³ Ultrasonography might show skin thickening, interstitial fluid, and tissue plane disruption.

Imaging results are not conclusive, however. For example, on mammography, mastitis can look similar to inflammatory breast cancer without an underlying mass. If a short course of antibiotics does not improve the patient’s symptoms, a biopsy is necessary.

MRI may provide better detection than mammography and can be used to guide skin punch biopsies. FDG PET/CT scans can reveal lymph node involvement or distant metastases.

Read more: Breast Cancer Awareness

Treatment of Inflammatory Breast Cancer

Guidelines recommend that patients with inflammatory breast cancer receive intensive treatment that includes systemic therapy, surgery, and radiation.^3,4,6 Clinical trial enrollment is also recommended for all eligible patients.

Treating Nonmetastatic Disease

In general, patients with nonmetastatic inflammatory breast cancer should receive similar treatment as patients with nonmetastatic, noninflammatory, locally advanced breast cancer.^3,6 However, sentinel lymph node biopsy and breast-conserving therapy are not recommended in patients with inflammatory breast cancer, even if they respond well to neoadjuvant therapy.³

Standard treatment for nonmetastatic inflammatory breast cancer includes systemic neoadjuvant therapy, surgery, radiation, and systemic adjuvant therapy when necessary.³ Neoadjuvant and adjuvant treatment typically consists of chemotherapy, with or without other therapies depending on HR and HER2 status.^3,4,6

Systemic Therapy for HER2-Negative, Nonmetastatic Disease

For patients with nonmetastatic, HER2-negative inflammatory breast cancer, NCCN guidelines recommend the following regimens as “preferred” neoadjuvant and adjuvant therapies:

Dose-dense doxorubicin and cyclophosphamide followed or preceded by paclitaxel every 2 weeks
Dose-dense doxorubicin plus cyclophosphamide followed or preceded by weekly paclitaxel
Docetaxel and cyclophosphamide
Olaparib for patients with germline BRCA1/2 mutations.⁶

In patients with high-risk, inflammatory triple-negative breast cancer (TNBC), preferred treatment consists of neoadjuvant pembrolizumab plus carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus cyclophosphamide and doxorubicin or epirubicin, followed by adjuvant pembrolizumab.

Capecitabine is the preferred treatment for patients with inflammatory TNBC who have residual disease after neoadjuvant treatment with taxane-, alkylator-, and anthracycline-based chemotherapy.

Other potential treatment options for patients with HER2-negative inflammatory breast cancer include:

Dose-dense doxorubicin and cyclophosphamide
Doxorubicin and cyclophosphamide every 3 weeks
Cyclophosphamide plus methotrexate and fluorouracil
Doxorubicin and cyclophosphamide followed by weekly paclitaxel
Doxorubicin plus cyclophosphamide followed by docetaxel every 3 weeks
Epirubicin and cyclophosphamide
Docetaxel plus doxorubicin and cyclophosphamide
Paclitaxel and carboplatin in select patients with TNBC
Neoadjuvant docetaxel and carboplatin in select patients with TNBC
Capecitabine maintenance after adjuvant chemotherapy in patients with TNBC.⁶

Systemic Therapy for HER2-Positive, Nonmetastatic Disease

For patients with nonmetastatic, HER2-positive inflammatory breast cancer, the following regimens are preferred for neoadjuvant and adjuvant therapy, according to NCCN guidelines:

Paclitaxel and trastuzumab
Docetaxel plus carboplatin and trastuzumab
Docetaxel, carboplatin, trastuzumab, and pertuzumab.⁶

The preferred treatment for patients who have no residual disease after neoadjuvant therapy is 1 year of HER2-targeted therapy with trastuzumab, with or without pertuzumab.

For patients who have residual disease after neoadjuvant therapy, ado-trastuzumab emtansine alone is preferred. If patients must stop ado-trastuzumab emtansine due to toxicity, 1 year of trastuzumab, with or without pertuzumab, is recommended. Patients who are node-positive at initial staging should receive trastuzumab and pertuzumab.

Other potential treatment options for this patient group include:

Docetaxel plus cyclophosphamide and trastuzumab
Doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab
Doxorubicin and cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab
Paclitaxel plus trastuzumab and pertuzumab
Doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab
Doxorubicin and cyclophosphamide followed by docetaxel, trastuzumab, and pertuzumab
Neratinib in the adjuvant setting only
Ado-trastuzumab emtansine in the adjuvant setting only.⁶

Surgery and Radiation

For patients with nonmetastatic inflammatory breast cancer who respond to neoadjuvant therapy, the NCCN-recommended treatment is total mastectomy, level I/II axillary dissection, and radiation to the chest wall with comprehensive regional nodal irradiation and inclusion of any portion of the undissected axilla at risk.⁶

Patients may receive adjuvant chemotherapy after surgery. Those with HR-positive disease should receive endocrine treatment. Patients with HER2-positive disease should complete up to 1 year of HER2-targeted therapy, which can be given concurrently with radiation and endocrine therapy.

For patients who do not respond to neoadjuvant therapy, additional chemotherapy and/or preoperative radiation are recommended. For patients who do not respond to additional treatment, individualized treatment is recommended.

Because inflammatory breast cancer typically has a poor prognosis and patients have a high risk of early recurrence, immediate reconstruction after surgery is not recommended.^3,4,6

Treating Metastatic Disease

Patients with metastatic inflammatory breast cancer should receive primary systemic therapy, which can include chemotherapy, hormone therapy, targeted therapy, and/or immuntherapy.^3,6

HR-Positive, HER2-Negative Metastatic Disease With Visceral Crisis

The NCCN-recommended first-line therapy in patients with metastatic, HR-positive, HER2-negative disease with visceral crisis and no germline BRCA1/2 mutations is chemotherapy.⁶ The recommended first-line therapy for patients with BRCA1/2 mutations is a PARP inhibitor (olaparib or talazoparib).

Preferred treatment options for first-line chemotherapy include:

Anthracyclines (doxorubicin or liposomal doxorubicin)
Taxanes (paclitaxel)
Anti-metabolites (capecitabine or gemcitabine)
Microtubule inhibitors (vinorelbine or eribulin).

Other first-line treatment options include:

Cyclophosphamide
Docetaxel
Albumin-bound paclitaxel
Epirubicin
Ixabepilone
Doxorubicin plus cyclophosphamide
Epirubicin plus cyclophosphamide
Cyclophosphamide plus methotrexate and fluorouracil
Docetaxel and capecitabine
Gemcitabine and paclitaxel
Gemcitabine and carboplatin
Carboplatin plus paclitaxel or albumin-bound paclitaxel.

NCCN guidelines recommend fam-trastuzumab deruxtecan-nxki as second-line therapy for patients with a HER2 immunohistochemistry (IHC) score of 1+ or 2+ and a negative in situ hybridization (ISH) result. Patients who are not candidates for fam-trastuzumab deruxtecan-nxki can receive sacituzumab govitecan or chemotherapy.

Third-line therapy and beyond should consist of chemotherapy or targeted therapy. Targeted therapy options include:

Alpelisib plus fulvestrant in patients with a PIK3CA activating mutation
Elacestrant in patients with an ESR1 mutation
Larotrectinib or entrectinib in patients with an NTRK fusion
Pembrolizumab or dostarlimab-gxly in patients with microsatellite instability-high or mismatch repair-deficient disease
Pembrolizumab in patients with high tumor mutation burden
Selpercatinib in patients with RET fusion.

Metastatic Inflammatory TNBC

The NCCN guidelines recommend chemotherapy as first-line treatment for patients with metastatic inflammatory TNBC who have a PD-L1 combined positive score (CPS) below 10 and no BRCA1/2 mutations.⁶

In patients with metastatic TNBC who have a PD-L1 CPS below 10 and BRCA1/2 mutations, first-line therapy should be a PARP inhibitor (olaparib or talazoparib) or platinum chemotherapy (cisplatin or carboplatin).

In patients with metastatic TNBC who have a PD-L1 CPS of 10 or higher, first-line therapy should be pembrolizumab and chemotherapy (albumin-bound paclitaxel, paclitaxel, or gemcitabine and carboplatin).

Second-line treatment options include sacituzumab govitecan and chemotherapy. In patients with germline BRCA1/2 mutations, second-line treatment should be a PARP inhibitor (olaparib or talazoparib).

Patients without germline BRCA1/2 mutations who have a HER2 IHC score of 1+ or 2+ and a negative ISH result should receive fam-trastuzumab deruxtecan-nxki as second-line therapy.

Third-line therapy and beyond should consist of chemotherapy or targeted therapy.

HER2-Positive Metastatic Disease

NCCN guidelines recommend that first-line therapy for patients who have metastatic, HER2-positive inflammatory breast cancer (HR-positive or -negative) should be pertuzumab plus trastuzumab and docetaxel or pertuzumab plus trastuzumab and paclitaxel.⁶

Recommended second-line therapy is fam-trastuzumab deruxtecan-nxki. Recommended third-line therapy is ado-trastuzumab emtansine or tucatinib plus trastuzumab and capecitabine.

Options for fourth-line or later therapy include:

Trastuzumab and docetaxel or vinorelbine
Trastuzumab and paclitaxel, with or without carboplatin
Capecitabine and trastuzumab or lapatinib
Trastuzumab and lapatinib (without cytotoxic therapy)
Trastuzumab and other chemotherapy agents
Neratinib and capecitabine
Margetuximab-cmkb and chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine)
Additional targeted therapy options (larotrectinib or entrectinib, pembrolizumab or dostarlimab-gxly, pembrolizumab, and selpercatinib).

This article originally appeared on Cancer Therapy Advisor

References

1. Inflammatory breast cancer. American Cancer Society. Updated March 1, 2023. Accessed October 20, 2023.

2. Chainitikun S, Saleem S, Lim B, Valero V, Ueno NT. Update on systemic treatment for newly diagnosed inflammatory breast cancer. J Adv Res. 2021;29:1-12. doi:10.1016/j.jare.2020.08.014

3. Chippa V, Barazi H. Inflammatory breast cancer. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2023 Jan-. Updated April 16, 2023.

4. Menta A, Fouad TM, Lucci A, et al. Inflammatory b reast cancer: What to know about this unique, aggressive breast cancer. Surg Clin North Am. 2018;98(4):787-800. doi:10.1016/j.suc.2018.03.009

5. Duct ectasia. American Cancer Society. Updated January 25, 2022. Accessed October 20, 2023.

6. NCCN Clinical Practice Guidelines: Breast Cancer, Version 4.2023. National Comprehensive Cancer Network. Published March 23, 2023. Accessed October 20, 2023.

Inflammatory Breast Cancer: A Rare and Aggressive Malignancy