HER2-overexpressing Metastatic Breast Cancer Research Articles

PI3K Pathway Activity and Response to First-Line Chemotherapy in Combination with Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer.

Abstract Background. Not all patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) respond to trastuzumab and most that initially respond, ultimately develop resistance to treatment. Activated PI3K signalling has been proposed to predict trastuzumab resistance.Patients and Methods. PI3K pathway activity was evaluated in tumor samples from pts with HER2-overexpressing MBC treated with first-line chemotherapy in combination with trastuzumab by: a) assessing PIK3CA mutation status by our recently developed High Resolution Melting Analysis (HRMA) for the detection of mutations in exons 9 and 20, performed in the HR-1 High Resolution Melter (Idaho Technology, USA) and b) PTEN expression levels using immunohistochemical analysis. All samples with mutant melting transitions were verified by DNA sequencing. PI3K pathway activation defined by the presence of PIK3CA hotspot mutations and/or low or absent PTEN was correlated to the response to trastuzumab-based therapy.Results. Fifty-six pts received trastuzumab in combination with vinorelbine (n=15) or taxane-based chemotherapy (n=41). Median age was 62 years, 55 pts (98.2%) had PS 0-1, 10 (17.9%) were premenopausal, 27 (48.2%) had hormone receptor negative tumors and 37 (66.1%) had visceral metastases. HRMA identified the presence of PIK3CA mutations in 22 (39.3%) pts [exon 9 mutations in 5 (8.9%) and exon 20 mutations in 17 (30.4%) pts]. Subsequent PIK3CA sequence analysis demonstrated exon 9 mutations (E542K and E545K) in 4 (7.1%) pts and exon 20 mutations in 17 (30.4%; H104R in 16, and H1047L in 1) corresponding to a PIK3CA hotspot mutation frequency of 35.7%. Only in one sample that showed a mutant melting transition by HRMA, DNA sequencing did not confirm the presence of a PIK3CA mutation in exon 9, possibly due to lower sensitivity. Absent or reduced PTEN expression was detected in 22 (39.3%) of 47 pts. In 9 (16.1%) pts, PTEN score could not be retrieved. A trend for lower response rates was observed for patients with PI3K hotspot mutations compared to pts with wild-type tumors (35% vs 60%, p= 0.074). No difference in response rates was identified for pts with low or absent compared to normal PTEN expression (p=0.920). However, activated PI3K pathway (presence of PI3K mutations and/or low or absent PTEN expression) was associated with significantly lower response rates compared to non-activated one (40.6% vs 72.2%; p=0.032).Conclusions. The activation of PI3K pathway is predictive of response to first-line chemotherapy plus trastuzumab in pts with HER2-overexpressing MBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2022.

TAK-285, a Novel HER2/EGFR Inhibitor, Penetrates the CNS in Rats with an Intact Blood Brain Barrier (BBB).

Abstract Background: Approximately one third of patients with HER2-overexpressing (HER2+) metastatic breast cancer develop brain metastases. Treatment options for patients whose brain metastases have progressed after radiotherapy are urgently needed. The currently approved HER2-targeted therapies, trastuzumab and lapatinib, have generally shown limited activity against brain metastases, likely due to the limited brain penetration of these drugs. Brain penetration is mediated by multiple factors including drug permeability, tissue binding, and the expression of efflux transporters (P-gp and BCRP) and their interactions with the drug. TAK-285 is a novel, orally active, dual HER2/EGFR inhibitor currently under clinical development. In this nonclinical work, we evaluated the permeability, interactions with efflux transporters, and brain penetration of TAK-285, along with lapatinib and neratinib, using in vitro and animal models.Material and Methods: The first study evaluated the permeability of TAK-285, lapatinib, and neratinib and their interactions with efflux transporters using the Caco-2 cell monolayer system in the absence or presence of efflux pump inhibitors. The second study evaluated brain penetration of TAK-285, lapatinib and neratinib after a single oral administration in rats with an intact BBB.Results: In the Caco-2 cell model, TAK-285 showed high permeability with an efflux ratio of 1.7, indicating it is not a substrate for efflux pumps. The efflux pump inhibitors LY335979 (an inhibitor of P-gp), Ko143 (an inhibitor of BCRP), and GF120918 (an inhibitor of BCRP and P-gp) had no marked effect on the efflux ratio of TAK-285, further confirming that TAK-285 is not a substrate for P-gp and BCRP. Lapatinib and neratinib showed low to medium permeability and appeared to be substrates for P-gp/BCRP in this testing system. In the rat brain penetration study, the brain-to-plasma AUC ratio for total (free and bound) TAK-285, lapatinib, and neratinib was 0.202, 0.0243, and 0.0263, respectively.Discussion: These nonclinical studies showed that, unlike lapatinib and neratinib, TAK-285 is not a substrate for the efflux transporters, P-gp and BCRP. Based on published information, all of the approved receptor tyrosine kinase inhibitors are substrates for efflux transporters. Additionally, in rats with an intact BBB, the brain-to-plasma AUC ratio for TAK-285 was substantially higher than that of lapatinib and neratinib. The AUC ratios observed in this study for lapatinib and neratinib are similar to the proportion of blood volume in the rat brain (ie, outside the CNS) relative to the total rat brain volume. This suggests the actual brain-to-plasma AUC ratio for TAK-285 in rats may be much greater than 8-fold of that of lapatinib and neratinib calculated based on these measured AUC ratios. Consequently, TAK-285 may have a unique role in the treatment of brain lesions in patients with HER2- or EGFR-dependent tumors. Furthermore, TAK-285 may not be subject to drug resistance conferred by efflux transporters. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5098.

Fatty acid synthase activity regulates HER2 extracellular domain shedding into the circulation of HER2-positive metastatic breast cancer patients

Clinicopathological assessment of the functional relationship between the HER2 oncogene and tumor-associated fatty acid synthase (FASN) is largely precluded because immunohistochemical and/or mRNA studies should be performed in biopsies from breast cancer patients. We here sought to determine whether serum FASN (sFASN) could associate with circulating HER2 extracellular domain (HER2 ECD) in the blood of metastatic breast cancer (MBC) patients. Concentrations of serum FASN and HER2 ECD were measured with ELISA in sera retrospectively obtained from 201 patients with metastatic breast cancer (MBC) and 31 healthy subjects. Mechanistical in vitro studies were performed using pharmacological inhibitors of HER2 and FASN as well as cultured cancer cells engineered to overexpress HER2 and FASN human genes. When the upper limit of normal sFASN was defined as the mean + 2SD of the control group, sFASN was elevated above this cut-off (12 ng/ml) in 70 MBC patients (35%). Eighty-nine MBC patients (44%) had elevated levels of HER2 ECD (HER2 ECD cut-off = 15 ng/ml). HER2 ECD-positive MBC patients slightly increased their sFASN levels compared with HER2 ECD-negative MBC patients. sFASN-positive MBC patients had significantly increased levels of HER2 ECD when compared with sFASN-negative MBC patients (mean HER2 ECD=34 ng/ml, 95% CI 26-41 ng/ml and 18 ng/ml -95% CI 15-21 ng/ml, respectively; p=0.002). Sixty percent of sFASN-positive patients concurrently exhibited high levels of HER2 ECD whereas 64% of sFASN-negative patients were negative for circulating HER2 ECD. In vitro studies revealed that BC cells bearing HER2 gene-amplification released higher levels of extracellular FASN than HER2-negative BC cells. Trastuzumab-induced blockade of HER2 ECD shedding failed to prevent FASN release and retrovirally-induced HER2 overexpression in MCF-7 cells did not increase extracellular FASN. Of note, pharmacological inhibition of FASN activity significantly decreased HER2 ECD levels in the supernatant of HER2-overexpressing BC cells while transient overexpression of FASN gene in HBL100 cells promoted FASN protein release and concomitantly increased HER2 ECD shedding into the extracellular milieu. Subsequent studies should explore if quantitative determination of FASN molecules in blood could become a rapid and accurate non-invasive test to monitor disease progression and survival in HER2-overexpressing MBC undergoing HER2-targeted therapies.

Lapatinib for the treatment of HER2-overexpressing breast cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of lapatinib for the treatment of advanced or metastatic HER2-overexpressing breast cancer based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope included women with advanced, metastatic or recurrent HER2-overexpressing breast cancer who have had previous therapy that includes trastuzumab. Outcomes were time to progression, progression-free survival, response rates, overall survival, health-related quality of life and adverse effects. The submission's evidence came from one randomised controlled trial (RCT) of reasonable methodological quality, although it was not powered to detect a statistically significant difference in mean overall survival. Median time to progression was longer in the lapatinib plus capecitabine arm than in the capecitabine monotherapy arm {27.1 [95% confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% CI 0.43 to 0.77; p = 0.00013]}. Median overall survival was very similar between the groups [67.7 (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 to 1.12; p = 0.177)]. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer's economic model to estimate progression-free and overall survival for patients with HER2-positive advanced/metastatic breast cancer who had relapsed following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease area. The base-case incremental cost-effectiveness ratios (ICERs) for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy were higher than would conventionally be considered cost-effective. When compared with trastuzumab-containing regimes, lapatinib plus capecitabine dominated. In sensitivity analyses the ICER for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy was robust to variation in assumptions. In all sensitivity analyses the ICERs remained higher than would conventionally be considered cost-effective. ICERs for trastuzumab-containing regimes were particularly sensitive to assumptions over the frequency of treatment, which had a large effect on the cost-effectiveness of lapatinib plus capecitabine. In conclusion, there was a general lack of evidence on the effectiveness of comparators included in the model and on key parameters such as dose adjustments and the model outputs need to be interpreted in the light of this uncertainty. At the time of writing, NICE were still considering the available evidence for this appraisal.

Lapatinib for the treatment of HER2-overexpressing breast cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of lapatinib for the treatment of advanced or metastatic HER2overexpressing breast cancer based upon a review of the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope included women with advanced, metastatic or recurrent HER2-overexpressing breast cancer who have had previous therapy that includes trastuzumab. Outcomes were time to progression, progression-free survival, response rates, overall survival, health-related quality of life and adverse effects. The submission’s evidence came from one randomised controlled trial (RCT) of reasonable methodological quality, although it was not powered to detect a statistically significant difference in mean overall survival. Median time to progression was longer in the lapatinib plus capecitabine arm than in the capecitabine monotherapy arm {27.1 [95% confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% CI 0.43 to 0.77; p = 0.00013]}. Median overall survival was very similar between the groups [67.7 (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 to 1.12; p = 0.177)]. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer’s economic model to estimate progression-free and overall survival for patients with HER2-positive advanced/metastatic breast cancer who had relapsed following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease area. The base-case incremental cost-effectiveness ratios (ICERs) for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy were higher than would conventionally be considered cost-effective. When compared with trastuzumab-containing regimes, lapatinib plus capecitabine dominated. In sensitivity analyses the ICER for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy was robust to variation in assumptions. In all sensitivity analyses the ICERs remained higher than would conventionally be considered cost-effective. ICERs for trastuzumab-containing regimes were particularly sensitive to assumptions over the frequency of treatment, which had a large effect on the cost-effectiveness of lapatinib plus capecitabine. In conclusion, there was a general lack of evidence on the effectiveness of comparators included in the model and on key parameters such as dose adjustments and the model outputs need to be interpreted in the light of this uncertainty. At the time of writing, NICE were still considering the available evidence for this appraisal.

Erratum

Please be advised that there is an error in Table I of “The Role of HER2-targeted Therapies in Women with HER2-Overexpressing Metastatic Breast Cancer” by Dent et al. which appeared in Current Oncology Volume 16, Number 4 on page 236 in print, and page 26 online [...]

5109 Brain metastases (BM) in HER2-overexpressing metastatic breast cancer (MBC): what changed in the trastuzumab therapy era? A monoinstitutional experience

To present the outcomes of flexible ureteroscopy (F-URS), shock wave lithotripsy (SWL), and observation in the management of asymptomatic lower calyceal stones.A total of 150 patients with asymptomatic lower calyceal stones were randomized into F-URS (group 1), SWL (group 2), and observation (group 3) groups. The main criteria for patient enrollment were having asymptomatic single lower pole stones <1 cm.In F-URS, the mean stone-free rate was 92% (46 of 50). The mean number of sessions for the SWL group was 1.48 ± 0.65. Stone-free rate was 90% (45 of 50). In the observation group, patients were followed up for a mean of 21.02 ± 3.65 months. Three stones passed spontaneously without any symptoms. Pain developed in 3 patients during follow-up, and 2 of them passed a stone and responded to analgesics without further treatment. Complication rates for groups 1 and 2 were similar, but group 2 had higher Clavien grades.For asymptomatic small-sized lower calyceal stones, SWL and F-URS are established treatment modalities. However, with low auxiliary treatment rates, observation may be an option for the management of nonsymptomatic small-sized lower pole kidney stones.

The role of HER2-targeted therapies in women with HER2-overexpressing metastatic breast cancer.

The role of targeted therapies in the treatment of women with breast cancer has been rapidly evolving. Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), was the first HER2-targeted therapy that clearly demonstrated a significant clinical benefit for women with HER2-overexpressing metastatic breast cancer (mbc). However, in recent years it has become increasingly apparent that, when trastuzumab is used in the first-line setting in combination with chemotherapy, most women eventually develop progressive disease. Determining the treatment options available to women who have progressed while on trastuzumab therapy has been hampered by a paucity of high-quality published data. In addition, with the standard use of trastuzumab in the adjuvant setting (for eligible HER2-positive patients), the role of anti-HER2 agents for patients who experience a breast cancer relapse has become a clinically relevant question. This manuscript reviews current available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other HER2-targeted agents in two key mbc indications:Treatment for women with HER2-positive mbc progressing on trastuzumab (that is, treatment beyond progression)Treatment for women with HER2-positive mbc recurring following adjuvant trastuzumab (that is, re-treatment)The suggestions set out here will continue to evolve as data and future trials with trastuzumab and other HER2-targeted agents emerge.

Weekly Gemcitabine and Trastuzumab in the Treatment of Patients With HER2-Overexpressing Metastatic Breast Cancer

Background The use of trastuzumab in combination with either a taxane or vinorelbine has improved the efficacy of treatment for women with HER2-positive (HER+) breast cancer. We investigated the activity and toxicity of the gemcitabine/trastuzumab combination as first- or second-line treatment in women with HER2+ metastatic breast cancer (MBC). Patients and Methods Forty-one women with HER2+ MBC were treated with gemcitabine 1000 mg/m 2 intravenously (I.V.) days 1, 8, and 15 and trastuzumab 4-mg/kg I.V. loading dose and then 2 mg/kg weekly. Cycles were repeated every 28 days. Patients were evaluated after 8 weeks of treatment; responders/stable patients continued treatment until progression. Results Patients received a median of 28 weeks of treatment. Eleven of 37 evaluable patients (30%; 95% CI, 17%–46%) had major responses. The median progression-free survival (PFS) was 4 months (95% CI, 1.9–5.3 months), with a 1-year PFS of 17%. Four of 15 patients (27%) who had previously received trastuzumab for MBC had partial responses. The gemcitabine/trastuzumab combination was well tolerated. Conclusion The combination of gemcitabine and trastuzumab is an active regimen but appears less active than trastuzumab in combination with either taxanes or vinorelbine. The role of gemcitabine/trastuzumab (versus gemcitabine alone) in women who have already received a trastuzumab-containing regimen for HER2+ MBC is not defined by this study.

Treatment of HER2-Positive Metastatic Breast Cancer Following Initial Progression

Significant advances in molecular-targeted therapies have provided more effective and less aggressive forms of therapy for patients with HER2-overexpressing metastatic breast cancers. Despite the initial encouraging results of many therapeutic randomized trials that have been undertaken in this setting, de novo and acquired resistance to trastuzumab, the first anti-HER2 monoclonal antibody to demonstrate significant activity in this setting, can occur. Because recent studies strongly support a role for trastuzumab in not only the management of metastatic disease but also the adjuvant setting for HER2-overexpressing breast cancers, the clinical problem of trastuzumab resistance is becoming increasingly important. Specific recommendations for the optimal treatment of HER2-overexpressing metastatic disease are challenging because considerable advances in the field have been made. This article will review some of the main points to be considered for decision-making in anti-HER2 treatment in the metastatic setting: (1) the benefit of continued trastuzumab after progression on a first-line trastuzumab-containing regimen, (2) novel agents that have been recently added to the plethora of drugs available to treat HER2-overexpressing breast cancers, and (3) molecular mechanisms that contribute to trastuzumab resistance. These issues are imperative in identifying novel therapeutic targets with the goal of increasing the magnitude and duration of response to trastuzumab-based treatment.

Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens

Background: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy.Patients and methods: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH.Results: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for ≥24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%).Conclusions: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.

New biweekly combination of trastuzumab, docetaxel, and gemcitabine for HER2-positive metastatic breast cancer: First early results from a phase II multicentric trial on behalf of Gruppo Oncologico Italia Meridionale

1096 Background: The clinical activity of the combination of chemotherapy plus trastuzumab in HER-2 overexpressing metastatic breast cancer has been well documentated. We report the first results in terms of efficacy and safety of a phase II trial on biweekly combination of trastuzumab plus docetaxel and gemcitabine as first line therapy in HER-2-positive metastatic breast cancer patients. Methods: Patients at first relapse or with synchronous metastasis, were treated with trastuzumab (4 mg/kg, loading dose 6 mg/kg) plus gemcitabine (1000 mg/m2) plus docetaxel (50 mg/m2) as biweekly schedule. Primary end-point was overall response rate (ORR), secondary end-point time to progression (TTP), clinical benefit rate (CBR; PR+ CR + prolonged SD for ≥ 24 weeks), and tolerability. Based on previous data, an ORR greater than 60% was considered to indicate clinical activity in this two stage design trial. Results: A total of 26 patients with histologically confirmed, measurable MBC, tumors scored as +3 positive for HER-2 by immuno-histochemistry or FISH +, no pretreated with chemotherapy or trastuzumab for metastatic disease have been enrolled, 22 actually evaluable for response and toxicity. Median age was 49 years (range 34–66), visceral metastases were present in most patients (73%). Median number of cycles was 8 (range 3–12). The ORR was 86% (95% CI, 80–91%), with two CR (9 %) and 17 PR (77%). 3 patients had SD, 1 prolonged (14%). The CBR was 91% (95% CI, 87%-94%). No progression of disease was observed. Median TTP was 7 months (range 5- 9+ months). The worst toxicity was WHO grade 2 neutropenia and grade 2 gastric pain. Conclusions: In this phase II study, the biweekly combination of trastuzumab, gemcitabine, and docetaxel in HER-2-positive breast cancer is very active. The toxicity observed was manageable and did not lead to treatment discontinuation. Thus, the patients accrual is ongoing to the preset target of 50 patients. No significant financial relationships to disclose.

Breast tumor cells isolated from in vitro resistance to trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing.

An understanding of model systems of trastuzumab (Herceptin) resistance is of great importance since the humanized monoclonal antibody is now used as first line therapy with paclitaxel in patients with metastatic Her2 overexpressing breast cancer, and the majority of their tumors has innate resistance or develops acquired resistance to the treatment. Previously, we selected trastuzumab-resistant clonal cell lines in vitro from trastuzumab-sensitive parental BT-474 cells and showed that cloned trastuzumab-resistant cell lines maintain similar levels of the extracellular Her2 receptor, bind trastuzumab as efficiently as the parental cells, but continue to grow in the presence of trastuzumab and display cell cycle profiles and growth rates comparable to parental cells grown in the absence of trastuzumab (Kute et al. in Cytometry A 57:86-93, 2004). We now show that trastuzumab-resistant and trastuzumab-sensitive cells both surprisingly display trastuzumab-mediated growth inhibition in athymic nude mice. This demonstrates that resistance developed in vitro is not predictive of resistance in vivo. The observation that in vitro resistant cells are sensitive to trastuzumab in vivo could be explained by antibody dependent cellular cytotoxicity (ADCC). Therefore, both parental and trastuzumab-resistant cells were assayed for ADCC in real time on electroplates with and without trastuzumab in the presence of a natural killer cell line (NK-92), and granulocyte or mononuclear cellular fractions isolated from human peripheral blood. Mononuclear cells and NK-92 cells were more effective in killing both parental and trastuzumab-resistant cells in the presence of trastuzumab. Both trastuzumab-resistant cells and trastuzumab-sensitive cells showed similar susceptibility to ADCC despite displaying divergent growth responses to trastuzumab. The granulocyte fraction was able to kill these cells with equal efficacy in the presence or absence of trastuzumab. These results support a model of trastuzumab tumor cell killing in vivo mediated primarily by ADCC from the mononuclear fraction of innate immune cells and suggest that in the clinical setting not only should changes in signaling transduction pathways be studied in acquired tumor resistance to trastuzumab, but also mechanisms by which tumors impede immune function should be evaluated.

Beyond Trastuzumab: Overcoming Resistance to Targeted HER-2 Therapy in Breast Cancer

Overexpression of the human epidermal growth factor receptor 2 (HER-2) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior, and response to systemic therapy. Trastuzumab is a monoclonal antibody directed against HER-2 which has revolutionized the management of both early and advanced breast cancer. It may exert its anti-cancer effects through inhibition of intracellular signaling, upregulation of p27, impaired angiogenesis, induction of immune-mediated destruction, and blockade of cleavage of the extracellular domain of HER-2. In spite of its robust clinical activity, most women with metastatic HER-2 overexpressing breast cancer eventually progress on trastuzumab therapy. Possible mechanisms of resistance include: altered receptor antibody interaction, PTEN loss and enhanced Akt signaling, p27 loss, signaling through other receptors. Preclinical experiments, clinical experience with the use of trastuzumab beyond progression, and a recent phase III clinical trial with Lapatinib, a dual EGFR/HER-2 tyrosine kinase inhibitor, demonstrate that the HER-2 signaling axis remains an important therapeutic target even after progression on trastuzumab. A variety of novel strategies are currently in development to exploit this pathway following the onset of resistance, such as receptor antibodies, sheddase inhibitors, signal transduction inhibitors, heat shock protein inhibitors, proteasome inhibitors, anti-angiogenic agents, and immune-stimulatory therapies, either as single agents or in combination with trastuzumab. Rational clinical trial design, with attention to appropriate patient selection and prospective collection of biological material, is needed to ensure that the new generation of anti-HER-2 targeted therapies realizes its promise in the treatment of trastuzumab-resistant disease.

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Among the patients who received a trastuzumab-containing regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2-14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0-45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (<or=50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (</=50 years) who had recurrent breast cancer with liver metastases.

Final results from a phase II evaluation of lapatinib (L) and bevacizumab (B) in HER2-overexpressing metastatic breast cancer (MBC).

Abstract Abstract #3133 Background:&amp;#x2028; HER2 overexpression has been shown to upregulate VEGF expression in pre-clinical breast cancer models. Overexpression of both HER2 and VEGF has been associated with worse clinical outcome than overexpression of either receptor alone. In pre-clinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further study. L, an oral dual tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts.&amp;#x2028; Methods: &amp;#x2028; This single-arm study was designed to evaluate L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC patients. The primary endpoint is crude progression-free survival (PFS) rate at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks thereafter. HER2-overexpression was defined as local FISH-positive or IHC 3+ results. Serial evaluation of circulating tumor and endothelial cells and HER2 extracellular domain was performed.&amp;#x2028; Results:&amp;#x2028; Enrollment to this study ended in March 2008 (n=52). Data are presently available on 32 of 52 pts enrolled before January 1, 2008. Pts received a median of 5 prior MBC therapies (range 0-15); 88% received prior T (median 19.7 months; range 1.2-56.8 months). The most frequently reported AEs included diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and emesis (46%). Four asymptomatic LVEF declines were reported (three grade 2 events; one grade 1 event), as were nine cases of hypertension (eight grade 1 or 2 events; one grade 3 event) and one grade 3 GI hemorrhage. 27/32 patients were evaluable for response; five withdrew prior to first radiologic assessment (two due to toxicity, three due to investigator/pt request). The crude 12-week PFS rate was 63% (20/32 did not progress by Week 12); overall response rate (complete/partial response) was 13%, and the clinical benefit rate (complete/partial response or stable disease for ≥ 24 weeks) was 34%.&amp;#x2028; Conclusions:L+ B is well tolerated and has shown promising activity in heavily pretreated HER2+ MBC pts. Final efficacy and safety data will be presented on the full study cohort. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3133.

Circulating tumor cell and endothelial cell data from a phase II evaluation of lapatinib and bevacizumab in HER2-overexpressing metastatic breast cancer.

Abstract Abstract #3154 Background: Overexpression of both HER2 and VEGF is associated with worse outcome than overexpression of either receptor alone. In preclinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. Bevacizumab (B) plus trastuzumab and lapatinib (L) plus pazopanib have shown activity in patients (pts) with HER2+ MBC. We evaluated the combination of L+B in a phase 2 trial in HER2+ MBC pts. To explore new biomarkers of treatment effect, we measured circulating tumor cells (CTCs) with two different methods of CTC enumeration: CellSearch (Veridex LLC), and immunomagnetic enrichment followed by flow cytometry (IE/FC), as well as circulating endothelial cells (CECs) in pts receiving study treatment.&amp;#x2028; Methods: This study evaluated L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC pts. The primary endpoint is crude progression-free survival (PFS) at 12 wks. Serial evaluation of CTC and CEC was performed. Blood was obtained from consenting pts at baseline, weeks 2, 6 then every 12 weeks until end of study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. CTC data were correlated with assay method and with best response. CECs were defined as CD34/31+, CD45-, or CD34/146+, CD45-, and were assayed by FC.&amp;#x2028; Results: Enrollment to this study ended in March 2008 (n=52). Clinical data is presented at this meeting (Dickler et al). 47 patients have evaluable CTC and CEC data at baseline and/or first follow-up; 32 patients have response data. CTC determined by CellSearch or IE/FC showed significant correlation at baseline (R=0.58; P=0.012). CTC by CellSearch at first followup correlated with treatment response (P=0.01) with levels above 5 CTC/sample associated with progression; there was no correlation with baseline values. There were too few positive IE/FC values to evaluate correlation with outcome. The change in CEC/CD146 from baseline to first followup for is of borderline significance in this preliminary analysis (P=0.07) between PR (N=2, Mean Change Score/MCS=-4.345) and SD/PD (N=18, MCS=0.8); a decrease of CEC/CD146 from baseline to first followup suggests greater likelihood of response.&amp;#x2028; Conclusions: L+B is an active regimen in pts with MBC. CTC measurements correlated between two separate methodologies, and for the CellSearch assay predicted response to therapy. A decrease in CEC from baseline to first followup correlated with response to this combined targeted therapy, consistent with our previous results with other B-based therapy. PFS and response correlations for the full study cohort will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3154.

A multicenter phase II study of non-pegylated liposomal doxorubicin (MYOCET®) in combination with trastuzumab and docetaxel as first line therapy in metastatic breast cancer.

Abstract Abstract #3156 The objective of the phase II study is to evaluate the cardiotoxicity, general safety, and efficacy of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first line treatment of metastatic breast cancer.&amp;#x2028; Patients and methods: Patients (n = 31) with metastatic HER2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) every 3 weeks and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in left ventricular ejection fraction (LVEF) of ≥ 20 units or a decline to ≤ 45%. Patients were allowed to receive adjuvant doxorubicin or epirubicin to cumulative doses up to 240 mg/m2 or 450 mg/m2, respectively.&amp;#x2028; Results: The mean LVEF at baseline was 62.8 ± 7.1% and decreased to 60.2 ± 6.5% at cycle 2, but did not change significantly during the rest of the study; mean values at cycle 8 and at the end of the study were 58.7 ± 7.0% and 57.3 ± 9.5% respectively. One case of symptomatic CHF occurred during the study.&amp;#x2028; The most common adverse events were hematologic toxicities, alopecia, asthenia and fever. The Overall Response Rate was 65.5% (CR 31%, PR 34.5%).The median progression free survival was 15.5 months (95% CI 11-24 months). The average overall survival was 27.9 months.Conclusions: These results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a good cardiac safety profile at a long term follow up, comparatively to recent published results data in HET study. A promising efficacy including CR and PFS has been noted in 1st line MBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3156.

Weekly Paclitaxel and Trastuzumab as a First-Line Therapy in Patients with HER2-Overexpressing Metastatic Breast Cancer: Magnitude of HER2/neu Amplification as a Predictive Factor for Efficacy

We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as firs-tline chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of ≤4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP.

A Review of Trastuzumab-Based Therapy in Patients with HER2-positive Metastatic Breast Cancer

The ERBB2 or HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2 has been demonstrated to improve survival when combined with chemotherapy for the treatment of HER2 overexpressing metastatic breast cancer (MBC). Further studies have endeavoured to clarify the optimum chemotherapy regimen in combination with trastuzumab for MBC and its use together with novel biological agents. This review summarises these data together with preclinical studies exploring the mechanism of trastuzumab action and causes of drug resistance. The frequent incidence of brain metastases in patients on trastuzumab is highlighted, and data on the continuation of trastuzumab following CNS and non-CNS progression reviewed.