bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm)
Authors: Townsend A. R. , Millward M. , Price T. , Mainwaring P. , Spencer A. , Longenecker A. , Palladino M. A. , Lloyd G. K. , Spear M. A. , Padrik P. 
Published: August 2020

3582 Background: The novel structure (non-peptide based) of NPI-0052 (NPI) appears to lead to unique proteasome inhibition (PI), toxicology and signal transduction profiles. Preclinical research suggests improvements in therapeutic ratio and activity in hematologic and solid tumor models, leading to clinical trials in patients with myeloma, lymphomas, leukemias, and solid tumors. Methods: Patients with solid tumor, lymphoma or leukemia diagnoses without standard treatment options were treated with IV NPI on Days 1, 8 and 15 of 28-day cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). Enrollment then began in 10 patient lymphoma and CLL RP2D cohorts. PI (D1 and D15) and PK (D1 and D15) were assayed. Results: 30 patients were treated at doses ranging from 0.1 mg/m2 to 0.9 mg/m2. 0.7 mg/m2 was selected as the RP2D secondary to DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait at 0.9 mg/m2. At the RP2D fatigue, parosmia/dysgeusia, transient peri-infusion site pain and lymphopenia were commonly ascribed to NPI. At the RP2D PK data showed: half-life = 31 ± 28 min; AUCtotal = 270 ± 219 ng/mL*min; Cmax = 33.4 ± 34.2 ng/mL; clearance = 7.17 ± 0.40 L/min; volume of distribution (Vz) = 223.3 ± 229.7 L. PI was assayed in blood, indicating a dose:response relationship with mean inhibition of chymotrypsin-like activity up to of 88% Day 1 and 100% Day 15, and inhibition of caspase-like and trypsin-like activity of up to 51% and 72%. PI remained between doses in whole blood (RBC), but recovered between doses in PBMC. Stable disease was induced in 31% of patients, including one each with mantle cell, Hodgkin's lymphoma, follicular lymphoma, sarcoma, prostate carcinoma, and two with melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range to an MTD, while producing a toxicity profile that is tolerable and dissimilar to bortezomib in spite of reaching higher PI levels. These data indicate potential for a greater range of uses than other proteasome inhibitors and lead to additional studies being initiated in hematologic malignancies and solid tumors alone and in combination. [Table: see text]
High β-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: A retrospective analysis
Authors: Horak C. E. , Lee F. Y. , Xu L. , Galbraith S. , Baselga J. 
Published: August 2020

3587 Background: High βIII-tubulin (βIII) expression confers resistance to many anti-microtubule agents (Sève, Lancet 2008; 9: 168). The anti-microtubule agent ixabepilone (Ixa) demonstrates efficacy in βIII over-expressing tumor models resistant to taxanes and has clinical activity in patients with TN BC. The incidence and expression of βIII by BC subtype have not been delineated. Methods: Retrospective analyses of βIII mRNA expression were conducted in two microarray datasets of BC cohorts. Using intrinsic gene clustering, BC tumors from the Ixa neoadjuvant study CA163–080 (080) and the International Genome Consortium (IGC) were defined as basal-like (BL), luminal-like, Her2-overexpressing (Her2+) or normal-like subtypes. For study 080, IHC status subtyping defined TN, Her2+ and Her2-ER+PR+ patients. Mean expression of TUBB3, the gene encoding for βIII, was determined for each subtype. Clinical responses for 080 patients were compared to βIII expression levels. Results: For both cohorts, mean expression of TUBB3 was higher in BL and Her2+ tumors (one-way ANOVA and Tukey's HSD test; both p < 0.001). TUBB3 expression was rank-ordered: low, medium and high. In 080 and IGC cohorts, high expressors represent >50% of patients in BL and Her2+ subtypes and ∼20% of other BC subtypes. Subtyping 080 patients by receptor expression status demonstrated mean TUBB3 expression was higher for TN compared to Her2+ and Her2-ER+PR+ patients (t-test; p = 0.009). TN patients (n = 11/46) in study 080 had a trend to higher pCR rate than the overall population (n = 29/161), 26 vs. 18%. Receiver operating characteristics (ROC) analysis with AUC=0.66 demonstrates that high TUBB3 expression may predict for Ixa response in the overall 080 population. Conclusions: BC patients with TN, BL and Her2+ tumors have higher βIII expression. For the 080 study, responses to Ixa were higher for TN BC patients, and ROC analysis correlated response to βIII levels in the overall population. These data suggest high βIII in BL and TN BC may contribute to the aggressiveness of these subtypes and predict for Ixa clinical response. Additional studies are needed to address the activity of taxanes relative to βIII expression in TN BC. [Table: see text]
Use of peripheral blood genomic markers whose expression levels reflect that of breast tumor genomic markers to predict drug treatment and sensitivity
Authors: Lee S. , Xu X. , Tan P. , Lee J. , Iau P. , Sukri N. , Tan S. , Lim S. , Chuah B. , Goh B. 
Published: August 2020

3588 Background: Tumor gene expression signatures have been used to predict drug response, and we have previously reported drug-induced signatures to be more informative than the untreated baseline signatures. However, repeated tumor sampling during treatment is not feasible for most patients. We studied peripheral mononuclear cell (PBMC) gene expression levels in association with tumor gene expression levels in an attempt to identify peripheral blood markers that may serve as more accessible surrogates to predict drug treatment and response. Methods: Chemonaive breast cancer patients were treated with an alternating sequential regimen of doxorubicin and docetaxel and randomized to start with either drug. RNA from primary tumor before and 3 weeks, and from PBMC before and 24 hours after the first cycle of each drug was hybridized on the Affymetrix HG-U133+2 array containing 54,675 probe sets. Results: Pre- and post-treatment tumors from 47 patients were studied, including 35 with paired PBMC samples. 230 pre- and 85 posttreatment PBMC probe sets showed strong correlation in expression level (Pearson correlation coefficient >0.9) with the corresponding pre- and posttreatment tumor probe set, and included genes involved in transcription regulation and binding. Of the 975 tumor probe sets whose changes distinguished doxorubicin from docetaxel treatment, 12 corresponding PBMC probe sets were identified (p < 0.001) whose changes at 24 hours distinguished the two treatments with 77% accuracy. Of the 1,081 and 1,526 tumor probe sets whose changes predicted treatment response to doxorubicin and docetaxel, 19 and 15 informative PBMC probe sets predicted response to each drug with 100% and 80% accuracy, and included TNF receptor associated protein 1 and trefoil factor 1 for doxorubicin-, and folliculin and dynein for docetaxel-response. When the PBMC probe sets were validated in an independent test set treated with docetaxel (n = 23), 87% was correctly classified as docetaxel-treated, while 89% of non-responders clustered together. Conclusions: Peripheral blood contains genomic markers whose expression levels closely reflect that of breast tumor markers, and may be promising as surrogates to predict drug treatment and sensitivity. No significant financial relationships to disclose.
Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803
Authors: Sargent D. J. , Yothers G. , Van Cutsem E. , Cassidy J. , Saltz L. , Wolmark N. , Shi Q. , Buyse M. , de Gramont A. ,   The Adjuvant Colon Cancer Endpoints (ACCENT) Group
Published: August 2020

4011 Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint. [Table: see text] [Table: see text]
Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581
Authors: Bertagnolli M. M. , Niedzwiecki D. , Hall M. , Jewell S. D. , Mayer R. J. , Goldberg R. M. , Colacchio T. A. , Warren R. S. , Redston M. 
Published: August 2020

4012 Background: LOH at 18q is associated with poorer overall survival in patients with colon cancer; however available studies are retrospective and vary in analysis methods. We recently completed an 18qLOH assay method validation study, and after standardizing technique, this prospective study investigated the role of 18qLOH among patients with low-risk stage II colon cancer. Methods: In Cancer and Leukemia Group B (CALGB) protocol 9581, we randomized 1738 stage II patients to post-operative treatment with a 500 mg loading dose of monoclonal antibody 17–1A followed by four infusions of 100 mg every 28 days or observation. The primary endpoint was overall survival (OS); disease free survival (DFS) was a secondary endpoint. Status of 18qLOH was assessed in patients with available tissue and interpretable PCR results. Patients were excluded if their tumors were uninformative for 18qLOH or if their tumors displayed microsatellite instability. Results: We report 18qLOH data on 156 patients. Patient characteristics including treatment, age, gender, performance status, site and grade of tumor, were similar between all patients enrolled and the subset of patients with tumor samples analyzed. The DFS and OS for treated and observed patients were no different (5-yr DFS: 0.81 and 0.80, p= 0.96; 5-yr OS: 0.88 and 0.86, p=0.44 at a median of 6.8 yrs of follow-up) and the data were pooled across the study's arms. Of the tumors examined, 101 (65%) were positive for 18qLOH. A significantly lower proportion of patients with 18qLOH-positive tumors had proximal tumors (46.5% vs 65.5%; p=0.02). Significantly decreased DFS and OS were observed in patients with 18qLOH-positive tumors. Five-year DFS among patients with 18qLOH-positive tumors was 0.78 vs 0.93 among patients with 18qLOH-negative tumors [HR 0.39; 95% CI (0.16, 0.94); logrank p=0.03 based on 33 events]. Five-year OS among patients with 18qLOH-positive tumors was 0.85 vs 0.98 among patients with 18qLOH-negative tumors [HR 0.25; 95% CI (0.07, 0.83); logrank p=0.01 based on 24 events]. Conclusions LOH at 18q was prognostic for DFS and OS among patients with available tissue for analysis after resection of low-risk stage II colon cancer who were not treated with chemotherapy in the adjuvant setting. [Table: see text]
Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo-)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Safety results of a randomized, phase III trial
Authors: Hofheinz R. , Wenz F. , Post S. , Matzdorff A. , Laechelt S. , Mueller L. , Link H. , Moehler M. , Burkholder I. , Hochhaus A. 
Published: August 2020

4014 Background: 5-FU based CRT is regarded standard perioperative treatment in LARC. Here we report safety data of a non-inferiority phase III trial investigating (neo-)adjuvant CRT with Cape in comparison with 5-FU. Methods: Patients (pts) aged ≥18 years with LARC UICC stages II or III were recruited in this two-arm, two-strata randomized phase-III trial (arm A: Cape, arm B: 5-FU; stratum [S] I: adjuvant, S II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + Cape 1,650 mg/m2 days 1–38 plus five cycles of Cape 2,500 mg/m2 d 1–14, rep. d 22 (S I: 2 x Cape, CRT, 3 x Cape; S II: CRT, TME surgery followed by Cape x 5). Arm B: CRT: 50.4 Gy + 5-FU 225 mg/m2 c.i. daily [S I] or 5-FU 1,000 mg/m2 c.i. d 1–5 and 29–33 [S II] plus 4 cycles of bolus 5-FU 500mg/m2 d 1–5, rep. d 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery followed by 5-FU x 4). Primary endpoint was survival, secondary endpoints comprised safety and disease-free survival. Results: Of 401 randomized pts a total of 392 are evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). Both arms were well balanced with respect to age, sex, WHO status, T- and N- stages. Regarding duration of treatment, 78% (Cape) and 80% (5-FU) completed all scheduled treatment cycles in S I, and 46% (Cape) and 40% (5-FU) in neoadjuvant stratum S II. In S II a total of 38% (Cape) and 43% (5-FU) did not continue chemotherapy after tumour resection. Concerning early efficacy endpoints in S II, pts treated with Cape (evaluable thus far n=121) exhibited a higher rate of T-downstaging (defined as ypT0–2; 52 vs 39%; p=0.16) and N0 (71 vs 56%; p=0.09). Regarding overall safety (NCI-CTC), pts receiving Cape experienced significantly less leukopenia (25 vs 35%; p=0.04), but more hand-foot syndrome (31 vs. 2%; p<0.001). Stomatitis/mucositis, diarrhea, nausea/vomiting, and radiodermatitis were not significantly different between both arms. Conclusions: Given the observed safety profile and the trend in improved downstaging in neoadjuvant stratum, Cape exhibits a potential to replace 5-FU as perioperative treatment of LARC. Efficacy results on the primary endpoint are expected for 2010. [Table: see text]
Impact of age and comorbidities on treatment effect, tolerance, and toxicity in metastatic colorectal cancer (mCRC) patients treated on CALGB 80203
Authors: Meyerhardt J. A. , Jackson McCleary N. , Niedzwiecki D. , Hollis D. , Venook A. , Mayer R. , Goldberg R. 
Published: August 2020

4038 Background: Little is known regarding the interaction of comorbid conditions (CC) and age when treating pts for mCRC. We sought to determine the impact of CC and age (<70 and ≥70 yrs) on survival and toxicity in these pts. Methods: We utilized a cohort of 238 pts with mCRC enrolled in CALGB 80203, a curtailed, multicenter 2x2 phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) ± cetuximab. Endpoints were overall survival (OS; time to death), progression-free survival (PFS; time to recurrence or death), and grade 3/4 toxicity. Pts completed a self-administered questionnaire on diet and lifestyle that included a modified Charlson's comorbidity survey. Cox models were adjusted for treatment (rx) arm, gender, and prior rx. Results: In CALGB 80203, 77% were < 70 and 23% ≥70. Thirty-five percent of pts had at least one CC (34% < 70 yrs; 41% ≥ 70 yrs). At least one grade 3/4 toxicity was experienced by 87% of pts ≥70 v 66% <70 (p=0.002), primarily hematologic (56% v 31%, p=0.003). Amongst 238 pts, 94% and 84% experienced a PFS event and OS event, respectively. No pts are censored prior to 3 yrs. Median follow-up was 23 mos. The adjusted hazard ratio (HR) for ≥70 v <70 of PFS was 1.0 (0.7–1.4) and of OS was 1.1 (0.8–1.6). Similarly, there were no significant differences in HR for PFS and OS by # CC. The table demonstrates no evidence of interaction between CC and age. Conclusions: While the early closure of CALGB 80203 presents sample size limitations for subset analyses, we did not observe an impact on PFS or OS by age and/or CC. Older pts did experience more toxicity from rx. Further studies with larger datasets are warranted. [Table: see text] [Table: see text]
Modifiable factors that influence colorectal cancer lymph nodes sampling and examination
Authors: Valsecchi M. E. , Leighton J. , Tester W. 
Published: August 2020

4047 Background: Colorectal cancer is the fourth most common malignancy in the United States. The single most important prognostic factor is lymph node involvement. Multiple guidelines recommend a minimum of 12 nodes should be sampled in order to insure accurate staging and treatment. However this standard of care requirement is not always achieved. The objective of this study is to identify potential modifiable factors that may explain this inadequacy between the optimal approach and routine practice. Methods: The medical charts of all patients treated for colorectal cancer stage I-III between 1999–2007 at Albert Einstein Medical Center were reviewed. The association between multiple variables and the presence of ≥12 lymph nodes reported were examined using logistic regression models. Results: A total of 337 patients were included; 173 (51%) had ≥12 lymph nodes retrieved with a mean of 12.7 (SD±7.6). Demographic characteristics: 78% older than 60 years old; 161 patients (47.8%) male; white (27%), black (67%) and other race (6%). Using a univariate analysis the following variables were statistically associated with ≥12 lymph nodes reported: Colon size (20.6±14.7 vs. 29.9±23.1 cm, P<.001); Mesocolon thickness (3.8±0.9 vs. 4.2±0.9 cm, P<.001); Tumor size (4.14±2.3 vs. 4.6±2.1, P=.03); Site of tumor (Right vs. Left, P<.001); Pathologist (P=.06); Pathologist's Assistant (P=.006); Type of surgery (Right or Sub-Total Colectomy vs. Others, P<.001), Individual Surgeon (P=.009). The results of the multivariate logistic regression analysis, adjusting for age, sex and race, are presented in the Table . Conclusions: This studied showed that multiple factors influence the number of lymph nodes sampled. The role of the surgeon, the pathologist and specially the pathologist's assistant are potentially improvable factors with appropriate education. [Table: see text] No significant financial relationships to disclose.
Interlaboratory assay reproducibility study for loss of heterozygosity on chromosome 18 (18q LOH) in colon cancer
Authors: Jessup J. M. , Dobbin K. , Hamilton S. , Thibodeau S. , Redston M. , Taube S. , Wang Z. , Benedetti J. ,   Program for the Assessment of Clinical Cancer Tests (PACCT) 18q LOH Team
Published: August 2020

4052 Background: 18q LOH may be a useful marker in stage II colon carcinoma to assess who needs adjuvant chemotherapy. The objective of this study was to evaluate the intra- and inter-laboratory reproducibility of an assay for 18q LOH that is similar to the integral assay used in E5202, the current Intergroup phase III stage II colon carcinoma clinical trial. Methods: Specimens from 130 stage II/III colon cancer patients were obtained from the Cooperative Human Tissue Network and evaluated at three different laboratories. Samples were divided into subsamples, coded and distributed. Each laboratory used similar equipment in an established PCR protocol with 5 dinucleotide repeats. Starting materials used both histologic sections and extracted DNA samples of tumor and non-neoplastic tissue obtained only by scalpel microdissection. LOH was defined as tumor/normal peak ratio that was >1.35 or <0.67 without microsatellite instability (MSI). Tumors were categorized as either MSI+, LOH + or -, uninformative/monoallelic, or unevaluable (DNA not amplifiable). Standard tests assessed reproducibility of both the numerical ratios and the tumor 18q LOH status. Results: Sample quality issues prevented analysis of 13 tumors (10%). The frequency of 18q LOH was 64%. The probability of agreement on the same tumor evaluated twice was 92% (Cohen's kappa 0.83). Intra-class correlation coefficients for individual markers were consistently over 0.90. Tissue specimens must have high (>85%) tumor cell content for reproducibility. Differences among patients affected reproducibility much more than effects of laboratory and sample type (DNA vs. histologic section). Conclusions: This study validates reproducibility of the 18q LOH assay for both clinical categorization of status and numerical ratios if samples are high quality and appropriate for scalpel microdissection. [Table: see text]
Clinical usefulness of mtTFA expression as a predictive marker in colorectal cancer patients treated with FOLFOX
Authors: Yoshida Y. , Hasegawa J. , Nezu R. , Kim Y. , Hirota M. , Yoshikawa K. , Kawano K. , Izumi H. , Kohno K. 
Published: August 2020

4059 Background: We previously reported that mitochondrial transcription factor A (mtTFA; also designated Tfam) preferentially recognizes cisplatin-damaged DNA via physical interaction with p53 and is upregulated by the treatment with cisplatin and 5-FU (Yoshida et al, Cancer Res. 2003). The aim of this study was to evaluate whether expression of mtTFA predicts clinical outcome in patients with metastatic colorectal cancer treated with modified FOLFOX6 (mFOLFOX6). Methods: From January 2006 to April 2008, 59 patients who had metastatic lesions from colorectal cancer treated with mFOLFOX6 at the Osaka Rosai Hospital were included in this study. They consisted of 25 women (42.4%) and 34 men (57.6%), with a median age of 62 years (29–84). Patients were treated with oxaliplatin 85mg/m2 plus leucovorin 200mg/m2 as a 2-h infusion at day 1, followed by 5-FU bolus 400mg/m2 and 46-h continuous infusion of 2400 mg/m2. Treatment was repeated in 2-week intervals for at least 4 cycles. The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemistry. Results: Among 59 patients, one complete response and 32 partial responses were observed (response rate, 55.9%) . The positive rates was 44.1% (26/59; CR 1, PR 7, SD/PD 18) for mtTFA and 59.3% (35/59; CR 1, PR 19, SD/PD 15) for p53, respectively. Strong expression of mtTFA was detected in 8 of 33 CR/PR (24.2%) and in 18 of 26 SD/PD (69.2%), indicating that the expression of mtTFA correlated significantly with response to chemotherapy (P<0.01). On the other hand, there was no significant correlation between response to chemotherapy and p53 expression (P=0.82). mtTFA expression was significantly associated with overall survival (P=0.036) and progression free survival (P=0.037). Multivariate analysis revealed that mtTFA expression significantly impacted on OS (Hazard ratio 2.10, P=0.036). Conclusions: Immunohistochemical study of mtTFA may be useful in prediction of the clinical outcome of metastatic colorectal cancer patients treated with FOLFOX. No significant financial relationships to disclose.