A Multidisciplinary Approach to IBC: A Major Advance
Perhaps the most important progress made in the field of IBC has been the adoption of a multidisciplinary approach to its diagnosis and management. The use of improved diagnostic and staging modalities followed by a sequential treatment management approach in the form of pre-operative chemotherapy followed by surgery and radiation therapy has significantly improved the prognostic outcomes associated with this aggressive disease.
Advances in imaging
The past 2 decades have seen a significant improvement in the imaging techniques used in IBC. These improved techniques have played key roles in tumor characterization, thereby facilitating image-guided biopsy, defining the extent of loco-regional disease, diagnosing distant metastases, and playing an important role in the evaluation of response to pre-operative chemotherapy.
The introduction of digital mammography with enhanced contrast resolution has allowed for improved detection of associated IBC-related abnormalities, including skin thickening, trabecular and stromal thickening, and diffuse increased breast density—which are all changes that reflect dermal lymphatic invasion. High-resolution ultrasonagraphy allows for the identification of any focal mass lesion, thereby facilitating image-guided biopsy for assessment of the involvement of loco-regional lymph nodes, which ultimately helps in the planning of locoregional treatment. MRI, when used in the diagnosis of IBC, has been found to have a high sensitivity for detection of the primary breast parenchymal lesion, as well as for global skin abnormalities; MRI can thus help guide high-yield skin punch biopsies. PET/CT has also been investigated as a tool that can potentially help in the diagnosis and staging of IBC. In a large retrospective study of 41 women with IBC that looked at the role of PET/CT as an initial staging tool, Carkaci et al reported hypermetabolic uptake in 98% of the patients. The investigators also noted that PET/CT detected the presence of ipsilateral axillary lymph nodes in 90% of women. Interestingly, 20 patients in this study were found to have distant metastatic disease, 7 of whom were not known to have metastases before they underwent PET/CT. Wang et al looked at the roles of all three imaging modalities in women with IBC. They concluded that breast MRI was the most accurate for detecting primary breast parenchymal lesions, that ultrasonography was useful for detecting the extent of loco-regional lymph node involvement, and that PET/CT was useful for providing additional information on the presence or absence of distant metastatic disease.
The optimal pre-operative regimen for the management of IBC has yet to be fully delineated due to the fact that information from large prospective clinical trials is not available. Much of the information that is available has been extrapolated from data on patients with non-IBC and from retrospective data on IBC patients. The Early Breast Cancer Trialists’ Collaborative Group’s 15-year update revealed that 6 months of an anthracycline-based polychemotherapy regimen reduced the annual breast cancer death rate by 38% among women younger than 50 years of age and by 20% among women aged 50 to 69 years. One of the first and largest studies to look at the question of anthracyline use in women with IBC comes from the University of Texas M.D. Anderson Cancer Center. The investigators pooled information on 178 women with IBC who were enrolled prospectively in 4 clinical trials; all women received a pre-operative anthracyline-based regimen followed by definitive local treatment. The investigators reported a median overall survival of 40 months, with an impressive 28% of patients being alive and disease-free at 15 years. In a more recent study by Baldini et al, the investigators looked at 68 women with IBC who were enrolled in 2 prospective trials. All women received an anthracycline-based pre-operative regimen followed by definitive local treatment and additional adjuvant chemotherapy. The investigators on this study reported 5- and 10-year overall survival rates of 44% and 32%, respectively.
Taxanes form an integral part of treatment of women with node-positive non-IBC. The role of taxanes has been investigated in women with IBC as well. Cristofanilli et al retrospectively looked at 240 women with IBC enrolled in 6 prospective clinical trials; they specifically looked at the question of whether adding taxanes to an anthracycline-based pre-operative regimen provided benefit. The authors reported that the addition of taxanes resulted in improved median, overall, and progression-free survival; the improvements reached statistical significance, specifically among women with estrogen receptor–negative disease (median overall survival, 54 months vs 32 months in patients who did not receive taxanes; median progression-free survival, 27 months vs 18 months in patients who did not receive taxanes). The incorporation of both anthracylines and taxanes into the pre-operative regimen is now considered standard of care for women with IBC.
An important component of the use of pre-operative chemotherapy is the assessment of response to treatment, with pCR considered to be an intermediate surrogate marker for improved survival. The question of whether pCR is a prognostic marker in IBC has also been investigated. Hennessy et al demonstrated that among women with IBC who had cytologically confirmed axillary lymph node metastases, 5-year recurrence-free and overall survival rates in the group of patients who attained pCR in the axillary lymph nodes (82.5% and 78.6%, respectively) were higher than the rates in those who had evidence of residual disease (37.1% and 25.4%, respectively). Ueno et al reported 15-year survival rates in women with IBC receiving pre-operative chemotherapy of 44%, 31%, and 7% in those patients who achieved a complete response, a partial response, and a less than partial response, respectively. Thus, from the available data it appears that among women with IBC, response to pre-operative chemotherapy plays a similar prognostic role to that observed among women with non-IBC.
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]