Inflammatory breast cancer (IBC) is an aggressive subtype of locally advanced breast cancer (LABC), with an incidence that varies across different geographic locations but typically accounts for approximately 1% to 5% of all newly diagnosed breast cancers diagnosed in the United States.1 The multidisciplinary management approach to IBC, comprised of a sequential process of preoperative chemotherapy followed by surgery and radiotherapy, has only marginally improved overall prognosis, which remains dismal with a 40% survival at 5 years.2
Several molecular determinants of IBC have already been identified that may serve as prime targets for the future development of therapeutic agents and contribute to improvements in prognosis.3-5 Of particular interest in both respects is the overexpression and/or gene amplification of HER2. The introduction of trastuzumab, a humanized monoclonal antibody targeted against the HER2 protein, has been shown in combination with chemotherapy to significantly improve survival among women with both early6, 7 and advanced stage breast cancer.8 Furthermore, the incorporation of trastuzumab into preoperative regimens has also been associated with high pathologically complete response rates.9 With several studies documenting an increased frequency of HER2 overexpression and/or gene amplification in IBC, trastuzumab is an ideal agent for incorporation into the therapy for this disease. Several studies have evaluated the efficacy of preoperative trastuzumab with chemotherapy in patients with IBC,10-15 demonstrating pathologically complete response rates ranging from 17% to 40%. Gianni et al15 recently reported on a cohort of 327 patients enrolled on a phase 3 prospective randomized clinical trial, the objective of which was to evaluate the addition of trastuzumab to an anthracycline-based and taxane-based preoperative chemotherapy regimen for patients with HER2-positive LABC. The authors reported that 27% of the patients with HER2-positive disease had IBC and that the addition of trastuzumab to preoperative chemotherapy significantly increased the 3-year event-free survival rate compared with preoperative chemotherapy alone (70.1% vs 53.3%; P = .0007), and thus further concluded that trastuzumab-based preoperative chemotherapy should be considered a standard option for patients with HER2-positive LABC (including IBC).
Lapatinib (Tykerb, GlaxoSmithKline, Research Triangle Park, NC), a reversible inhibitor of the HER1 (ErbB1) and HER2 (ErbB2) tyrosine kinases,16 is another targeted agent whose efficacy currently is being evaluated among women with LABC, including those with IBC.17-20 In combination with capecitabine, lapatinib has been shown to reduce the risk of disease progression by 51% compared with capecitabine alone among patients with HER2-positive LABC or metastatic breast cancer who have developed disease progression while receiving trastuzumab-containing regimens.17 Cristofanilli et al20 reported on a cohort of 21 chemotherapy-naive patients who had HER2-positive IBC who received a combination of preoperative lapatinib and paclitaxel. According to study protocol, patients initially received 14 days of daily lapatinib (at a dose of 1500 mg) after which it was given in combination with weekly paclitaxel (at a dose of 80 mg/m2) for 12 weeks. The authors reported good tolerance to the regimen with an associated clinical response rate of approximately 80%. Combinations of lapatinib are currently being studied prospectively in larger cohorts of patients with IBC, including a phase 3, placebo- controlled trial assessing the combination with pazopanib (GW-786034; GlaxoSmithKline, London, UK) an orally administered second-generation tyrosine kinase that blocks tumor cell proliferation by its inhibitory action against vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3; platelet-derived growth factor receptor-α (PDGFR-α) and PDGFR-β; and c-kit.