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Background: Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate composed of the humanized monoclonal antibody trastuzumab, the potent cytotoxic agent DM1 (a microtubule inhibitor), and a stable thioether linker. To estimate typical pharmacokinetic (PK) parameter values and interpatient variability, a population PK model for T-DM1 was previously developed from 1 phase 1 (0.3 to 4.8 mg/kg in qw or q3w regimens) and 2 phase 2 (3.6 mg/kg q3w) trials (Gupta, J Clin Pharmacol2012). The model reported here has been updated with additional data from 2 randomized trials (phase 2 TDM4450g and phase 3 EMILIA, 3.6 mg/kg q3w). Another phase 2 trial (TDM4688g) was used for external validation of the model. The effect of demographic and pathophysiological covariates on the PK of T-DM1 was explored to better understand the clinical factors that might affect exposure and clinical outcome for individual patients. Methods: For the current analysis, 9934 T-DM1 serum concentration-time data points from 671 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a 2-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, or likely to have clinical relevance, were explored for possible correlation with the key T-DM1 PK parameters of clearance (CL) and central volume of distribution (Vc). These covariates include those related to demographics, renal and hepatic function, disease status, and treatment history. Results: The estimated CL for T-DM1 is 0.68 L/day, Vc is 3.13 L, and the terminal half-life is 3.94 days. Interindividual variability (IIV) of the base model is 25.6% and 17.5% for CL and Vc, respectively. Patients with greater body weight, sum of longest dimension of target lesions, serum concentration of shed HER2 extracellular domain, and aspartate aminotransferase concentrations, as well as patients with lower serum albumin and baseline trastuzumab concentrations, have statistically faster CL. Patients with greater body weight also have statistically larger Vc. Incorporation of these covariates (P<0.001 by likelihood ratio test) decreased IIV of CL and Vc to 19.1 % and 11.7%, respectively. All covariates together explain 44.4% and 55.8% of IIV in CL and Vc, respectively. The model sensitivity analysis suggests that a patient with a statistically significant PK covariate value at the 5th or 95th percentile of the population will have a <20% difference in cumulative exposure (as represented by area under the T-DM1 concentration-time curve) compared with a typical patient with a median covariate value. Conclusions: A relatively small IIV for the estimated T-DM1 PK parameters of CL and Vc was observed. None of the evaluated covariates had a clinically meaningful magnitude of effect on T-DM1 exposure (<20% difference for patients with 5th and 95th percentiles vs patients with median value of covariates) that would justify a further dose adjustment. The body weight-based dose of 3.6 mg/kg q3w without further correction for other factors is considered appropriate in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The quality of biospecimens and associated data must be consistent and collected according to standardized methods in order to achieve international harmonization and coordination among biobanking networks. Sharing successful strategies between the Baylor College of Medicine (BCM) Cancer Center and Breast Center Buenos Aires (BCBA) is the driving force for the creation of an Argentinean Breast Cancer oriented Biobank with a shared data management system. Objective: To create a bilingual web-based tool for biospecimen management, inventory, clinical and breast cancer data registration according to international standards of data security quality assurance (ISO 27001). Methods/System Characteristics: The system permits users to enter and retrieve data concerning the collection, storage, quality assurance and distribution of biospecimens, and provides clinical and other patient data for samples while maintaining strict patient confidentiality. It has a multi-tier architecture, developed using Service-Oriented Architecture (SOA) software design principles in .net 4.0, and uses a SQL server database backbone. The system allows multidimensional data analysis trough On Line Analytical Processes (OLAP) and operates with standard web clients, such as Internet Explorer. User Profiles/Access Levels: Clinical staff (e.g., clinical research coordinator, phlebotomist, pathologist, PA, MD) conduct participant and consent registration and preregistration, epidemiological questionnaire data entry, barcode label generation, form printing, and clinical and pathological cancer data entry. * Biospecimen resource staff (e.g., lab technicians) track and store data about biospecimen collection, inventory, tracking and distribution, generate sample barcode labels, and maintain sample allocation and freezer maps for the system. * Scientists have the ability to search for biospecimens and associated data for their own translational research projects. * Breast Cancer Database: Detailed clinical, pathological, treatment and follow-up breast cancer information are captured for each patient, including TNM, biopsy and definitive surgery of primary tumor and events, systemic and radiation treatment, recurrences and metastasis, follow-up. A summary screen provides a snapshot of these data to the viewer. Pathology reports and sample collection forms are attached in each corresponding biopsy or surgery screen for easy viewing and quality assurance. Conclusion: This Biobank Management System was designed by a multidisciplinary team to improve and streamline the workflow for each member of the biobank by: allowing preregistration capabilities before consenting individuals or collecting samples, automatic generation of clinical and sample ID labels, and real-time statistics with certified secure sensible information confidentiality. This system's value is its wide range of uses, from the day-to-day management of a multicenter biobank to the storage of detailed clinical cancerrelated data in a user-friendly and intuitive data entry environment. [ABSTRACT FROM AUTHOR]

Background: We previously showed in HER2+ models of breast cancer (BC) that potent inhibition of the HER receptor layer can lead to re-expression of estrogen receptor (ER) or activation of the ER pathway. Consequently, the anti-apoptotic ER gene product Bcl2 is upregulated, resulting in enhanced tumor cell survival and treatment resistance. In this study, we investigated whether Bcl2 and ER expression levels are simultaneously increased by neoadjuvant treatment with the dual HER1/2 tyrosine kinase inhibitor lapatinib in HER2+ BC patients. Methods: In a neoadjuvant phase II clinical trial 49 HER2+ BC patients were treated with lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before surgery. Tumor specimens were prospectively collected at different time-points during lapatinib treatment (baseline, and weeks 2 and 4). Bcl2, ER, progesterone receptor (PR), total (t) and phosphorylated (p)-HER2, and Ki67 were assessed by immunohistochemistry. Spearman correlation was used to evaluate the association among the biomarkers at baseline, and the correlation of their changes over time. Fisher's Exact test and non-parametric Wilcoxon rank sum test were used respectively to determine if the frequency and the magnitude of Bcl2 expression changes were associated with baseline ER status. Results: 35/49 HER2+ tumor specimens (71%) were available for baseline evaluation of Bcl2 and ER. Of those, 12 (34%) were ER-positive (Allred score 3) and 23 (66%) ER-negative. Baseline Bcl2 expression correlated positively with ER (r = .75; p < .0001) and PR (r = .53; p = .0015), and inversely with t-HER2 (r = -.43; p = .0097). ER baseline expression correlated positively with PR (r = .57; p = .0004), and inversely with t and p-HER2 (r = -.55; p = .0005, and r = -.37; p = .0282, respectively) and Ki67 (r = -.39; p = .0271). Bcl2 changes at week 2 (w2) positively correlated with changes in both ER and PR levels (r = .70; p = .0002 and r = .57; p = .0076, respectively). Additionally, the increase in Bcl2 expression, observed in 9 of the 23 (39%) tumors with tissue available at w2, was significantly more frequent (p = .0147) and of greater magnitude (p = .0001) in ER-pos vs. ER-neg tumors -- 8/9 ER-pos tumors at w2 (including 3 converted from ER-neg by lapatinib) had increased Bcl2, while only 1 of the 14 (7%) ER-neg tumors (at baseline and w2) had increased Bcl2. The expression of ER itself at w2 also increased in 3 out of the 6 (50%) tumors which were originally ER-pos and had tissue available at w2, and in all of them Bcl2 increased in parallel. Of note, the single baseline ER-pos tumor that showed a reduction in ER at w2 had a parallel decrease in Bcl2. Similar observations or trends were found at week 4. Conclusion: Our study suggests that Bcl2 is upregulated as a result of enhanced/restored ER activity upon anti-HER2 therapy with lapatinib in HER2+ tumors. This further supports the use of endocrine along with anti-HER-2 therapy to block this escape pathway which could otherwise cause treatment resistance. In addition, the ER re-expression with lapatinib treatment observed in this study emphasizes the need to re-biopsy HER2+/ER--patients receiving anti-HER2 therapy and to add endocrine therapy if the tumor becomes ER-positive. [ABSTRACT FROM AUTHOR]

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals.

Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.

HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal.