tbuckley/cabot-search huggingface dataset:
Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.
Authors: Aditya Bardia, Steven J. Isakoff, Dejan Juric, Darrell R. Borger, Dora Dias-Santagata, Anthony John Iafrate, Keith Flaherty, Beverly Moy, Leif William Ellisen
Journal: Journal of Clinical Oncology (2013)

533 Background: Major barriers to enrollment in therapeutic clinical trials (&lt;5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.
Phase II study of biweekly carboplatin and paclitaxel as first-line treatment for elderly patients with advanced non-small cell lung cancer.
Authors: H. Terai, K. Soejima, M. Nakamura, K. Naoki, H. Yasuda, R. Satomi, S. Nakayama, S. Yoda, S. Ikemura, T. Sato, K. Asano
Journal: Journal of Clinical Oncology (2011)

e18013 Background: Incidence of elderly advanced non-small cell lung cancer (NSCLC) is increasing and the establishment of optimal treatment for the elderly patients is desired. Currently, as the elderly are underrepresented in clinical trials, only limited data exist. Standard chemotherapy by platinum doublet of elderly patients with advanced NSCLC is still controversial. This study has been conducted to assess the efficacy and toxicity of biweekly carboplatin plus paclitaxel in elderly patients with advanced NSCLC. Methods: Patients ≥70 years old with cytological or histological confirmation of advanced (stage IIIB/IV) NSCLC were included. Other eligibility criteria were PS≤2, measurable lesions according RECIST criteria, adequate organ function. Patients with prior systemic therapy for NSCLC and/or symptomatic brain metastases were not allowed. Patients received biweekly paclitaxel 90 mg/m2 and carboplatin 2.5 AUC on days 1 and 14 of each 28-day cycle. The primary endpoint was the overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and the toxicity profile. Results: We enrolled 47 pts from multiple institutions (Jan. 2007 – Oct. 2010). Males were 76.6%, median age was 77 years (range 70-85). PS was 0-1 in 95.7%. The median number of treatment cycle was 3 (1-6). The objective responses were CR 0; PR 10; SD 12; PD 14; and NE 11, resulting in an ORR of 21.3% (95% confidence interval [CI], 9.6- 33.0). The overall disease control rate was 46.8% (95% CI, 32.5-61.1). Median PFS was 4.17 month (95% CI: 2.18- 6.16). Hematological toxicities of grade 3/4 included neutropenia (28%), leucopenia (19%) and anemia (11%). Nonhematological toxicities (all grade 3) included infusion reaction (2%), anorexia (2%), infection (13%), thrombosis (2%), fatigue (2%), diarrhea (2%) and gastrointestinal bleeding (2%). No grade 4 nonhematological toxicity was observed. There was 1 possible treatment-related death due to interstitial pneumonia. Conclusions: The combination of biweekly carboplatin and paclitaxel is an active first line treatment with a tolerable toxicity profile for advanced NSCLC in elderly patients.
Positron emission tomography/computed tomography for optimized colon cancer staging and follow-up.
Authors: Bodil E. Engelmann, Annika Loft, Andreas Kjær, Hans J. Nielsen, Anne Kiil Berthelsen, Tina Binderup, Kim Brinch, Nils Brünner, Gunilla Høyer-Hansen, Thomas A. Gerds, Michael Holmsgaard Kristensen, Engin Y. Kurt, Jan E. Latocha, Gunnar Lindblom, Carsten Sloth, Liselotte Højgaard
Journal: Journal of Clinical Oncology (2014)

408 Background: Optimal management of colon cancer requires detailed assessment of extent of disease. Diagnostic accuracy of 18 F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT) in primary colon cancer staging and for detection of recurrence was investigated. Methods: PET/CT for preoperative staging was performed on 66 prospectively included patients with primary colon cancer. Diagnostic accuracy for PET/CT and CT alone was analysed. Forty-two stage I-III colon cancer patients had PET/CT follow-up examinations every six months for two years. Serological levels of Tissue Inhibitor of Metalloproteinases (TIMP-1), Carcinoembryonic Antigen (CEA), and liberated domain I of urokinase Plasminogen Activator Receptor [uPAR(I)] and FDG-uptake related tumour gene expression were analysed. Results: Accuracy for T-, N- and M-staging by PET/CT were 82 % [95% Confidence Interval (CI) 70; 91], 66 % [CI 51; 78] and 89 % [CI 79; 96]; for CT 77 % [CI 64; 87], 60 % [CI 46; 73] and 69 % [CI 57; 80]. Cumulative relapse incidences for stage I – III colon cancer at 6, 12, 18 and 24 months were 7.1 % [CI 0; 14.9]; 14.3 % [CI 3.7; 24.9]; 19.0 % [CI 7.1; 30.9] and 21.4 % [CI 9.0; 33.8]. PET/CT diagnosed all relapses detected during the first two postoperative years. High preoperative TIMP-1 levels were associated with significant hazards towards both risk of recurrence and shorter overall survival. FDG-uptake in colon cancer showed significant correlation to hexokinase 2, the hypoxia marker carboanhydrase IX and the proliferation marker ki67. Conclusions: This study indicates PET/CT to be a valuable tool for staging and follow-up in colon cancer. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow-up.
Safety and evidence of activity of MSC1936369, an oral MEK1/2 inhibitor, in patients with advanced malignancies.
Authors: N. Houede, S. J. Faivre, A. Awada, E. Raymond, A. Italiano, T. Besse-Hammer, M. Donica, N. Rejeb, C. Luepfert, S. Ongarello, J. Delord
Journal: Journal of Clinical Oncology (2011)

3019 Background: MSC1936369 is a highly selective inhibitor of MEK1/2 with potent antitumor activity in cells lines and xenograft models with activated (mainly BRAF and KRAS) mutations in the MAPK pathway. Objectives: To define the maximum tolerated dose (MTD), safety, pharmacokinetic (PK), pharmacodynamic (PD) and antitumor activity of two dosing schedules. Methods: 3+3 design, dose-escalation in two independent parallel schedules (S): S1 day (d) 1-5, 8-12, 15-19 or S2 d 1-15 of a 21-d cycle. MSC1936369 once/d, 100% dose increments until grade (G) 2 toxicity then modified Fibonacci scheme. Results: 105 patients (pts) treated: 49 in S1 in 11 dose levels (DL) 1-120mg/d and 56 in S2 in 14 DLs, 1-255mg/d. Median age [range] 60 yrs [34–83] S1, 58 yrs [31–77] S2; men 59% S1, 68% S2; ECOG PS 0-1. Most frequent tumors: colorectal (43% S1, 29% S2) and melanoma (14% S1, 29% S2). Median number of cycles [range]: S1 3 [1–13], S2 2 [1–11]. S1 dose-limiting toxicities (DLTs): 28mg/d (n=6) G3 liver function test elevation (1 pt); 120mg/d (n=11) G2 retinal vein occlusion (1 pt), halting further dose-escalation. S2 DLTs: 195mg/d (n=12) G3 skin rash (1 pt) and G3 pharyngitis (1 pt); 255mg (n=6) G3 acneiform rash (1 pt) and G3 serous retinal detachment and macular edema (SRD) (1 pt). MTDs were defined: S1 120mg/d, S2 195mg/d. Most common adverse events (AEs): skin rash, diarrhea, asthenia, anorexia, nausea, vomiting, peripheral edema, anemia and visual disorders (VD) with or without SRD. AEs were usually reversible even for G3. Drug-related discontinuations were more frequent in S1, mainly for VD. PK: Cmax and AUC increase with dose, median Tmax 1 hr [range 0.5–8 hrs]. 80% pERK inhibition in PBMC is observed at ≥28mg/d lasting up to 8 hrs at higher doses. It correlates with PK, IC80 ~60ng/mL. BRAF status is available in 11/19 melanoma pts at ≥28mg/d: 6 mutated (mut), 5 wild-type. 5 pts had tumor shrinkage all with MAPK activating mutations (4/6 BRAFmut, 1 NRASmut); 3/5 achieved partial response (PR). Conclusions: MTD was reached in S1 at 120mg/d and S2 at 195mg/d. PK is dose proportional and associated with PD target inhibition. At active doses, sustained PRs and stable diseases with tumor shrinkage were seen in BRAF- and NRAS-mut melanomas.
Pembrolizumab for previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: Phase 2 KEYNOTE-180 study.
Authors: Manish A. Shah, Jaafar Bennouna, Lin Shen, Peter C. Enzinger, Qiao Li, Ildiko Csiki, Minori Koshiji, Toshihiko Doi
Journal: Journal of Clinical Oncology (2016)

TPS4139 Background: PD-L1 is frequently overexpressed in esophageal cancer. Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor and blocks interaction with PD-L1 and PD-L2. In the multicohort, phase 1b KEYNOTE-028 trial, pembrolizumab showed manageable toxicity, a 30.4% ORR, and median duration of response not reached in 23 patients (pts) with PD-L1+ advanced esophageal cancer. The multicenter, phase 2 KEYNOTE-180 trial (NCT02559687) is designed to further evaluate pembrolizumab as a monotherapy in pts with previously treated advanced/metastatic esophageal cancer. Methods: Key eligibility criteria include age ≥ 18 y, advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction (EGJ), measurable disease, documented progression during or after 2 prior standard lines of therapy, ECOG PS 0-1, no active autoimmune disease or brain metastases, and provision of a tumor sample for retrospective biomarker analysis. Pts with metastatic Siewert type I EGJ adenocarcinoma must have known HER2 status and, if HER2+, must have documented progression on treatment containing trastuzumab. Eligible pts are to receive pembrolizumab 200 mg Q3W for 35 cycles (~2 y) or until progression, unacceptable toxicity, or investigator or pt decision. Response is to be assessed every 9 wk per RECIST v1.1 and RECIST adapted for immunotherapy response patterns. Treatment may be discontinued for pts who have a CR, and eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed for survival every 9 wk. The primary efficacy end point is ORR per RECIST v1.1 by central imaging vendor review. Secondary end points include PFS, OS, and duration of response. Exploratory analyses include evaluation of immune-related gene expression profiles and PD-L1 expression status as predictors of pembrolizumab efficacy. Enrollment in KEYNOTE-180 began in December 2015 and will continue until approximately 100 pts are enrolled. Clinical trial information: NCT02559687.
Predicting response to neoadjuvant chemoradiotherapy in esophageal cancer by textural features derived from pretreatment FDG-PET scans.
Authors: Jorn Beukinga, Jan-Binne Hulshoff, Marianna Sijtsema, Sanne van Dijk, Christina Muijs, Johannes Burgerhof, Gursah Kats-Ugurlu, Riemer Slart, Kees Slump, Veronique E. Mul, John Theodorus Plukker
Journal: Journal of Clinical Oncology (2016)

93 Background: 18-F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is currently the imaging method of choice in assessing response of neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (EC) patients. PET/CT derived texture analysis is potentially more useful than common PET/CT measurements in response assessment and might also be of predictive value in different cancer types. The aim of this study was to develop a model to predict response to nCRT in EC based on pretreatment FDG-PET derived textural features in combination with clinical parameters. Methods: We reviewed 80 locally advanced EC patients who underwent pretreatment FDG-PET/CT and radiation planning CT scans between 2009 and 2015. Patients received nCRT according to the CROSS regimen (carboplatin/paclitaxel/41.4Gy) followed by esophagectomy. We analyzed 7 clinical, 16 geometry-based, and 87 different texture features derived from pretreatment FDG-PET images of the radiotherapy gross tumor volume. Ordinal logistic regression analysis was performed to construct a prediction model for treatment response, which was pathologically classified in complete, partial and no response on the Mandard tumor regression grade (1 vs. 2-3 vs. 4-5). The performance of this model was estimated by comparison with clinical outcome. Results: Pathologic examination revealed 16 (20.0%) complete, 46 (57.5%) partial, and 18 (22.5%) non- responders. Response analysis yielded the following independent predictive textural features: SUVmin, small zone low gray level emphasis, and contrast; and the independent predictive clinical parameters: nodal stage, endoscopic tumor length, and gender. The model has a sensitivity/specificity, positive/negative predictive value, and accuracy of 69%/97%, 85%/93%, and 91% for the prediction of complete response and 61%/79%, 46%/88%, and 75% for non-response, respectively. Conclusions: The prediction model constructed in this study, shows a good overall performance level in predicting response to nCRT in EC patients, but requires further external validation and refinement before it can be used for clinical decision making.
Dual inhibition of VEGF pathway: Phase I trial of bevacizumab and cediranib in advanced solid tumors.
Authors: I. Garrido-Laguna, R. Kurzrock, J. J. Wheler, G. S. Falchook, S. A. Piha-Paul, S. Fu, A. Naing, C. Hinojosa, R. Mistry, A. Scamardo, K. S. Culotta, S. Ekmekcioglu, S. Wen, L. H. Camacho, S. P. Ivy, D. S. Hong
Journal: Journal of Clinical Oncology (2011)

3065 Background: We evaluated the safety of a combination of bevacizumab (B) and a TKI against VEGFR-cediranib (C). Methods: This was a phase I study with 3+3 design in patients (pts) with advanced solid tumors. C was given po daily for 21 days and B i.v. every two weeks (days 1 and 15). We measured changes in serum total nitrate in response to therapy. Results: 51 pts were dosed. 2 pts at DL4 had DLT of hypertension (HTN) grade 3 and 4. DL3 was initially deemed the MTD (C30 mg/day and B5mg/kg/2weeks). However at the DL3 dose-expansion of the initial 18 pts, 2 pts had a CNS bleed with HTN, 1 pt had grade 5 hemoptysis and 3 pts had thrombopenia (grade 3 and 4) DLTs. Although DL3 did not exceed the >33% definition of MTD (7 DLTs/24 pts), given the severe adverse events (AEs), DL3 was deemed too toxic and all remaining pts at DL3 were reduced to DL2 (C20mg/day and B5mg/kg/2weeks) and additional 8 pts were enrolled at DL2. No DLT was observed at DL2 and was deemed the RP2D dose. PKs on patients at DL3 based on C mean drug exposure showed a 50-75% increase in AUC (0-24h) on cycle 1day 1 when compared to historical controls from single agent studies. The most common drug related AEs were HTN (54%), fatigue (42%), anorexia (38%), diarrhea and proteinuria (27%). The most common grade 3-4 AEs were CNS bleed (8%), HTN and nausea (6% each). 42 pts were evaluable by RECIST.17 pts had SD for >4 months (including 9 pts with soft tissue sarcomas). 2 sarcoma pt had PR : alveolar soft tissue part sarcoma (ASPS) (-43%, +16months [m]) and synovial (-32%, +10m). Other SD sarcoma pts included: ASPS (17%, -27%, -16%) of 4, 7, +24 months, spindle cell (-9%, 8m), leiomyosarcoma (-17%, 6m) and 2 synovial sarcoma pts (-8%,-18%) of 10,+5m. PRs were also seen in basal cell ca (-33%, +13m), inflammatory breast (-54%, 3m). Median PFS was > in pts with decreases in total nitrate by day 14 but not statistically significant (4.2 months vs. 1.9, p=0.25). Conclusions: The combination of C 20mg/day and B 5mg/kg/2weeks was well tolerated and is the RP2D/MTD. At doses above the MTD, dual targeting of the VEGF pathway led to increased exposure to C and increased toxicity, specifically CNS bleeds and HTN. Activity in soft tissue sarcomas and other tumor types were seen. This study was supported by U01CA62461 (RK).
The knowledge and attitudes of cancer pain management of residents and nurses in university hospital in Daegu city, Korea
Authors: H. Song, Y. Do, J. Kim, J. Lee
Journal: Journal of Clinical Oncology (2008)

20701 Background: Pain is the most feared symptom in cancer patient. In general, pain is under-treated. Barriers to effective pain management of health care professionals includes inadequate training in pain management, poor assessment of pain, concern about side effect management, fear of addiction, low priority given to pain treatment, and inadequate reimbursement. The importance of education in improving treatment of pain is well recognized. Methods: The purpose of this study is to evaluate the knowledge and attitude of cancer pain management of residents and nurses in University hospital in Daegu city, and the Korean medical oncologists. A total of 48 residents and 51 registered nurses in Dongsan Medical Center, Keimyung University in Daegu and 183 nationwide medical oncologists were surveyed. Self-administered questionnaire covered 2 domains of 40 items; knowledge of general principles of cancer pain management and opioid use, were used. Results: With compare to medical oncologists, resident and nurses had statistically significant mis-knowledge in 5 items in general principles of cancer pain management (effective cancer pain management rate, VAS, the 5th vital sign, character of neuropathic pain, WHO ladder step) and 7 items about opioid use (addiction, tolerance, efficacy of strong opioids, knowledge about opioids, education rate, efficacy of parenteral opioids, ceiling effect). With compare to resident, nurses had statistically significant mis-knowledge in 4 items in general principles of cancer pain management (effective cancer pain management rate, poor assessment of health care professionals, VAS, WHO ladder step) and 14 items about opioid use (addiction, tolerance, effect on survival, opioid use to herself, incidence of side effect, knowledge about opioids, education rate, efficacy of parenteral opioids, patients’ refusal rate, seriousness of side effects, treatment of tolerance, by the clock, ceiling effect, reserves of opioid for intractable pain). Conclusions: The knowledge of cancer pain management of residents and especially nurses should be improved. No significant financial relationships to disclose.
Development and economic trends in cancer therapeutic drugs: An updated analysis of modern and historical treatment costs compared to the contemporary GDP per capita.
Authors: Philip Savage
Journal: Journal of Clinical Oncology (2013)

259 Background: Cancer drug development is a major industry and clincial success story with new cancer treatment drugs delivering improved healthcare for many more patients each year. Generally new cancer treatment drugs are viewed as being of 'high cost' and there is considerable debate as to how these new treatments can be funded for routine use. Accurate data on the trends of the relative costs of new treatments compared with earlier high cost cancer drugs is limited. In this sudy we have aimed to document all the newly licenced cancer drugs, by year of introduction, and compare the cost of a standard course of treatment relative to the current per capita GDP to allow an assessment of how relative costs of new drugs have changed over time. Methods: Drugs are classified by years of introduction, therapeutic classification, and an assessment of relative treatment cost using a contemporary 'standard' treatment compared with the relevant UK GDP per capita. Results: Prior to 1960, there were 5 cancer drugs available, 2 new drugs were introduced in the 1960s, 18 in the 1970s, 14 in the 1980s, 24 in the 1990s, 23 between 2000-2009 and 15 between 2010-12. Data will be presented on the cost relative to per capita GDP of a standard treatment for each new drug released from 1987 to current. The summary data indicates that the cost at introduction of an average new cancer drug treatment has increased from 33% of per capita GDP for 1995-99, 53% for 2000-2004, 67% for 2005-2009 and is now 114% for 2010-2012. Conclusions: The cost of new cancer drug treatments appears to be rising in absolute and relative terms. The data in this abstract may be of value to those interested in the history of cancer treatment development and the associated current economic issues.
Association of XRCC3 and XPD751 SNP with response to platinum-based chemotherapy in advanced NSCLC patients.
Authors: X. Chen, C. Zhou, H. Sun, S. Ren, L. Zhang, S. Zhou
Journal: Journal of Clinical Oncology (2011)

e18045 Background: The purpose of this study was to investigate whether X-ray repair cross-complementing group 3 alleles Thr241Met, xeroderma pigmentosum group D variant alleles Lys751Gln affected clinical outcomes of 1st line platinum-based chemotherapy in advanced non-small cell lung cancer patients. Methods: 355 patients enrolled into this study and their genotyping of X-ray repair cross-complementing group 3 Thr241Met,xeroderma pigmentosum group D Lys751Gln were detected by the TaqMan assay plus the real time PCR method in theri peripheral blood lymphocytes. SPSS version 12.0 was used to do the X2 and Kaplan-Meier survival analysis. Results: The median age was 59.5 years old and 68.5% of the patients were male. No relationship was found between the wild-type, heterozygous and homozygous polymorphic variants SNPs of XRCC3 241, XPD751 and genders, ages, histology, smoking status. Progression free survival (PFS) and overall survival (OS) were similar between the patients with wild-type, heterozygous and homozygous polymorphic variants of XRCC3 and XPD751. However, in the subgroup analysis, OS in the patients with XRCC3 C/C was significant longer than the patients with C/T or T/T in the vinorelbine subgroup(14.0m vs 9.3m, P=0.042)and the taxanes subgroup (18.5m vs 7m, P=0.01). Conclusions: XRCC3 gene Polymorphisms may play different roles to predict the efficacy of platinum-based doublet chemotherapy according to different chemotherapy regimen, which warrant further prospective large-scale study.