The diagnosis and management of inflammatory breast cancer

A 46-year-old perimenopausal black woman presented complaining of a sudden change in the appearance of her left breast. She recalled that the size of her left breast almost doubled during four weeks time. Her past medical history was otherwise noncontributory. She denied any associated constitutional symptoms, fevers or weight loss. She has no family history of breast cancer and no history of benign breast biopsies. Her last screening mammogram was six months prior and it did not reveal any significant abnormalities. She had an excellent performance status, and otherwise negative review of systems.

Upon physical examination, her left breast appeared significantly larger than the right; there was also diffuse erythema throughout the left breast. There was no appreciable lymphadenopathy in the axilla, supraclavicular or cervical regions. The skin of the left breast appeared thickened with an “orange-peel” like feeling.

A mammogram revealed a 6-cm lesion on the left breast in addition to some abnormal calcifications on the right breast. A core biopsy of the left mass demonstrated invasive ductal carcinoma, Scarff-Bloom-Richardson grade 3, ER/PR-negative, and HER-2/neu positive.

Luqman K. Dad

Biopsy of the calcifications on the right breast revealed sclerosing adenosis and microcalcifications, but was otherwise negative for malignancy. The patient subsequently underwent complete staging workup, including a CT chest/abdomen/pelvis, bone scan, and MRI of the breast. There was no evidence of distant metastases; the patient’s MRI yielded extensive changes involving the left breast consistent with a multicentric inflammatory carcinoma, with the dominant mass measuring 8.2 cm. Her clinical staging was: cT4dN0M0, stage IIIb, inflammatory breast carcinoma of the left breast.

After a discussion at multidisciplinary conference, the recommendations were made for preoperative chemotherapy with anthracycline plus or minus taxane and trastuzumab (Herceptin, Genentech) not concurrent with the anthracycline, followed by assessment of response. With a response, the patient would then undergo left modified radical mastectomy and left level I/II axillary dissection. After which she would receive radiation therapy to the chest wall and comprehensive nodal irradiation. Of note, the patient elected for simple mastectomy on the right breast as prophylaxis in the setting of the findings of calcifications. After radiation therapy, the patient would complete the planned chemotherapy regimen, including one year of trastuzumab.

Which of the following statements about the diagnosis and management of inflammatory breast cancer is true?

A) Final diagnosis requires pathologic demonstration of dermal lymphatic involvement only.

B) Diagnosis requires demonstration of both dermal lymphatic involvement and clinical signs of inflammation.

C) Complete response to neoadjuvant chemotherapy requires mastectomy and adjuvant radiation therapy.

D) Complete response to neoadjuvant chemotherapy requires mastectomy; however, adjuvant radiation therapy is not required.

Answer: C

Which factor is most important in determining prognosis in patients with inflammatory breast cancer?

A) Tumor response to chemotherapy.

B) Patient age.

C) Presence of dermal lymphatic invasion on pathology.

D) Amplification of HER-2/neu.

E) ER status.

F) All of the above equally effect prognosis.

Answer: A

Case Discussion

Inflammatory breast cancer is a clinically defined subcategory of locally advanced breast cancer. Hallmarks of this disease include: rapid disease onset and the clinical findings of skin erythema, edema (peau d’ orange), brawny breast induration, warmth and asymmetric involvement. In the United States, the majority of inflammatory breast cancer patients present without systemic metastases, even in the presence of profound local disease.

Inflammatory breast cancer carries a worse prognosis compared with other T4 breast tumors, suggesting a distinct biological entity. The pathologic and molecular features of inflammatory breast cancer typically reflect the p53 mutation, overexpression of HER-2, E-cadherin, RhoC GTPase, and proangiogenic factors. These tumors tend to lack expression of hormone receptors for estrogen and progesterone, and the LIBC gene. Before the advent of combination chemotherapy, inflammatory breast cancer was uniformly fatal. Currently, local control rates for patients treated with chemotherapy, mastectomy and postmastectomy radiation therapy approach 70% to 80%, and five-year OS rates are 30% to 40%.

As demonstrated by Buchholz and colleagues in the experience of The University of Texas M.D. Anderson Cancer Center, the majority of inflammatory breast cancer patients who undergo neoadjuvant chemotherapy become eligible for the optimal surgical approach of mastectomy and axillary lymph node dissection. The extensive dermal lymphatic involvement of this disease makes achieving negative surgical margins a considerable challenge; OS has been proven to be significantly affected by this factor, particularly in patients with inflammatory breast cancer. The factor with the strongest relationship with locoregional control has been found to be response to neoadjuvant chemotherapy.

Patients who undergo a mastectomy for inflammatory breast cancer should be recommended to receive postmastectomy radiation. Because of this, immediate reconstruction is discouraged due to possible negative effects on cosmetic outcome and challenges related to appropriate target coverage. In an attempt to improve locoregional control rates, from a radiation perspective, dose escalation beyond what is recommended for noninflammatory breast cancers has been evaluated by various centers. There has been slight improvement in locoregional control with dose escalation from 60 Gy to 66 Gy delivered in twice-daily fractionation; however, the benefits must be weighed with the increased possible late toxicities.

The largest outcome analysis for inflammatory breast cancer, published by Cristofanilli and colleagues, demonstrated a significantly worse prognosis for inflammatory breast cancer compared with noninflammatory locally advanced breast cancers. The researchers postulated that this may be related to the unique biology of this type of cancer. They described the possibility that there may be a “homing” of microscopic disease through a regulated multistep process. Furthermore, the expression of proangiogenic factors facilitate the disease’s spread through the lympatics and vasculature. Thus, the current state of the science in treating inflammatory breast cancer involves the exploration of novel-targeted therapeutic strategies, as this disease entity must be treated uniquely compared with noninflammatory breast cancer locally advanced breast cancers.

Several novel agents are currently under investigation for the treatment of inflammatory breast cancer, including antiangiogenic factors such as SU5416, ZD6474, and bevacizumab (Avastin, Genentech). Future research will indefinitely involve the further defining of the specific genetic profile of this highly aggressive disease to help us improve our tailored treatments and to work toward improved outcomes for our patients.

Luqman K. Dad, MD, is currently a Resident Physician in the Department of Radiation Medicine at Roswell Park Cancer Institute. He would like to acknowledge Dr. Mohamed Khan and the Multidisciplinary Breast Team at Roswell Park for their continued guidance and support during his residency training.

For more information:

• Bristol I. Int J Radiation Oncology Biol Phys. 2008;474-494.
• Cristofanilli M. Clinical Breast Cancer. 2004;415-419.
• Cristofanilli M. Cancer. 2007;1436-1444.
• Dawood S. Seminars in Oncology. 2008;64-71.
• Dawood S. Expert Rev Anticancer Ther. 2010;209-220.
• Halpern EC. Perez and Brady’s: Principles and practice of radiation oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins: 2007:xii
• Liao Z. Int J Radiation Oncology Biol Phys. 2000;1191-2000.
• Overmoyer B. Clinical Breast Cancer. 2010;27-32.
• Panades M. J Clin Oncol. 2005;1941-1950.
• Singletary S. Seminars in Oncology. 2008;7-10.
• Woodward WA. Seminars in Oncology. 2008; 35:78-86.