HER2-neu Positive Breast Cancer Research Articles

A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

Risk factors of brain metastasis in a series of Egyptian breast cancer patients: A single-institution experience.

50 Background: Incidence of cerebral metastasis is increasing among breast cancer patients. Many factors have been reported associated with increased risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in breast cancer patients. Methods: We retrospectively analyzed histologically proven breast cancer patients who presented to Cairo Oncology Center (COC) in the period from 1999 till 2008, with follow up period of 6 months at least for those in adjuvant setting. The following factors were analyzed: age, tumor size and grade, nodal status, ER, PgR and HER2 over-expression status. Results: Our study included 2,338 patients. 96 patients (4.1%) experienced brain metastasis during the course of their disease. 3 patients had brain metastasis among other sites of distant spread at first presentation to COC. 30 out of 96 patients (31.25%) with localized breast cancer had brain metastasis at first relapse with 13 (13.5%) of them had isolated brain metastasis. In a median follow-up of 37.1 months (6-277) the median time to develop brain metastasis was 26.5 months (0-144). Based on univariate analysis, the following variables were associated with shorter time to develop brain metastasis: tumor size more than 5 cm (HR = 2.1, 95% CI 1.14-3.87), lymph node involvement at diagnosis (HR = 1.57, 95%CI 1.17-2.10), ER negativity (HR = 1.58, 95%CI 1.33-1.73), PgR negativity (HR = 1.55, 95%CI 1.29-1.72) and HER2-neu over-expression (HR = 2.68, 95%CI 1.51-4.75). On multivariate analysis, only patients with lymph node involvement at diagnosis and those with HER2-neu positive breast cancer were associated with shorter time to develop brain metastasis. Conclusions: We concluded that HER2 over-expression as well as lymph node involvement are the 2 main factors associated with shorter time to develop brain metastasis. These patients could be good candidates for trials investigating the role of any prophylactic intervention to decrease their risk to develop brain metastases.

Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC→T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC→TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study.

Abstract Background: Evaluation of the long-term benefit of biologically-based regimens of trastuzumab in the early breast cancer population, and optimization of trastuzumab integration to maximize efficacy and minimize cardiac toxicity.Material and Methods: We randomized HER2-positive (FISH+) breast cancer patients with axillary lymph node positive or high risk negative, to either standard AC (60/600 mg/m2 q3wk x4) followed by T (100 mg/m2 q3wk x 4) or two trastuzumab-containing regimens; AC followed by T with trastuzumab x 1 year or TCarbo (75 mg/m2/AUC6 q3wk x 6) with trastuzumab x 1 year. Patients were prospectively stratified by number of positive nodes (0, 1-3 vs 4+) and hormone receptor status. Patients with ER and/or PR positive (HR+) tumors received hormone-directed therapy for 5 yrs after chemotherapy. The primary endpoint was disease-free survival (DFS) with 80% power (0.05 significance level) to detect an absolute difference of 7%. Secondary endpoints include overall survival (OS) and safety, including cardiac toxicity (symptomatic events and asymptomatic LVEF decline). The first two protocol-specified analyses for this study were performed at 300 and 450 disease-related events. We now report the results of the third protocol-specified analysis conducted after 650 events, expected by end of June 2009.Results: A total of 3222 patients (1072 in AC-T, 1076 in AC-TH and 1074 in TCH) were recruited between April 2001 and March 2004. Baseline characteristics of the study population will be included. Cox analysis of DFS and OS (unadjusted and adjusted for nodal status) and cardiac toxicity data will be presented for the three treatment arms.Discussion: The results of this trial help define the role of trastuzumab in the breast cancer HER2-positive adjuvant setting, as well as the risks/benefits of adjuvant trastuzumab within the context of overall safety including cardiac toxicity. This latter objective is of particular importance given that many of these women may be cured of their disease in the adjuvant setting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 62.

Analysis of Topoisomerase IIa and HER2 Status in 126 Patients from the US Oncology 9735 Trial of Adjuvant Chemotherapy with Docetaxel/Cyclophosphamide (TC) vs Doxorubicin/Cyclophosphamide (AC) in Early Breast Cancer.

Abstract Background: HER2/neu (HER2) positive breast cancers are associated with worse survival, resistance to cyclophosphamide/methotrexate/fluorouracil, and hypothesized to be sensitive to anthracyclines. It has been postulated that only a subset of HER2 positive breast cancers are sensitive to anthracyclines. Investigators have been working on how to identify this subset of patients, thus sparing patients from anthracyclines that have potential cardiac and bone marrow toxicities. Overexpression of the topoisomerase IIa gene (TOP2A) is the putative biomarker for sensitivity to anthracyclines. Testing tumors for overexpression of this gene may help identify patients who will not benefit from anthracylines. TOP2A is located in the same amplicon as the HER2 gene and can be assessed for overexpression by a FISH assay.Materials and Methods: Paraffin tissue blocks were obtained in 126 patients entered on US Oncology trial 9735 which recruited patients between 1997 and 2000. Data on HER2 status and outcome was previously reported (JCO 27:1177-1183, 2009). TOP2A status was then assessed by fluorescent in situ hybridization (FISH) using the LSI TOP2A Spectrum Orange Probe (Vysis). A total of 20 cells were counted and a gene ratio of greater than 2.0 was considered positive. Clinical data and outcome were available for statistical analysis.Results: We found that none of the 97 HER2 negative cases demonstrated overexpression of TOP2A by FISH analysis. TOP2A was overexpressed in 43% of the 29 HER2 positive cases. An analysis of outcome will be presented at the meeting, although the number of cases limits this observation.Discussion: Our study supports the observation that TOP2A is not overexpressed in HER2 negative disease and is only observed in a subset of cancers overexpressing HER2. Clinical correlation of outcome will be necessary to confirm whether or not TOP2A is a reliable biomarker of sensitivity to anthracyclines. The ongoing US Oncology trial of TC vs. TAC in HER2 negative breast cancer (USOR Trial 06-090) should provide that evidence.Supported in part by a grant from sanofi-aventis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2134.

Baseline and recurrence levels of soluble HER2 (sHER2) in early-stage HER2-neu positive breast cancer (HER2+BC) from the NCCTG adjuvant Intergroup trial N9831

539 Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels <50, 24% (15/63) of Arm A patients had very high recurrence sHER-2 levels (≥50) as compared to 9% (2/23) on Arm C (p=0.10). Patients with recurrence sHER-2 levels ≥15 had shorter survival time following recurrence with 3 year overall survival of 51% compared to 76% for the <15 sHER-2 group (HR = 2.77; 95% CI: 1.20–6.43, p = 0.02). Conclusions: Based on serial specimens during treatment, the concurrent trastuzumab arm (C) had constant sHER-2 levels, whereas the standard chemotherapy arm (A) had increasing sHER-2 levels. In arm A, recurrence sHER-2 levels increased significantly from baseline while recurrence sHER-2 levels did not change in arm C. Additionally, pts with high sHER-2 levels at recurrence had shorter overall survival following recurrence. Partial support: CA25224, CA114740 , Genentech, Siemens, and the BCRF. [Table: see text]

Topoisomerase II-alpha (TOP2A) gene co-amplification does not predict response to therapy and survival in Her-2 neu positive metastatic breast cancer

21108 Background: Preliminary data from a phase III trial of adjuvant traztuzumab (BCIRG, SABCS 2005, abstract 1045) suggested that co-amplification of the genes for HER2 and topisomerase II alpha (TOP2A) on chromosome 17 resulted in improved disease free survival with chemotherapy regimens containing both and anthracycline and traztuzumab. We sought to determine if co-amplification of HER2 and TOP2A was a predictor of response and benefit (or lack thereof) to herceptin containing chemotherapy in the metastatic setting, since few women receive both therapies concurrently for MBC. Methods: A tissue mircoarray (TMA) with 3-fold redundancy was constructed using 0.6mm cores from primary or metatstatic paraffin embedded tumor from 124 cases from Magee-Women's Hospital which were Her2 2+ or 3+ by IHC, or amplified by FISH, on pathology report. Four micron thick TMA sections were used for HER2 immunohistochemical (CB11 monoclonal antibody, Ventana Medical Systems, Tucson, AZ) and HER2 and TOP2A FISH analysis (HER2/CEP 17 and TOP2A/CEP 17 dual color probes from Vysis Inc. Downers Grove, IL). HER2 (or TOP2A) gene to chromosome 17 ratios of 2.0 or more was considered as amplification. Results: Tissue blocks from 52 tumors delivered clearly interpretable amplification for Her2 by FISH on reanalysis. The remaining 72 tumors are undergoing further reanalysis. Of the 52 tumors with Her2 amplification, 15 (29%) had co- amplification of TOP2A. Median survival was 44 months (95% CI, 31–69) for women with TOP2A coamplified tumors and 35 months (95% CI, 29- 63) for women with non-coamplified tumors (p=0.448, NS). Median time to progression on first therapy was 17 months (95% CI, 14–20) for women with TOP2A coamplified tumors and 15 months (95% CI, 12–17) for women with non-coamplified tumors (p=0.939, NS) Conclusions: In this analysis, TOP2A and HER2 gene co-amplification did not correlate with worse TTP on first metatstatic therapy or worse OS from metatstatic disease. No significant financial relationships to disclose.

Systemic adjuvant therapies and radiotherapy to the conserved breast: Strategies revisited

The rapid increase in the use of both radiotherapy and systemic therapy for patients with early breast cancer requires reconsideration of the strategies that have been used in the past for combining both treatments. In these considerations the impact of both radiotherapy as well as systemic therapy on local control and survival of breast cancer have to be considered. An important point for discussion has often been the sequencing of radiotherapy and systemic treatment. Nowadays the possibilities of trastuzumab for her-2 neu positive breast cancer leads to the question whether or not this can be combined with radiotherapy. Finally new possibilities of sophisticated radiotherapy approaches allow further minimizing the late toxicity of radiotherapy.

Adjuvanter Einsatz von Trastuzumab (Herceptin®) beim primären Mammakarzinom - aktuelle Datenlage und Bewertung der Stellungnahme des Kompetenz Centrums Onkologie des MDK Nordrhein

The results of four randomized international multicentric trials evaluating the therapeutic benefit of Herceptin in the adjuvant treatment of HER2-neu positive primary breast cancer have been reported. These reports showed that even after short term follow up one year of Herceptin resulted in improved disease free, metastases free and overall survival. Design and results of these four studies and the recommendations of national and international societies for the use of Herceptin in the adjuvant setting will be discussed.

Adjuvanter Einsatz von Trastuzumab (Herceptin®) beim primären Mammakarzinom - aktuelle Datenlage und Bewertung der Stellungnahme des Kompetenz Centrums Onkologie des MDK Nordrhein

The results of four randomized international multicentric trials evaluating the therapeutic benefit of Herceptin in the adjuvant treatment of HER2-neu positive primary breast cancer have been reported. These reports showed that even after short term follow up one year of Herceptin resulted in improved disease free, metastases free and overall survival. Design and results of these four studies and the recommendations of national and international societies for the use of Herceptin in the adjuvant setting will be discussed.

Taxanes as adjuvant therapy for breast cancer

The report of the results of the first generation taxane trials has made evident that these drugs should play a key role in the adjuvant treatment of node-positive operable breast cancer. Although direct comparisons among the different taxane regimens is still lacking, the American AC-paclitaxel dose-dense regimen, the TAC regimen, the French FEC-docetaxel and the Spanish FEC-paclitaxel regimens seem to offer the best results. The TC regimen (docetaxel-cyclophosphamide) is another option, particularly in patients at high risk for cardiac toxicity. Trastuzumab should now be part of the standard adjuvant treatment of HER-2neu positive breast cancer, probably administered in combination with a taxane regimen.