bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characteristics and prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX.
Authors: Lee Dae-Won , Han Sae Won , Lee Hyun Jung , Rhee Ye-Young , Bae Jeong Mo , Cho Nam-Yun , Lee Kyung-Hun , Kim Tae Yong , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kang Gyeong Hoon , Kim Tae-You
Published: March 2020

3550

Background: There have been controversies in prognostic impact of mucinous histology in colorectal cancer (CRC) and its implication in pts treated with adjuvant FOLFOX is unclear. This study aimed at elucidating the molecular characteristics and prognostic implication of mucinous histology in pts treated with adjuvant FOLFOX. Methods: Stage II and III CRC pts who received adjuvant FOLFOX were analyzed. Pts were grouped according to the mucinous content: > 50%, mucinous adenocarcinoma (MAC); < 50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, nonmucinous adenocarcinoma (NMA). Clinicopathologic features, MSI status (N = 518), CpG island methylator phenotype (CIMP) (N = 322) BRAF mutation (N = 269) and disease-free survival (DFS) were compared. Results: Among a total of 521 pts, 27 (5.2%) had MAC, 41 (7.9%) AIM, and 453 (86.9%) NMA. MAC and AIM had higher frequency of proximal location and lower angiolymphatic invasion. MAC had higher proportion of T4 tumors. AIM had higher frequency of age ≥65 years and female. In terms of molecular characteristics, MAC and AIM showed similarly higher proportion of MSI-high and CIMP-high compared to NMA. BRAF mutation also showed similar trend. In contrast to the similarities between MAC and AIM, DFS was significantly different. MAC showed significantly worse DFS compared with AIM and NMA, whereas AIM and NMA showed similar DFS. Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted HR 7.96, 95% CI 3.76-16.8). Conclusions: AIM and MAC has distinct clinico-pathologic features and molecular characteristics compared with NMA. Only MAC but not AIM has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX compared with NMA. [Table: see text]
Association of DNA promoter hypermethylation of decoy receptor 1 (DCR1) with poor response to irinotecan in metastatic colorectal cancer.
Authors: Van Criekinge Wim , Bosch Linda JW , Trooskens Geert , Snaebjornsson Petur , Haan Josien , Pelosof Lorraine Cheryl , Koopman Miriam , Tol Jolien , Louwagie Joost , Dehaspe Luc , van Grieken Nicole C.T. , Ylstra Bauke , Verheul Henk M.W. , van Engeland Manon , Nagtegaal Iris D. , Herman James Gordon , Punt Cornelis J. A. , Carvalho Beatriz , Meijer Gerrit A.
Published: March 2020

3552

Background: Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Methods: The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase 3 CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88). Results: Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)). Conclusions: CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy.
Colorectal cancer gene expression profiling using nanostring nCounter analysis.
Authors: Ciombor Kristen Keon , Deane Natasha G , Lewis Keeli B , Chen Xi , Zhang Bing , Washington Mary Kay , Shi Chanjuan , Beauchamp R. Daniel
Published: March 2020

3555

Background: A more accurate method of identifying stage 2 and 3 colorectal cancer (CRC) patients at highest risk for recurrence after surgical resection is needed. Gene expression signatures utilizing microarray-derived gene expression data from fresh frozen primary CRCs to predict risk of recurrence have been developed by us and others. Advances in technology platforms for gene expression measurements and their applicability to formalin-fixed, paraffin-embedded (FFPE) specimens offer new opportunity to develop clinically useful diagnostics based on molecular profiles. Methods: 58 patient FFPE samples of all stages stored from 1-12 years were collected from the Vanderbilt GI SPORE Translational Pathology and Imaging Core and annotated with appropriate clinicopathologic data. 414 genes were selected from our 34-gene prognostic classifier and other published CRC gene signatures, as well as gene elements associated with intestinal stem cell biology and epithelial-to-mesenchymal transition (EMT). RNA was extracted from the tumors, and gene expression analysis was completed using the nCounterplatform. Results: Quality of extracted RNA from tumor blocks was similar among the tumors and adequate for analysis. No significant differences were seen in signal strength (p=0.94, Kruskal-Wallis test) or intra-class variation (correlation coefficient = 0.99) across material extracted from new and old blocks. Fold change values for the 70 most highly differentially expressed genes on the nCounter platform correlated well with Affymetrix U133 plus 2 microarray (R2=0.819). Genes associated with EMT clustered according to prognosis, with poorer prognoses seen in patients with high TWIST expression or low E-cadherin and SMAD4 expression. There was a trend toward better survival outcomes with high expression of E-cadherin and SMAD4 (p=0.072, log-rank test). Conclusions: This preliminary study demonstrates the feasibility of this approach to determine gene expression patterns in FFPE tumor tissue samples. Our data suggest that this approach may be applied to identify clinically applicable prognostic gene expression profiles that may be validated in archived patient samples that are well annotated with patient outcome data.
Preoperative radiotherapy (preop RT) in rectal cancer: Impact of chemotherapy on the outcome—Long-term results of the randomized 22,921 phase III trial of EORTC.
Authors: Bosset Jean Francois , Calais Gilles , Mineur Laurent , Maingon Philippe , Radosevic-Jelic Ljiljana , Daban Alain , Bardet Etienne , Beny Alexander , Ollier Jean Claude , Bolla Michel , Marchal Dominique , VAN Laethem Jean Luc , Klein Vincent , Giralt Jordi , Clavere Pierre , Cellier Pascal , Collette Laurence
Published: March 2020

3560

Background: This 2x2 factorial design clinical trial evaluated the addition of Fluorouracil-based chemotherapy (CT) to preop RT and the use of adjuvant CT in patients with resectable T3-T4 M0 rectal cancer. The 5-year results showed that adding CT preoperatively or postoperatively had no significant effect on overall survival (OS) nor on disease-free survival (DFS) but a divergence seemed to emerge respectively at 2 and 5 years in the postop CT group. We report results with a median of 10.4 years. Methods: A total of 1011 patients were allocated in four treatment arms: preop RT ; preop RT + 2 CT courses ; preop RT + 4 postop CT courses ; preop RT-CT + postop CT. Preop RT was 45 Gy over 5 weeks. A one 5-day course of CT consisted of 5-Fu 350 mg/m²/d and Leucovorin 20 mg/m²/d. The effect of preop CT and adjuvant CT on OS and DFS was assessed by Logrank test (2-sided 5% significance level) stratified respectively for postop and for preop treatment. Written informed consent was obtained from all patients before randomization. Results: There is no significant difference in OS, nor in DFS between the groups receiving preop CT or not (p = 0.91 and p = 0.38 respectively). There is no significant difference in OS nor in DFS between the groups treated by postop CT or not (p = 0.32 and p = 0.29 respectively). The 10-year cumulative incidence of local recurrences is ~9 % in all the CT groups and 17.4 % in the preop RT alone group (p = 0.0044). The 10 year cumulative incidence of distant metastases (DM) is ~35 % in all treatment groups. Conclusions: With more that 10-years follow-up there is no benefit in rectal cancer by adding Fluorouracil-based chemotherapy preoperatively nor postoperatively to preop RT in terms of OS, DFS, nor in term of DM. Clinical trial information: 00002523.
Efficacy and toxicity of second-line AIO plus irinotecan (IRI) after pretreatment with AIO plus oxaliplatin (L-OHP) in the sequential therapy of metastatic colorectal cancer (CRC).
Authors: Wein Axel , Boxberger Frank , Siebler Juergen , Wolff Kerstin , Ostermeier Nicola , Busse Dagmar , Maennlein Gudrun , Hohenberger Werner , Neurath Markus F. , Hofheinz Ralf
Published: March 2020

3561

Background: The FOLFIRI followed by FOLFOX6 (or vice versa) schedule has been considered as the gold standard of sequential treatment in CRC (Tournigand C. JCO 2004). In contrast to those bi-weekly schedules, the wide-spread weekly chemotherapy administration (e.g. AIO regimen), has not been investigated as yet for second-line treatment. The AIO + IRI schedule has provided promising results in the first-line treatment of CRC (Köhne C.-H. JCO 2005). Therefore, we now investigated the efficacy and toxicity of this schedule in second-line treatment in a phase II study. Methods: From 5/02 to 6/10, 60 palliative patients (pts.) with histologically proven CRC were enrolled in an oligocentric phase II study based on the following regimen: weekly IRI (80 mg/m2 i.v.) as 1h-infusion (inf.): d1, 8, 15, 22, 29, 36, qd 57 followed by 5-FU (2000 mg/m2 i.v.) combined with sodium folinic acid (500 mg/m2, d1, 8, 15, 22, 29, 36, qd 57) as a 24h-inf. via port-a-cath. This study focused on the efficacy and toxicity of second-line treatment with AIO + IRI. Results: Last date of evaluation: November 30, 2012; evaluable for efficacy: n = 58 pts., evaluable for toxicity: n = 59 pts.; men/women: 28/72%; median age: 65y; primary tumor location: rectum/colon: 45/55%.; toxicity data: higher grade toxicity (grade 3-4): leukocytopenia: 5.1%; thrombocytopenia: 1.7%; vomiting: 3.4%; diarrhea: 13.5%; hand-foot-syndrome: 1.7%; alopecia (grade 2) 3.4%; efficacy data: PFS: 4.2 m; median OS 14.2 m, RR: 10%; AIO + IRI following AIO + L-OHP achieved a median OS of 25.0 months. Conclusions: In the field of second-linetreatment of CRC the AIO plus IRI regimen offers both a favorable toxicity profile and promising results in terms of efficacy compared with the FOLFIRI regimen.
EGFL7 polymorphism to predict tumor response in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI and bevacizumab (BV).
Authors: Li Joseph Ethan , Zhang Wu , Loupakis Fotios , Yang Dongyun , Wakatsuki Takeru , Ning Yan , Stintzing Sebastian , El-Khoueiry Rita Elie , Volz Nico Benjamin , Marmorino Federica , Schirripa Marta , Salvatore Lisa , Antoniotti Carlotta , Cremolini Chiara , Lenz Heinz-Josef
Published: March 2020

3565

Background: Angiogenesis involves endothelial cell (EC) sprouting, proliferation, and differentiation and recruitment of mural cells to stabilize new vessels. The proteins Epidermal Growth Factor Domain-Like 7 (EGFL-7) and Activin Receptor-like Kinase 1 (ALK1) play critical roles. EC-secreted EGFL7 antagonizes Notch to promote EC proliferation, sprouting, and motility. EGFL7 also regulates mural cell recruitment and extracellular matrix deposition. ALK1 is an EC-restricted TGF-β Type 1 receptor with downstream repression of Vascular Endothelial Growth Factor (VEGF) signaling. ALK1 also promotes pericyte-EC adhesion. EGFL7 or ALK1 inhibition enhances antitumor efficacy when combined with BV in murine models. Both are overexpressed in many cancers and may be critical for efficacy of anti-VEGF therapy. We tested whether EGFL7 (rs1051851, rs2297538) and ALK1 polymorphisms (rs2293094, rs11169953, rs706819) will predict efficacy of BV-based therapy in mCRC pts. Methods: Genomic DNA was extracted from peripheral whole blood samples from 455 mCRC pts treated with first-line BV and FOLFIRI. SNPs were analyzed by PCR-based direct DNA sequencing and evaluated for association with tumor response rate (RR), overall survival (OS), and progression free survival (PFS). Results: Male/female: 272/183; median age: 62 (range: 25-81); median PFS and median OS: 10.9 (95%CI: 10.1-11.6) and 29.9 (95%CI: 25.9-34.6) months, respectively; response to therapy: 59% (215 pts); median follow-up:23.6 (range: 1.8-60.4) months. Pts carrying the EGFL7 rs1051851 G/G alleles had a 62% RR versus 56% in pts with A/G and 29% in patients with A/A (p=0.0130, Cochran-Armitage trend test). The result remained significant after adjustment for baseline pt characteristics (p=0.026, Multivariable logistic regression test). There was no statistically significant association between tested polymorphisms and OS or PFS. Conclusions: The EGFL7 SNP rs1051851 may predict tumor response in mCRC pts treated with FOLFIRI and BV. To our knowledge, this is the first study demonstrating predictive significance of genetic variations in EGFL7. Prospective validation of this study is warranted.
Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.
Authors: Klingbiel Dirk , Missiaglia Edoardo , Yan Pu , Tejpar Sabine , Roth Arnaud , d'Ario Giovanni , Delorenzi Mauro , Bosman Fred
Published: March 2020

3577

Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (≥75% positive) and low expression (<75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p<0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3–0.6, p<0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5–1.1, p=0.13), with a significant interaction (p=0.05). Similar results were observed for RFS (HR 0.5, p<0.001 vs. HR 0.7, p=0.07; interaction p=0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p=0.008; RFS: HR 0.6, p=0.02), but not in F-FU/FA treated pts (OS and RFS: HR=1, p=1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered. Clinical trial information: NCT00026273.
Small bowel adenocarcinoma phenotyping and prognostic factors.
Authors: Aparicio Thomas , Svrcek Magali , Laforest Anais , Zaanan Aziz , Beohou Kanean , Afchain Pauline , Mitry Emmanuel , Taïeb Julien , Di Fiore Frédéric , Gornet Jean-Marc , Thirot-Bidault Anne , Sobhani Iradj , Malka David , Lecomte Thierry , Locher Christophe , Bonnetain Franck , Laurent-Puig Pierre
Published: March 2020

3585

Background: SBA is a rare tumor with poor prognosis. Data regarding SBA molecular alterations are lacking. Methods: We searched for several candidate oncogenic alterations and characterised the immunophenotype according to the primary tumour location in pts with SBA (all stages; ampullary tumours excluded) treated in 11 centres from 1996 to 2008. Tissue microarrays were constructed from tumour samples, and DNA was extracted from formalin-fixed, paraffin-embedded samples. HER2, β-catenin, TP53, and mismatch repair (MMR) protein expression was assessed by immunohistochemistry. A molecular analysis assessed microsatellite instability, KRAS mutation and BRAFV600E mutation. Results: We obtained samples from 63 SBA pts (median age, 58 years; tumour stage: I-II, n=19 (30%); III, n=22 (35%); IV, n=20 (32%); locally advanced, n=2 (3%)). HER2 overexpression (3+) was observed in 2/62 (3%) pts. Overexpression of TP53 was observed in 26/62 (42%) pts. Abnormal expression of β-catenin was observed in 12/62 (19%) pts. MMR deficiency (dMMR) was observed in 14/61 (23%) pts, consistent with Lynch syndrome in 7/14 (50%) pts. All of the dMMR tumours were in duodenum or jejunum. Only one of dMMR tumour was stage IV. A KRAS mutation was observed in 21/49 (43%) pts. BRAFV600E mutation was observed in only 1/40 pt. Median overall survival (OS) was 36.6 months (95% confidence interval [CI], 26.9-72.2). In univariate analysis, stage I-II (p<0.001) and dMMR phenotype (p=0.02) were significantly associated with longer OS. In multivariate analysis, only disease stage independently predicted longer OS (p<0.001). For stage IV pts, median OS was 17.9 months (CI, 12.6-36.6). For stage I-III pts median recurrence-free survival (RFS) was 26.7 months (CI: 14.6-42.4). A trend for a better RFS was observed if tumour was dMMR HR: 0.39 (CI, 0.10-1.44], p=0.15. Conclusions: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high rates of KRAS mutations. The seemingly higher rate of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA in pts. A trend for good prognosis was associated with dMMR.
Estrogen and colorectal cancer incidence and mortality in the Women's Health Initiative clinical trial.
Authors: Lavasani Sayeh Moazami , Chlebowski Rowan T. , Prentice Ross L , Kato Ikuko , Wactawski-Wende Jean , Johnson Karen , Young Alicia , Hubbell F Allan , Simon Michael S.
Published: March 2020

3594

Background: The preponderance of observational studies associate estrogen alone use with lower colorectal cancer incidence. In contrast, no difference in colorectal cancer incidence was seen in the Women's Health Initiative (WHI) randomized, controlled trial (RCT) of estrogen versus placebo after 7.1 years mean intervention. We now assess the influence of estrogen alone use on longer-term colorectal cancer incidence and mortality after an additional 5.6 years post-intervention follow-up. Methods: The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 10,739 postmenopausal women who had undergone prior hysterectomy and who were randomly assigned to receive daily 0.625 conjugated equine estrogen (n = 5279) or matching placebo (n = 5409). Colorectal cancer diagnosis rates and mortality were assessed after a mean of 7.1 years (standard deviation [SD] 1.1) of intervention and 12.7 years follow-up. Results: Colorectal cancer incidence in the treatment and control groups were almost equivalent, 0.15% diagnoses/year v 0.13% in the estrogen therapy arm and the placebo group, respectively (Hazard ratio [HR], 1.12; 95% Confidence Interval [CI], 0.83-1.52; P = 0.46). Bowel screening examinations were comparable in both groups throughout. For women age 70-79 at study entry, hormone therapy was associated with an increased risk of colorectal cancer, HR 1.71; 95% CI, (1.02-2.86). For women age 50-59 and 60-69, the respective HR’s and 95% CI were 0.86 (0.43-1.71) and 0.98 (0.64-1.49), p-interaction 0.165. For women with a waist circumference of > 88 cm, there was an increased risk of colorectal cancer, HR 1.53; 95% CI, 0.95-2.45 compared to 0.95 (0.66-1.39) for waist circumference of < 88 cm, p-interaction 0.124. Although not statistically significant, there was a higher number of colorectal cancer deaths in the hormone therapy arm (33 v 24 deaths; 0.05% v 0.04%; HR, 1.42; 95% CI, 0.84-2.41; P = 0.19). Conclusions: There were no significant differences in colorectal cancer incidence or mortality after long-term follow-up in the WHI RCT of conjugated equine estrogen. There was a suggestion of an elevation in colorectal cancer risk among older women randomized to estrogen. Clinical trial information: NCT00000611.
Prognostic significance of tumor stromal and epithelial claudin 2 in metastatic colorectal cancer.
Authors: Mezheyeuski Artur , Guren Tormod Kyrre , Glimelius Bengt , Pfeiffer Per , Kure Elin , Ikdahl Tone , Skovlund Eva , Sorbye Halfdan , Tveit Kjell Magne , Pietras Kristian , Sandstrom Per , Bojmar Linda , Portyanko Anna , Ostman Arne
Published: March 2020

3597

Background: Tight junctions (TJ) are the most apical epithelial cell–cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semi-quantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n=315, p=0.018; cl2-S, n=319, p=0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR=1.30; 95% CI 1.08-1.56; p=0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N=182), when compared with the rest of the cases (n=129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p=0.003) in univariate analyses (HR=1.55, 95% CI 1.16-2.08, p=0.003) and in multivariate analyses (HR=1.52, 95% CI 1.13-2.05, p=0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.
Hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil, and oxaliplatin plus intravenous cetuximab (Cet) (Optiliv) after failure on one versus two or three chemotherapy protocols in patients (pts) with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) (European phase II clinical trial NCT00852228).
Authors: Ducreux Michel , Innominato Pasquale F. , Hebbar Mohamed , Smith Denis Michel , Lepère Céline , Focan C. N. J. , Guimbaud Rosine , Carvalho Carlos , Tumolo Salvatore , Awad Sameh , Truant Stephanie , Castaing Denis , Karaboué Abdoulaye , De Baere Thierry , Kunstlinger Francis , Bouchahda Mohamed , Boige Valerie , Rougier Philippe , Adam Rene , Levi Francis ,   ARTBC International
Published: March 2020

3599

Background: Optiliv allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, despite failure of 1-3 prior chemotherapy protocols (Lévi et al. Proc ASCO GI 2013). Purpose: To assess tolerability and efficacy of Optiliv according to previous chemotherapy exposure. Methods: Pts received iv Cet (500 mg/m²) and chronomodulated or conventional HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 wks. Liver surgery was performed according to q6wks multidisciplinary reviews. Pts were categorized according to Optiliv as 2nd (N=29 pts) vs 3rd-4th chemotherapy line (N=35 pts). Results: Pt characteristics were similar in both groups. Overall, there were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2) and predominantly liver lesions. LM-CRC were bilateral in 51 pts (79.7%), with a median of 10 metastases (1-50), 6 segments involved (1-8), and largest diameter of 52 mm (15-172). 61 pts (2nd line, 27; 3rd-4th line, 34) received a median of 6 courses (1-15). Grade 3-4 toxicities per pt were similar in both groups except for abdominal pain (2nd line, 15% vs 3rd-4th line, 35%, p=0.07), diarrhea (7% vs 24%, p=0.09), thrombocytopenia and febrile neutropenia (0 vs 9%, p=0.25). Four CR were achieved in 2nd line (15%) vs none in 3rd-4th line. Respective objective response rates were 63% and 38% (p=0.05). R0-R1 resections were performed in 11/27 pts (41%) on 2nd line vs 6/34 pts (18%) on 3rd-4th line (p=0.06), resulting in respective median progression-free survival (PFS) of 14.2 months [7.8 - 20.7] vs 7.3 [5.5 - 9.1] (p=0.002). Median overall survival (OS) was not reached at 3 years in the pts on Optiliv as 2nd line vs 15.2 months in the more heavily pretreated pts (p<0.001). Conclusions: Intravenous Cet and triplet hepatic artery infusion resulted in the doubling of secondary surgical resection rate of LM-CRC, PFS and OS in 2nd lineas compared to 3rd-4th line. Optiliv now deserves upfront testing. Clinical trial information: NCT00852228.
Prevention of 5-FU-induced health-threatening toxicity by pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.
Authors: Boisdron-Celle Michele , Capitain Olivier , Metges Jean-Philippe , Faroux Roger , Borg Christophe , Galais Marie-Pierre , Kaassis Mehdi , Bennouna Jaafar , Bouhier Leporrier Karine , Francois Eric , Baumgaertner Isabelle , Guerin-Meyer Veronique , Cojocarasu Oana , Roemer-Becuwe Celia , Stampfli Claire , Rosenfeld Ludovic , Lecomte Thierry , Berger Virginie , Morel Alain , Gamelin Erick
Published: March 2020

3601

Background: While 5-FU is the foundation of many in GI oncology treatments, pts with DPD deficiency can experience early-onset severe (5%) even fatal (0.3%) toxicities. This study aimed to confirm the pharmaco-economic benefits of pre-therapeutic screening for DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (NCT01547923). Methods: Two parallel cohorts of pts treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD deficiency screening; Group B: no evaluation. Enrollment was based on 5-FU administration guidelines of each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) (1,2,3). The 2 groups were to be compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed in the case of proven 5-FU-related toxic death. Results: 1,130 pts were included from 06/01/2008 to 07/31/2012. Group A: no severe toxicity despite 1 pt with complete deficiency (pt not treated with 5-FU), 20 pts with partial deficiency had safe PK-monitored 5-FU (ODPM Protocol) with only one hospitalization due to toxicity. Group B: One death due to complete DPD deficiency, confirmed retrospectively. Enrollment prematurely closed after experts’ unanimous decision citing ethical concerns. 21 pts with partial DPD deficiency. 5 reported toxicity-related hospitalizations. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A pt had safe treatment whereas Group B pt died due to 5-FU toxicity. Pre-therapeutic DPD deficiency screening using this multi-parametric approach should be performed before 5-FU-based treatment and PK-guided dose adaptation allows for safe treatment of even partially DPD deficient patients. Clinical trial information: NCT01547923. [Table: see text]
Impact of early tumor shrinkage on clinical outcome in KRAS wild-type colorectal liver-limited metastases treated with cetuximab plus chemotherapy: Lessons from a randomized controlled trial.
Authors: Ye Le-chi , Zhong Yunshi , Liu Tianshu , Wei Ye , Ren Li , Zhu Dexiang , Qin Xinyu , Fan Jia , Chen Jingwen , Chang Wenju , Lin Qi , Xu Jianmin
Published: March 2020

3610

Background: Recently, early tumor shrinkage (ETS) was reported to predict outcome in metastatic colorectal cancer treated with cetuximab (cet). This study was to evaluate the impact of ETS on long-term outcome in patients (pts) with wild-type-KRAS unresectable CLLM receiving cet plus chemotherapy (CT, FOLFIRI or mFOLFOX6). Methods: 138 pts treated in a randomized controlled trial (70 in armA received CT plus cet and 68 in armB received CT alone) previously reported (Jianmin et al, ESMO 2012, abstract-557, ClinicalTrials.gov, number NCT01564810) were included into this analysis. ETS was defined as a reduction of ≥20% in the sum of the longest diameters of target lesions compared to baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and overall survival (OS). Results: 132 pts were available for evaluation, and ETS occurred more frequently in armA than that in armB (45/68 vs. 26/64, p= .003). Irrespective of treatment arm, pts achieved ETS were associated with longer OS (armA: 38.0 vs. 18.7months, p< .001; armB 30.6 vs.17.7months, p= .003) and PFS (armA: 11.8 vs. 4.8months, p< .001; armB 8.0 vs.4.6months, p= .001) when compared to pts with no-ETS. Among pts with ETS, there were statistic difference between armA and armB in terms of PFS (11.8 vs. 8.0months, p= .041) but not of OS (38.0 vs. 30.6months, p= .30); the converted resection rates for liver metastases were 40.0% (18/45) in armA and 19.2% (5/26) in armB, which were no significantly different (p= .072). For pts without liver surgery, pts observed ETS also gained an increased survival benefit over those no-ETS in armA with regards to OS (p= .01) and PFS (p< .001) though it was not full certified in armB (OS: p= .054; PFS: p= .041). For pts in armA, cet-induced skin toxicity correlated with the occurrence of ETS (p= .048). In addition, cox regression for OS using indicated a hazard ratio of 0.39 (95%CI 0.21–0.72, p = .003). Conclusions: ETS ≥20% at 8 weeks may serve as a predictor of favorable outcome in pts with wild-type-KRAS CLLM receiving cet plus CT.
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.