tbuckley/cabot-search huggingface dataset:
Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of <i>KRAS</i> and <i>BRAF</i> biomarker status with treatment outcome.
Authors: E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne
Journal: Journal of Clinical Oncology (2010)

3570 Background: The phase III CRYSTAL study showed that patients (pts) with KRAS wild-type (wt) tumors benefit from the addition of cetuximab to FOLFIRI as first-line treatment for metastatic colorectal cancer (mCRC). BRAF is a downstream effector of KRAS. Methods: Tumor KRAS and BRAF mutation status (wt or mutant [mt]) was determined for an expanded patient population using polymerase chain reaction and melting curve assays. Treatment arms were compared according to mutation status (log rank and Cochran-Mantel-Haenszel tests). Results: Of 1,198 pts in the primary analysis population, 1,063 (89%) were evaluable for KRAS mutation status; double the previous ascertainment rate. In pts with KRAS wt tumors, all efficacy endpoints were significantly improved in pts receiving cetuximab + FOLFIRI compared with FOLFIRI alone. Tumor BRAF status was evaluable in 625/666 pts with KRAS wt tumors. BRAF mutation was a marker of poor prognosis in both treatment arms (see Table). Conclusions: For all efficacy endpoints, including survival, this analysis confirms the value of KRAS mutational status as a predictor of treatment outcome in pts with mCRC receiving cetuximab plus FOLFIRI first-line. BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to FOLFIRI but the sample size may be too small to be conclusive. KRAS wt n=666 KRAS wt/BRAF wt n= 566 KRAS wt/BRAF mt n=59 FOLFIRI n=350 Cetuximab + FOLFIRI n= 316 FOLFIRI n=289 Cetuximab + FOLFIRI n=277 FOLFIRI n=33 Cetuximab + FOLFIRI n= 26 Median OS months ([95% CI) 20.0 (17.4–21.7) 23.5 (21.2–26.3) 21.6 (20.0–24.9) 25.1 (22.5–28.7) 10.3 (8.4–14.9) 14.1 (8.5–18.5) Hazard ratio (95% CI) 0.796 (0.670–0.946) 0.830(0.687–1.004) 0.908(0.507–1.624) p 0.0093 0.0549 0.7440 Median PFS months(95% CI) 8.4 (7.4–9.2) 9.9 (9.0–11.3) 8.8 (7.6–9.4) 10.9 (9.4–11.8) 5.6 (3.5–8.1) 8.0 (3.6–9.1) Hazard ratio (95% CI) 0.696 (0.558–0.867) 0.679 (0.533–0.864) 0.934 (0.425–2.056) p 0.0012 0.0016 0.8656 OR rate (%) (95% CI) 39.7 (34.6–45.1) 57.3 (51.6–62.8) 42.6 (36.8–48.5) 61.0 (55.0–66.8) 15.2 (5.1–31.9) 19.2 (6.6–39.4) Odds ratio (95% CI) 2.0693 (1.5154–2.8258) 2.1750 (1.5505–3.0511) 1.0842 (0.2644–4.4456) p <0.0001 <0.0001 0.9136 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA Merck KGaA/Merck Serono Amgen, Merck KGaA/Merck Serono, Merck Serono, Pfizer, Roche, sanofi-aventis Merck Serono, Pfizer, sanofi-aventis
Long-term follow-up of phase III trial of docetaxel and cisplatin (DP) versus mitomycin, vindesine, and cisplatin (MVP) with concurrent thoracic radiation therapy (TRT) for locally advanced non-small cell lung cancer (OLCSG 0007).
Authors: K. Kiura, N. Takigawa, K. Matsuo, S. Kuyama, S. Hosokawa, K. Fujiwara, A. Hisamoto, T. Kozuki, H. Ueoka, M. Tanimoto
Journal: Journal of Clinical Oncology (2011)

7048 Background: Although overall survival (OS) and progression-free survival (PFS) tended to be longer in the DP arm than in the MVP arm, there was no significant difference in the first report (ASCO 2008). Methods: Between July 2000 and July 2005, 200 patients were randomly assigned to DP or MVP arm. Chemotherapy consisted of docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on days 1, 8, 29, and 36 in the DP arm and mitomycin 8 mg/m2 on days 1 and 29, vindesine 3 mg/m2 on days 1, 8, 29, and 36, and cisplatin 80 mg/m2 on days 1 and 29 in the MVP arm. TRT began on day 1 at a dose of 60 Gy (2 Gy per fraction). OS and PFS were calculated using the Kaplan-Meier method. As a primary endpoint was set as OS in 2 years, we applied early-period weighted logrank tests. Results: Patients characteristics were as follows: PS of 0/1 46/53, 50/51; median age (range) 65 (40-75), 64 (34-75); weight loss (<5% / >5%) 88/11, 89/12; stage IIIA/IIIB 33/66, 33/68, for the DP arm and for the MVP arm, respectively. Median follow up time was 6.4 years in December 2010. OS in each arm was shown below. The OS was in favor to the DP arm (P = .042 by an early-period weighted logrank ). The PFS was also greater in the DP arm than in the MVP arm (P = .032). The favorable outcomes were mostly derived from early observation period. Median PFS (2.1 years) and OS time (2.2 years) were favorable in the DP arm compared with 1.6 years and 1.9 years, respectively, in the MVP arm, although there were no significant differences. When restricted with young patients (< 65 years old), 15 (30.6%) of 49 in the DP arm and 9 (17.3%) of 52 in the MVP arm survived more than 5 years. Conclusions: DP chemotherapy with concurrent TRT seemed better efficacy for the early period, however, the benefit became to disappear in the long-term follow-up. Young patients treated with the DP arm might have benefits even in the later period. DP arm MVP arm OS Event Rate 95% CI Event Rate 95% CI 1 y 17 82.8% 73.8–88.9% 32 68.2% 58.2–76.4% 2 y 39 60.3% 49.9–69.2% 52 48.5% 38.4–57.8% 3 y 62 36.4% 26.9–45.9% 61 39.4% 29.8–48.8% 5 y 73 24.7% 16.5–33.6% 78 22.2% 14.7–30.8%
Phase I results from a study of lapatinib with gemcitabine and cisplatin (GC) in advanced/metastatic bladder cancer.
Authors: Gedske Daugaard, Lisa Sengeløv, Mads Agerbaek, Cora N. Sternberg, Carla Van Herpen, Sandra Collette, Sandrine Marreaud
Journal: Journal of Clinical Oncology (2013)

252 Background: Lapatinib (Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor approved for the treatment of breast cancer. GC is a standard chemotherapy regimen for advanced/metastatic bladder cancer and there are preclinical and clinical data suggesting the role of EGFR and HER2 in urothelial carcinoma. This phase I study examined the safety of lapatinib in combination with GC in patients (pts) with bladder cancer. Methods: The primary phase I objective was to determine the maximum tolerated dose of lapatinib 750–1,250 mg that could be administered safely with GC in bladder cancer pts. A 3+3 dose escalation was used with lapatinib 750 mg, 1000 mg and then 1250 mg. Lapatinib was dosed daily and G (1000 mg/m² days 1, 8, 15) + C (70 mg/m² day 2) every 28 days. Results: 18 pts with median age 63 yrs (range 50-77) and ECOG PS 0/1 (66.7% with WHO-PS 0 and 33.3% with WHO-PS 1) were included. 3/6, 3/5 and 6/7 pts completed at least one cycle according to the protocol and received lapatinib 750 mg, 1000 mg and 1250 mg + GC, in cohorts 1, 2 and 3, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 or 2 (3 pts each); in cohort 3 (2 x 3 pts), 1 of 6 pts had DLT (Gr4 related febrile neutropenia and renal failure). One discontinued due to pt decision after 1 cycle. Ten pts received 6 cycles and one 7 cycles. The response rate among the 11/12 eligible patients was 73% (1 CR, 7 PR, 3 SD and 1 not assessable). Further toxicity data together with responses in relation to EGFR and HER2 status will be presented. Conclusions: Within the limits of a phase I study, lapatinib 750–1,250 mg + GC appears safe and tolerable with considerable activity at the maximum planned dose in bladder cancer. Clinical trial information: NCT00623064.
Genetic Factors Associated with Inhibitor Development in Hemophilia A: Initial Results From the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
Authors: Jan Astermark, John Schwarz, Sharyne M. Donfield, Donna M. DiMichele, Bruce M. Ewenstein, Edward D. Gomperts, George W. Nelson, Johannes Oldenburg, Amy D. Shapiro, Gerald Spotts, Cheryl A. Winkler, Erik Berntorp
Journal: Blood (2009)
Systemic immune responses induced by intratumoral plasmid IL-12 electroporation in patients with melanoma.
Authors: E. Cha, A. Daud, D. G. McNeel, R. Heller, L. Fong
Journal: Journal of Clinical Oncology (2011)

2574 Background: Intratumoral electroporation of a DNA plasmid expressing IL-12 (pIL-12) into melanoma lesions resulted in regression of untreated metastases in 10 of 19 evaluable patients. Although levels of IL-12 and IFN-gamma from electroporated tumors were detected, no significant levels of either cytokine were detected in sera. Intratumoral electroporation with pIL-12 could produce an adaptive antigen-specific immune response against melanoma to mediate these systemic clinical responses. Methods: In vivo pIL-12 electroporation was delivered into cutaneous or subcutaneous lesions on days 1, 5, and 8. Peripheral blood obtained from 15 patients from weeks 1, 4 and 6 were assessed for T cell responses to peptide pools of gp100, MAGE-3 and MART-1 by IFN-gamma ELISPOT assays. Sera from baseline and week 4 were screened for cancer-testis antigen (CTA)-specific IgG antibodies by probing immunoblots spotted with phage expressing 30 characterized CTAs. To further profile differentially induced antigen-specific IgG responses, sera from 5 responders and 5 nonresponders were also probed onto microarrays containing over 8000 human proteins and evaluated by unsupervised hierarchical clustering analysis. Evaluable patients were categorized by clinical activity (complete, partial response, stable disease or disease progression). Results: ELISPOT analyses showed increases in IFN-gamma producing T cells specific for MAGE-3 (4 of 15 patients) and MART-1 (3 of 15) between weeks 1 and 4. Systemic antibody responses to CTAs were also induced by week 4, although these immune responses were not significantly associated with clinical outcome. Protein microarray profiling identified 52 antigens that displayed IgG binding with at least a 2-fold differential between responders and nonresponders. Among this set are an epidermally-localized protein (4.2-fold, p = 0.008) and a testis-restricted antigen (3.0-fold, p = 0.037). Conclusions: Intratumoral electroporation with pIL-12 in melanoma induces immune responses to known and novel antigens. These results suggest that immune responses to a subset of these antigens may provide predictive value to pIL-12 treatment and will need to be confirmed in future studies.
Androgen deprivation for prostate cancer and the development of cardiovascular disease, its risk factors, and all-cause mortality.
Authors: K. L. Maletz, R. D. Ennis, G. C. Smith, S. Kalnicki
Journal: Journal of Clinical Oncology (2011)

e15178 Background: The overall benefit of androgen deprivation (AD) therapy may involve a trade off between improved prostate cancer control and increased cardiovascular (CV) mortality. Our study examines the risk of development of CV disease and risk factors, as well as all-cause mortality (ACM), for patients on AD for prostate cancer. Methods: Patients with localized biopsy-proven prostate cancer between 2001 and 2008 were identified using a medical records database. CV risk factors (diabetes, hypertension, hypercholesterolemia and obesity) and systolic heart failure were identified by medical record and lab findings while remaining CV endpoints (myocardial infarction, coronary artery disease and sudden cardiac death) were found by outpatient and inpatient billing data. Correlation with chi-squared or t-statistic and proportional hazard models were calculated with CV endpoints and CV risk factors. Results: Cohort consisted of 1660 patients with prostate cancer observed for a mean of 68.3 ± 28.6 months. AD was used in 287 patients as primary (31%) or adjuvant (69%) therapy with radiation or prostatectomy. Age at diagnosis was 65.1 ± 9.0 years for patients without AD and 71.7 ± 8.5 years for AD (p<0.001). Higher incidence of diabetes (22% versus 15%), hypertension (69% versus 54%), coronary artery disease (32% versus 16%) and systolic heart failure (7.1% versus 2.4%) occurred with AD (p<0.01). When adjusted for age at diagnosis, only the development of systolic heart failure (adjusted HR, 1.92; p=0.033) and diabetes (adjusted HR,1.39; p=0.043) were associated with use of AD. ACM was associated with prevalent and incident diabetes, hypertension and systolic heart failure, but not AD. Analysis of a high-risk subgroup of patients with prior systolic heart failure or myocardial infarction revealed no association between AD and ACM. Conclusions: AD is associated with a higher risk of diabetes and systolic heart failure, but not with other CV risk factors, CV endpoints or ACM in this cohort. Additional work is needed to further characterize the relationship between AD and systolic heart failure, as well as diabetes, and its role in ACM.
Compliance with established pneumonia core measures at MD Anderson Cancer Center in the emergency center.
Authors: Carmen E. Gonzalez, Tami N. Johnson, Lisa M. Kidin, Scott Evans, Yvette DeJesus, Kenneth V. I. Rolston, Ronald Stewart Walters
Journal: Journal of Clinical Oncology (2012)

189 Background: Pneumonia is the major cause of death due to infectious diseases in the United States. In the cancer patient, pneumonia is the overall leading infectious cause of death. Pneumonia Core Measures (PCM) and Clinical Pathways are frequently used by healthcare organizations to ensure the delivery of high-quality care and pathogen-directed therapy. A multidisciplinary team was organized at the University of Texas MD Anderson Cancer Center (MDACC) Emergency Center (EC) into a Pneumonia Team to optimize care and to enhance compliance with current PCM. Methods: A retrospective review of EC patients during pneumonia season was completed. Results: Three areas for improvement in the EC were identified. The areas include lack of EC staff’s knowledge on PCM, lack of standardized order-sets for pathogen-directed treatment, and cancer patients presenting with pneumonia syndromes that fall outside established Community-Acquired Pneumonia (CAP) guidelines. The identified problems were addressed through three strategies: Intense EC staff education initially and yearly prior to pneumonia season (September-March). Microbiologic analysis of the pathogens responsible for the pneumonias in our unique cancer population at MDACC. Development and implementation of an institutional pneumonia algorithm and an order-set. The Pneumonia Team also identified a gap between our patient population and the current PCM. Pneumonia patients at MDACC EC are divided into two distinct groups, solid tumor and hematologic cancers. The microbiology analyzed in both groups is consistent with Healthcare-Associated Pneumonia (HCAP) and not CAP. Microbiology analysis identified gram positive, gram negative, fungal, viral and multi-drug resistant organisms. The initial analysis demonstrated that 87% of our patients met criteria for HCAP and only 12% met CAP. Based on this percentage, antibiotic selection for our CAP patients comprises a small portion of our total population. Conclusions: Our current algorithm and order-set optimize care and minimize variation to match our patient population. These findings provide important considerations for policy makers in regard to pneumonia measurements in a cancer setting.
A phase II trial of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid, or islet cell cancer: Ovarian cancer (OC) subset—A study of the Princess Margaret, Mayo, Southeast phase II, and California Cancer (CCCP) N01 Consortia NCI#8233.
Authors: R. Morgan, A. M. Oza, R. Qin, K. M. Laumann, H. Mackay, E. L. Strevel, S. Welch, D. Sullivan, R. M. Wenham, H. X. Chen, L. A. Doyle, D. R. Gandara, C. Erlichman
Journal: Journal of Clinical Oncology (2011)

5015
Concurrent Amplification of MYC and 1q21 in Multiple Myeloma: Focal and Segmental Jumping Translocations of MYC
Authors: Jeffery Sawyer, Erming Tian, Brian A Walker, Niels Weinhold, Charles Swanson, Janet L Lukacs, Regina Binz, Gael Sammartino, Sharmilan Thanendrarajan, Carolina Schinke, Maurizio Zangari, Faith E Davies, Frits van Rhee, Gareth J Morgan
Journal: Blood (2016)
Two phase I studies of PTI-188, a radiolabeled murine antimelanin antibody, in patients with metastatic melanoma (MM).
Authors: M. Lotem, T. Peretz, S. Mizrachi, Y. Liberman, E. Dadachova, A. Casadevall, A. de Kater, N. Friedmann, G. B. Thornton, M. Klein
Journal: Journal of Clinical Oncology (2011)

8555 Background: Two completed single-dose Phase I studies explored the feasibility of treating MM by targeting melanin with a 188-Rhenium-labeled IgM mAb (PTI-188) to deliver high energy β radiation to tumors. This strategy is attractive because it does not rely on patients' genotype or immune status, and thus has potential to be used alone or in combination with other therapies in a wide pt population. The objectives of these Phase I studies were to evaluate the safety, pharmacokinetics, dosimetry and anti-tumor activity of a single dose of PTI-188. Methods: Pts with stage IIIC/IV MM who progressed after chemotherapy, immunotherapy, radiotherapy or surgery were enrolled in both studies, at least 3 pts/cohort. In Phase IA, pts were given the same dose of PTI-188 (10 mCi/10 mg) while a cold antibody pre-load was escalated from 0-50 mg in 4 cohorts. In Phase IB, pts were assigned to cohort 1 (20-30 mCi/20mg) or cohort 2 (40-60mCi/50mg). Whole body planar and tomographic (SPECT/CT) scintigraphy were performed post-infusion to determine tumor targeting and dosimetry. Toxicity and efficacy were evaluated at weeks 2 and 6 post-treatment, and monthly thereafter. Results: No dose limiting toxicities or clinically meaningful effects in safety lab tests were seen in the 13 pts dosed in Phase IA and 7 pts in Phase IB, suggesting the MTD was not met. No treatment related serious AEs occurred. Transient human anti-murine Abs were observed in 9 pts. Tomographic imaging revealed PTI-188 uptake in melanoma tumor deposits mostly in the soft tissues. The highest radiation absorbed dose to normal organs was in the kidney (13% of the allowable dose to kidney at the highest dose level of PTI-188). The mean effective half-life of PTI-188 was 12.4 hr across cohorts. Although no therapeutic benefit was expected in a single dose Phase I study, 6 pts met the RECIST criteria for stable disease at 6 weeks. 2 pts had durable disease stabilization for 14 weeks and 1 for 22 weeks. Preliminary ad-hoc analysis indicates a median overall survival of 20 months (n=17). Conclusions: The data demonstrate that a single dose of PTI-188 was well tolerated, localized in melanoma metastases and suggest antitumor activity.
Differences in Haematological and Non Haematological Toxicity during Treatment with Imatinib in Early and Late Chronic Phase Chronic Myeloid Leukemia Patients
Authors: Massimo Breccia, Roberto Latagliata, Laura Cannella, Ida Carmosino, Caterina Stefanizzi, Michelina Santopietro, Giuliana Alimena
Journal: Blood (2008)
Metabolic complications with the use of mTOR inhibitors for cancer therapy: A systematic review and meta-analysis.
Authors: Shanthi Sivendran, Jian Ying, Benjamin Adam Gartrell, Neeraj Agarwal, Kenneth M. Boucher, Toni K. Choueiri, Guru Sonpavde, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2013)

398 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). The risk of metabolic complications with these agents is not well characterized. Methods: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. 16 eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia were extracted. Incidence rates and incident rate ratios were calculated. Results: In total, 24 trials (including 4,261 patients) were included. The average incidence rate of any grade metabolic adverse events and grade 3-4 metabolic adverse events was 0.70 per patient and 0.11 (95% CI, 0.08, 0.15) per patient respectively. Analysis of the 3,317 patients across 8 RCT’s revealed that the log incidence rate ratio (IRR) of any grade metabolic adverse events with mTOR inhibitor therapy compared with control was 1.08 (95% CI, 0.84, 1.31) using a random-effects model. The risk of grade 3-4 adverse events was also increased with an IRR of 1.52 (95% CI, 1.05, 1.99). The IRR of all grade hyperglycemia was 1.08 (95% CI, 0.76, 1.40) and of grade 3-4 hyperglycemia was 1.66 (95% CI, 1.12, 2.20). The IRR of all grade hypertriglyceridemia was 0.91 (95% CI, 0.56, 1.26) and of grade 3-4 hypertriglyceridemia was 0.70 (95% CI,- 0.43, 1.83). The IRR of all grade hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65) and of grade 3-4 hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. Conclusions: The risk of all grade and grade 3-4 metabolic adverse events are increased in patients treated with mTOR inhibitors compared with control. However, grade 3-4 metabolic adverse events remain relatively uncommon.
<i>DCC</i> and <i>RET </i>pathway analysis to identify factors associated with advanced colorectal cancer.
Authors: Stacey Shiovitz, Li Hsu, Conghui Qu, Tabitha A. Harrison, Sonja Berndt, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Loic Le Marchand, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Martha L. Slattery, Emily White, Ulrike Peters, William M. Grady
Journal: Journal of Clinical Oncology (2014)

457 Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10 -6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10 -3 . SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10 -3 . SNPs in NTN1 and RET reached significance only at p = 1.73x10 -2 and 1.53x10 -2 , respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.