bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of postoperative serum carcinoembryonic antigen (CEA) with disease-free survival in patients with stage III colon cancer: ACHIEVE phase III randomized clinical trial.
Authors: Kotaka Masahito , Manaka Dai , Eto Tetsuya , Hasegawa Junichi , Takagane Akinori , Nakamura Masato , Kato Takeshi , Munemoto Yoshinori , Nakamura Fumitaka , Bando Hiroyuki , Taniguchi Hiroki , Gamoh Makio , Shiozawa Manabu , Nishi Masayasu , Horiuchi Tetsuya , Mizushima Tsunekazu , Yamanaka Takeharu , Yoshino Takayuki , Ohtsu Atsushi , Mori Masaki 
Published: May 2020

4069 Background: ACHIEVE, as part of the IDEA collaboration, was a multicenter trial randomizing patients with stage 3 resected colon cancer to either 3 versus 6 months of adjuvant FOLFOX/CAPOX. We previously reported that the hazard ratios (HRs) in disease-free survival (DFS) of 3 versus 6 months duration according to risk stage (low-risk [T1-3 and N1] or high-risk [T4 or N2]) and regimen (FOLFOX or CAPOX) as well as in overall population were consistent with those observed in the whole IDEA. This study aimed to clarify the significance of post-operative serum carcinoembryonic antigen (CEA) on DFS in stage 3 colon cancer. Methods: Eligibility included post-operative serum CEA value of ≤10 ng/ml at registration in the ACHIEVE trial, which enrolled 1313 patients between 2012 and 2014, out of whom 1291 pts were the modified ITT (mITT) population and used in this study. The cutoff values of CEA analyzed for prognostic analyses were the median value (1.8 ng/ml) in the mITT, the upper limit of normal (ULN) level (5.0 ng/ml), and the half of ULN (2.5 ng/ml). The association of post-operative CEA with DFS were measured by Cox regression analyses. Results: Of the 3 cutoff values, the ULN (5.0 ng/ml) was associated with DFS more strongly than the median (1.8 ng/ml) or half of ULN (2.5 ng/ml), with a HR of 1.75 (95%CI, 1.24-2.46) (Table). The 99 patients (7.7%) were identified as the CEA > ULN and 1192 (92.3%) as < ULN. In univariate analysis, regimen (CAPOX or FOLFOX), ECOG PS (0 or 1), T factor (T1-3 or T4), N factor (N1 or N2-3) and CEA ( < ULN or > ULN) were significantly associated with DFS. Multivariate Cox regression identified CEA > ULN as an independent poor risk factor (HR = 1.45; 95%CI, 1.03-2.05). Shorter DFS in patients with CEA > ULN than in those with CEA < ULN was consistently observed in each subgroup of baseline factors, including treatment duration, regimen, age, gender, PS, T-stage, N-stage, no of lymph nodes examined, and tumor location; no interaction was observed between CEA and these factors. Conclusions: Post-operative serum CEA is also a strong prognostic factor for DFS in stage 3 colon cancer. Clinical trial information: 000008543 . [Table: see text]
Efficacy of third-line anti-EGFR-based treatment (tx) versus (vs) Regorafenib/TAS-102 (R/T) according to primary tumor site in RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts).
Authors: Vivolo Raffaella , Bria Emilio , Zurlo Ina Valeria , Bensi Maria , Dell'Aquila Emanuela , Anghelone Annunziato , Corsi Domenico C. , Caira Giulia , Santini Daniele , Ingrosso Diletta , Emiliani Alessandra , Calegari Maria Alessandra , Citarella Fabrizio , Pozzo Carmelo , Grande Roberta , Basso Michele , Tortora Giampaolo , Salvatore Lisa 
Published: May 2020

4082 Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, which a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to primary tumor site in third line. Methods: Pts affected by RAS/BRAF wt mCRC treated with third-line anti-EGFR-based tx or R/T were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to tumor site. Primary endpoint was PFS; secondary endpoints were OS and RR. PFS and OS analyses were performed using Kaplan-Meier method, and survival curves were compared using the log-rank test. RR was evaluated according to RECIST criteria and it was compared in the two groups using Fisher’s exact test. Statistical significance was set at p = 0.05 for a bilateral test. Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 76 RAS/BRAF wt mCRC pts, treated with third-line anti-EGFR-based tx or R/T, were enrolled. Of those, 19 (25%) pts had R-sided tumor (9 pts received anti-EGFR tx and 10 pts received R/T) and 57 (75%) pts had L-sided tumor (30 pts received anti-EGFR tx and 27 pts received R/T). As shown in the table, a significant PFS and OS benefit in favor of anti-EGFR tx vs R/T was observed in L-sided pts, while no difference both in PFS and OS was observed in R-sided pts. RR was significantly higher in L-sided pts treated with anti-EGFR vs R/T, no difference was shown in R-sided pts. At the multivariate analysis, tx regimen was indipendently associated with PFS in L-sided pts, but not in R-sided pts. Conclusions: Our study confirmed the results deriving from the retrospective analysis of the phase III study 20020408. Our results demonstrated a different benefit from third-line anti-EGFR tx according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T, while no difference was observed in R-sided tumors. [Table: see text]
Predictive and prognostic value of HER2 gene expression and HER2 amplification in patients with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).
Authors: Battaglin Francesca , Ou Fang-Shu , Qu Xueping , Bertagnolli Monica M. , Hochster Howard S. , Niedzwiecki Donna , Goldberg Richard M. , Mayer Robert J. , Zemla Tyler J. , Blanke Charles David , Venook Alan P. , Kabbarah Omar , Lenz Heinz-Josef , Innocenti Federico 
Published: May 2020

4086 Background: The randomized phase III CALGB/SWOG 80405 trial found no difference in overall survival (OS) in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. We investigated the potential prognostic and predictive value of HER2 amplification and HER2 gene expression using NGS and Nanostring data. Methods: Primary tumor DNA from 559 patients (pts) was profiled for HER2 amplification by NGS (Foundation One). Tumor tissue from 925 pts was tested for Nanostring gene expression using an 800 gene panel. OS and progression free survival (PFS) were the endpoints as time-to-event variables. Cox proportional hazard models with gene expression fitted with linear spline (one internal knot at median) were used, adjusting for pts baseline characteristics, treatment assignment, and molecular features (microsatellite instability, BRAF, all RAS). Results: Of 505 tumors with both NGS and Nanostring data, 16 harbored HER2 amplification (copy number variation > 6), limited to microsatellite stable tumors and significantly associated with HER2 expression ( P < 0.001) and wild-type RAS ( P = 0.036). HER2 amplification was neither prognostic nor predictive for OS or PFS. Conversely, HER2 expression higher than median was associated with longer PFS ( P = 0.018) but not OS ( P = 0.13). Among pts with HER2 not amplified, higher HER2 expression was associated with better OS (hazard ratio [HR], 0.83; 95%CI, 0.72-0.97; P = 0.016) and PFS (HR, 0.85; 95%CI, 0.74-0.98; P = 0.027) when the expression was less than median. Additionally, in pts with no HER2 amplification and HER2 expression lower than median, treatment with Cet was associated with worse PFS compared to Bev (HR, 1.46; 95%CI, 1.12-1.90; P = 0.005). This effect was not observed with expression higher than median regardless of HER2 amplification status. Conclusions: To our knowledge, this is the largest analysis of HER2 amplification and gene expression in mCRC pts treated with standard therapy. Our results provide novel insight on the predictive and prognostic value of HER2 gene expression in pts treated with Cet- and Bev-based regimens. Upon validation, these findings could inform pts selection and the design of more effective treatment options for pts with low HER2 expression. Clinical trial information: NCT00265850.
Utilization of adjuvant chemotherapy in “ideal candidates” with stage III colon cancer.
Authors: Soleja Mohsin , Goksu Suleyman Yasin , Sanford Nina Niu , Beg Muhammad Shaalan , Kainthla Radhika , Sanjeevaiah Aravind , Jones Amy Little , Farkas Linda , Verma Udit , Hsieh David , Kazmi Syed Mohammad Ali 
Published: May 2020

4103 Background: Prior studies have observed under-utilization of adjuvant chemotherapy (ACT) in stage III colon cancer. Our aims were to observe the rate of utilization of ACT in very healthy or “ideal candidates”, identify reasons for omission and socioeconomic factors associated with ACT use, and observe patient outcomes. Methods: We queried patients from the National Cancer Database (NCDB) with stage III colon cancer, age<65, and Charlson-Deyo score of 0 who underwent resection in the United States between 2004-2015. Patients who received ACT were compared to patients who had surgery only (SO). We used chi-square test for categorical variables, Kaplan-Meier and Cox regression method for survival analyses. Results: Out of 243,388 stage III colon cancer patients during the study time, a total of 49,046 patients met the specific criteria of “ideal candidate”. Out of these, 88.5% received ACT and 11.5% underwent SO. The primary reason for chemotherapy omission was: no reason given (54.2%), patient/guardian refusal (26.7%), physician recommended against (9.3%), patient died (3%), unknown (6.7%). Patients who received ACT were more likely to be female, non-Hispanic white, have a higher level of education, travel shorter distance for cancer treatment, have private insurance or higher income as compared to counterpart ( all p<.001). Patients who received ACT had significantly better overall survival (5-year survival rate 74% vs. 54%, p<.001). This persisted after multivariable Cox regression analysis [HR:0.48 (CI:0.45-0.50), p<.001]. Conclusions: We observed a high rate of utilization (88.5%) of ACT in patients with stage III colon cancer who were under age 65 and without comorbidities. However, the omission of chemotherapy in this population remains a problem, partially due to patient refusal. Socioeconomic factors associated with lower utilization were primarily related to insurance status (private vs non-private). Patients who received ACT had significantly improved survival as compared to SO group. [Table: see text]
Pharmacokinetically-guided preoperative FOLFOX chemotherapy for locally advanced colon cancer patients.
Authors: Ceniceros Lucia , Baixauli Jorge , Aldaz Azucena , Arredondo Jorge , Pastor Carlos , Chopitea Ana , Granero Lucia , Martinez Patricia , Ponz-Sarvisé Mariano , Lapuente Fernando Manuel , Hernandez-Lizoain Jose Luis , Rodriguez Javier 
Published: May 2020

4104 Background: Preliminary results from ongoing randomised trials suggest that neoadjuvant chemotherapy (NAC) may be an alternative approach to conventional adjuvant therapy. We assessed the feasibility and activity of incorporating a pharmacokinetically (PK) guided dose adjustment of 5-FU within preoperative Folfox. Methods: Radiologically staged LACC pts, T4 or T3 with extramural depth >5mm beyond the muscularis propia, were planned to receive 4-6 biweekly cycles of Oxalipatin (85mg/m²), Leucovorin (400 mg/m²), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m² in 46h and subsequent cycles tailored according to PK monitoring in order to reach a target 5-FU area under the curve (AUC) between 20-30 mg∙h∙L-1). Dihidrouracil deshidrogenase was determined before the first cycle in order to detect pts with 5-Fu intolerance. Three serum samples were obtained during the 5-Fu infusion in the first two cycles. Pathological tumor regression was graded according to the MSKCC classification and toxicity to the NCI-CTCAE 4.0. Results: From June 2012 to August 2017, 45 pts (M/F: 35/10; median age 63) with LACC (T3: 66.7%; T4: 31.1%; T2: 2.2%; N+:66.6%) were evaluated. Median dose of 5-FU was 4500 mg. 48.9% of the pts required a 5-FU dose increase to reach the target AUC. Side effects profile included G3 neutropenia (3 pts), G2 diarrhea (2 pts) and G2 asthenia (9 pts). NAC was discontinued in 3 pts due to small bowell obstruction requiring surgery (no progressive disease during NAC). R0 resection rate was 100% (93.3% laparoscopy-assited). MSKCC score included grades 4, 3+ and 3 in 11.1%, 26.7% and 28.9% of pts, respectively. A complete pathological response was found in 5 pts (11.1%). Median number of harvested nodes was 16 (7-51), 80% ypN0. Those pts with AUC 25-30 had a 3-fold higher likelihood of achieving a MSKCC 3, 3+ and 4 responses. Median time to hospital discharge was 7 days (range 4-22). After a median follow-up of 60 months (44-66), 5-year actuarial PFS is 88.8%. Conclusions: Preoperative PK-adjusted FOLFOX in LACC pts is safe and well tolerated, achieving remarkable rates of major pathological responses and R0 resections.
Tumor-informed assessment of molecular residual disease and its incorporation into practice for patients with early and advanced-stage colorectal cancer (CRC-MRD Consortia).
Authors: Kasi Pashtoon Murtaza , Dayyani Farshid , Morris Van K. , Kopetz Scott , Parikh Aparna Raj , Starr Jason Scott , Cohen Stacey , Grothey Axel , Lieu Christopher Hanyoung , O'Hara Mark H. , Loranger Kate , Westbrook Laura , Sharma Shruti , Krinshpun Shifra , Hook Nicole , Zimmermann Bernhard , Billings Paul R. , Aleshin Alexey 
Published: May 2020

4108 Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p<0.0001 Chi-square: 70.33). Additionally, in patients with radiologically measurable active metastatic disease, ctDNA detection rate was 100%. On the contrary, patients with advanced/metastatic disease who had partial response to treatment or no evidence of disease (NED) showed 28.5% and 19.2% of ctDNA-positivity, respectively. Conclusions: This is the first large, real-world study reporting on the results from a clinically validated MRD assay. For the first time we delineate MRD rates and quantify ctDNA concentration in patients with early-stage and advanced CRC. Furthermore, we provide an initial readout that effective ongoing treatment in patients with CRC may be correlated with ctDNA clearance. Ongoing analysis expanded to a cohort of 1200 clinical cases including correlation with genomic and serial testing will be presented. [Table: see text]
Patient and tumor characteristics as determinants of overall survival (OS) in BRAF V600 mutant (mt) metastatic colorectal cancer (mCRC) treated with doublet or triplet targeted therapy.
Authors: Ros Montañá Javier , Martini Giulia , Baraibar Iosune , Villacampa Guillermo , Comas Raquel , Ciardiello Davide , Garcia Ariadna , Hernandez Yague Xavier , Queralt Bernardo , Salud Salvia Antonieta , Argiles Guillem , Cuadra Jose Luis , Toledo Rodrigo A , Chicote Irene , Mulet Nuria , Vivancos Ana , Palmer Hector G. , Dienstmann Rodrigo , Tabernero Josep , Elez Elena 
Published: May 2020

4112 Background: BRAF V600 mt mCRC is an aggressive disease with poor OS under standard chemotherapy. Treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+ antiEGFR+/- MEK inhibitor, has been shown to improve outcomes. Prognostic factors in this targeted treated population remain to be studied. Methods: Prospective international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. Univariate Cox models for OS were constructed and the strongest predictors in stepwise variable selection were used to develop a prognostic score. The final multivariate model with selected predictors was stratified by prior lines. Results: In total, 42 patients were enrolled. Median age 60.7 y (33-83), 61% female, 61% right-sided tumors, 26% received 2 or more prior chemotherapy lines. One patient (2.6%) achieved complete response and 36% had partial response with median follow-up of 14.3 months. Median progression-free survival was 5.5 months (CI95% 4.4-10.4) and median OS (mOS) was 10.7 months (CI95% 8.4-22.1). In univariate models, ECOG performance status (1 vs 0), CEA levels (high - > 3.5 ng/mL- vs low - < 3.5 ng/mL), CA 19.9 (high vs. low), LDH (high vs. low), number of metastatic sites and presence of liver metastasis were significant prognostic factors. On the other hand, MSI status and peritoneal or nodal metastasis did not associate with outcome. In multivariable model, strongest determinants of OS were ECOG and baseline CEA levels. If high-risk for both factors (ECOG 1 and CEA high, 46% of the patients), mOS was 5.6 months (CI95% 4.2-NA); if intermediate-risk (either ECOG 1 or CEA high, 33%), mOS was 13.5 months (CI95% 10.6-NA); if low-risk (ECOG 0 and CEA low, 21%), mOS not reached (CI95% 16.5-NA). Differences between intermediate- and high-risk prognostic groups compared to low-risk were significant (HR = 5.9, p = 0.03; and HR = 25.9, p < 0.001, respectively). Conclusions: Patients characteristics such as ECOG and surrogates of tumor burden like CEA levels remain important OS determinants in BRAF V600 mt mCRC treated with doublet or triplet targeted therapy. In fact, there are not prognostic scores regarding BRAF mt mCRC treated with targeted therapies. Our study suggests that these prognostic factors may be considered as stratification factors in future clinical trials.
The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE-061.
Authors: Fuchs Charles S. , Özgüroğlu Mustafa , Bang Yung-Jue , Di Bartolomeo Maria , Mandalà Mario , Ryu Min-hee , Vivaldi Caterina , Olesinski Tomasz , Caglevic Christian , Chung Hyun Cheol , Muro Kei , Van Cutsem Eric , Kobie Julie , Cristescu Razvan , Aurora-Garg Deepti , Lu Jia , Shih Chie-Schin , Adelberg David , Cao Z. Alexander , Shitara Kohei 
Published: May 2020

4512 Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma with tumor progression after first-line therapy (N =592). We explored the association of tissue tumor mutational burden (tTMB) status and clinical outcomes in patients with GC enrolled in KEYNOTE-061, including the relationship with PD-L1 combined positive score (CPS) and microsatellite instability-high (MSI-H) status. Methods: In patients from KEYNOTE-061 with evaluable tumor and matched normal whole exome sequencing (WES) data (N = 420; pembrolizumab, 218; paclitaxel, 202), the association of tTMB (continuous log10 scale) with confirmed ORR and PFS by blinded central radiology review per RECIST v1.1, and OS was evaluated within each treatment arm using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS). The clinical utility of tTMB was assessed using the prespecified cutoff of 175 mut/exome. Clinical data cutoff: October 26, 2017. Results: tTMB was significantly associated (α=0.05) with ORR, PFS, and OS in patients treated with pembrolizumab (one-sided P<0.001) but not paclitaxel (two-sided P>0.600). The area under the receiver operating characteristics curve for tTMB and response (pembrolizumab vs paclitaxel) was 0.68 (95% CI, 0.56-0.81) vs 0.51 (95% CI, 0.39-0.63). Patient outcomes by tTMB cutoff are reported in Table. There was low correlation between tTMB and PD-L1 CPS in both treatment arms (r<0.18). tTMB remained significantly associated with all clinical end points with pembrolizumab after adjusting for PD-L1 CPS and with PFS and OS after excluding MSI-H patients. Conclusions: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and response to pembrolizumab in patients with GC. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. Clinical trial information: NCT02370498 . [Table: see text]
Evaluation of spatiotemporal heterogeneity of PDL1 expression in gastroesophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy.
Authors: Zhou Katherine I. , Peterson Bryan , Serritella Anthony , Reizine Natalie , Wang Yan , Catenacci Daniel V.T. 
Published: May 2020

4528 Background: PDL1 expression is a predictive marker for response to anti-PD1/PDL1 agents (IO) for GEA. As a prognostic biomarker, data are conflicting. Molecular heterogeneity of various biomarkers for GEA has been established. To characterize heterogeneity of PDL1 expression and its clinical relevance, we compared PDL1 expression in primary (10) and metastatic (met) tumors of newly diagnosed stage IV advanced GEA (aGEA), and before and after chemotherapy treatment (tx) for stage II–IV GEA. We assessed the prognostic relevance of PDL1 expression in aGEA. Methods: We retrospectively reviewed a cohort of 130 patients (pts) diagnosed with GEA in 2013–2019, with a total of 328 tumor samples with PDL1 expression data. PDL1 was defined as positive if combined positive score (CPS) was ≥1 using the 22C3 pharmDx assay. Analysis was performed by McNemar’s test for paired PDL1 and univariate Cox proportional-hazards model for overall survival (OS). Results: Of 328 tumors, 45% were PDL1+ and 55% PDL1-. CPS ranged 0–100 (median 1, IQR 0–5), and CPS was ≥10 for 19% of tumors. Concordance between PDL1 status of paired baseline 10 and baseline met tumors was 63% (32/51) (Table). Of 31 PDL1+ baseline 10 tumors, 52% (16/31) had PDL1- paired baseline met tumors, while of 20 PDL1- baseline 10 tumors, only 15% (3/20) had PDL1+ paired baseline met tumors. Only 35% (18/51) of met tumors were PDL1+, compared to 61% (31/51) PDL1+ 10 tumors ( p< 0.003). Post-tx tumors exhibited 62% (46/74) concordance of PDL1 status compared to pre-tx 10 tumors. Of 43 PDL1+ baseline tumors, 35% (15/43) were PDL1- post-tx; of 31 PDL1- baseline tumors, 42% (13/31) were PDL1+ post-tx ( p= 0.71). In pts with aGEA at diagnosis, OS did not significantly differ depending on baseline 10 tumor PDL1 status (median OS of 17.9 [95% CI 14.6–26.5] months for PDL1- and 16.7 [12.0–26.3] months for PDL1+; p= 0.6), nor depending on baseline met PDL1 status. Conclusions: PDL1 expression demonstrated notable baseline discordance between 10 and met tumors, particularly directional from PDL1+ 10 tumor to PDL1- met. Discordance before and after chemotherapy was also observed, but with similar proportions of PDL1+ pre-tx and post-tx tumors. These findings may have predictive IO therapeutic implications if confirmed in larger independent analyses. [Table: see text]