Inflammatory breast cancer (IBC) is a rare and aggressive subtype of locally advanced breast cancer (LABC). Its diagnosis is primarily clinical; however, a pathological confirmation of invasive cancer is required. Historically, IBC was a uniformly fatal disease. A major advance in the last three decades has been the introduction of a multidisciplinary approach to the management of this aggressive disease, incorporating pre-operative chemotherapy, surgery, and radiation therapy; this approach has significantly improved survival. Our review focuses on the progress made in the field of IBC research over the last decade, with particular attention to advances in the areas of epidemiology, molecular biology, and clinical management.
Over the past decade, inflammatory breast cancer (IBC), a rare and aggressive subtype of locally advanced breast cancer (LABC), has received much attention at the level of public awareness as well as at the level of research. The diagnosis of IBC is primarily clinical, although a pathological confirmation of invasive cancer is required. The most widely used definition of IBC is that which has been put forward by the American Joint Committee on Cancer; this definition states in part that IBC is “a clinicopathologic entity characterized by diffuse erythema and edema of the breast, often without an underlying palpable mass.” The incidence of IBC varies across different geographic locations but typically accounts for approximately 1% to 5% of all newly diagnosed breast cancers in the United States. The rarity of the disease makes large prospective clinical trials difficult, with the result that much of the information we have on IBC is based on retrospective studies. Furthermore, the subjective nature of the clinical diagnostic criteria has led to wide variability in clinical reports at both the epidemiological and molecular levels.
Historically, IBC was a uniformly fatal disease, with a 5-year actuarial overall survival of less than 5%, a median survival of only 15 months, and local recurrence rates as high as 50% when treated with surgery alone or in combination with radiation therapy.[4,5] A major advance of the last three decades has been the introduction of a multidisciplinary approach to the management of this aggressive disease that incorporates pre-operative chemotherapy, surgery, and radiation therapy. As a result, survival outcomes have improved significantly, with 15-year survival rates of 20% to 30% reported.[6,7] However, despite this progress, most women in whom IBC is diagnosed eventually experience a recurrence and die from the disease—highlighting the need for further research.
Specifically, current research is focused on the following objectives:
• Refining the clinical diagnostic parameters to decrease subjectivity.
• Delineating diagnostic markers to enhance diagnostic accuracy.
• Developing predictive and prognostic markers to aid in treatment planning.
• Characterizing IBC at the molecular level.
• Developing targeted therapies based on an enhanced understanding of the biology of IBC, with the hope that such an approach will positively impact prognostic outcomes.
High-throughput molecular analysis has provided great insight into the understanding and characterization of non-IBC breast tumors. This has perhaps been one of the biggest advances in the field of breast cancer. Such technology has rarely been used in the realm of IBC, in part because of IBC's comparative infrequency and thus the small number of diagnostic samples. However, the last decade has seen an upsurge in the understanding of IBC at both a clinical and a molecular level.
Epidemiology and Risk Factors
Epidemiological research on IBC has not enjoyed the kind of progress seen with other subtypes of breast cancer. This lag in progress is primarily due to the rarity of the disease, which has resulted in small numbers of patients with IBC being available to any single institution; it is also due to the lack of an agreed upon case definition for IBC, which has made it difficult for institutions to collaborate. Nonetheless, data have emerged from large population-based studies. One important observation that has been made is that, unlike with non-IBC breast tumors and despite the overall low incidence of IBC (it accounts for only 1% to 5% of all newly diagnosed breast cancer cases), the incidence of IBC in the United States appears to be increasing. This may in part be the result of increased awareness among both patients and oncologists.
It is interesting to note that there is striking geographic variation in the incidence of IBC, with the lowest incidence reported in North America and a higher incidence reported in North African countries—especially Morocco, Algeria, Tunisia, and Egypt, where the incidence of IBC has been reported to be between 10% and 15%. However, it is uncertain in these countries whether case registration is complete and whether strict definitions are used for IBC detection.
Variations in incidence have also been reported among different ethnic groups in the United States. In a large population-based study of 3,626 women with IBC diagnosed between 1994 and 1998, Wingo et al reported an IBC rate of 1.3 per 100,000 for all races combined, with African Amer-ican women having the highest risk (1.6 per 100,000) and Asian and Pacific Islander women having the lowest risk (0.7 per 100,000). Other key observations concerning women in whom IBC has been diagnosed include their younger age at presentation compared with women with non-IBC, their lower median survival compared with patients with LABC (2.9 years vs 6.4 years), and the significantly in-creased odds of IBC developing in women with a high body mass index. Currently, the mammary tumor virus is being investigated as a potential risk factor for IBC based on the observation that in North America a higher incidence of the viral sequence (71%) has been observed in women with IBC than in women with sporadic breast cancers; a similar incidence has also been observed in IBC tumor samples from Tunisia.
1. Breast. In: Green FL, Page DL, Fleming ID, et al, editors. AAJCC cancer staging manual, 6th ed. New York: Springer-Verlag: 2002. p. 225-81
2. Levine PH, Steinhorn SC, Ries LG, Aron JL. Inflammatory breast cancer: the experience of the Surveillance, Epidemiology, and End Results (SEER) program. J Natl Cancer Inst. 1985;74:291-7.
3. Bozzetti F, Saccozzi R, De Lena M, et al. Inflammatory cancer of the breast: analysis of 114 cases. J Surg Oncol. 1981;18:355-61.
4. Barker JL, Nelson AJ, Montague ED. Inflammatory carcinoma of the breast. Radiology. 1976;121:173-6.
5. Zucali R, Uslenghi C, Kenda R, et al. Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cancer. 1976;37:1422-31.
6. Low J, Berman A, Steinber S, et al. Long term follow up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy. J Clin Oncol. 2004;22:4065-74.
7. Ueno NT, Buzdar AU, Singletary SE, et al. Combined modality treatment of inflammatory breast carcinoma: twenty years of experience at M.D. Anderson Center. Cancer Chemother Pharmacol. 1997;40:321-329
8. Bertucci F, Finetti P, Cervera N, et al. Gene expression profiling and clinical outcome in breast cancer. OMICS. 2006;10:429-43.
9. Mourali N, Muenz LR, Tabbane F, et al. Epidemiologic features of rapidly progressing breast cancer in Tunisia. Cancer. 1980;46:2741-6.
10. Wingo PA, Jamison PM, Young JL, Gargiullo P. Population-based statistics for women diagnosed with inflammatory breast cancer (United States). Cancer Causes Control. 2004;15:321-8.
11. Chang S, Buzdar AU, Hursting SD. Inflammatory breast cancer and body mass index. J Clin Oncol. 1998;16:3731-5.
12. Pogo BG, Holland JF, Levine PH. Human mammary tumor virus in inflammatory breast cancer. Cancer. 2010;116(11 Suppl):2741-4.
13. Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast cancer: A review. J Clin Oncol. 1992;10:1014-24.
14. Gruber G, Ciriolo M, Altermatt HJ, et al. Prognosis of dermal lymphatic invasion with or without clinical signs of inflammatory breast cancer. Int J Cancer. 2004;109:144-8.
15. Kleer CG, van Golen KL, Merajver SD. Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants. Breast Cancer Res. 2000;2:423-29.
16. Turpin E, Bieche I, Berthaeau P, et al. The increased incidence of ERBB2 over expression and TP53 mutation in inflammatory breast cancer. Oncogene. 2002;21:7593-7.
17. Kleer CG, van Golen KL, Braun T, et al. Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol. 2002;14:458-64.
18. van Golen KL, Davies S, Wu ZF, et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res. 1999;5:2511-9.
19. Van der Auwera I, Van Laere SJ, Van Den Eynden GG, et al. Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin Cancer Res. 2004;10:7965-71.
20. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol. 2007;18:1021-9.
21. Bertucci F, Finetti P, Rougemont J, et al. Gene expression profiling for molecular characterization of inflammatory breast cancer and prediction of response to chemotherapy. Cancer Res. 2004; 64:8558-65.
22. Bertucci F, Finetti P, Rougemont J, et al. Gene expression profiling identifies molecular subtypes of inflammatory breast cancer. Cancer Res. 2005;65:2170-8.
23. Van Laere S, Van der Auwera I, Van den Eynden GG, et al. Distinct molecular signature of inflammatory breast cancer by cDNA microarray analysis. Breast Cancer Res Treat. 2005;93:237-46.
24. Van Laere SJ, Van den Eynden GG, Van der Auwera I, et al. Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling. Breast Cancer Res Treat. 2006;95:243-55.
25. Van Laere S, Van der Auwera I, Van den Eynden G, et al. Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis. Br J Cancer. 2007;97:1165-74.
26. Bièche I, Lerebours F, Tozlu S, et al. Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Clin Cancer Res. 2004;10:6789-95.
27. Dressman HK, Hans C, Bild A, et al. Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy. Clin Cancer Res. 2006;12(3 Pt 1):819-26.
28. Nguyen DM, Sam K, Tsimelzon A, et al. Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype. Clin Cancer Res. 2006;12:5047-54.
29. Boersma BJ, Reimers M, Yi M, et al. A stromal gene signature associated with inflammatory breast cancer. Int J Cancer. 2008;122:1324-32.
30. Van Laere S, Beissbarth T, Van der Auwera I, et al. Relapse-free survival in breast cancer patients is associated with a gene expression signature characteristic for inflammatory breast cancer. Clin Cancer Res. 2008;14:7452-60.
31. Yang WT. Advances in imaging of inflammatory breast cancer. Cancer. 2010;116(11 Suppl):2755-7.
32. Yang WT, Le-Petross HT, Macapinlac H, et al. Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings. Breast Cancer Res Treat. 2008;109:417-26.
33. Carkaci S, Macapinlac HA, et al. Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: preliminary data. J Nucl Med. 2009;50:231-8.
34. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365:1687-1717.
35. Ueno NT, Buzdar AU, Singeltary SE, et al. Combined modality treatment of inflammatory breast carcinoma: twenty years of experience at M.D Anderson Center. Cancer Chemother Pharmacol. 1997;40:321-9.
36. Baldini E, Gardin G, Evangelista G, et al. Long-term results of combined-modality therapy for inflammatory breast cancer. Clin Breast Cancer. 2004;5:358-63.
37. Cristofanilli M, Gonzalez-Angulo AM, Buzdar AU, et al. Paclitaxel improves the prognosis in estrogen receptor negative inflammatory breast cancer: the M.D Anderson Cancer Center experience. Clin Breast Cancer. 2004;4:415-9.
38. Kuerer HM, Newman LA, Smith TL, et al. Clinical course of breast cancer patients with complete pathological primary tumor axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol. 1999;17:460-9.
39. Hennessy BT, Gonzalez-Angulo AM, Hortobagyi GN, et al. Disease-free and overall survival after pathological complete disease remission of cytologically proven inflammatory breast carcinoma axillary lymph node metastases after primary systemic chemotherapy. Cancer. 2006;106:1000-6.
40. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-72.
41. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-84.
42. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-92.
43. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676-85.
44. Hurley J, Doliny P, Reis I, et al. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-postive locally advanced breast cancer. J Clin Oncol. 2006;24:1831-8.
45. Van Pelt AE, Mohsin S, Elledge RM, et al. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003;4:348-353.
46. Limentani SA, Brufsky AM, Erban JK, et al. Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J Clin Oncol. 2007;25:1232-8.
47. Burstein HJ, Harris LN, Gelman R, et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol. 2003;21:46-53 .
48. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.
49. Dawood S, Gong Y, Broglio K, et al. Trastuzumab in primary inflammatory breast cancer (IBC): high pathological response rates and improved outcome. Breast J. 2010. [Epub ahead of print]
50. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-43.
51. Burris HA 3rd, Hurwitz HI, Dees EC, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005;23:5305-13.
52. Spector NL, Blackwell K, Hurley J, et al. EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response. J Clin Oncol. ASCO Annual Meeting Proceedings 2006. Part I. Vol 24. No. 18S (June 20 Supplement); 502.
53. Boussen H, Cristofanilli M, Zaks T, et al. Phase II study to evaluate the efficacy and safety of neoadjuvant lapatinib plus paclitaxel in patients with inflammatory breast cancer. J Clin Oncol. 2010;28:3248-55.
54. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-76.
55. Alvarez RH, Valero V, Hortobagyi GN. Emerging targeted therapies for breast cancer. J Clin Oncol. 2010;28:3366-79.
56. Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol. 2006;24:769-77.
57. Overmoyer B, Fu P, Hoppel C, et al. Inflammatory breast cancer as a model disease to study tumor angiogenesis: results of a phase IB trial of combination SU5416 and doxorubicin. Clin Cancer Res. 2007;13:5862-8.
58. Yamauchi H, Ueno NT. Targeted therapy in inflammatory breast cancer. Cancer. 2010;116(11 Suppl):2758-9.
59. Vlastos G, Fornage BD, Mirza NQ, et al. The correlation of axillary ultrasonography with histologic breast cancer downstaging after induction chemotherapy. Am J Surg. 2000;179:446-52.
60. Flemming RY, Asmar L, Buzdar AU, et al. Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma. Ann Surg Oncol. 1997;4:452-61.
61. Stearns V, Ewing CA, Slack R, et al. Sentinel lymphadenopathy after neoadjuvant chemotherapy for breast cancer may reliably represent the axilla except for inflammatory breast cancer. Ann Surg Oncol. 2002;9:235-42.
62. Woodward WA, Buchholz TA. The role of locoregional therapy in inflammatory breast cancer. Semin Oncol. 2008;35:78-86.
63. Bristol IJ, Woodward WA, Strom EA, et al. Locoregional treatment outcomes after multimodality management of inflammatory breast cancer. Int J Radiat Oncol Biol Phys. 2008;72:474-84.
64. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al. Trends for inflammatory breast cancer: is survival improving? Oncologist. 2007;12:904-12.
65. Dawood S, Merajver SD, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol. 2010 Aug 9. [Epub ahead of print]