tbuckley/cabot-search huggingface dataset:
Progression of low- to high-grade prostate cancer: Molecular profiling of tissue obtained by serial targeted biopsy.
Authors: Ganesh S. Palapattu, Andi K. Cani, Jiaoti Huang, Daniel H. Hovelson, David Lu, Daniel Margolis, Shyam Natarajan, Rohit Mehra, Jeffrey Scott Montgomery, Todd Matthew Morgan, Scott A. Tomlins, Leonard S. Marks
Journal: Journal of Clinical Oncology (2015)

5017 Background: Progression of prostate cancer (PCa) from low- to high-grade is believed to be uncommon. Here, we combined serial targeted biopsy to resample specific PCa sites over time with molecular profiling to determine clonality of high grade cancer. Methods: Nine men in active surveillance for low-risk PCa (Gleason Score = 6; GS6) were subjects of this IRB-approved pilot employing the Artemis MR-US fusion biopsy system. Each PCa site was electronically tracked and 1 year later additional tissue obtained from the same intra-prostatic site. Five of 9 men were re-classified on follow-up biopsy to GS ≥ 7. ERG immunohistochemistry (IHC) and targeted multiplexed PCR based next generation sequencing (NGS) was performed at each time point. DNA was co-isolated from 6-7 x 4μm formalin fixed paraffin embedded (FFPE) sections/sample. NGS was performed using a custom Ion Torrent Ampliseq panel (containing 3,434 amplicons interrogating oncogenes and tumor suppressors) and the Ion Torrent Proton sequencer. Data was analyzed using validated in-house methods. Results: Across the 18 paired samples from 9 patients, 7 pairs (early/late) were evaluable for ERG IHC. In all 7 evaluable cases, PCa in paired specimens was uniformly ERG+ (4 pairs) or ERG- (3 pairs). NGS generated an average of 847x coverage/sample. Copy number analysis identified no high level gains or losses. 3 prioritized driving somatic mutations were identified across the cohort (SPOP F133L in Pt#4, BRCA2 K2524fs in Pt#7 and KMT2B Q2076X in Pt#1), each of which occurred only in the later sample in the pair. Of these 3 men on repeat biopsy, Pt#1 and #4 had GS7 and Pt#7 had GS6 disease. Conclusions: In this first of its kind study, our data suggest that i) GS ≥ 7 cancers may arise clonally from GS6 cancers through acquired genetic alterations, ii) targeted prostate biopsy allows repeat sampling of a clonal focus, and iii) comprehensive molecular profiling of minute FFPE samples is possible. Our work also supports prior observations that some GS6 cancers possess oncogenic mutations. These findings could have important implications for the management of low risk PCa.
Benefits (survival) and risks (30 days mortality) of phase I trials in oncology
Authors: B. Djulbegovic, C. Moreno, A. Kumar, R. Lush, P. N. Munster, A. I. Daud, C. R. Garrett, G. R. Simon, J. E. Lancet, D. M. Sullivan
Journal: Journal of Clinical Oncology (2008)

6508 Background: The ethical issues of conducting phase I trials revolve around the purported aim of phase I trials to assess safety/toxicity of new cancer therapies without having benefit of patients as one of the stated goals. However, the existing, albeit limited, empirical data do point that patients enrolled in phase I trials can in effect benefit from novel therapies. In the most comprehensive study to date, Horstmann et al (NEJM 2005; 352:895) found that 4–18% of patient tumors do respond to therapy. In their study, treatment-related mortality was 0.49%. However, neither this, nor any other study in the literature reported data on patients' survival, which is clearly a most important outcome for patients. Methods: Data from 1,361 individual consecutive patients enrolled from January 1998 to October 2007 in 159 trials at the Moffitt Cancer Center were available for the analysis. 244 patients enrolled in more than 1 phase I trials and were excluded from this analysis. Both high-dose and standard dose single agent and combination chemotherapy trials with investigational agents were available for the analysis. Kaplan-Meier survival analyses were used to calculate duration of survival (benefits), while the proportion of patients dying during first 30 days was employed as a surrogate for treatment-related mortality (risks). Results: Patients with all cancers are included in the analysis, but the majority of patients had a hematological malignancy (N=389), lung cancer (N=245) or a gastrointestinal malignancy (N=114). Median survival for the entire cohort was 1.2 years, but approximately 25% of the patients lived longer than 3 years with about 10% surviving at 6 years or beyond. 10.7% (96/895) of patients died during first 30 days of treatment from all causes including rapid tumor progression. Conclusions: A substantial number of patients enrolled in phase I trials have a meaningful survival. The notion that phase I trials enroll dying patients with no prospect for benefits should be dispelled. No significant financial relationships to disclose.
The Role of the Rituximab Partner Chemotherapy Regimen In Young Patients with Good-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Results of the 6-Year Follow-up of the Mint Study of the Mabthera International Trial (MInT) Group.
Authors: Niels Murawski, Evelyn Kuhnt, Sandra Grass, Wolfgang Hiddemann, Eva Cavallin-Stahl, Georg Hess, Mathias Witzens-Harig, Ingrid Vasova, Ulrich Jäger, Michal Osowiecki, Scott North, Ruth Pettengell, Viola Pöschel, Markus Löffler, Michael Pfreundschuh
Journal: Blood (2010)
Phase III trials in the molecularly targeted era: Characteristics of randomized clinical trials of cytotoxic versus molecularly targeted agents
Authors: L. Lee, E. X. Chen
Journal: Journal of Clinical Oncology (2008)

6641 Background: The advent of molecularly targeted agents (MTAs) has challenged the traditional study designs of Phase I and II trials established for cytotoxic agents (CTAs) due to differing mechanisms of action, toxicity profiles and predominantly cytostatic effects. The purpose of this study was to compare characteristics of RCTs evaluating MTAs and CTAs. Methods: We reviewed ASCO meeting abstracts from 2003–2007 for Phase III RCTs evaluating systemic anticancer therapy. Data on trial design, experimental arms, endpoints, and outcomes were extracted. Characteristics of RCTs evaluating only CTAs were compared with those involving at least one MTA, either alone or in combination with a CTA. Results: Of 230 eligible trials identified, 179 (78%) involved CTAs only and 51 (22%) involved a MTA. With more recent year, the number of RCTs evaluating CTAs decreased while the number of those evaluating MTAs has increased. MTAs were evaluated more frequently in less prevalent tumor types, such as renal cell carcinoma and gastrointestinal stromal tumours. Compared to CTAs, a significantly higher percentage of RCTs for MTAs were conducted in patients with advanced disease than in the adjuvant setting (p=0.001). In the advanced disease setting, the mean number of patients enrolled per trial was significantly higher for those evaluating MTAs (697 vs 598, p=0.008). Only 24% of all MTA RCTs based patient eligibility on positive testing for specific molecular markers. Overall survival was the primary endpoint in 51% of all CTAs and in 54% of all MTA trials. In studies of advanced disease, progression-free survival was the primary endpoint in 23% of MTA and 15% of CTA RCTs. The proportion of RCTs with positive outcomes is similar for both MTAs and CTAs (39% vs 35%). Conclusions: Over time, the number of RCTs evaluating MTAs has increased. MTA RCTs enrolled more patients and were conducted more frequently in less common tumor types. Despite different mechanisms of action, overall survival is still the most common primary endpoint used to assess efficacy in RCTs evaluating systemic therapy, regardless of whether MTAs or CTAs are involved. No significant financial relationships to disclose.
Intensity-modulated radiation therapy combined with concurrent and adjuvant chemotherapy in anaplastic thyroid carcinoma: A single-institution study.
Authors: K. C. Bible, J. R. Molina, J. C. Kasperbauer, R. V. Lloyd, B. McIver, J. C. Morris, I. D. Hay, V. Suman, R. C. Smallridge, R. L. Foote
Journal: Journal of Clinical Oncology (2010)

5591 Background: Only 10% of patients with anaplastic thyroid cancer (ATC) historically survive one year despite surgery and conventional radiotherapy. In response, we modified our approach to ATC, combining intensity modulated radiation therapy (IMRT) with aggressive chemotherapy in patients with stages IVA and IVB disease. Methods: From 2003 to 2007 twenty four ATC patients were seen at our institution. Ten presenting with metastatic (IVC) disease underwent palliative treatment, while four presenting with locoregional disease (IVA or IVB) underwent treatment at other institutions. Of the remaining 10 patients with regionally confined ATC, all elected to pursue an aggressive approach under our direction. Surgical intervention included complete resection (3), incomplete resection (positive margins in 3, gross residual disease in 3), and biopsy only in 1 patient - leaving only 3 of 10 patients pathologically free of disease following surgery. Pathology, centrally reviewed by a single expert pathologist (R.V.L.), demonstrated ATC alone in six - and ATC arising in a background of differentiated thyroid carcinoma in four. In all cases of mixed histology, ATC was dominant. Therapy following surgery consisted of IMRT combined with radiosensitizing and adjuvant chemotherapy, intending four cycles of docetaxel 60 mg/m2 and doxorubicin 60 mg/m2 IV with pegylated Filgrastim support - unless toxicities dictated otherwise. Results: No deaths resulted from therapy, and morbidity was modest. Median follow-up (including patients who died) was 30 months, with 6 patients (60%) still alive 25-82 months after diagnosis. Five patients (50%) were alive and cancer free >2 years following diagnosis. Overall survival in this consecutive series at one and two years respectively was 70% and 60% - compared to 10% historical survival at one year in analogous patients previously treated at our institution with conventional radiation therapy alone following surgery. Conclusions: Although preliminary, these findings suggest that an aggressive approach combining IMRT and chemotherapy has potential to improve outcomes in ATC patients with regionally confined disease at diagnosis. No significant financial relationships to disclose.
Epirubicin (E) followed by cyclophosphamide, methotrexate, 5-fluorouracil (CMF) versus paclitaxel (T) followed by epirubicin and vinorelbine (EV) in patients (pts) with high-risk operable breast cancer
Authors: F. Boccardo, A. Rubagotti, P. Guglielmini, P. Sismondi, A. Farris, D. Amadori, B. Agostara, A. Gambi, G. Catalano, M. Faedi
Journal: Journal of Clinical Oncology (2009)

e11521 Background: &gt; 3 N+ pts have a poor outcome, even in the presence of otherwise favourable phenotypic features. CT, alone or combined with endocrine therapy (ET) in hormone receptor (HOR)+ pts, is the gold standard for these women. However questions still exist about the optimal CT regimen. Methods: 244 &gt;3N+ pts were randomized to either four 3-weekly courses of E (100 mg/sqm,d 1)followed by four 4-weekly cycles of CMF (600, 40, 600 mg/sqm, dd 1,8)(E-CMF:N=122)or four 3-weekly courses of T (175 mg/sqm, d1) followed by four 3-weekly cycles of EV (E:75 mg/sqm, da 1; V: 25 mg/sqm dd 1,8;.) (T-EV:N=122). After CT, tamoxifen (plus a LH-RH analog in menstruating women ) was given for 5 years to all HOR+ pts.S was the primary end-point. Results: At 82 mos median f-up, S and RFS did not differ significantly between groups (7-yr S: E-CMF:76%,T- EV:74%;adjust. HR: 0.89;0.54–1.49;p=0.7; 7-yr RFS: E-CMF:67%,T-EV:63%;adjust. HR: 0.95;0.61–1.47;p=0.8;).Cox analysis confirmed no difference between treatments. However RFS forest plots showed some heterogenity in CT effect according to HOR and HER2 status: E- CMF was superior to E-TV in HOR + pts (HR=0.43; CI 0.20–0.93 p=0.03),irrespective of HER2 status, but it was inferior (HR=1.91;CI 0.48- 7.64;p=0.4) in triple negative pts. The two regimens showed different toxicity profiles;however toxicities were manageable and there were no difference in the %of pts receiving all the 8 planned CT cycles (E-CMF: 87.6%;T-EV:81.1% p=0.2) or who discontinued CT (E-CMF: 12.8%; T-EV: 18.9% p=0.2). Conclusions: T-EV was not superior to E-CMF which,combined with ET, still represents an adequate choice for this high risk pts subset, especially for HOR+ pts. No significant financial relationships to disclose.
Irinotecan/capecitabine (XELIRI) plus bevacizumab versus irinotecan/fluorouracil/leucovorin (FOLFIRI) plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer: A randomized phase III trial of the Hellenic Cooperative Oncology Group (HeCOG).
Authors: D. G. Pectasides, I. Xanthakis, T. Makatsoris, E. Samantas, I. Varthalitis, G. Papaxoinis, P. Papakotoulas, E. Bournakis, C. Papandreou, G. Fountzilas
Journal: Journal of Clinical Oncology (2010)

3541 Background: The purpose of the trial was to compare two standard chemotherapy regimens combined with bevacizumab (Bev) in patients with metastatic colorectal cancer. Methods: Patients previously untreated for metastatic disease were randomized in: Arm A (irinotecan 240 mg/m2 day 1, capecitabine 1,000 mg/m2 days 1-14 and Bev 7.5 mg/kg day 1, every 3 weeks; XELIRI-Bev) and Arm B (irinotecan 180 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 400 mg/m2 bolus on day 1 followed by a fluorouracil 2,400 mg/m2 46 hours infusion, and Bev 5 mg/kg day 1, every 2 weeks; FOLFIRI-Bev). Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response and toxicity. Results: From January 2006 to January 2008, 285 eligible patients were enrolled (143 in arm A, 142 in arm B). Median age was 66 years (range 28-84), 171 patients (60%) were males and 186 (65%) had PS (ECOG) = 0. The liver was involved in 190 patients (67%), while 153 (54%) had only one organ involved. Fifty-five patients (38%, CR = 4%, PR = 34%) in arm A and 57 (40%, CR = 3%, PR = 37%) in arm B had responded (p = 0.81), whereas 28 patients (20%) in arm A and 40 (28%) in arm B had stable disease. After a median follow-up of 28.7 months (0.2-43.8), 86 vs 102 disease progressions, and 81 vs 75 deaths had occurred in arms A and B, respectively. Median PFS was 14.6 (95% CI = 12.4-16.7) and 15.8 (95% CI = 13.4-18.2) months (p = 0.48), while median OS was 20.0 (95% CI = 16.7-23.3) and 26.2 (95% CI = 22.0-30.4) months (p = 0.14), for arms A and B, respectively. Most frequent grade 3-4 toxicities (arm A vs. arm B) were neutropenia (12% vs. 22%, p = 0.048), leucopenia (6% vs. 4%), diarrhea (18% vs. 11%), metabolic disorders (8% vs. 18%, p = 0.028), and vomiting (7% vs. 0%, p = 0.014). Conclusions: This trial did not show significant differences in efficacy between XELIRI-Bev and FOLFIRI-Bev in patients with metastatic colorectal cancer treated in the first-line setting. However, the toxicity profile was different. Translational research on angiogenesis factors is ongoing. No significant financial relationships to disclose.
Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer
Authors: S. Paik, S. Shak, G. Tang, C. Kim, J. Baker, M. Cronin, D. Watson, J. Bryant, J. Costantino, N. Wolmark
Journal: Journal of Clinical Oncology (2005)

510 Background: The 21 gene Recurrence Score (RS) assay (Oncotype DX) has been validated to quantify the risk of distant recurrence in tamoxifen (tam)-treated pts with N-, ER+ breast cancer. To determine whether the RS assay predicts prognosis, response to tamoxifen, or both, we studied the pts randomized to placebo and tam in NSABP B-14. Methods: Pts were eligible if tumor blocks were available and contained at least 5% invasive cancer. Expression was quantified by the pre-specified 21 gene RT-PCR assay, and the RS was calculated by the pre-specified algorithm. Cox models were used to evaluate the association between potential predictive variables and distant-recurrence free survival (DRFS). Results: There were 645 evaluable pts (355 placebo and 290 tam). A subset of individual genes (Cyclin B1, Survivin, MYBL2, STK15, Ki-67, PR, and GSTM1), the proliferation gene group score and the RS were significantly associated with DRFS in the placebo pts (p<0.05). ER was not associated with DRFS in the placebo pts (p = 0.30), and was not prognostic. In analysis of both arms, the test for interaction of tam treatment and ER was highly significant (p=0.0007), indicating quantitative ER expression predicts tam benefit. The test for interaction of tam treatment and PR was not significant (p=0.64). The absolute and relative tam benefits for each RS risk group are in the Table below. In contrast to quantitative ER expression which is only predictive of tam response, the 21 gene RS assay is both prognostic and predicts the response to tamoxifen. Conclusions: Not all ER + pts benefited equally from tamoxifen. The largest benefits of tamoxifen were observed with high quantitative ER and low RS, while smaller benefits were observed with low quantitative ER and high RS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health Genomic Health
Dose scheduling and pharmacokinetic (PK) study of trastuzumab in patients (pts) with HER2/neu overexpressing breast cancer?
Authors: A. Felici, S. Di Segni, M. Contestabile, B. Nuvoli, A. Fabi, P. Papaldo, G. Ferretti, I. Sperduti, G. Citro, F. Cognetti
Journal: Journal of Clinical Oncology (2007)

1109 Has been demonstrated that 10–20 μg/mL is the minimum serum trough concentration (C min ) of trastuzumab that causes maximal tumor growth inhibition. This concentration was shown to be achievable using a weekly (4 mg/kg loading dose followed by 2 mg/kg weekly) and a three-weekly (8 mg/kg loading dose followed by 6 mg/kg) schedule, but only indirect comparisons of the two schedule have been performed. We prospectively analysed the PK distribution of trastuzumab in three different schedules, as follows: weekly (cohort I), bi-weekly (trastuzumab 6 mg/kg loading dose followed by 4 mg/kg, cohort II) and three-weekly schedule (cohort III). The PK analysis was performed in 18 pts (4 pts receiving the loading dose of cohort III, 8 pts receiving the maintenance dose of cohort III, 3 pts receiving the maintenance dose of cohort II, and 3 pts receiving loading dose of cohort I). Of the 18 pts analyzed, 9 were metastatic. The median age was 54 years (range 39–76), the median weight was 61,5 kg (range 53–80). At diagnoses, 10 pts had stage I disease, 5 and 3 pts had stage II and III respectively, ER was negative in 10 pts and PgR was negative in 12 pts; Ki67 was highly expressed in 14 pts; Her/neu was overexpressed and amplified in 16 and 2 pts respectively. To evaluate preliminary interpatient variability, 3 pts receiving 6mg/kg of trastuzumab repeated the PK analysis after four cycles: the comparison between two groups was not statistically significative. Comparison of Cmax and AUC mean between groups was statistically significative (P&lt;0.05, Bonferroni test) except for 8 mg/kg vs 6 mg/kg AUC.All the doses and schedules analysed are able to reach the minimum serum concentration of trastuzumab that causes the maximal tumor growth inhibition. [Table: see text] No significant financial relationships to disclose.
Wnt signaling somatic alterations in apc-associated fap adenomas
Authors: A. Obrador-Hevia, F. Chin, S. Gonzalez, F. Vilardell, D. Cordero, J. Greenson, V. Moreno, C. Caldas, G. Capella
Journal: Journal of Clinical Oncology (2009)

e22046 Background: APC mutations are believed to constitutively activate the wnt pathway in colorectal tumors. Our goal was to comprehensively characterize Wnt signaling components in a set of APC-associated FAP tumors both at the DNA and RNA levels. Methods: Sixty adenomas from FAP cases harboring pathogenic APC mutations were included (10 adenomas and 1 normal mucosa per case). Somatic APC and KRAS alterations, β-catenin immunostaining and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analyzed. aCGH was also assessed in 26 FAP adenomas and 24 additional paired normal-adenoma-carcinoma samples. Results: A second APC alteration was present in 30 (50%) of adenomas (26 LOH and 4 point mutations). LOH was only occasionally associated with loss of genetic material. In 3 of 6 cases APC mRNA was overexpressed in macroscopically normal mucosa. In these cases diminished APC levels mRNA were observed in 11 of 30 adenomas analyzed.. In the remaining 3 cases APC mRNA was already underexpressed in normal mucosa with only 3 of 30 adenomas showing further underexpression. In FAP normal mucosae MYC was overexpressed (logratio range: 3.37–5.66). All adenomas showed further MYC (logratio range: 1.78–2.92) and AXIN2 overexpression (logratio range: 1.62–4.65), corregulating with APC mRNA levels (r=0.31 for MYC; r=0.59 for AXIN2). β-catenin nuclear immunostaining was detected in 80% of adenomas correlating with MYC mRNA levels. SFRP1 was underexpressed in all tumors (logratio range= -3.06–27). While copy number changes were rare in adenomas (median number :2.5; range 0–5). DNA changes were more often detected in areas containing wnt genes when FAP and sporadic tumors were jointly analyzed (p=0.02). Conclusions: Wnt pathway is altered, at the DNA and/or RNA level, in all APC mutant FAP tumors. MYC overexpression is a universal event that correlates with APC and AXIN2 expression levels as well as bcatenin nuclear accumulation. No significant financial relationships to disclose.
A phase II, open-label, single-arm, efficacy, and safety study of MDV3100 in patients with hormone-naïve prostate cancer.
Authors: E. S. Baskin-Bey, G. M. Holtkamp, M. R. Smith, T. Ouatas, D. Phung, B. Tombal
Journal: Journal of Clinical Oncology (2011)

177 Background: MDV3100 is a novel androgen receptor (AR) antagonist in clinical development for the treatment of prostate cancer (PCa). Compared to bicalutamide, MDV3100 has higher in vitro AR binding affinity and no evidence of partial agonism. Preliminary phase I-II data show antitumor activity with MDV3100 in men with advanced PCa who were concurrently using androgen deprivation therapy (ADT; Scher HI, et al. Lancet. 2010;375:1437-46). Phase II and III studies in men with progressive and earlier-stage PCa are ongoing. This abstract describes the design of a phase II study of MDV3100 in men with hormone-naïve PCa (HNPCa) who are candidates for ADT. Methods: This 25-week, open-label, single-arm, efficacy and safety study of MDV3100 (160 mg/d orally) will be initiated at ∼20 investigational sites in late 2010 (planned countries: Austria, Belgium, Czech Republic, Denmark, Germany). Inclusion criteria include histologically confirmed, locally advanced PCa (all stages), noncastrate testosterone (T; ≥230 ng/dL), prostate-specific antigen (PSA) ≥2 ng/mL (screening), Eastern Cooperative Oncology Group score of 0, and life expectancy ≥1 year. Exclusion criteria include, among others, previous/current hormonal therapy or chemotherapy for PCa. The primary endpoint is PSA response, defined as an ≥80% decrease from baseline to wk 25. A binary PSA response per patient (wk 25) will be determined, allowing for generation of a PSA response rate (95% CI) from all patients for the study. Secondary endpoints include: PSA dynamics; pharmacokinetics; change in gonadotropin, T, dihydrotestosterone, estradiol, sex-hormone binding globulin, and prolactin levels; and safety/tolerability. Exploratory endpoints include changes in bone mineral density, bone turnover markers, metabolic parameters, and quality of life. Results: The planned enrollment is 60 patients. With a 20% dropout rate, the study will have 80% power to reject the unwanted PSA response rate of ≤50% (5% significance). Efficacy and safety data will be published later. Conclusions: Previous data were in men with castrate levels of T (≤50 ng/dL). This trial will be the first to investigate the use of MDV3100 monotherapy in HNPCa. [Table: see text]