bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated centralized MDT resectability assessment during first-line treatment in 1086 Finnish metastatic colorectal cancer (mCRC) patients nationwide (prospective RAXO study).
Authors: Osterlund Pia J. , Kallio Raija Sinikka , Kellokumpu Ilmo , Soveri Leena-Maija , Ålgars Annika , Salminen Tapio , Murashev Maija-Leena , Lamminmaki Annamarja , Halonen Päivi , Ristamäki Raija , Lantto Eila , Ovissi Ali , Nordin Arno , Aroviita Laura , Jekunen Antti Pekka , Lindvall-Andersson Renee , Nyandoto Paul , Kononen Juha Teppo , Poussa Tuija , Isoniemi Helena ,   The RAXO Study Group
Published: May 2019

3517 Background: Resection of oligometastatic mCRC is curable in up to half and is probably underused in real-life oncology practice. In 2011, a prospective nationwide centralized evaluation of resectability was initiated to assess upfront and conversion to resectability. Methods: The RAXO-study included 1086 mCRCs referred for oncological treatments at all 21 Finnish oncology units (40% of eligible mCRCs in Finland). The MDT at Helsinki tertiary referral center (TRC) assessed resectability of liver, lung and other metastases upfront and twice during first-line therapy. Resectability evaluation was provided online and resections were performed according to clinical praxis, with major resections at TRCs. Results: Median age was 66.5 (range 24-90) yrs, 60% males, ECOG was 0 in 295 (27%), 1 in 600 (55%) and 2-3 in 191 (18%). Tumor was right-sided in 310 (29%), left in 769 (72%) and multiple in 7 (.6%). In the MDT assessment, 435 (40%) were considered resectable, 28% upfront and 12% after conversion. Resections or local ablative therapy were performed in 396 (91% of resectable, R0-1 in 74% and R2 in 17%), with 368 liver-, 91 lung- and 96 other operations. One metastatic site (n = 407), 2 (n = 369) and 3-6 (n = 310) were or became resectable in 65, 33 and 15%, respectively, and R0-1 resected in 54, 30 and 6%, respectively (P < 0.001). In multivariate analysis age < 66.5 (OR 1.51), ECOG 0 (OR 2.40); left-sided primary (OR 1.55), metachronous metastases (OR 1.49), 1-2 metastatic sites (OR 1.86) increased R0-1 resection rates; whereas primary/relapse in situ (OR 0.49), metastases in lung (OR 0.22), peritoneum (OR 0.30) or lymph nodes (OR 0.23) decreased R0-1 rates (P < 0.05). In univariate analyses BRAF wt (OR 0.34), normal CEA (OR 0.31) or normal Ca19-9 (OR 0.45) associated with R0-1 rates. Median OS was 2.4 yrs (CI95% 2.3-2.6) in all, 6.7 yrs in R0-1 (HR 0.15; CI95% 0.11-0.19), 2.8 yrs in R2 (0.50; 0.36-0.68) and 1.7 yrs in non-resected (reference group). Median PFS was 1.1 yrs (1.0-1.1) in all patients, 2.4 yrs in R0-1 (0.24; 0.20-0.28), 1.4 yrs in R2 (0.55; 0.42-0.71) and 0.8 yrs in non-resected patients. P < 0.001 for all comparisons. Conclusions: Repeated centralized MDTs in real-life mCRC patients show high resectability (40%) and resection rates (36%), even if multiple metastatic sites are present. Curative resection associates with good survival. Clinical trial information: NCT01531621.
Prognostic value of tumor deposits for disease free survival in patients with stage III colon cancer: A post hoc analysis of IDEA France phase III trial (PRODIGE-GERCOR).
Authors: Delattre Jean Francois , Cohen Romain , Henriques Julie , Falcoz Antoine , Emile Jean-François , Fratte Serge , Chibaudel Benoist , Dauba Jérôme , Dupuis Olivier Jean Marie , Bécouarn Yves , Bibeau Frédéric , Taieb Julien , Andre Thierry , Vernerey Dewi , Svrcek Magali 
Published: May 2019

3519 Background: Tumor deposits (TDs) are isolated tumor foci in the pericolic, perirectal or mesocolic fat without residual lymph node (LN) tissue. TDs seem to impact the prognosis of stage III colon cancer (CC) patients (pts) but are only considered in TNM staging in the absence of LN metastases (LNM). We aimed at evaluating the prognosis value for disease free survival (DFS)of TDs in International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France phase III study (NCT00958737) that compared 3 versus 6 months of adjuvant FOLFOX or CAPOX for stage III CC pts. Methods: All pathological reports of pts included in IDEA France trial were retrospectively analyzed. DFS according to the presence or absence of TDs was evaluated using Kaplan-Meier estimator. Multivariable Cox model analysis was performed to evaluate the association between TDs and DFS. This analysis did not included immunohistochemical biomarkers. Results: Among the 2022 pts included in IDEA France study, 1942 (96%) were analyzed. 80 pts were excluded: no pathological report (n = 68), pts without treatment (n = 12). TDs were found in 184 pts (9.47%), of whom 74 with N1a/b (40%), 55 with N1c (30%) and 55 with N2 LN stage (30%). All characteristics were similar according to the presence of TDs, except for tumor/node (TN) stage (T4 and/or N2 are more frequent in pts with TDs; p = .0046). The 3-year DFS rates were 65.59% [95% confidence interval (95%CI) 58.04-72.12] and 74.71% [95%CI 72.57-76.71] for pts with and without TDs, respectively (p = 0.0079). In multivariable analysis, TDs were associated with higher risk of recurrence or death (hazard ratio (HR) = 1.36, 95%CI 1.05-1.75, p = .0201), as well as T4 and/or N2 (HR = 2.21, 95%CI 1.03-1.59, p < .001), 3 months of adjuvant treatment (HR = 1.29, 95%CI 1.09-1.52, p = .0029), obstruction (HR = 1.28, 95%CI 1.03-1.59, p = .0233) and male (HR = 1.24, 95%CI 1.04-1.46, p = .0151). Adding TDs count to the LNM count, 35 out of 1454 N1a/b/c CC pts (2.4%) were reclassified as N2 and experienced worse 3 years DFS than confirmed N1 CC pts (p = .0151). Conclusions: TD is an independent and valuable prognostic factor for DFSin stage III CC pts and should be considered whatever the LNM status.
The role of maintenance strategy in metastatic colorectal cancer (mCRC): A systematic review and meta-analysis.
Authors: Sonbol Mohamad Bassam , Mountjoy Luke , Firwana Belal , Almader-Douglas Diana , Mody Kabir , Hubbard Joleen Marie , Borad Mitesh J. , Ahn Daniel H. , Murad M. Hassan , Bekaii-Saab Tanios S. 
Published: May 2019

3524 Background: In mCRC, induction combination chemotherapy with targeted agents is considered the mainstay of treatment. This is typically followed by maintenance therapy vs. observation which had been examined in various trials. However, it remains unclear how best optimize maintenance strategy. We aim to evaluate comparative effectiveness to support best maintenance strategy. Methods: We searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials (RCT) evaluating different maintenance strategies in previously untreated mCRC patients (pts): observation (obs), bevacizumab (bev), fluoropyrimidine (FP), FP+bev, or continuing induction regimen (CTX). Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Results: Twelve trials at low risk of bias (5540 pts) were included. Network meta-analysis shows no benefit of CTX over obs in terms of PFS (HR 0.7; 95% CI 0.46-1.09) and OS (HR 0.95; 95% CI 0.85-1.07). Compared to obs, maintenance therapy shows PFS benefit (HR 0.58; 95% CI 0.43-0.77) with only a trend in OS (HR 0.91; 95% CI 0.83-1.009). All maintenance strategies (FP, FP+bev, and bev) show significant improvement in PFS over obs. On SUCRA analysis, maintenance treatment (FP or FP+bev) has the highest likelihood of achieving better PFS (67.1% for FP and 99.8% for FP+bev) and OS (81.3% for FP and 73.2% for FP+bev). Conclusions: A maintenance strategy with at least a FP with or without the addition of bevacizumab is preferred. However, given the lack of a clear OS benefit, obs is an acceptable alternative. Optimal maintenance strategies should be dependent on factors including patient preferences, cost and toxicities. [Table: see text]
Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence: Results of an accent meta-analysis of seven studies.
Authors: Taieb Julien , Pederson Levi , Shi Qian , Alberts Steven R , Wolmark Norman , Van Cutsem Eric , De Gramont Aimery , Kerr Rachel , Grothey Axel , Lonardi Sara , Yoshino Takayuki , Yothers Greg , Andre Thierry 
Published: May 2019

3525 Background: Microsatellite instable/deficient mismatch repair (MSI) metastatic colorectal cancers have been reported to be of poor prognosis. The interaction between MSI and BRAFV600E mutation complicates the picture. Methods: Patients with resected stage III CC from 7 studies with disease recurrence and data available for MSI and BRAFV600E status were analyzed. The primary endpoint was survival after recurrence (SAR) to assess the prognostic roles of MSI and BRAFV600E, respectively. Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features (data collected 12/1998 to 11/2009). Results: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI tumors (n = 220) had significantly better SAR (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.69-0.98; P = .029) than patients with microsatellite stable /proficient MMR (MSS) tumors (n = 1766). This was also observed when looking at patients treated by the standard FOLFOX adjuvant regimen only (aHR, 0.76; 0.58-1.00; P = .048). Same trends were observed when looking at MSI/dMMR patients outcome in BRAFV600E wild-type (aHR, 0.84; P = .10) and mutant (aHR, 0.88; P = .43) subgroups separately, without reaching statistical significance. As previously described poor SAR was observed in BRAFV600E mutants vs wild type patients (n = 244; aHR, 2.06; 95% CI, 1.73-2.46; P < .0001) and this was also true in BRAFV600E mutants MSI/dMMR patients (n = 77, aHR, 2.65 ; 95% CI, 1.67-4.21; p < .0001). Other factors associated with a poor SAR were : olderage, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence (by 1y increase). Conclusions: In stage III colon cancer patients recurring after adjuvant chemotherapy and before the era of immuno-oncologic agents, MSI/dMMR was associated with a better survival compared to MSS. BRAFV600E mutation seems to be a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.
Genomic alterations after EGFR blockade in patients with RAS wild-type metastatic colorectal cancer: Combined tissue and blood-based analysis from SCRUM-Japan GI-SCREEN and GOZILA.
Authors: Nakamura Yoshiaki , Yamashita Riu , Okamoto Wataru , Narita Yukiya , Komatsu Yoshito , Kagawa Yoshinori , Takahashi Naoki , Esaki Taito , Kato Takeshi , Sunakawa Yu , Denda Tadamichi , Nishina Tomohiro , Takashima Atsuo , Kobayashi Takaaki , Shiozawa Manabu , Oki Eiji , Satoh Taroh , Adachi Yuta , Odegaard Justin , Yoshino Takayuki 
Published: May 2019

3528 Background: Anti-EGFR therapy (tx) in RAS wild-type (wt) metastatic colorectal cancer (mCRC) induces resistance through acquired genomic alterations. We aimed to define such alterations in Nationwide Cancer Genome Screening Project tissue and blood specimens, using next generation sequencing (NGS). Methods: Tumor specimens in patients (pts) with RAS wt mCRC were obtained from SCRUM-Japan GI-SCREEN (tissue) and GOZILA (circulating tumor DNA [ctDNA] from blood). Genomic alterations were compared using the Oncomine Comprehensive Assay (SCRUM) and Guardant360 (GOZILA), before anti-EGFR tx and after progression. Results: 373 total actionable alterations were identified in 71 pts with available matched tissue and ctDNA; 255 (68%) were acquired after anti-EGFR tx progression. Frequently seen acquired oncogenic alterations included KRAS mutations (27%) and amplifications (amps) of EGFR (41%), CDK6 (24%), BRAF (20%), MYC (17%), MET (14%), PIK3CA (11%), FGFR1 (11%), and KRAS (10%). Fusions of RET, ALK, and FGFR3 were newly acquired in 1-4%. Acquired alterations co-arose in multiple pathways, including the cell cycle, PI3K-AKT, and MAPK, although 29% of pts had none. Acquired mutations were less frequently clonal versus primary mutations (p<0.0001), but clonal acquired mutations were seen in several oncogenes, including EGFR, KRAS, and PIK3CA. A subset of acquired KRAS, MET, CCND2, and EGFR amps had high (>7) adjusted plasma copy numbers (ApCN). Acquired ERBB2 amps were identified in 3 pts (4%) with a median ApCN of 4, one of whom (ApCN=4.2), treated with dual HER2 blockade, progressed after 2 cycles. Conclusions: Our integrated analysis revealed that anti-EGFR tx of pts with RAS WT mCRC led to acquired genomic alterations in multiple oncogenic pathways. Although most acquired alterations were subclonal, a subset of oncogenic alterations had relatively high clonality and ApCN, suggesting potential targets for overcoming acquired resistance to anti-EGFR tx. Early progression in a pt with an ApCN of 4.2 suggests low-level/subclonal acquired alterations may not be effective treatment targets.
Intratumoral CD3+ and CD8+ T-cell densities in patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC) receiving programmed death-1 (PD-1) blockade.
Authors: Chakrabarti Sakti , Huebner Lucas J. , Finnes Heidi Diann , Muranyi Andrea , Singh Shalini , Clements June , McWilliams Robert R. , Hubbard Joleen Marie , Shanmugam Kandavel , Sinicrope Frank A. 
Published: May 2019

3532 Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3+ and CD8+ T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3+ and CD8+ TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (< or > 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3+ and CD8+ TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for > 12 months; differences were greatest for CD8+ CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3+ and CD8+ TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]
RAS-amplified colorectal cancers: Microsatellite stability status, RAS/BRAF mutations, and prediction of anti-EGFR resistance.
Authors: Schrock Alexa Betzig , Sandhu Jaideep Singh , Wang Chongkai , Ouyang Ching , Miller Vincent A. , Ali Siraj Mahamed , Fakih Marwan 
Published: May 2019

3533 Background: Pre-clinical models implicate RAS amplifications ( RASa) as a mechanism of resistance to anti-Epidermal Growth Factor Receptor (EGFR) therapies. Yet, there is little guidance on the impact of RASa, as identified by next generation sequencing (NGS), on anti-EGFR response. Methods: We investigated the Foundation Medicine (FM) database for RASa in CRC and characterized this population based on patient (pt) characteristics and other concurrent genomic alterations. We subsequently investigated City of Hope (COH) mCRC molecular data set (using FoundationOne) and described the RASa population characteristics and response to anti-EGFR. Results: FM cohort included 21,315 CRC unique pt cases. 365 (1.5%) pts had RASa, of which 123 (0.6%) had ≥ 20 copy number (CN) ( RASa≥20). The incidence of MSI-H, RAS and BRAF short variant mutations in the overall, RASa, and RASa≥20 populations were (MSI-H: 5%, 0%, 0%), ( RAS: 54%, 32%, 2%), and ( BRAF: 6%, 1%, 0%), respectively. Copy number variation inversely correlated with likelihood of RAS mutation. COH cohort included 396 mCRC. 13 pts (3.3%) had RASa. The median RAS CN was 25 (7 - 79); 8/13 pts had RASa≥20. All but 3 COH pts with RASa had a RAS/BRAF-WT tumors. Pts with concurrent RAS mutations had relatively low RAS CN (7, 8, &13). Tumors with RASa were predominantly left-sided (12/13). 7/13 pts were treated with anti-EGFR therapy. All 7 pts were RAS/ BRAF wild-type: 6 left-sided; 3 pts 1st/2nd lines (1 pt oxaliplatin-based and 2 pts irinotecan-based) and 4 pts chemo-refractory (all irinotecan-based). All 4 chemo-refractory pts had RASa≥20and progressed on anti-EGFR on 1st post-treatment CT (PFS in all pts ≤ 3 mo). One 1st line pt had SD (PFS = 4 mo). One 2nd line pt had SD (PFS = 7 mo) and one had PD as best response. Conclusions: NGS identifies RASa and RASa≥20in 1.5% and 0.6% of CRC, respectively. RASa≥20 tumors are MSS and, generally lack RAS/ BRAF mutations, and predict for resistance to anti-EGFR. This supports the potential relevance of 20-CN cut-point for the exclusion of pts from anti-EGFR. These findings would benefit from additional validation from retrospective analyses of completed prospective anti-EGFR clinical trials.
Impact of gender on the safety profile of chemotherapy plus bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Zucchelli Gemma , Moretto Roberto , Schirripa Marta , Intini Rossana , Rossini Daniele , Santini Daniele , Pizzo Claudio , Antoniotti Carlotta , Borelli Beatrice , Marmorino Federica , Urbano Federica , Burgio Valentina , Libertini Michela , Prisciandaro Michele , Buonadonna Angela , Bustreo Sara , Allegrini Giacomo , Ricci Vincenzo , Cremolini Chiara , Falcone Alfredo 
Published: May 2019

3534 Background: Based on retrospective experiences, gender seems to affect the safety profile of chemotherapy (CT), with a higher incidence of CT-related adverse events (AEs) among females than males. Here we focus on the impact of gender on the toxicity of FOLFOXIRI/bevacizumab (bev) as compared with doublets (FOLFOX or FOLFIRI)/bev in two randomized phase III studies by GONO: TRIBE and TRIBE2. Methods: The risk of experiencing CT-related AEs in males and females was estimated in univariable analysis in the overall safety population and according to treatment arms (doublets/bev and FOLFOXIRI/bev). In order to assess the independent weight of gender on the risk of developing AEs, multivariable logistic regression models were built. Results: Among 1187 patients enrolled in TRIBE and TRIBE2 studies, 1176 (684 males, 58%, and 492 females, 42%) were included in the safety population. Overall, women had a significantly higher risk of CT-related AEs, in particular gastrointestinal and hematologic AEs, asthenia and alopecia, independently of the treatment arm. The risk of CT-related AEs was increased with FOLFOXIRI/bev vs doublets/bev independently of gender (p for interaction: 0.329). Notably, among women treated with FOLFOXIRI/bev 50% and 68% experienced any grade of vomiting and nausea, respectively. Conclusions: Female mCRC patients have a higher risk to develop CT-related AEs. In women treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis. [Table: see text]
A randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic colorectal cancer metastasectomy (LICC): Final results.
Authors: Schimanski Carl Christoph , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Voehringer Matthias , Oellinger Robert , Lordick Florian , Heinemann Volker , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Schoen Michael R. , Greil Richard , Smith-Machnow Victoria , Schmidtmann Irene , Moehler Markus Hermann 
Published: May 2019

3537 Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L-BLP25 or placebo. L-BLP25 930 µg was administered as 8 weekly subcutaneous doses followed by 6 week maintenance intervals until recurrence or a maximum of 2 years. Cyclophosphamide 300 mg/m2 (CP) or matching saline (NS) was given intravenously 3 days prior to first L-BLP25/placebo. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS), secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. Differences in RFS and OS were analyzed with exploratory log-rank tests on the intention-to-treat population. Results: Of 121 pts enrolled between Oct 2011 and Dec 2014, 79 pts received L-BLP25+CP, 42 placebo+NS. Baseline characteristics were well balanced. Median age was 60 years. Median RFS was 6.1 (90% CI: 5.8-8.8) vs. 11.4 months (90% CI: 5.0-20.3) and estimated 3-year OS rate 69.1% vs. 79.1% for L-BLP25 and placebo, respectively. Two-factorial Cox regression models showed no impact of MUC1 expression or treatment on RFS or OS. The most common L-BLP25-related grade 3/4 adverse events were diarrhea, anemia and back pain. There was one death in the L-BLP25 arm due to Merkel cell carcinoma assessed by the investigator as being potentially related to vaccination. Conclusions: The LICC trial failed to meet its primary endpoint of significantly improving RFS and OS with L-BLP25. MUC1 expression was not associated with outcome. Clinical trial information: NCT01462513.