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.
Novel targeted agents
Our deeper understanding of the molecular biology of IBC has led to the identification of several prime molecular targets that may help with the development of therapeutic agents, with the goal of further improving prognostic outcomes (Table). The overexpression and/or gene amplification of HER2 is of particular interest for several reasons. First, as described earlier, there appears to be an increased frequency of HER2 positivity in IBC tumors, which makes HER2 an important target. Second, prospective clinical trials in women with non-IBC tumors have demonstrated that the incorporation of trastuzumab (Herceptin; a humanized monoclonal antibody that targets the HER2 protein) into chemotherapy regimens has not only resulted in a significant improvement in survival among women with HER2-positive early[40,41] and advanced-stage breast cancer, but has also been shown to increase pCR rates in these same populations when incorporated pre-operatively. The efficacy of trastuzumab in IBC has also been investigated.[44-49]
Gianni et al recently reported on the results of a prospective phase III randomized clinical trial that looked at the incorporation of one year of pre-operative and adjuvant trastuzumab into the treatment of 235 women with LABC, of whom 63 had IBC. All women received an anthraycline- and taxane-based pre-operative regimen. The authors reported a 3-year event-free survival of 71% in the women who received trastuzumab and of 56% in those who did not. The pCR rate was also reported to be higher in the women who received trastuzumab than in those who did not (38% vs 19%). In a recent small retrospective study, Dawood et al reported on a cohort of patients with HER2-positive IBC who had received pre-operative trastuzumab. The authors reported a pCR rate of 62.5%, with 37.5% of patients achieving a partial response. From the data described, it appears reasonable to assume that trastuzumab improves prognostic outcomes and increases pCR rates among women with HER2-positive IBC—and to conclude that trastuzumab should be considered an essential component of treatment in this subset of patients.
The efficacy of lapatinib (Tykerb), a reversible tyrosine kinase inhibitor of HER1 (ErbB1) and HER2 (ErbB2) tyrosine kinases, is also being investigated in women with IBC.[50-53] Results from a phase II study of 42 women with HER2-positive IBC who were treated with pre-operative lapatinib and paclitaxel included an overall clinical response rate of 78.6% and a pCR rate of 18.2%. Lapatinib-based combinations are currently being investigated in larger prospective cohorts of patients with IBC.
VEGF (vascular endothelial growth factor) receptor has also been shown to be highly expressed in IBC, which makes it another potential therapeutic target. Bevacizumab (Avastin), a recombinant humanized monocolonal antibody that binds to VEGF, has been investigated in combination with chemotherapy and has been shown to improve progression-free survival in women with metastatic breast cancer.[54,55] This agent is currently being investigated in women with IBC. Wedam et al reported on a pilot study of 21 patients with untreated IBC or LABC who received 1 cycle of pre-operative bevacizumab followed by 6 cycles of pre-operative bevacizumab in combination with doxorubicin (Adriamycin) and docetaxel (Taxotere). The investigators reported an overall response rate of 67% (95% CI = 43%–85.4%), with one patient attaining a pCR. Semaxanib (SU5416), a small molecular that inhibits VEGF-mediated signaling through the FLK-1 and KDR tyrosine kinase receptor, is also being investigated in IBC. In a phase IB study, Overmoyer et al reported on a group of 21 patients with stage III and IV IBC who received a pre-operative combination of SU5416 and doxorubicin. The investigators reported an overall response rate of 90%. Six patients (32%) achieved a complete clinical response, and 13 (68%) achieved a clinical partial response. At a median follow-up of 50 months, the median event-free survival was reported as 31 months (range, 7 to 54 months). The investigators noted that neutropenia was a dose-limiting toxicity and that congestive cardiac failure occurred in 22% of patients.
Other targets that are currently being investigated in IBC include the WNT1-inducible signaling pathway protein 3, epidermal growth factor receptor (EGFR), p27Kip1, and the Ras homolog gene family member C guanosine triphosphatase.
Advances in surgery
Following the administration of pre-operative chemotherapy, treatment is targeted toward local control. The current standard of care following an adequate clinical response to pre-operative chemotherapy is a modified radical mastectomy of the affected breast. Before the introduction of pre-operative chemotherapy, a modified radical mastectomy was technically not possible in the majority of cases due to the extent of the disease on the chest wall, which made it difficult to achieve negative margins. Pre-operative chemotherapy made surgery a technically feasible option. Several facts highlight the important role of definitive surgery in IBC: first, the fact that although nearly 70% of patients with IBC present with locoregional disease, only a small percentage have evidence of distant metastases at diagnosis, and second, the fact that in approximately 60% of cases, data indicate that physical examination and imaging modalities can underestimate the true extent of residual disease in the affected breast parenchyma and its overlying skin following pre-operative treatment. Retrospective data also confirm the effectiveness of mastectomy, which has a positive impact on local and distant recurrence rates in women with IBC. The role of sentinel lymph node biopsy has also been investigated in women with IBC. However, the unacceptably high rate of inaccuracy of sentinel lymph node biopsy in women with IBC precludes its use in this setting at this time.
Advances in radiation therapy
Post-mastectomy radiation therapy is the standard of care to further improve local control. Research has focused on using accelerated-hyperfractionated radiation therapy in the treatment of women with IBC in order to prevent rapid repopulation of IBC tumor cells between treatments, which has been hypothesized to be a mechanism of radiation therapy resistance. In 2008, Bristol et al reported on a cohort of 192 women with nonmetastatic IBC who were able to complete a planned course of pre-operative chemotherapy, undergo a modified radical mastectomy, and receive post-mastectomy radiation therapy at the M.D. Anderson Cancer Center. Most often, post-mastectomy radiation therapy was delivered in a dose-dense, twice-daily fractionation to 66 Gy. The investigators reported that in this population, the 5-year actuarial locoregional control was 84%, the distant metastasis-free survival was 47%, and the overall survival was 51%. The authors further noted that the patients that appeared to benefit the most from the escalation of the post-mastectomy radiation dose to 66 Gy were those who responded poorly to chemotherapy, those with positive margins, and those younger than 45 years.
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]