bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408).
Authors: Patterson Scott D. , Peeters Marc , Siena Salvatore , Van Cutsem Eric , Humblet Yves , Van Laethem Jean-Luc , Andre Thierry , Tian Ying , Sidhu Roger , Oliner Kelly S. 
Published: March 2020

3617 Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.
Quantitative analysis of the impact of deepness of response on post-progression survival time following first-line treatment in patients with mCRC.
Authors: Mansmann Ulrich Robert , Sartorius Ute , Laubender Ruediger Paul , Giessen Clemens Albrecht , Esser Regina , Heinemann Volker 
Published: March 2020

3630 Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy with or without monoclonal antibodies is prognostic for PFS and OS. The ‘Deepness of response (DpR)’ concept aims to relate tumor shrinkage to post-progression survival (PPS). If tumor shrinkage occurs, DpR is the percentage of shrinkage observed at the nadir compared with baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can be used to quantify the tumor load. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows the prediction of a pt PPS time based on DpR. Methods: Based on data from the randomized CRYSTAL and OPUS trials, 4 treatment regimens (FOLFIRI +/- cetuximab and FOLFOX4 +/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and to relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. A Spearman correlation was used to study the relationship between DpR and PPS for KRAS wild-type (wt) pts with progressive disease. Results: Results are reported using LD-based measures for 841 pts with KRAS wt tumors and imaging data. The 348 pts treated with FOLFIRI alone had a median DpR of 33.3% (interquartile range [IR]: 8.0%, 58.0%) while the 315 pts treated with FOLFIRI + cetuximab had a significantly higher median DpR of 50.9% (IR: 18.4%, 78.6%), p<0.0001. The 96 pts treated with FOLFOX4 alone had a median DpR of 30.7% (IR: 4.0%, 55.9%) and the 82 pts treated with FOLFOX4 + cetuximab had a significantly higher median DpR of 57.9% (IR: 24.0%, 92.9%), p=0.0008. Correlation between DpR and PPS for pts with documented progression is statistically significant in each treatment group for both LD-based and volume-based measurements (p<0.0001 for the CRYSTAL study and p<0.005 for the OPUS study). Conclusions: Our results emphasize the value of DpR as a new efficacy outcome measure for clinical trials. The tumor-shrinking capacity of cetuximab was shown to be associated with its ability to prolong PPS.
Minor response rate to predict patient survival.
Authors: Zhao Binsheng , Lee Shing Mirn , Qi Jing , Mozley P. David , Mauro David J. , Schwartz Lawrence H. 
Published: March 2020

3635 Background: RECIST is widely used to evaluate anticancer therapy efficacy, yet its response cutoff values have not been proven biologically or measurement-error relevant. Our previous study showed that the variability in measuring relative change in total tumor burden (TTB%) was +/-10% in metastatic colorectal cancer (mCRC). Our study investigated the impact of a finer gradation of response categories in predicting survival. Methods: 468 patients enrolled in a phase II/III clinical trial evaluating a systemic therapy in mCRC were analyzed. TTB on baseline and 6-week (+/- 3-wk) scans were obtained per RECIST 1.0. Overall survival (OS) was defined from the start of treatment and the date of the scan using the landmark method. The TTB% was summarized using RECIST category and a finer gradation that included cut-offs established in our variability study (<-30%, -30% - -10%, -10% - 10%, 10% - 20%, >20%). The OS and TTB% correlation was evaluated by the Kaplan Meier method and Cox regression. The discriminatory powers of the response summaries were examined using Harrel’s c statistics and concordance probability. Results: Out of the 468 patients, 141 died. The median survival time for patients with a TTB% at 6 weeks of [-30%, -10%] (n=116), [-10%, 10%] (n=171), [10%, 20%] (n=43), >20% (n=62) were 417, 287, 223 and 172 days, respectively. Among those with a change of < -30% (n=76), over half of patients were still alive. The hazard ratio for OS compared to those with a change of <-30% are listed in the Table. The inclusion of additional categories increased both Harrel’s c-statistic (0.69 vs 0.73) and concordance probability (0.63 vs 0.69). Combining the [-10%, 10%] and the [10%, 20%] categories yielded very similar statistics compared to having all 5 categories. Both definitions of OS yielded consistent results. Conclusions: Evidence suggests that, in the context of this study, the minor change category of [-30%, -10%] at 6-wk correlates with longer survival compared to the change category of [-10%, 20%], suggesting a possible re-evaluation of conventional response cut-off values. [Table: see text]
Real-world comparative economics of a 12-gene assay for prognosis in stage II colon cancer.
Authors: Yu Tiffany , Alberts Steven R. , Behrens Robert J. , Renfro Lindsay A. , Srivastava Geetika , Soori Gamini S. , Dakhil Shaker R. , Mowat Rex B. , Kuebler J. Phillip , Kim George P. , Mazurczak Miroslaw , Hornberger John C. 
Published: March 2020

3640 Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al. Value Health 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p<0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $3,228 for drugs, $750 for administration, and $3,168 for adverse events management. Overall, average total direct medical costs decreased $1,683. The net effect on average patient well-being was a gain of 0.102 QALYs. Total change in medical costs is most influenced by the cost of death due to colon cancer, time-preference discount rate, and the change in aCT recommendations. Savings are expected to persist even if the cost of oxaliplatin dropped by >75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these aCT changes reduce direct medical costs and improve patient well-being.
Association of aspirin use with improved 5-year survival in colorectal cancer patients with PIK3CA mutation.
Authors: Kothari Nishi , Yeatman Timothy Joseph , Fisher Kate , Schell Michael J. , Kim Richard D. 
Published: March 2020

3644 Background: Recent work has shown an association between longer survival and aspirin use in colorectal cancer (CRC) patients with mutated PIK3CA. It has been hypothesized that this survival advantage could occur via blocking the PI3K pathway and allowing apoptosis of mutated cancer cells. The goal of this work is examine the use of aspirin and outcome in CRC patients with PI3KCA mutation. Methods: PIK3CA mutation status was assessed in paraffin-embedded tumor samples from 471 CRC patients between 1998-2010. PIK3CA mutation was assessed by exome sequencing using an Illumina Next Generation (NGS) platform with 50-100X coverage on all patients. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. The usage of aspirin was collected retrospectively with electronic chart review. Results: Out of 471 patients, 73 were found to have unique PIK3CA mutations by NGS (15.4%). The most common mutations were found at codon 9 (38%) and codon 20 (21%). Patients had a median follow up of 47 months. Initial stage at diagnosis for PIK3CA mutants were as follows: 11 pts were stage I, 31 pts were stage II, 24 pts were stage III and 16 patients were stage IV. Of patients who died, those taking ASA had a 5% cancer related mortality compared to 23% cancer related mortality in non-ASA users. In contrast, the non-cancer related mortality was 25% in ASA users and only 8% in non-ASA users. Cancer specific rates for five year survival were 90% in the ASA group and 57% in the non-ASA group for all stages. In stage IV patients, there was 80% five year survival in the ASA users and 32% in the non-ASA group. Conclusions: There was a trend toward improvement in five year survival for colorectal cancer patients with PIK3CA mutations who used ASA. This trend persisted even in stage IV patients. Notably, non-cancer related deaths were higher in the ASA users, most likely secondary to medical comorbidities that necessitated ASA use. As follow up continues and this data set matures, future work will focus on validating these preliminary results and relating specific PIK3CA mutations to ASA response.
HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5FU on the ESPAC trials.
Authors: Neoptolemos John P. , Greenhalf William , Ghaneh Paula , Palmer Daniel H. , Cox Trevor F. , Garner Elizabeth , Campbell Fiona , Mackey John Robert , Moore Malcolm J. , Valle Juan W. , Mcdonald Alec , Tebbutt Niall C. , Dervenis Christos , Glimelius Bengt , Charnley Richard M. , Lacaine Francois , Mayerle Julia , Rawcliffe Charlotte Louise , Bassi Claudio , Buchler Markus W. ,   The European Study Group for Pancreatic Cancer
Published: March 2020

4006 Background: Some studies in patients with resected pancreatic cancer have suggested that expression of the human equilibrative nucleoside transporter (hENT1) may be predictive of improved survival from gemcitabine but these have either been based on retrospective non-randomized studies or in one study the principal treatment was chemoradiation. The samples collected from the adjuvant ESPAC1/3 randomized trials have provided a unique opportunity to assess to REMARK standards the therapeutic predictability of hENT1 in patients undergoing resection for pancreatic cancer. Methods: Tissue Microarrays (TMAs) were prepared using paraffin embedded tumor specimens from patients randomized to gemcitabine or 5FU/Folinic acid in the ESPAC-1 and -3 trials. Cores were given an H-Score depending on the level of staining with the 10D7G2 anti-hENT1 antibody. Groups were compared using Kaplan-Meier and Cox proportional hazards. Results: Scores were obtained for 176 gemcitabine treated and 176 5FU treated patients. The overall median H-Score was 48 and patients were classified as having high hENT1 if the mean score for their cores was above this. Median overall survival for gemcitabine treated patients was 23.4 (95% CI: 18.3, 26.0) months versus 23.5 (95% CI: 19.8, 27.3) months for 5FU treated patients (χ21 = 0.24, P = 0.623). In the gemcitabine group A significantly lower survival (χ21 = 9.87, P = 0.002) was noted with low hENT1 (median survival 17.1 (95% CI: 14.3, 23.8) versus 26.2 (95% CI: 21.2, 31.4) months). Median survival was 25.6 (95% CI: 20.1, 27.9) and 21.9 (95% CI: 16.0, 28.3) months respectively for high and low hENT1 in the 5FU group, a non-significant difference (χ21 = 0.83, P = 0.362). Multivariate analysis confirmed hENT1 expression as a predictive marker in gemcitabine (Wald χ2 = 7.10, P = 0.008) but not 5-fluorouracil (Wald χ2 =0.34, P = 0.560) groups. Conclusions: The study supports use of gemcitabine in patients with high tumor hENT1 expression and 5-fluorouracil in patients with low hENT1.
Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.
Authors: Poplin Elizabeth , Wasan Harpreet , Rolfe Lindsey , Raponi Mitch , Ikdahl Tone , Bondarenko Ihor , Davidenko Irina , Bondar Volodymyr , Garin August , Boeck Stefan Hubert , Heinemann Volker , Bassi Claudio , Evans T. R. Jeffry , Voong Cynthia , Kaur Paramjit , Isaacson Jeffrey D. , Allen Andrew R. 
Published: March 2020

4007 Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.
A Bayesian network meta-analysis of systemic regimens for advanced pancreatic cancer.
Authors: Chan Kelvin K. , Coyle Doug , Cameron Chris , Lien Kelly , Ko Yoo-Joung 
Published: March 2020

4015 Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) in randomized control trials (RCTs). Few have been compared with each other directly in RCTs and the relative efficacy and safety among them are unclear. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Contorlled Trials and ASCO meeting abstracts up to Jan 2013 to identify RCTs that included metastatic pancreatic cancer comparing the following regimens: G, G+5-flourouracil (GF), G+capecitabine (GCap), G+S1 (GS), G+cisplatin (GCis), G+oxaliplatin (GOx), G+erlotinib (GE), G+Abraxane (GA) and FOLFIRINOX. Studies were reviewed by two authors and discrepancies were resolved by consensus or by a third author. Data including overall survival (OS), progression-free survival (PFS), response rate (RR), and side-effects were extracted. A Bayesian network meta-analysis with random effects was performed using WinBUGS to compare all regimens simultaneously. Results: Twenty-two studies involving 6,252 patients were identified, with 21 RCTs involving G, 4 with GF, 3 with GCap, 2 with GS, 6 with GCis, 3 with GOx, 1 with GE, 1 with GA and 1 with FOLFIRINOX. Median OS, PFS and RR for G arms from all trials were similar, suggesting the absence of significant clinical heterogeneity among RCTs. For OS, the results of the Bayesian network meta-analysis found that the probability that FOLFIRINOX was the best regimen was 71%, while it was 19% for GS, 7% for GA and 2% for GE respectively. The OS hazard ratio (HR) for FOLFIRINOX vs. GS was 0.82 (95% credible region (CR): 0.53-1.35), the OS HR for FOLFIRINOX vs. GA was 0.77 (95% CR: 0.51-1.23), and the OS HR for FOLFIRINOX vs. GE was 0.67 (95% CR: 0.45-1.08). Similar ranking and probabilities were observed for the best regimen for PFS. Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in OS and PFS when compared with GS, GA, or GE by indirect comparisons. In the absence of direct pairwise comparisons of these regimens from RCTs, network meta-analysis helps synthesize evidence and inform decision making.
25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303.
Authors: Van Loon Katherine , Owzar Kouros , Jiang Chen , Kindler Hedy Lee , Mulcahy Mary Frances , Niedzwiecki Donna , O'Reilly Eileen Mary , Fuchs Charles S. , Innocenti Federico , Venook Alan Paul 
Published: March 2020

4022 Background: Data from animal and cell line models suggest that vitamin D metabolism is important in pancreatic tumor maintenance and may contribute to this tumor’s chemoresistance. While vitamin D has been implicated in a variety of cancers, the prevalence of vitamin D deficiency among patients with advanced pancreatic cancer (APC) and the effect of baseline vitamin D levels on survival outcomes are unknown. Methods: CALGB 80303 was a randomized controlled trial of patients with APC which demonstrated no difference in OS among patients treated with gemcitabine (GEM) vs. GEM + bevacizumab. We retrospectively measured baseline serum 25(OH)D levels and examined associations between baseline 25(OH)D levels and selected patient characteristics. Using the Cox rank score test, we examined the association between 25(OH)D level and PFS and OS. The differences in the levels among racial populations were tested using the Kruskal-Wallis test. Results: Of 256 patients with available serum, the median 25(OH)D level was 21.7 (range 4–77). 44.5% of patients were vitamin D deficient (25(OH)D <20), 32.4% were insufficient (25(OH)D ≥20 and <30), and 23% were sufficient (25(OH)D≥30). Serum 25(OH)D levels were lower in patients self-reported as black compared to white patients and patients of other/undisclosed race (median 10.7 [4.0–36.3] vs. 22.4 [4.0–77.0] vs. 20.9 [12.6 – 31.8], respectively; p<0.00001). Adjusting for race, baseline 25(OH)D levels were not associated with PFS (HR 1.00, 95% CI 0.98–1.01) or OS (HR 1.00, 95% CI 0.99-1.01). Conclusions: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of APC. Black patients had significantly lower 25(OH)D levels than white patients. In this cohort of patients with APC receiving GEM-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.