Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, younger age of onset as compared with other cancers, local and distant metastases, and lower overall survival. The multidisciplinary management of IBC includes neoadjuvant systemic chemotherapy, surgery, radiotherapy, and hormonal therapy in hormone receptor–positive disease. Pathological complete response represents an important prognostic factor suggesting IBC as the ideal in-vivo model for therapeutic development. Molecular subtyping demonstrated higher frequency of basal-like an HER2 disease in IBC compared with non-IBC indicating the areas of novel therapeutic interventions. The prospective testing of HER2–targeted therapies (eg, trastuzumab and lapatinib) demonstrated the validity of this concept and the potential to change the outcome of this aggressive disease.

Over the last two decades we have seen significant advances made in the realm of breast cancer. The advent of gene expression profiling allowed for the identification of the presence of several molecular subtypes of this disease each associated with a unique natural history, prognostic outcome, and potentially unique targets of therapy (1,2). Insight into the molecular diversity of breast cancer has served as a corner stone to the development of a personalized approach to the management of breast cancer that includes accurate prognostic stratification, prediction of response to commonly used systemic therapeutics as well as personalized monitoring of the disease (3). Available tools critical to predicting prognostic outcome and therapeutic efficacy have not been investigated, and indeed thought not to work, among patients with inflammatory breast cancer (IBC) thus hampering a personalized approach to management of this disease. The recognition that IBC is a unique and rare clinical subtype of locally advanced breast cancer associated with a more aggressive, rapid disease course and poorer prognostic outcome translated into an understanding about the need for a dedicated research effort for this disease (4) (Figure 1). Indeed the American Joint Committee on Cancer specifically classifies IBC as T4d and clinically defines it as “a clinicopathologic entity characterized by diffuse erythema and edema of the breast, often without an underlying palpable mass” (5).

Figure 1.

Newly diagnosed right inflammatory breast cancer. The breast demonstrates the typical features of diffuse erythema, peau d’orange, ulceration and appears clearly distinguishable from the contralateral normal breast (A). In the lateral view is appreciable the extension of the erythema and the grossly abnormal axillary adenopathy (B).

Figure 1.

Newly diagnosed right inflammatory breast cancer. The breast demonstrates the typical features of diffuse erythema, peau d’orange, ulceration and appears clearly distinguishable from the contralateral normal breast (A). In the lateral view is appreciable the extension of the erythema and the grossly abnormal axillary adenopathy (B).

Several important distinct features of IBC set it apart from non-IBC. First, data indicate that despite a combined modality approach to management of this disease that incorporates neoadjuvant chemotherapy, surgery, and radiation therapy, a diagnosis of IBC is associated with reduced overall survival (6). Second, evidence indicates that, over time, the introduction of efficacious chemotherapeutic- and biological-targeted therapies had a more significant impact on survival outcome among patients with non-IBC compared with those with IBC (7). Third, although all molecular subtypes described in non-IBC are present in IBC, they appear with different frequencies with luminal A subtype having a lower frequency (19% vs 42%, P < .001) and HER2-enriched subtype having a higher frequency (22% vs 9%, P < .001) among patients with IBC compared with non-IBC (8).

Our understanding of the importance of a personalized approach to the management of breast cancer and the recognition that IBC is a distinct entity has certainly allowed for the important transition of IBC from being a once uniformly fatal disease to a promising, but still disappointing, 5-year survival of approximately 30% (6,9). One of the most important advances in the management of IBC has been a recognition of the importance of up front neoadjuvant chemotherapy that has ultimately led to improved surgery and better locoregional control of disease (10–20) (Table 1). However, several important questions remain. First, it is well recognized that attaining a pathological complete response (pCR) following a course of neoadjuvant chemotherapy is considered to be a surrogate marker of improved prognostic outcome (21). As such, the US Food and Drug and Administration has recently put forth a proposal to use this surrogate endpoint for rapid drug efficacy assessment within the confines of clinical trials that are investigating new drugs thereby, allowing for the potential of an accelerated drug approval process as it considers this endpoint “to reasonably predict clinical benefit” (22). The question that arises is whether pCR can within the confines of IBC also predict for improved prognostic outcome? Can it reasonably be used as a surrogate endpoint in clinical trials investigating this disease? Answering questions such as these for IBC is largely hampered by the rarity of this disease resulting in our reliance largely on retrospective data and small prospective clinical trials. In one of the largest single institution retrospective studies associated with longest follow-up for IBC, Ueno et al. (23) reported a 44%, 31%, and 7% 15-year survival rate among women with IBC who received neoadjuvant chemotherapy and achieved a complete response, a partial response, and a less than partial response, respectively. Hennessy et al. (24) have also demonstrated an associated improved prognostic outcome after attaining a pCR in the axillary lymph nodes among patients with IBC compared with those who had residual disease (5-year overall survival 78.6% vs 25.4%).

Table 1.

Summary of selected prospective studies neoadjuvant studies*

Study Year of publication Number of patients Regimen used pCR 
Van Pelt et al. (10) 2003 22 LABC (9 IBC) Trastuzumab and docetaxel 40% 
Burstein et al. (11) 2003 40 (6 with IBC) Trastuzumab and paclitaxel 18% 
von Minckwitz et al. (12) 2005 913 (T2-T3, N0-N2) Doxorubicin/docetaxel versus AC followed docetaxel 7% vs 14.3% (P < .001) 
Limentani et al. (13) 2007 31 LABC (9 IIIB including IBC) Docetaxel, vinorelbine, and trastuzumab 39% 
von Minckwitz et al. (14) 2008 1390 (30 with IBC) Docetaxel/adriamycin/cyclophosphamide 21% 
Untch et al. (15) 2010 1509 (114 with IBC) Epirubicin/cyclophosphamide followed by docetaxel. Trastuzumab was given among patients with HER2-positive disease and no trastuzumab among patients with HER2-negative disease 31.7% (HER2-positive) versus 15.7% (HER2-negative) 
Gianni et al. (16) 2010 235 (63 with stage III IBC) Chemotherapy (doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil) ± trastuzumab 38% (T) vs 19% (no T) 
Untch et al. (17) 2011 736 (58 with T4 tumors) Edd→Tdd→CMF vs EC→T 20.9% vs 14.3%
P = .019 
Untch et al. (18) 2011 217 (34 with T4 tumors and 4 with IBC) HER2-positive EC followed by paclitaxel + trastuzumab 39% 
Von Minckwitz et al. (19) 2013 588 (including IBC) Paclitaxel + liposomal doxorubicin + anti-HER2 (lapatinib and trastuzumab among patients with HER2-positive disease) or bevacizumab (among patients with TNBC). Patients randomized to ± carboplatin 58.7% vs 37.9% (P < .05) among TNBC
33.1% vs 36.3% (not significant) among HER2- positive group 
Pierga et al. (20) 2013 52 IBC (HER2-positive) FEC + bevacizumab followed by docetaxel + bevacizumab + trastuzumab 63.5% 
Study Year of publication Number of patients Regimen used pCR 
Van Pelt et al. (10) 2003 22 LABC (9 IBC) Trastuzumab and docetaxel 40% 
Burstein et al. (11) 2003 40 (6 with IBC) Trastuzumab and paclitaxel 18% 
von Minckwitz et al. (12) 2005 913 (T2-T3, N0-N2) Doxorubicin/docetaxel versus AC followed docetaxel 7% vs 14.3% (P < .001) 
Limentani et al. (13) 2007 31 LABC (9 IIIB including IBC) Docetaxel, vinorelbine, and trastuzumab 39% 
von Minckwitz et al. (14) 2008 1390 (30 with IBC) Docetaxel/adriamycin/cyclophosphamide 21% 
Untch et al. (15) 2010 1509 (114 with IBC) Epirubicin/cyclophosphamide followed by docetaxel. Trastuzumab was given among patients with HER2-positive disease and no trastuzumab among patients with HER2-negative disease 31.7% (HER2-positive) versus 15.7% (HER2-negative) 
Gianni et al. (16) 2010 235 (63 with stage III IBC) Chemotherapy (doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil) ± trastuzumab 38% (T) vs 19% (no T) 
Untch et al. (17) 2011 736 (58 with T4 tumors) Edd→Tdd→CMF vs EC→T 20.9% vs 14.3%
P = .019 
Untch et al. (18) 2011 217 (34 with T4 tumors and 4 with IBC) HER2-positive EC followed by paclitaxel + trastuzumab 39% 
Von Minckwitz et al. (19) 2013 588 (including IBC) Paclitaxel + liposomal doxorubicin + anti-HER2 (lapatinib and trastuzumab among patients with HER2-positive disease) or bevacizumab (among patients with TNBC). Patients randomized to ± carboplatin 58.7% vs 37.9% (P < .05) among TNBC
33.1% vs 36.3% (not significant) among HER2- positive group 
Pierga et al. (20) 2013 52 IBC (HER2-positive) FEC + bevacizumab followed by docetaxel + bevacizumab + trastuzumab 63.5% 

* AC = adriamycin, cyclophosphamide; CMF = cyclophosphmaide, methotrexate, 5-fluorouracil; EC = epirubicin, cylcolophosphamide; FEC = 5-fluorouracil, epirubicin, cylcolophosphamide; IBC = inflammatory breast cancer; LABC = locally advanced breast cancer; pCR = pathological complete response; TNBC = triple-negative breast cancer.

Second, what are the best agents to use for neoadjuvant chemotherapy for IBC? One of the first studies to look at the incorporation of neoadjuvant anthracyclines reported on 178 women with IBC enrolled prospectively on four clinical trials (23). The authors reported a median overall survival of 40 months with 28% of patients being alive at 15 years. Looking at a cohort of 68 women with IBC who received neoadjuvant anthracycline-based chemotherapy, Baldini et al. (25) reported 5- and 10-year overall survival rates of 44% and 32%, respectively. The incorporation of taxanes into an anthracycline-based neoadjuvant regimen has also been shown to significantly improve survival outcome among women with IBC with median overall survival approaching 54 months (26).

Third, can we improve efficacy of neoadjuvant regimens to increase pCR rates and thus subsequently prognostic outcome among patients with IBC? To do this one would need to look at specific targets currently under investigation in IBC. As previously stated, compared with non-IBC tumors, IBC tumors tend to have an increased incidence of HER2 overexpression. The introduction of trastuzumab, specifically targeting HER2, has decreased the risk of recurrence by approximately 50% and has essentially changed the natural history of HER2-overexpressing tumors (27,28); an observation that has also been noted among HER2-overexpressed IBC tumors (29). The efficacy of trastuzumab has also been investigated in the neoadjuvant setting in a phase III study that investigated 235 women with HER2-positive locally advanced breast cancer 63 of whom had IBC (16). The investigators reported a higher pCR rate (38% vs 19%) and higher 3-year event-free survival (71% vs 56%) among women who received trastuzumab compared with those who did not. Furthermore, the efficacy of lapatinib, a receptor-tyrosine kinase inhibitor targeting the intracellular domain of the Her receptor, has been investigated in a phase II study of 42 women with HER2-positive IBC treated with neoadjuvant lapatinib and paclitaxel (30). An overall clinical response rate of 78.6% and a pCR rate of 18.2% was reported. With preclinical data indicating increased angiogenesis and lymphangiogenesis among IBC tumors compared with non-IBC tumors novel targets of the vasculolymphatic pathways are actively being explored (31). Afatinib, a tyrosine kinase that inhibits HER2 and epidermal growth factor receptor (EGFR), is currently being investigated in a phase II study among patients with HER2-overexpressing IBC (ClinicalTrials.gov identifier NCT01325428). With approximately 30% of IBC showing EGFR overexpression, that is known to be associated with a poor prognostic outcome, panitumumab, a monoclonal antibody against epidermal growth factor receptor, is currently being investigated in a phase II trial among patients with non-HER2–overexpressing IBC (ClinicalTrials.gov identifier NCT01036087) (31). Bevacizumab, a recombinant humanized monocolonal antibody that binds to vascular endothelial growth factor, has been investigated in combination with preoperative chemotherapy among patients with IBC with clinical response rates of approximately 67% being reported (32). When combined with preoperative trastuzumab and chemotherapy among patients with HER2-positive IBC a pCR of approximately 65% has been reported (20). Semaxanib (SU416), a small molecule that inhibits vascular endothelial growth factor-mediated signaling through the FLK-1 and KDR tyrosine kinase receptor is also being explored in IBC (33).

Chemokines and their receptor are also potential targets including CXCR4 and CCR7, expression of which are related with a worse prognosis in IBC. A series of preclinical studies has also addressed the role of chemokine receptors and adhesion molecules considering the highly metastatic nature of IBC. Among them, data looking at treatment with an antihuman CXCR4 antibody or a peptide analog of its ligand have shown promising results (34). E-cadherin, a transmembrane glycoprotein, is known to be overexpressed in IBC with preclinical data using an antibody to E-cadherin (HECD-1) shown to cause dissolution of pulmonary lymphovascular emboli in IBC xenografts (35). Other novel targets being investigated in IBC include WNT1-inducible signaling pathway protein 3, EGFR, p27kip1, and Ras homolog gene family member C guanosine triphosphatase (31).

We have certainly witnessed an unprecedented improvement in our understanding of the peculiar clinical and biological features of IBC. However, this disease is still associated with a poor prognostic outcome and the future will lie in our capacity to further explore therapeutic interventions with specific molecular targets differentially expressed in IBC. In this respect, the use of the neoadjuvant model and the early incorporation of novel agents in this setting appear particularly suited for IBC. Furthermore, these efforts require design of large, multicenter, prospective studies, and this is a significant issue when dealing with a relative rare and misdiagnosed disease. Designing trials with pCR as a surrogate endpoint will indeed not only help in reducing patient numbers needed for these trials but will also allow for rapid assessment of efficacy parameters. The World IBC consortium is to be commended for collecting and reporting on the largest series of IBC samples (8). It is collaborations such as these that will allow for a deeper understanding of IBC as well as for larger prospective trials to be conducted.

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