bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of panobinostat (LBH589) in combination with trastuzumab in pretreated HER2-positive metastatic breast cancer (mBC): Preliminary safety and tolerability results
Authors: Conte P. , Campone M. , Pronzato P. , Amadori D. , Frank R. , Schuetz F. , Rea D. , Wardley A. , Britten C. , Elias A. 
Published: August 2020

1081 Background: Panobinostat is a potent inhibitor of histone deacetylase (HDAC) and has demonstrated single-agent activity and synergistic effects in combination with trastuzumab or docetaxel in HER2 positive BC xenografts. Methods: Previously treated mBC patients (pts), who progressed on or within 6 months of trastuzumab-based therapy, were enrolled in this multicenter study. Pts were dosed with either i.v. (Day 1+8) or oral panobinostat (three times per week, continuously) every three weeks in combination with standard weekly dose trastuzumab. To establish maximum tolerated dose, three (10, 15, and 20 mg/m2) and four (15, 20, 30 and 40 mg) cohorts are planned for treatment with i.v. and oral panobinostat, respectively. The pharmacokinetic (PK) profile is also measured. Results: Eighteen pts have been enrolled in this ongoing trial. Median age 54 yrs (33–60). Six pts were ER and PR negative, eight pts had liver metastasis, eight pts had lung metastasis, and two pts had central nervous system metastasis. All patients received prior taxanes and/or anthracyclines. All progressed on or within 6 months of trastuzumab-based treatment. The first cohort completed accrual with 13 pts (seven received oral and six received i.v. panobinostat). No dose-limiting toxicity (DLT) was reported in the i.v. arm, and only one DLT, uncomplicated grade 4 thrombocytopenia, was reported in the oral arm. The second cohort is ongoing, eight pts have been enrolled (five in i.v. and three in oral), and no DLTs have been reported yet. Additional safety results include: one pt with grade 3 leucopenia and grade 1 or 2: nausea in six pts; vomiting, four pts; diarrhea, five pts; stomatitis, three pts; and fatigue, three pts. One pt had grade 2 asymptomatic QT prolongation. In the first cohort, two pts experienced tumor reduction of 29% (both had liver metastasis), and four pts received over eight cycles of the combination. Conclusions: The preliminary results in the first cohort demonstrated that the combination is well tolerated and shows promising activity. Additional patient safety and full PK data will be presented. [Table: see text]
Cardiac safety of the lapatinib/letrozole combination as first-line therapy in patients (pts) with metastatic breast cancer (MBC)
Authors: Zembryki D. , Gomez H. , Koehler M. , Koehler M. , Johnston S. , Pippen J. , Florance A. , O'Rourke L. , Maltzman J. , Pivot X. 
Published: August 2020

1095 Background: Cardiotoxicity of traztuzumab therapy increases in pts pretreated with anthracyclines (A), radiotherapy to left breast, hypertension, or low baseline ejection fraction (EF). We report the cardiac safety profile of lapatinib, an oral, dual EGFR/HER-2 tyrosine kinase inhibitor, in a chemotherapy naïve or A-exposed pts with MBC. Methods: Women (n = 1286) with endocrine sensitive, previously untreated MBC received lapatinib and letrozole (L+L) or letrozole and placebo (L+P): 33% received previous A; 48% previous tamoxifen; <1% previous trastuzumab (T); <2% previous aromatase inhibitor. EF was evaluated by MUGA or echocardiogram at baseline, every 8 wk and at study withdrawal. Rate of cardiac events (NCI CTCAE grading), median time to onset, and duration of EF depression were assessed. Results: Cardiac events (CE; MEDRA terms: ejection fraction decreased, left ventricular dysfunction, ventricular dysfunction and cardiac failure) were infrequent in both arms. Grade 3/4 and 1/2 CE were reported in 0.9% and 4.0% of pts, respectively, in the L+L arm, and in 0.3% and 2.1%, respectively, in the L+P arm. The only symptomatic CE was a grade 4 event in the L+L arm. There was no apparent relationship between previous A exposure and CE frequency and severity. Median L exposure was 40 wk on L+L, 38 wk on L+P. Median time to onset and duration of EF decrease were 21.8 and 8.1 wk, respectively, on L+L, and 34.6 and 5.4 wk, respectively on L+ P. On the L+L arm, the dose was adjusted/interupted for 8 CE cases, discontinued for 6, and unchanged for 22. On the L+P arm, interuption of L was reported for 2 CE cases, discontinuation for 5, and in 7 CE events there was no change in therapy. Eight CE on L+L and 1 CE on L+P had not resolved as of the last report. Conclusions: This is the first long-term evaluation of lapatinib cardiac signals in a controlled trial in a trastuzumab-naïve MBC pt population. The frequency of cardiac events and degree of absolute EF decrease was low and occurred at similar rates in pts with or without anthracycline exposure. These encouraging cardiac safety data in first line metastatic BC study are promising for the ongoing study of lapatinib in patients with early HER-2+ BC treated on ALTTO trial. [Table: see text]
The effect of age on overall survival (OS) in patients with metastatic breast cancer (MBC) treated with capecitabine
Authors: Blum J. L. , Hu X. , Odom D. , Sherrill B. , Glück S. 
Published: August 2020

1097 Background: Both in monotherapy and in combination with a taxane, C has been shown to improve OS in patients with MBC. Since C is often used in older adults because of tolerability and ease of administration (PO vs IV), and lack of alopecia, an exploratory analysis was conducted to see if an association exists between age and OS among patients with MBC treated with C. Methods: Data from the intermittent dose (2510 mg/m2) 2 wks on/1 wk off arms of 5 phase II/III monotherapy or combination therapy with C registration trials involving patients with MBC were analyzed. Intent-to-treat (ITT) was defined as all randomized patients who took at least 1 dose of study medication. Patients were divided into 3 groups by age. A Kaplan-Meier method was used to estimate the age-category specific survival by trial. Next, Cox proportional hazard regression analysis was conducted using pooled data from the 5 trials with stratification by trial and key baseline characteristics. Analyses were conducted at the 95% confidence level. Results: A total of 570 ITT patients were included in the analysis (median age 55.0 years; range, 26–83): 193 (34%) were 18–49 years old; 246 (43%) 50–64 years old; and 131 (23%) ≥65 years old. A baseline Karnofsky score ≥90 was observed in 65.3%, 56.5%, and 50.4% of patients, respectively. The median treatment duration (range) was 93.0 (2–397) days in the 18 to 49-year-old group, 109.5 (2–448) days in the 50 to 64-year-old group, and 80.0 (5–371) days in the ≥65-year-old group. Unadjusted log-rank tests for each of the 5 trials showed no significant differences in OS between age categories. In the pooled analysis, Cox regression did not detect significant differences in survival based on age. Using age ≥65 years as the reference group, the hazard ratios were 1.06 (95% CI 0.81, 1.41) for age 18–49 years and 0.99 (95% CI 0.77, 1.29) for age 50–64 years. The Cox model revealed consistent results after further controlling for the Karnofsky score and number of metastatic sites. Conclusions: No statistically significant effect of age on OS was observed in patients with MBC treated with C. OS outcomes appear comparable across predefined age groups of patients with MBC treated with C. [Table: see text]
Identification of candidate biomarkers of therapeutic response to docetaxel in hormone-refractory prostate cancer by proteomic profiling
Authors: Horvath L. , Zhao L. , Lee B. , Brown D. , Molloy M. , Marx G. , Boyer M. , Breit S. , Sutherland R. , Henshall S. 
Published: August 2020

11010 Background: Docetaxel (DTX)-based chemotherapy improves symptoms and survival in men with advanced hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to DTX but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of DTX-resistance in HRPC. Methods: Protein profiling using iTRAQ mass spectrometry compared the PC3-Rx and DTX-sensitive PC3 cells and DTX-resistant PC3-Rx developed by DTX dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Plasma/serum samples were collected from 41 men with metastatic HRPC treated with DTX-based chemotherapy (36 with paired samples pre- and post- cycle 1 DTX). Serum/plasma levels of MIC-1 were measured by ELISA. The association between MIC-1 levels, PSA response and overall survival (OS) were assessed by non-parametric tests and Kaplan-Meier survival analysis. Results: The IC50 for DTX in PC3-Rx was 10-fold higher than that in parent PC-3 cells. Protein profiling identified that MIC-1 levels were elevated 2.4 fold and AGR2 decreased 2.4 fold in DTX resistant cells. Knockdown of AGR2 expression in PC3 cells resulted in increased DTX resistance (p=0.03). PC-3 cells treated with recombinant MIC-1 also became resistant to DTX (p=0.001). Conversely, treating PC3-Rx cells with MIC1-siRNA restored sensitivity to DTX (p=0.002). In HRPC patients, pre-treatment MIC-1 levels did not correlate with PSA response to treatment (p=0.6). In contrast, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with DTX resistance (p=0.006) and shorter overall survival (p=0.002). Conclusions: These results suggest that both AGR2 and MIC-1 play a role in DTX resistance in HRPC. Furthermore, changes in serum/plasma MIC-1 levels are associated with DTX resistance in a correlative human cohort. While a larger study is needed to validate these findings, the data provide evidence that MIC-1 as a potential predictive biomarker and both MIC-1 and AGR2 are potential therapeutic targets in DTX resistance. No significant financial relationships to disclose.
Nanoscale analysis of changes in signaling proteins in patients treated with single agent atorvastatin for low-grade or refractory NHL
Authors: Fan A. C. , Orban M. W. , Shirer A. E. , Rajwanshi R. , Kong C. , Natkunam Y. , Lee H. E. , Coutre S. , Felsher D. W. 
Published: August 2020

11011 Background: In preclinical studies using our transgenic lymphoma model, lymphoma regression upon atorvastatin treatment was associated with increased apoptosis and changes in phosphorylation of key signaling pathways including MAPK and STAT. To determine if statins affect tumor signaling in patients, we designed a single arm phase II study, “Atorvastatin in Patients with Low Grade or Refractory Non-Hodgkin's Lymphoma.” Methods: Patients received 80 mg atorvastatin daily and underwent tumor sampling and PBMC collection by fine needle aspiration (FNA) and blood draw on days 1 and 8. The primary endpoint was to measure a 50% increase in tumor apoptosis on treatment day 8 compared with day 1. To characterize changes in protein profiles, we have developed the use of a novel nano-immunoassay system (NIA) to simultaneously measure both phosphorylated and unphosphorylated protein isoforms. NIA and multi-color flow cytometry were used to evaluate intracellular signaling protein profiles for each patient's tumor cells, monocytes, and T cells. Results: All 14 patients have completed treatment. The primary endpoint was reached in 9 of 14 patients with 50% increase in apoptosis. We distinguished three patterns of signaling changes. First, as expected, pathways that were initially activated in tumor cells decreased upon treatment with atorvastatin, with up to a 70% decrease in phospho-STAT3 and phospho-STAT5. Second, pathways that were initially suppressed in tumor cells (including phospho-PLCγ), normalized upon treatment. Third, expression levels of proteins in apoptotic pathways, including p38, increased upon atorvastatin treatment. Finally, changes in signaling associated with atorvastatin are cell specific: effects on tumor cells were distinct from effects on non-tumor T cells and monocytes. Conclusions: Single agent atorvastatin has a measurable effect on tumor bioactivity in patients with lymphoma. NIA and multi-color phosphoFACS can be used to monitor changes in cell signaling in very small clinical samples during therapeutic interventions. Determining whether specific signaling molecules may be a biomarker for identifying lymphoma patients that respond to atorvastatin is worthy of further investigation. [Table: see text]
TGF-α and amphiregulin levels in non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib/placebo in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21
Authors: Goss G. D. , Addison C. , Shepherd F. , Seymour L. , LeMaitre A. , Ding K. 
Published: August 2020

11023 Background: In BR.21, erlotinib prolonged survival of previously treated NSCLC pts. We examined the predictive/ prognostic effects of the EGFR ligands, TGFa and amphiregulin(Am). Methods: Plasma was collected prior to treatment in consenting pts. TGFa and Am were analyzed by ELISA (R&D Systems). Samples were blinded, measured in duplicate and ligand concentrations determined following interpolation of a standard curve generated from known quantities of recombinant proteins. Sensitivity was ∼3pg/ml. Cutoff points for TGFa were <10 (low) and ≥10 (high); for Am <1.5 (low) vs 1.5–10 (intermediate) vs >10 (high). Standard statistical methods were used to correlate biomarker data with baseline characteristics and outcomes. Results: In 731 randomized pts, 539 were evaluable for both markers; there was a significant interaction (p=0.03) between the evaluable and inevaluable cohorts (erlotinib benefit favoring the evaluable cohort); evaluable pts were more likely to be male, > 60 and to have EGFR amplification. Baseline high TGFa was associated with poorer ECOG PS (p=0.03) while high Am was associated with worse PS (p<0.0001), anemia (p<0.0001), non response to prior therapies (p=0.01) and no-prior platinum therapy (p=0.02). Although TGFa was not prognostic for OS (HR=1.0, p=0.99), high Am was (HR: Middle vs low: 0.94, 95% C.I 0.49 -1.81; high vs.low: 2.04, 95% C.I 1.43 - 2.91; p=0.0002). High TGFa was a poor prognostic factor for PFS (HR 1.4, p=0.07) as was elevated Am (HR: Middle vs low: 1.02, 95% C.I 0.56 -1.85; high vs. low: 1.67, 95% C.I 1.19 - 2.35, p=0.01). In multivariate analyses including both ligands, high Am remained prognostic, but neither ligand was predictive. Conclusions: High levels of baseline Am appears to be a poor prognostic factor, while low levels of TGFa showed a trend to predict benefit from erlotinib in univariate analyses. [Table: see text] [Table: see text]
Skp2, a prognostic marker and potential therapeutic target in metastatic melanoma
Authors: Wang G. , Hanniford D. , Rose A. , Gaziel A. , Pavlick A. , Zhou X. , Wang J. , Pagano M. , Hernando E. , Osman I. 
Published: August 2020

11034 Background: Skp2, a known oncogene, is overexpressed in several types of tumors and is associated with worse recurrence rate and overall survival in primary melanoma patients. Moreover, the anti-proliferative effects of Skp2 siRNA on various tumor cell lines have prompted the preclinical testing of Skp2 small molecule inhibitors. In this study, we assessed the clinical relevance and molecular mechanism(s) underlying Skp2 overexpression in metastatic melanoma patients. Methods: Skp2 protein levels were measured in 122 metastatic melanoma specimens using immunohistochemistry (IHC), and the association between Skp2 overexpression and post-recurrence survival was examined. Moreover, 22 cell lines (2 normal primary melanocytes, 2 primary immortal melanocytes, 4 primary melanoma cell lines, and 18 metastatic melanoma cell lines) were evaluated for Skp2 genomic amplification using Single Nucleotide Polymorphism (SNP) arrays (Affymetrix 6.0) and Skp2 gene expression using mRNA arrays (Affymetrix U133A 2.0) and quantitative RT-PCR. We also screened 18 cell lines for Skp2 mutation by sequencing. Results: Skp2 overexpression, defined as >25% tumor cells, was associated with shorter 3-yr post-recurrence survival (37%) compared to Skp2 expression ≤25% (55%) (HR=1.89, 95%, CI= 1.04, 3.42, p=0.04). Skp2 overexpression was significantly associated with the site of melanoma metastasis: visceral (n= 12; 89%), lymph node (n=49; 36%), brain (n=15; 14%), and soft-tissue (n=36; 6%) (p<0.001). SNP array revealed genomic amplification at the Skp2 locus in 6 (33%) metastatic cell lines and one primary melanoma cell line. Skp2 genomic amplification was associated with increased transcript expression. No Skp2 mutations were identified. Conclusions: Skp2 protein overexpression is associated with worse prognosis in metastasis in melanoma. Our results also support that gene amplification, rather than a Skp2 gene mutation, may be the major mechanism responsible for Skp2 aberrant expression in metastatic melanoma. No significant financial relationships to disclose.
Identification of tumor tissue origin by a microRNA-based molecular assay
Authors: Rosenwald S. , Gibori H. , Gilad S. , Cohen L. , Leizerman I. , Barshack I. , Nonaka D. , Tobar A. , Aharonov R. , Rosenfeld N. 
Published: August 2020

11036 Background: Hundreds of thousands of patients are diagnosed each year with metastatic cancer. For ∼10% of these, the tumor primary site is never identified, and they are defined as Cancer of Unknown Primary (CUP). Identification of tumor tissue-of- origin has significant therapeutic implications and presents a major diagnostic challenge. In previous work we showed that by combining expression profiles of tissue-specific microRNAs with a biologically-motivated classification scheme, tumor tissue-of-origin can be identified with high accuracy. Here we describe the development of this approach into a practical diagnostic assay. Methods: We developed protocols for extraction of high-quality RNA that retain the microRNA fraction from FFPE archival tissue samples. Proprietary, highly specific qRT-PCR was used to profile microRNA expression levels in hundreds of samples. Results: A training set of nearly 400 primary and metastatic tumors samples with known primary sites, representing 25 different tumor types, was used to define a standardized diagnostics assay (miRview mets). The assay uses a qRT-PCR protocol to measure a panel of 48 microRNA biomarkers. The assay was validated on a test set of nearly 200 primary and metastatic tumors whose primary sites were blinded. The classification protocol identifies either a single, high-confidence origin or two possible low-confidence predictions. Overall, correct primary site was identified for 83% of the tumors. For 70% of the cases a single high-confidence prediction was made; these cases had a higher accuracy: 90% of the primary sites predicted with high confidence were accurately identified. Conclusions: Previous studies highlighted the tissue-specificity of microRNA expression. We developed this potential into a diagnostic assay that identifies tumor origins with high accuracy. This assay provides an important new tool for diagnosing tumor tissue origin. [Table: see text]
Breast cancer risks in individuals testing negative for known family mutations in BRCA1 or BRCA2
Authors: Domchek S. M. , Gaudet M. M. , Stopfer J. E. , Kemel Y. , Powers J. , Balistreri L. , Tigges-Cardwell J. , Nathanson K. L. , Offit K. , Robson M. E. 
Published: August 2020

11044 Background: Genetic testing for BRCA1 and BRCA2 mutations in individuals from families with known deleterious mutations can identify both those at high risk of disease and those who are not. Recent studies have raised concern that women who test negative for mutations previously identified in their families (“true negatives,” TN), may nonetheless have a higher incidence of breast cancer than women in the general population. To evaluate this question, we have examined a prospectively followed cohort of TN to assess their risk of breast cancer. Methods: The women included were first and second degree relatives of known BRCA1 and BRCA2 mutation carriers, had undergone genetic testing and were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates from 1992–2005. Results: Among 375 TN women followed for a mean of 4.9 years (total 1,962 person-years), 2 invasive and 2 in situ breast cancers were diagnosed. Four invasive breast cancers were expected, whereas 2 were observed, for an age-adjusted SIR of 0.52 (95% confidence interval 0.13–2.09). One case of in situ breast cancer was expected, whereas 2 were observed (SIR=2.30; 95% CI 0.57–9.19). There were no cases of ovarian cancer observed, whereas 0.4 cases were expected. Conclusions: In this prospective study of women who were unaffected at the time of genetic testing and who were negative for a known familial mutation in BRCA1 or BRCA2, no excess risk of invasive breast cancer was observed. Although we cannot exclude a modest increase in risk (RR<2), our data suggest that such women should adhere to population based guidelines for breast cancer screening. No significant financial relationships to disclose.
Evaluation of tumor-associated lymphocytes as a predictor of response to neoadjuvant chemotherapy in breast cancer: Results from the GeparDuo and GeparTrio trial
Authors: Denkert C. , Loibl S. , Noske A. , Müller B. M. , Kronenwett R. , Budczies J. , von Törne C. , Engels K. , Solbach C. , von Minckwitz G. 
Published: August 2020

11054 Background: Preclinical investigations suggest an involvement of the immune system in chemotherapy response; however, this contribution has not been validated in prospective clinical trials so far. Methods: We investigated the inflammatory infiltrate in a total of 1058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline-taxane-based studies. As a training cohort, we used 218 core biopsies from the GeparDuo study. The results were validated in a completely independent cohort of 840 samples from the GeparTrio study. In addition, molecular parameters of lymphocyte recruitment and activation in breast cancer tissue were evaluated by kinetic PCR. Results: While the overall rate of pathological complete response (pCR) in the GeparDuo cohort was 12.8%, it was significantly increased to 42.7% in the tumors with more than 60% intratumoral or stromal lymphocytes. In a multivariate regression analysis, the percentage of intratumoral lymphocytes (iTu-Ly) was an independent significant parameter for pCR (P = 0.013) in the GeparDuo cohort. In the validation set from the GeparTrio trial, the inflammatory infiltrate was a strong predictor of pCR in univariate (P < 0.0005) and multivariate logistic regression (P < 0.0005). For tumors with 60% iTu-Ly the pCR rate was 40% with an odds ratio (OR) of 8.5 (4.0–18.2) which were similar to those values in hormone receptor negative samples (pCR: 36%; OR: 6.0 [4.0–9.1]). The expression of inflammatory marker genes and chemokines related to B and T infiltration in tumor tissue was significantly linked to the presence of a lymphocytic infiltrate and mRNA expression data showed a significant association of T cell markers with a pCR (P < 0.003). Conclusions: An increased lymphocytic inflammatory infiltrate in breast cancer is a new independent predictor of response to anthracyclin-taxane neoadjuvant chemotherapy and might be helpful to identify patients with benefit from cytotoxic chemotherapy. [Table: see text]