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.
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