Search

Background: Personalized healthcare tailors treatments to patients and their disease characteristics through the use of genetics and other biomarkers. Genetic differences among individuals may explain variations in drug treatment response, including side effects. With such information physicians could make more informed decisions about drugs and dosing for a given individual, thereby improving patient care. Although there has been some success, to a large extent genetic variation related to drug response remains unexplained. Bevacizumab, a humanized monoclonal antibody against the angiogenic factor VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). The InVite study will evaluate the feasibility of performing genomewide association studies using self-reported information collected via an online platform from patients with MBC who have been treated with bevacizumab. Using novel methodology in a convenient, user-friendly, and scientifically rigorous format, InVite ultimately aims to identify potential pharmacogenetic associations in this patient population. Trial design: InVite is a pilot, non-interventional, observational, web-based, prospective cohort study designed to collect patient-reported safety, efficacy, and genetic data from patients with MBC treated with bevacizumab. Data on demographics, breast cancer disease status, cancer treatment history, bevacizumab-related outcomes, and certain safety events will be collected directly from patients entirely via online surveys. Patients will be asked to complete surveys at the time of enrollment and then every 3 months for 1 year after enrollment. A saliva sample for DNA collection will be gathered using an at-home kit. Evaluations of data quality and collection feasibility will be conducted intermittently. There will be an optional substudy to allow for blood sample collection for DNA analysis. Eligibility criteria: ≥18 years of age, residing in the US, locally recurrent breast cancer or MBC, currently being or having been treated with bevacizumab starting on or before Dec 31, 2011, fluent in English, and access to a computer with an internet connection. Specific aims: The primary objective is to assess the feasibility of recruiting subjects and collecting biospecimens and self-reported data online. The secondary objective is to characterize the patient population. Exploratory objectives include analyzing potential associations between genetic polymorphisms and 1) bevacizumab-induced hypertension, the most common bevacizumab-related adverse event, and 2) patient-reported time-to-progression. Statistical methods: Baseline demographics, clinical and treatment characteristics of enrolled patients will be summarized. Each polymorphism genotyped will be tested for association with the defined endpoint using appropriate statistical modeling. Present and target accrual: Accrual as of May 23, 2012 is 82 patients. Target accrual is 1000 patients. [ABSTRACT FROM AUTHOR]

Background: While representing the largest fraction of women diagnosed with primary breast cancer, older postmenopausal women with ER+, HER2-- tumors are less responsive to chemoendocrine therapy than younger women and have been underrepresented in molecular profiling of randomized trials. IBCSG Trial IX, a randomized controlled trial in postmenopausal women, median age 61y, with node negative disease, failed to demonstrate the benefit of preceding tamoxifen (T) by 3 cycles of CMF for ER+ tumors. We sought to determine if MS, a proliferation score, could identify a subset of women who differentially benefit from addition of chemotherapy to T in this trial. Methods: From 1988-1999, 1669 eligible patients (1040 with ER+, HER2-- tumors) were randomized to CMF ->T vs T. Disease-free survival (DFS) was the primary trial endpoint; breast cancer-free interval (BCFI) which excludes second (non-breast) malignancies and censors deaths without prior cancer event was also evaluated. Analysis was limited to the first 7 years of follow-up. From 671 (ER+, HER2--) available subjects, 568 were successfully profiled by RT-PCR. The mRNA expression levels of 14 equally-weighted proliferation genes and 3 normalization genes were used to generate MS; predetermined binary categorization of MS was used. Analysis of this post hoc, pre-specified study used results from centralized laboratory IHC and Cox models to assess the predictive value of MS on DFS and BCFI, adjusting for traditional risk factors of local treatment, age, ER, PR, Ki67, tumor size and grade. Results: Subgroups of MS (low, 169 samples (30%) and high, 399 samples (70%)) were identified. MS by treatment interaction was significant for DFS and BCFI (each p ≤ 0.004). Among patients with low MS, CMF -> T improved DFS (HR 0.19, 95% CI 0.06-0.59) and BCFI (HR 0.19, 95% CI 0.05-0.72) vs T; 7y DFS was 95% vs 83% with CMF -> T vs T. Among patients with high MS, CMF T did not improve DFS (HR 1.27, 95% CI 0.79-2.05) or BCFI (HR 1.37, 95% CI 0.80-2.33) and 7y DFS of 81% for CMF T and T. Continuous MS was moderately correlated with log Ki67 (r = 0.47) but not correlated with ER or PR. The MS by treatment interaction remained significant with Ki67 in the model. Conclusions: Low MS was associated with differential benefit favoring those women receiving CMF -> T vs T alone for both DFS and BCFI in the first 7 years. The effect was independent of traditional risk factors including Ki67. Hence this study, which is unconfounded by chemotherapy-induced ovarian ablation in younger women, identifies a subset of postmenopausal women with ER+, HER2- tumors that benefit from CMF chemotherapy. This seemingly incongruous observation is consistent with a) the prior observation that only the lowproliferation subgroup by PAM50 11-gene signature benefits from the addition of weekly paclitaxel to adjuvant FEC (GEICAM/9906), b) the ability of MS to identify a subset of women with tumors with disseminated luminal progenitor cells activated through the agonistic activity of tamoxifen, and c) the repetitive dosing of cyclophosphamide and taxol being hypothesized to act via tumor stroma/anti-angiogenesis. The relative contribution of these factors is under investigation. [ABSTRACT FROM AUTHOR]

Introduction: PARP inhibition has emerged as one of the most exciting and promising 'targeted' therapeutic strategies in the treatment of advanced triple negative breast cancer (TNBC) - the intended 'target,' being DNA repair (Anders CK, 2010). Although olaparib is known to have antitumor activity in BRCA-related TNBC cells, a limited number of preclinical and clinical studies have shown antitumor efficacy of olaparib in non-BRCA-related BC (Shimo T, 2012). Understanding the biology of TNBC cells has identified molecular targets including RTK(s), such as EGFR. Purpose: Here we tested the combination of a PARP inhibitor, olaparib (O) (AstraZeneca) plus carboplatin (C) with the EGFR/VEGFR inhibitor, vandetanib (V) (AstraZeneca) in a BRCA-wt TNBC model. Methods: Athymic mice bearing TNBC (BRCA-wt VEGFR expressing MDA-MB231& MDA-MB468 [EGFR amplified/overexpressed]) xenograft tumors (200 mm3) were treated with O plus C in combination with V (Arms: vehicle control 1, vehicle control 2, C+O, V, C+O+V). In vitro effects of V in combination with O plus C (or temozolomide) on clonogenic growth (3D on-TOP assay), proliferation (MTT and CelltiterGLO), apoptosis (Apoptosis Array), cell signaling marker(s) (Western Blot), and tumor cell phenotypes (fibronectin-directed migration, matrigel-invasion, and vascular mimicry) were investigated in a panel of five BRCA-wt and BRCA-mutated TNBC cell lines. The effects of V were tested on (a) cell signaling marker(s), (b) angiogenesis marker (HIF-1 alpha), and (c) angiogenesis related phenotypes (vitronectin-directed migration, and cord formation) in HUVEC. Results: (1) O plus C in combination with V caused a regression of the in vivo growth of established tumors by 50% which was evident in both the BRCA-wt TNBC models tested. Interestingly, a marked suppression of the progression of tumor-growth was observed in the O plus C arm. (2) In vitro, V alone (10 µM) inhibited baseline as well as EGF-induced phosphorylation of AKT (S473/T308), S6RP, 4EBP1 and ERK. (3) TNBC cells exhibited higher sensitivity to V in clonogenic assays when combined with a 10 µM fixed dose of O and C/temozolomide. (4) A combination of V with O plus C increased cleaved caspase-3, PARP cleavage, and pro-apoptotic signals, while inhibiting vascular mimicry, migration, and invasion in MDA-MB231, MDA-MB468, and SUM149 cells. (5) Treatment with V blocked cord formation, migration, EGF-induced HIF-1α accumulation, and phosphorylation of AKT, 4EBP1, and ERK in HUVEC. Conclusion: A profound anti-tumor efficacy of O plus C in combination with V in BRCA-wt TNBC model can be explained by a significant anti-proliferative/pro-apoptotic and anti-migratory/anti-invasive actions of the drugs (alone or in combination), as observed both in tumor cells as well as in endothelial compartments. The combination of O plus C plus V merits further investigation in TNBC. [ABSTRACT FROM AUTHOR]

Background: We have reported that a 97-gene signature, the Genomic Grade Index (GGI) can separate histological grade (HG) 2 breast tumors into low vs high GGI tumors with different outcomes. We have also developed a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tool including 6 reporter and 3 control genes that can reliably evaluate Genomic Grade (GG) in paraffin embedded tumors. Methods: We evaluated the qRT-PCR GG in women treated with either tamoxifen or letrozole monotherapy in the Breast International Group (BIG) 1-98 study with 8.1 year median follow-up. The association between continuous GG and distant recurrence-free interval (DRFI) was evaluated in Cox regression models stratified for the 2 vs 4 arm randomization option, chemotherapy and hormonotherapy use, with and without adjustment for clinicopathological characteristics. Estrogen, progesterone receptor (ER, PR), Ki67 and HG were centrally reviewed. The clinicopathological model included age and log2 tumor size, ER and PR as continuous variables, nodal status (N0 vs 1-3 vs >3), HG (1 vs 2 vs 3) and HER2 (negative vs positive). Similar analyses were performed for log2 Ki67 as continuous variable. Added prognostic value was assessed using the likelihood ratio statistic. Results: We obtained GG in 883 (62%) of 1428 samples. Non evaluable results were due to pre-analytical issues or technical failure. Among the 883 patients, 521 (59%) had N0 disease, 435 (49%) were treated with tamoxifen and 84 (10%) had distant recurrences. The GG classified 502 patients with HG2 tumors as either GG1 (N = 202, 40%), equivocal (N = 220, 44%) or GG3 (N = 80, 16%). In univariate analysis, increasing GG and Ki67 were significantly associated with lower DRFI (Table). When the 773 N0/1-3 patients were analyzed based on HG, the Kaplan-Meier estimate for 10-year DRFI was 98% (95% confidence intervals 96-100%) for the 123 HG1, 92% (88-95%) for the 456 HG2 and 84% (78-90%) for the 194 HG3 patients. In the N0/1-3 population, 10 year DRFI based on GG was 95% (96-100%) for the 290 GG1, 92% (89-95%) for the 309 GG equivocal and 84% (77-90%) for the 178 GG3 patients. Interestingly, when the 456 HG2 and N0/1-3 patients were analyzed based on GG, the 10-year DRFI was 95% (92-100%) for the 185 HG2/GG1 patients, 92% (88-96%) for the 202 HG2/GG equivocal patients, 86% (76-96%) for the 69 HG2/GG3 patients. In all patients either GG or Ki67 as continuous variable significantly improved the clinicopathological model in predicting distant recurrence (Table). Conclusion: Either Genomic Grade or centrally reviewed Ki67 provides independent prognostic information for risk of distant recurrence beyond clinicopathological characteristics in patients treated with endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Approximately 60-70% of breast cancers (BC) express estrogen receptor (ERa) and/or progesterone receptor (PR), the most common malignancy in women in the US and Europe. Many though not all patients with ER+ BC respond to hormonal therapy (e.g. tamoxifen and aromatase-inhibitor) but a large number will eventually develop resistance to long term therapy. Purpose: Development of resistance to endocrine therapy is a clinical issue in ER+ BC. Studies with human cell lines have shown that upregulation of PI3K-AKT-mTOR and MEK-ERK pathways contributes to resistance to endocrine therapy (Miller TWet al JCO 2011; Sanchez CG et al Breast Cancer Res 2011). Using leterozole-resistant ER+ BC model, we investigated the effects of PI3K-AKT-mTOR pathway inhibitor alone and in combination with MEK1/2 inhibitor. Methodology: The anti-proliferative, anti-migratory, and intracellular signaling (pAKT, pS6RP, p4EBP1 and pERK) effects of GDC-0941 (Class I PI3K inhibitor) or GDC-0980 (dual PI3K/mTOR inhibitor) alone and in combination with GDC-0973 (MEK1/2 inhibitor) were evaluated in aromatase overexpressed (MCF-7aro), letrozole-resistant (MCF-7aro/LetR) and long-term-estrogen-deprived (LTEDaro) BC cell lines by MTT assays, integrin-mediated migration assay and Western blots. Results: 1) Both GDC-0980 and GDC-0941 exhibited excellent in vitro cell killing activity in MTT assay in all cell lines with IC50's 10-30 nM & 0.2-1.5 µM respectively. PI3K pathway inhibitors were more potent when combined with GDC-0973; 2) Integrin-mediated migration was significantly higher in both MCF-7aro/LetR andLTEDaro cells than MCF-7 and MCF-7aro cells; 3) Both MCF-7aro/LetR and LTEDaro cells movement were significantly abrogated following the treatment of GDC-0980, and the combination of GDC-0980 plus GDC-0973 more effectively blocked integrin-mediated migration; 4) Inhibition of phosphorylation of AKT (S473/T308), S6RP and 4EBP1 (T37/46) was observed following PI3K pathway inhibitors; 5) pERK was upregulated following the treatment of GDC-0941 (PI3K inhibitor); 6) Basal level of pERK was significantly high in MCF7/LetR and MCF7/LTED cells, and GDC-0980 failed to change the level of pERK in those cell lines; and 7) Combination of PI3K pathway inhibitor plus MEK1/2 inhibitor significantly blocked activation of both pathways. Conclusion: Our/n vitro data suggest that therapeutic targeting of the PI3K-AKT-mTOR and the MEK-ERK signaling pathways should be effective in abrogating aromatase-inhibitor -resistance in ER+ BC. [ABSTRACT FROM AUTHOR]

Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) ≥1 characterized alteration(s), excluding variants of unknown significance. TP53 -associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238-46. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18-transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer.

A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m2/day, while eight patients received a dose of 30 g/m2/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m2/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 +/- 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.