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Introduction: Sustained HER2 signaling at the cell surface is an oncogenic mechanism in a significant proportion of breast cancers. While clinically effective therapies targeting HER2 such as mAbs and tyrosine kinase inhibitors exist, tumors overexpressing HER2 eventually progress despite treatment. Thus, abrogation of persistent HER2 expression at the plasma membrane to synergize with current approaches may represent a novel therapeutic strategy., Methods: We generated polyclonal anti-HER2 antibodies (HER2-VIA) by vaccinating mice with an adenovirus expressing human HER2, and assessed their signaling effects in vitro and anti-tumor effects in a xenograft model. In addition, we studied the signaling effects of human HER2-specific antibodies induced by vaccinating breast cancer patients with a HER2 protein vaccine., Results: HER2-VIA bound HER2 at the plasma membrane, initially activating the downstream kinases extracellular signal-regulated protein kinase 1/2 and Akt, but subsequently inducing receptor internalization in clathrin-coated pits in a HER2 kinase-independent manner, followed by ubiquitination and degradation of HER2 into a 130 kDa fragment phosphorylated at tyrosine residues 1,221/1,222 and 1,248. Following vaccination of breast cancer patients with the HER2 protein vaccine, HER2-specific antibodies were detectable and these antibodies bound to cell surface-expressed HER2 and inhibited HER2 signaling through blocking tyrosine 877 phosphorylation of HER2. In contrast to the murine antibodies, human anti-HER2 antibodies induced by protein vaccination did not mediate receptor internalization and degradation., Conclusion: These data provide new insight into HER2 trafficking at the plasma membrane and the changes induced by polyclonal HER2-specific antibodies. The reduction of HER2 membrane expression and HER2 signaling by polyclonal antibodies induced by adenoviral HER2 vaccines supports human clinical trials with this strategy for those breast cancer patients with HER2 therapy-resistant disease.

Purpose: We conducted a phase II, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of daily lapatinib plus weekly paclitaxel in treatment-naïve patients with inflammatory breast cancer (IBC)., Patients and Methods: The primary end point was pathologic complete response (pCR). Secondary end points included combined clinical response rate (based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria and clinically evaluable skin disease criteria). Patients were assigned to either cohort A (human epidermal growth factor receptor 2 [HER2] 2+ or 3+ by immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] -amplified +/- epidermal growth factor receptor [EGFR] expression) or cohort B (HER2-negative/EGFR-positive). A subpopulation of cohort A considered HER2-positive by the current definition of overexpression (3+ by IHC or FISH-amplified) was also analyzed. Patients received lapatinib at 1,500 mg/d for 14 days, then lapatinib at 1,500 mg/d plus weekly paclitaxel (80 mg/m(2)) for 12 weeks, followed by surgical resection or additional chemotherapy., Results: Forty-nine women were enrolled (cohort A, n = 42; cohort B, n = 7). Cohort B was terminated because of slow accrual and lack of efficacy observed in IBC patients with HER2-negative/EGFR-positive tumors enrolled onto the parallel study, EGF103009. pCR occurred in 18.2% (95% CI, 5.2% to 40.3%) of cohort A patients. Combined clinical response rate was 78.6% (95% CI, 63.2% to 89.7%) in all cohort A patients and 78.1% (95% CI, 60.0% to 90.7%) in the HER2-positive subset. Common adverse events included diarrhea, rash, alopecia, and nausea (> 50% of patients in both cohorts). The incidence of grade 3 diarrhea was 55%., Conclusion: Lapatinib monotherapy for 14 days followed by lapatinib plus paclitaxel for 12 weeks provided clinical benefit in IBC patients with HER2-overexpressing tumors without unexpected toxicity.

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.

Background: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease., Methods: From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950., Findings: Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related., Interpretation: Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer., Funding: GlaxoSmithKline.

Impairment of dendritic cells (DC), the most effective activators of anticancer immune responses, is one mechanism for defective antitumor immunity, but the causes of DC impairment are incompletely understood. We evaluated the association of impaired DC differentiation with angiogenesis-associated molecules D-dimer, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor (PAI-1) in peripheral blood from 41 patients with lung, breast, and colorectal carcinoma. Subsequently, we studied the effect of administration of the anti-VEGF antibody (bevacizumab) on DC maturation and function in vivo. Compared with healthy volunteers, cancer patients had a bias toward the immunoregulatory DC2, had deficits in DC maturation after overnight in vitro culture, and had a significant increase in immature myeloid cell progenitors of DC (0.50 +/- 0.31% vs. 0.32 +/- 0.16% of peripheral blood mononuclear cells, respectively, P = 0.011). A positive correlation was found between the percentage of DC2 and PAI-1 (R = 0.50) and between immature myeloid cells and VEGF (R = 0.52). Bevacizumab administration to cancer patients was associated with a decrease in the accumulation of immature progenitor cells (0.39 +/- 0.30% vs. 0.27 +/- 0.24%, P = 0.012) and induced a modest increase in the DC population in peripheral blood (0.47 +/- 0.23% vs. 0.53 +/- 0.30%). Moreover, anti-VEGF antibody treatment enhanced allo-stimulatory capacity of DC and T cell proliferation against recall antigens. These data suggest that DC differentiation is negatively associated with VEGF levels and may be one explanation for impaired anticancer immunity, especially in patients with advanced malignancies.

Although trastuzumab-based therapy has changed the treatment paradigm for ErbB2-positive breast cancers, most patients eventually develop progressive disease. Of particular interest is the issue of disease progression in the central nervous system, a safe haven from high molecular weight antibodies like trastuzumab, which have limited ability to cross the blood-brain barrier. This review will discuss therapeutic options for when disease progression has occurred on trastuzumab-based therapies, including central nervous system progression, continuation of trastuzumab-based therapy, addition of novel targeted therapies, and the use of small-molecule tyrosine kinase inhibitors targeting ErbB receptors.

Objective: According to data from Brazil's National Cancer Institute nearly 30% of the new patients who present with breast cancer have locally advanced disease. These patients are inoperable and tumor reduction is usually attempted with chemotherapy. First-line anthracyclin-based neoadjuvant chemotherapy is often effective; however, about 30% of the patients fail and to date there is no established second-line treatment. We have studied the concomitant use of radiation therapy and capecitabine in this setting, to determine the toxicity and efficacy of this regimen as a second-line neoadjuvant treatment., Patients and Methods: Twenty-eight patients with inoperable locally advanced breast cancer refractory to first-line anthracycline based treatment were enrolled between January 2003 and May 2004. Patients received radiation therapy (total dose 5000 cGy) and concomitant capecitabine (850 mg/m2) twice daily for 14 days every 3 weeks., Results: This treatment rendered 23 of the 28 patients (82%) operable. The 5 remaining patients did not undergo surgery because of disease progression. The median clinical tumor size decreased from 80 cm2 to 49 cm2. Microscopic residual disease was observed in 3 patients (13%) and another patient achieved a complete pathologic response. The median number of involved lymph nodes was 2 and treatment was well tolerated with no grade 3 or 4 events., Conclusion: Our data indicate that second-line neoadjuvant treatment with radiation therapy and capecitabine is feasible, well tolerated, and effective in patients with locally advanced breast cancer refractory to primary anthracycline-based treatment. These results suggest that a randomized study should be done to compare radiotherapy alone to capecitabine combined with radiotherapy.