bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of Recchia's immunomodulatory schedule (RIS) as a maintenance therapy in high-risk tumors after a response.
Authors: Sureda Manuel , Rebollo Joseba , Vazquez Begona , Bretcha Pere , Cañon Rosa , Duarte Maritza , Munoz Vicente , Brugarolas Antonio
Published: March 2020

3074

Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 µg per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62+). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.
Physicochemical, functional, and pharmacologic comparability between the proposed biosimilar rituximab GP2013 and originator rituximab as the foundation for biosimilarity.
Authors: da Silva Antonio , Kronthaler Ulrich , Meyer Ines , Fritsch Cornelius , Schneiderer Timo , Stangler Thomas , Visser Jan Marinus
Published: March 2020

3075

Background: Development of a biosimilar involves extensive characterization of the originator product and a target-directed iterative development process ensuring comparability to the originator with similar clinical efficacy, safety and quality. Here we report the physicochemical, functional and pre-clinical pharmacological characterization of a proposed rituximab biosimilar (GP2013). Methods: A variety of physicochemical methods were used to analyze primary and higher order structure, post-translational modifications and size heterogeneity. Functional characterization included a series of bioassays (in vitro target binding, ADCC, CDC and apoptosis) and SPR-based Fc receptor binding assays. Comparative PK and PD were assessed in cynomolgus monkeys, the pharmacologically most relevant species. Results: GP2013 has the same primary amino acid sequence and higher order structure as the originator rituximab and both were comparable with regard to charge variants, specific amino acid modifications, glycan pattern and size heterogeneity (low- and high-molecular weight variants & particles). Functionally GP2013 could not be distinguished from originator rituximab preclinically. In primates, PK analysis confirmed bioequivalence between GP2013 and originator rituximab with nearly identical AUC values and 90% CIs entirely within the standard acceptance range of 0.8-1.25. Bioequivalence of PD response was also shown, with 95% CIs of areas under the effect-time curves (AUEC) ratios for relative change from baseline in B-cell populations within the 0.8-1.25 acceptance range. Conclusions: Using a broad panel of analytical methods it was shown that GP2013 is highly similar to originator rituximab at the physicochemical level. In addition, the preclinical comparability exercise confirmed that GP2013 and originator rituximab are pharmacologically similar with regard to FcR and CD20 binding, ADCC, CDC and apoptosis potency, PK exposure and B-cell depletion. As such, we anticipate that the ongoing clinical trials will help provide confirmatory evidence of similar efficacy and safety to the originator product.
Superparamagnetic nanoparticles targeting cancer cells invading the extracellular matrix.
Authors: Elachy Samar , Ramadan Wegdan , Kalsa Remon , Abou El Azm Nihad , Refaat Tamer , Omar Walaa , Eissa Yasmine , Radi Sanaa H , Abd-El-Moneim Salah-Eldin , Paunesku Tatjana , Woloschak Gayle
Published: March 2020

3083

Background: Metastatic cancer cells secrete matrix metalloproteinases (MMP), which allow cancer cells to burrow their way to the nearby vasculature. Therefore, MMPs are potential targets for anticancer treatment. Nanoparticles (NPs) can be crafted to adhere to the ECM and subsequently be released in response to advance of invasive cells. The objective of the study is to elucidate the interaction of cancer cells in a three-dimensional culture, with functionalized SPIONS targeted to the extracellular matrix around them. Methods: SPIONS, 15-20 nm in size were functionalized using different coatings: ficoll 400, sucrose, lysine-arginine, dextran50,000. Cellular uptake studies using cervical adenocarcinoma HeLa cell lines were performed to determine the optimum formulation taken up by the cells, using electron microscopy and Prussian blue staining for optical microscopy. Two types of extracellular matrices were used: Rat-tail Collagen type I and ECM gel from Engelbreth-Holm-Swarm murine sarcoma with NPs embedded in them. To assess the capability of cells to invade the matrix, cells were grown on the surface of the matrices for 1 week To evaluate the ability to grow, expand and migrate inside the matrix, cells were embedded within the matrix and left for 14 days. Comparison was made in the presence or absence of SPIONS. Results: Sucrose-coated SPIONS were taken up the best by HeLa cell lines as evaluated by MRI. MMP-1 Secretion allowed HeLa cell invasion of collagen type-1 matrix unidirectionally. Cells could adhere, proliferate, differentiate and migrate in the absence of SPIONS. Cells positive for MMP-9 invaded ECM gel from Engelbreth-Hol-Swarm murine sarcoma matrix also only in the absence of SPIONS. Cells that were found engulfing SPIONS showed morphological features of apoptosis as nuclear pyknosis and karryorhexis. Conclusions: Targeting NPs to the ECM surrounding cancer cells that have developed a metastatic potential represents an attractive platform for cancer therapeutics. The findings show a great promise for development of new theranostic agents, that can be directed to the tumor environment using external magnetic fields, with subsequent suppression of invasion and even destroying malignant cells.
Effect of an adjuvant breast cancer vaccine on disease-specific survival of breast cancer patients with depressed lymphocyte immunity.
Authors: Elliott Robert Lange , Head Jonathan F.
Published: March 2020

3087

Background: Breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease-specific survival. Methods: We began preparing whole cell preparations for a vaccine study in 1995. Stage I and II breast cancer patients had host lymphocyte immunity against tumors associated antigens evaluated before and after vaccination. Those patients with depressed immunity, determined by a lymphocyte blastogenesis assay (LBA), were offered the whole cell vaccine. Patients were given six intradermal injections (three weekly followed by three monthly). Ten weeks after the last injection the LBA was repeated. Thirty-seven patients were vaccinated in the adjuvant setting with the whole cell autologous, allogeneic vaccine. Results: The vaccine was well tolerated with no severe toxicities. Some patients experienced slight pain and swelling at the injection site and slight chills and fever. The vaccinated patients had a mean follow-up of 12.7 years with mean follow-up of 8.9 and 9.2 years for the patients with normal and depressed immunity, respectively, in the historic control. The 10-year survival was 95% (20 of 21 patients) in the normal immunity historic control, 59% (33 of 56 patients) in the depressed immunity historic control and 89% (33 of 37 patients) in the patients with depressed immunity that were vaccinated in the present clinical trial. Conclusions: The disease-specific survival of the vaccinated patients with depressed immunity in this trial is significantly greater than that of the historic controls of unvaccinated patients with depressed immunity to their tumor associated antigens. This study confirms the importance of maintaining good host lymphocyte immunity after completion of standard therapy and validates the value of cancer immunotherapy in the adjuvant setting.
VXM01, an oral T-cell vaccine targeting the tumor vasculature: Results from a randomized, controlled, first-in-man study in pancreatic cancer patients.
Authors: Schmitz-Winnenthal Friedrich Hubertus , Grenacher Lars , Friedrich Tobias , Lubenau Heinz , Springer Marco , Breiner Klaus M. , Hohmann Nicolas , Haefeli Walter E. , Mikus Gerd , Weitz Juergen , Ulrich Alexis , Büchler Markus W. , Knebel Philip , Schmidt Thomas , Ge Yingzi , Niethammer Andreas G. , Beckhove Philipp
Published: March 2020

3090

Background: VXM01 is an orally available, bacterially transmitted DNA vaccine targeting VEGFR-2. Pre-clinically, VXM01 showed anti-tumor activity in multiple tumor types. This first-in-human study was designed to evaluate the safety and tolerability of VXM01. Secondary endpoints included VEGFR-2 specific T-cell responses, tumor perfusion changes, and related biomarkers. Methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 45 patients with advanced pancreatic cancer. VXM01 or placebo was given on days 1, 3, 5, and 7. Doses were escalated from 10(6) CFU to 10(10) CFU over 5 dose groups, each including 6 VXM01 and 3 placebo patients. VEGFR-2 specific T-cell activity was monitored by ELISpot and T(reg) specificity assays before, during and after the vaccination course. Tumor perfusion was assessed by DCE-MRI on days 0 and 38. Biomarkers included CA19-9, VEGF-A and collagen IV. Results: Patients were enrolled from 12/2011 to 10/2012. Most commonly observed AEs were leukopenia, abdominal pain, and diarrhea, which were all equally distributed between treatment and placebo group. While a mild elevation in average blood pressure was observed in the VXM01 group over the placebo group, the hypertension adverse event rate did not differ between both groups. No DLTs were observed. VEGFR-2 specific effector T-cell response was increased in 57% of evaluable VXM01 treated patients, during and after the vaccination course. In 25% of the VXM01 group, the T-cell response score post-vaccination was higher than maximum placebo levels. In contrast, VEGFR-2 specific T(reg) responses were overall reduced in vaccinated patients. DCE-MRI data indicated a >33% drop in K(trans)/tumor perfusion in 35% of evaluable VXM01 treated patients vs. 10% in the placebo group. Mean changes were -4% (VXM01) and +15% (placebo). Reduced tumor perfusion correlated with VEGFR-2 specific T-cell responses and biomarker responses. Conclusions: VXM01 appeared safe and was well tolerated without DLTs across 5 tested dose levels. The data suggest further that VXM01 induces and enhances a VEGFR-2 specific T-cell response and impacts tumor perfusion. Clinical trial information: ISRCTN68809279.
Systematic approach for development of new immunotherapeutics for lung cancers through cancer genomics analysis.
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke
Published: March 2020

3092

Background: Oncoantigens are defined to be proteins that are very specifically expressed in cancer cells and that have the oncogenic activity and high immunogenicity, and are considered to be promising targets for immunotherapy such as therapeutic cancer vaccines. Methods: We have established a strategy as follows to identify new oncoantigens; i) screening of highly transactivated genes in the majority of 120 lung cancers using cDNA microarray representing 27,648 genes coupled with enrichment of tumor cells by laser microdissection, ii) verification of no expression of each candidate gene in normal tissues by northern-blot analysis, iii) validation of the clinicopathological significance of its high level of expression with tissue microarray containing 300 lung cancers, iv) verification of a critical role of each gene in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL). We conducted phase I clinical trials of these therapeutic peptide vaccines for lung cancer patients. Results: We identified 35 oncoantigens and screened dozens of 10-amino-acid peptides, each of which corresponded to a part of TTK, LY6K, IMP-3, CDCA1, KIF20A, CDC45L, and FOXM1, and was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced in vitro CTL response. Phase I clinical studies indicated that five epitope peptides could strongly induce the CTL activity in cancer patients. For example, we conducted a phase I study for HLA-A*2402-positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of 1, 2 or 3 mg/body of each peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. This cancer vaccine therapy demonstrated tolerability and had very high immunogenicity of even 1 mg/body dose to induce antigen-specific CTLs in cancer patients. Conclusions: Through systematic genomics-based approach and clinical study, we have identified five epitope peptides, which could induce CTLs very effectively in cancer patients, and therefore it warrants further clinical studies. Clinical trial information: NCT01069575.
Phase I/II clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 in patients with unresactable, chemotherapy-resistant peritoneal carcinomatosis.
Authors: Lauer Ulrich , Zimmermann Martina , Sturm Julia , Koppenhoefer Ursula , Bitzer Michael , Malek Nisar P , Glatzle Joerg , Koenigsrainer Alfred , Moehle Robert , Fend Falko , Pfannenberg Christina , Auth Tanja , Yu Tony , Szalay Aladar A
Published: March 2020

3098

Background: For therapy-resistant peritoneal carcinomatosis (PC) viruses exhibiting oncolytic properties open up new perspectives. Our phase I/II study in patients with refractory PC (NCT01443260) is designed to assess the safety, MTD, and anti-tumor activity of GL-ONC1, a recombinant vaccinia virus (VACV) genetically engineered to selectively replicate in and destroy cancer cells. Methods: GL-ONC1 was administered intraperitoneally up to 4 times every 28 days under a standard 3+3 dose escalation design. Safety was assessed using CTCAEv4.0. Anti-tumor activity was determined by “fluid biopsies” obtained via repetitive paracenteses and by serial PET-CT scans. Patient samples were collected for pharmacokinetics, pharmacodynamics and viral shedding analysis. Results: Up to now, 4 patients have received 10 doses of GL-ONC1 ranging from 107 to 108 infectious viral particles per application.Adverse events have generally been limited to grade 1/2, being mostly transient flu-like symptoms as well as increased abdominal pain resulting from treatment-induced peritonitis. No DLT was reported. No viral shedding was observed. In one gastric cancer patient, effective intraperitoneal replication of GL-ONC1 was demonstrated for more than 3 weeks. Using either anti-EpCAM or anti-VACV specific antibodies, around 5% of all ascitic cells were found to be EpCAM-positive 3 days after treatment in this patient, and only around 5-10% of these cancer cells were VACV positive at the same time point. In contrast, 4 days later (i.e. 7 days after virotherapeutic treatment), less than 2% of all ascitic cells were still EpCAM-positive, and more than 90% of these cancer cells were VACV positive. Of note, VACV-positive cancer cells morphologically showed significant degenerative changes. Conclusions: Preliminary data demonstrate that GL-ONC1 is well tolerated when infused intraperitoneally. Importantly, a single intraperitoneal delivery of GL-ONC1 was found to be sufficient to cause a dramatic decline in the number of malignant cells in the ascitic fluid, suggesting that GL-ONC1 effectively removes tumor cells in the ascites of patients with PC. Clinical trial information: NCT01443260.
Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).
Authors: Koopman Miriam , Simkens Lieke HJ , Ten Tije Albert J. , Creemers Geert-Jan , Loosveld Olaf JL , de Jongh Felix E. , Erdkamp Frans , Erjavec Zoran , van der Torren Adelheid ME , Van der Hoeven Jacobus JM , Nieboer Peter , Braun J. J. , Jansen Rob L. , Haasjes Janny G. , Cats Annemieke , Wals Jacob J. , Mol Linda , Dalesio Otilia , van Tinteren Harm , Punt Cornelis J. A.
Published: March 2020

3502

Background: The optimal duration of chemotherapy and bevacizumab in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation in mCRC pts not progressing during induction treatment with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after 6 cycles of CAPOX-B, not eligible for metastasectomy and eligible for future treatment with oxaliplatin, were randomized between observation (arm A) or maintenance treatment with capecitabine 625 mg/m2 bid dailycontinuouslyand bevacizumab 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were treated with CAPOX-B until second progression (PFS2, primary endpoint). For pts not able to receive CAPOX-B upon PFS1, PFS2 was considered equal to PFS1. Secondary endpoints were overall survival (OS) and time to second progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1. All endpoints were calculated from the time of randomization. Results: A total of 558 pts were randomized. Median follow-up is 33 months. The median number of maintenance cycles in arm B was 9 (range 1-54). The median PFS1 in arm A vs B was 4.1 vs 7.4 months (HR 0.44, 95% CI 0.37-0.54, p<0.0001). Upon PFS1, 72% of pts received CAPOX-B in arm A and 44% in arm B. The median PFS2 was 10.4 vs 10.4 months (HR 0.86, 95% CI 0.7-1.04, p=0.12). The median TTP2 in arm A vs B was 11.5 vs 15.4 months (HR 0.58, 95% CI 0.48-0.72, p<0.0001), and the median OS was 17.9 vs 21.7 months (HR 0.77, 95% CI 0.62-0.96, p=0.02), respectively. Conclusions: Maintenance treatment with capecitabine plus bevacizumab after 6 cycles CAPOX-B did not significantly prolong PFS2, which may be due to the lower number of pts in arm B that received CAPOX-B following PFS1. Maintenance treatment significantly prolonged PFS1, TTP2 and OS. Our data support the use of bevacizumab plus capecitabine until progression or unacceptable toxicity. Updated results will be presented. Clinical trial information: NCT00442637.
Heterogeneity of acquired KRAS and EGFR mutations in colorectal cancer patients treated with anti-EGFR monoclonal antibodies.
Authors: Morelli M. Pia , Overman Michael J. , Dasari Arvind , Kazmi Syed Mohammad Ali , Vilar Sanchez Eduardo , Eng Cathy , Kee Bryan K. , Deaton Laurel , Garrett Chris R. , Diehl Frank , Angenendt Philipp , Kopetz Scott
Published: March 2020

3512

Background: Although KRAS and EGFR extracellular domain acquired mutations were detected in two small cohorts and correlated with acquired resistance to anti-EGFR monoclonal antibodies (MAb), the frequency, co-occurrence, and distribution of these acquired mutations is unknown. In this study we evaluated the presence of acquired KRAS and EGFR mutations in cfDNA from CRC patients (pts) treated with anti-EGFR monoclonal antibody. Methods: Plasma was collected from EGFR-MAb refractory mCRC pts as part of the ATTACC (Assessment of Targeted Therapies Against Colorectal Cancer) program. Eligible pts had documentation of pre-treatment KRAS wild type tumor. The cfDNA was extracted from the plasma and analyzed by BEAMing technology for acquired KRAS and EGFR mutation. Results: The plasma from 55 patients was analyzed for EGFR and KRAS mutation. The S492R EGFR mutation was detected in 4 pts (7%) treated with cetuximab. Acquired KRAS mutations were detected in 26 of the 55 KRAS wt samples analyzed (47%). Although codon 61 and 146 mutations are rare in untreated CRCs (2% and 1% of the MDACC population, respectively), these atypical KRAS mutations predominated in acquired resistance (Q61H=33% and A146T=10%). Mutations in more than one KRAS codon are exceedingly rare in the primary tumor. In our study we detected more than one KRAS or EGFR mutation in 30% of the population (p<0.001), suggesting the development of multiple independent clones in individual patients. Compared to 8 patients with known KRAS mutations, the average number of mutant reads in the 26 patients with acquired mutation was substantially lower (p<0.01) despite similar tumor burden. Of note, acquired concomitant KRAS mutations were also found in a BRAF V600 mutant patient previously treated with anti-EGFR MAb and a BRAF inhibitor. Conclusions: KRAS and EGFR acquired mutation are present at low concentrations in cfDNA from mCRC pts refractory to anti-EGFR MAb and they are not mutually exclusive, suggesting heterogeneity of the resistant clones. Anti-EGFR MAb refractory patients showed a higher incidence of atypical KRAS mutation and higher incidence of multiple codon KRAS mutations compared with overall CRC patient.
BRAF and KRAS mutations as additional risk factors in the context of clinical parameters of patients with colorectal cancer.
Authors: Popovici Vlad Calin , Budinska Eva , Roth Arnaud , Bosman Fred , Tejpar Sabine , Delorenzi Mauro
Published: March 2020

3522

Background: The BRAF and KRAS mutations have been proposed as prognostic markers in colorectal cancer (CRC). Of them, only the BRAF V600E mutation has been validated as prognostic for overall survival and survival after relapse, while the value of KRAS mutation is still unclear. Methods: In a cohort of 1423 stage II-III patients from the PETACC-3 clinical trial, the prognostic value of the BRAF and KRAS mutations was retrospectively assessed in all possible stratifications defined by the 5 factors (T and N stage, tumor site and grade, and microsatellite instability status), by log rank test for overall survival (OS), relapse-free survival (RFS), and survival after relapse (SAR). The presence of interactions was tested by Wald test. The significance level was set to 0.01 for Bonferroni-adjusted p-values (P*), and a second level for a trend towards statistical significance was set at 0.05 for unadjusted p-values (P). Results: BRAF mutation was a marker of poor OS only in microsatellite stable (MSS) and left-sided tumors, with no prognostic value in microsatellite instable (MSI-H) or right-sided tumors. In MSS/left-sided tumors, BRAF mutation represents a marker of higher risk than previously reported: OS HR=6.4 [95% CI: 3.6-11.5], P* < 0.0001. For SAR, BRAF was prognostic in more stratifications, with higher risk in MSS/left-sided tumors (HR=3.9 [95% CI: 2.1-7.2], P* = 0.0002) than in MSS/right-sided (HR=2.3 [95% CI: 1.2-4.4], P=0.01). A novel observation was that BRAF mutation was prognostic also for RFS, but only in MSS/left-sided tumors (HR=3.6 [95% CI:2-6.3], P*=0.0005]). Additionally, heterogeneity in OS and RFS among BRAF mutants was observed. In general, KRAS mutation did not reach the significance level required, but showed a trend to become a prognostic marker for RFS in MSS tumors with early lymph node involvement (N1) (HR=1.6 [95% CI:1.1-2.2], P=0.01). Conclusions: The prognostic utility of the BRAF and KRAS mutations has to be interpreted in the context of other factors. For the BRAF mutation, a clear interaction with MSI status and tumor site was observed, with BRAF mutation indicating a much higher risk in MSS/left-sided tumors than previously considered.
Subgroup analyses results of the PETACC8 phase III trial comparing adjuvant FOLFOX4 with or without cetuximab (CTX) in resected stage III colon cancer (CC).
Authors: Taïeb Julien , Tabernero Josep , Mini Enrico , Subtil Fabien , Folprecht Gunnar , Van Laethem Jean-Luc , Thaler Joseph , Bridgewater John A. , Sanches Evaristo , Petersen Lone , Collette Laurence , Van Cutsem Eric , Le Malicot Karine , Rougier Philippe , Salazar Ramon , Bedenne Laurent , Emile Jean Francois , Laurent-Puig Pierre , Lepage Come
Published: March 2020

3525^

Background: Potential benefit of adding CTX to the current standard treatment for stage III CC, was assessed. Subgroup analyses of demographic, clinical and molecular data may improve our understanding of this patient population. Methods: Patients (pts) were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1, with leucovorin 200 mg/m2, 5-FU 400 mg/m2 bolus IV, followed by 5-FU 600 mg/m2 22-hr IV on d1-2 (FOLFOX4), without (arm A) or with weekly CTX (arm B) 250 mg/m2 (initial dose 400 mg/m2). Primary endpoint was disease free survival time (DFS). Secondary endpoints included overall survival (OS), treatment compliance and safety. Enrolment was restricted to KRAS wt pts in 06/2008. Planned accrual of 1,407 KRAS wild-type (wt) pts provided 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided α=0.05, with interim analyses after 65% of planned events. Preplanned subgroup analyses were performed. Results: 1,602 KRAS wt pts (811 arm A, 791 arm B) and 742 mutated (m) KRAS (prior to the amendment), were randomized. BRAF status was determined in 1134 (71%) KRAS wt pts. Median follow-up was 40 months. This interim analysis showed no difference between arms for DFS (HR 1.05, 95% CI 0.85-1.29; p=0.66) or OS (HR 1.09, 95% CI 0.81-1.47; p=0.55) in KRAS wt pts or for DFS (HR 0.99, 95% CI 0.75-1.28; p=0.91) or OS (HR 0.98, 95% CI 0.67-1.44; p=0.92) in KRAS/BRAF wt pts (n=984). Similar results were seen in KRAS mutant (mt) pts without any detrimental effect. In KRAS wt pts worse outcomes were seen with CTX in pts >70 years (n=149, DFS: HR 1.97, 95% CI 0.99-3.93; p=0.05), in females (n=666, HR 1.45, 95% CI 1.03-2.03; p=0.03) and in pts with right-sided CC (n=570, HR 1.40, 95% CI 1.01-1.94; p=0.04). Conversely, a better outcome was seen in pts with pT4pN2 CC (n=146, HR 0.55, 95% CI 0.35-0.89; p=0.01). Conclusions: Adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt, KRAS/BRAF wt and KRAS mt CC. Subgroup analyses suggest that KRAS wt pts with pT4pN2 tumors may derive benefit from CTX. MSI status determination is ongoing to explore its potential interaction with poor outcome in female and/or with right-sided tumors pts. Clinical trial information: NCT00265811.
Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).
Authors: Salazar Ramon , Roepman Paul , Tabernero Josep , Schlicker Andreas , Majewski Ian , Moreno Victor , Rosenberg Robert , Kopetz Scott , Wessels Lodewyk F. A. , Bernards Rene , Simon Iris
Published: March 2020

3530

Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for molecular classification of breast cancer into subtypes that have clear relevance for prognosis and treatment. A similar classification is still missing for colorectal cancer (CRC). Methods: Using full genome expression data of 188 stage I-IV CRC patients, an unsupervised clustering revealed three major subtypes (A-, B-, C-type). A molecular subtype classification was developed and validated in 543 stage II and III patients. The subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular markers status and chemotherapy response. In addition, subtypes were determined on 173 samples from The Cancer Genome Atlas (TCGA) colon dataset with Agilent genome expression data. Results: C-type patients have the worst outcome, a mesenchymal phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A- or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype and benefit from adjuvant chemotherapy. A- and C-type groups are enriched for tumors having oncogenic BRAF mutations and a deficient DNA mismatch repair system. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A- and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Finally, CRC subtyping was confirmed in the colon TCGA dataset with 26 samples classified as A-type, 110 as B-type and 37 as C-type. In agreement with the different aggressiveness of the subtypes, A-type tumors were less prevalent in stage IV while C-type were less prevalent in stage I CRC. Conclusions: The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. These subtypes are clinically relevant, as they differ in their underlying biology and might require different treatment strategies.
Prognostic factors of recurrence of colorectal cancers with microsatellite instability after curative resection: An AGEO retrospective multicenter study.
Authors: Tougeron David , Sickersen Gaelle , Lecomte Thierry , Zaanan Aziz , Des Guetz Gaetan , Lecaille Cedric , Ferru Aurelie , Cauchin Estelle , Sefrioui David , Coriat Romain , Aparicio Thomas , Artru Pascal , Trouilloud Isabelle , Matysiak-Budnik Tamara , Taïeb Julien , Michel Pierre , Tourani Jean Marc , Levillain Pierre , Silvain Christine , Karayan-Tapon Lucie
Published: March 2020

3536

Background: Microsatellite instability (MSI) phenotype is found in approximately 12% of colorectal cancers (CRC). MSI CRC is associated with a low recurrence rate and 5-fluorouracil chemoresistance in adjuvant setting. Clinical and pathological prognostic factors of recurrence are well-identified after surgery of CRC but not in the subgroup of MSI CRC. Methods: This multicenter retrospective study included patients with stage I, II and III MSI CRC. The following prognostic factors were studied: age, sex, perforation, occlusion, tumor location, tumor differentiation, T4 stage, lymph node invasion, VELIPI criteria (vascular emboli, lymphatic invasion and perinervous invasion), BRAF mutation and adjuvant chemotherapy. Disease-free survival (DFS) was calculated using the Kaplan-Meier method. Prognostic factors of DFS were analyzed in multivariate analysis using Cox model. Results: A total of 294 MSI CRC patients were analyzed, including 10%, 49% and 41% stage I, II and III, respectively. Mean age was 67.2 ± 16.0 years. Occlusion was observed in 10% of cases. VELIPI criteria were found in 39%, including 26% with vascular emboli. BRAF mutation was detected in 27% of cases. All in all, 40% of patients received adjuvant chemotherapy, predominantly stage III (74%). Mean follow-up was 39.2 ± 33.2 months. The disease recurrence rate was 3%, 8% and 21% in stage I, II and III patients, respectively. The 3-year DFS rate was 85%. In univariate analysis, age, occlusion, lymph node invasion, T4 stage, vascular emboli and perinervous invasion were associated with decreased DFS (p<0.05). In multivariate analysis, only occlusion (RR=3.0; 95% CI 1.2-7.7, p=0.02) and vascular emboli (RR=4.5; 95% CI 1.6-12.7, p<0.01) were associated with decreased DFS. Recurrence rates for MSI CRC with and without vascular emboli were respectively, 22% versus 5% for stage II and 33% versus 15% for stage III. Conclusions: Occlusion and vascular emboli were independently associated with recurrence of MSI CRC but not lymph node invasion. We advocate vascular emboli analysis in routine clinical practice to facilitate adjuvant chemotherapy decision-making in MSI CRC.
Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer (mCRC).
Authors: Patel Sukeshi R. , Ketchum Norma , Pollock Brad H. , Sarantopoulos John , Weitman Steven , Mahalingam Devalingam
Published: March 2020

3541

Background: Recently, regorafenib (RGF), an oral multikinase inhibitor, was approved for patients (pts) with mCRC who have failed standard therapies. Compared to placebo, the phase III CORRECT study showed RGF improved median overall survival (mOS) from 5.0 to 6.4 months (mo) and median progression-free survival (mPFS) from 1.7 to 1.9 mo, regardless of K-Ras status. This suggests further VEGF inhibition is crucial in controlling mCRC progression. Many mCRC pts enroll on phase I studies with efficacy reported by some; however, a collective efficacy assessment aimed solely for mCRC in relation to class of agents has not been done. Methods: A historical cohort analysis included pts with mCRC enrolled amongst 28 phase I trials at the IDD, from 7/2008 – 9/2012. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: A total of 75 pts were included. Median age 59 (33–80), males 61 %, K-ras mutated 39 %. ECOG PS 0–1 96 %. ≥3 prior lines of therapy 68 %. Class of drugs included: VEGF Inhibitors 32 %, Cytotoxic 25 %, Microenvironment Inhibitors 13 %, Apoptosis/Autophagy Inhibitors 11 %, EGFR/Growth Factor TKIs 8 %, others 11 %. For the whole cohort of 75 pts, mPFS was 2.8 mo (95% CI: 2.0–3.7). As of 12/1/12, among 65 pts, mOS was 5.6 mo (95% CI: 4.4-7.0). In subgroup analysis, mPFS was 3.4 (95% CI: 1.4–4.5) vs 2.8 months (95% CI: 2.0–3.5) for pts on VEGF and non-VEGF Inhibitors (HR 0.79, 95% CI: 0.43–1.44, p = 0.44), respectively. VEGF Inhibitor treated pts had a mOS of 5.5 months (95% CI: 1.6–10.0 months) vs 5.6 months (95% CI: 4.4–7.6) with non-VEGF Inhibitors (HR 1.02, 95% CI: 0.58–1.78, p = 0.96). Efficacy was similar regardless of K-Ras status. Conclusions: In pretreated mCRC, median PFS and OS for pts enrolled in phase I trials, irrespective of agent, was comparable to efficacy of RGF. Therefore, after failure of standard therapies, mCRC pts should be encouraged to enroll in clinical trials with efficacy reported in both VEGF and non-VEGF inhibitors.
5FU/LV with or without irinotecan in patients with resected stage II-III rectal cancer: Final analysis of R98 intergroup study.
Authors: Delbaldo Catherine , Ychou Marc , Zawadi Ayman , Douillard Jean-Yves , André Thierry , Guerin-Meyer Veronique , Lepère Céline , Dupuis Olivier , Faroux Roger , Jouhaud Annie , Quinaux Emmanuel , Piedbois Pascal
Published: March 2020

3542

Background: The goal of the study was to test whether adding Irinotecan to a 5-FU/LV adjuvant regimen improves disease free survival (DFS) or overall survival (OS) in optimally resected stages II-III rectal cancers. Primary end-point was DFS. Methods: Six hundred patients were planned to be randomized between 5-FU/LV (control arm) or 5-FU/LV + irinotecan (experimental arm). As only 357 patients had been included from 03/1999 to 12/2005 (178 in control and 179 in experimental arm), the IDMC recommended to close accrual. The trial was stratified by control arm: Mayo-Clinic regimen (A: LV 20 mg/m², 5-FU 425 mg/m² bolus days (d) 1- 5 reapeted at d29,57,92,127 and 162) or LV5-FU2 regimen (A’: LV 200 mg/m², 5-FU 400 mg/m² bolus and 5-FU 600 mg/m² 22-hours infusion d1-2, q 2 w for 12 cycles). The experimental arm (B) was LV5-FU2 + irinotecan 180 mg/m² d1. Results: All 357 randomized patients were evaluable for efficacy. Patient characteristics were well balanced (median age 62 years, stage II 31 %, stage III 69 %, N0 31 %, 68 % received preoperative radiotherapy, and 80 % had sphincter conservation). With follow-up of 156 months, DFS and OS are not statistically increase (81vs 92 events for DFS in experimental and control arm, hazard ratio (HR)=0.805, p=0.154;63 vs 72 events for OS, HR=0.874, p=0.433). Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5FU2 control (33 % vs 16 %, p=0.03), but not when compared with the Mayo Clinic arm (32% vs 36%, p=0.84). Grade 3-4 diarrhea tend to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction p=0.44). Conclusions: In patients with resected stage II-III rectal cancer, adding irinotecan to 5FU/LV led to a non significant increase of DFS and OS. The analysis was planned to have a 60 % power to detect a significant difference with 220 events. With a long term follow up of 8 years only 173 events were observed in our trial. Lack of power and good patient prognosis (thirty one percent of node negative patients) may have impacted the results.
Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal.
Authors: Cubillo Antonio , Rodriguez-Pascual Jesus , López-Ríos Fernando , Plaza Carlos , García Elena , Alvarez-Gallego Rafael , De Vicente Emilio , Quijano Yolanda , Hernando Ovidio , Rubio Carmen , Hidalgo Manuel
Published: March 2020

3543

Background: Chemotherapy (Ch) options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the efficacy in terms of progression free survival (PFS) of a biomarker panel to guide treatment selection in this setting. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were accrued. Pts were prospectively analyzed with a predefined set of 10 molecular targets, including: KRAS, BRAF, and PI3K mutations and Topoisomerase-1(Top-1), ERCC-1, Thymidylate synthase (TS) and Thymidine phosphorylase (TP) expression by inmunohistochemistry ( IHC) performed in a tumor biopsy. Ch combination schema plus Cetuximab (C) or Bevacizumab (B) at standard doses was customized based on: Topo-1 +:Irinotecan (I). Topo-1- and ERCC-1 -:Oxaliplatin(O). Topo-1- and ERCC1 +:investigator option (I or O). TS -:Fluoropyrimidines (FP).TS +:No FP. TP -:5-FU, TP +:Capecitabine. Maintenance C or B treatment was allowed. Primary outcome measure was PFS. Results: 74 pts were accrued and all of them received biomarker guide treatment. All of them began personalized. Interim analysis on 61 pts (38 males, median age 65) showed.Topo-1 + in 33 pts (54%),ERCC-1- in 36( 59%) TS + in 44 (73%), TP – in 61 ( 100%), K-ras nativein 34 ( 55%), BRaf mutated in 2 (3,2%). With a median follow up time of 9,1 months (m). Median PFS (95% CI) is 8,6 (6,2-10,9) m, with a 41,3% (27,4-55,2) 12mPFS . Overall clinical benefit (Response + Stabilizations) was 74,5% (65,6-83,4).Toxicities Grade ≥ 3 included 18% neutropenia, 4,9% asthenia and 3,3% anemia. 12 pts (23%) received loco-regional treatment ( surgery or radiosurgery). Median Overall survival has not been reached. Conclusions: Target- Guided Personalized Ch in first line CRC pts is feasible and results in promising PFS with low toxicity. Update of final results and more detailed data will be presented. Clinical trial information: NCT01453257.
ALK and ROS1 gene rearrangements detected in colorectal cancer (CRC) by fluorescence in situ hybridization (FISH).
Authors: Weickhardt Andrew James , Nguyen Teresa T. , Paskulin Diego D. , Le Anh T. , Aisner Dara , Schulte Nathan , Chionh Fiona J.M. , Mariadason John , Tebbutt Niall C. , Doebele Robert Charles , Varella-Garcia Marileila
Published: March 2020

3545

Background: Activation of ROS1 and ALK tyrosine kinases through gene fusions lead to unchecked cell proliferation and transformation. ROS1 and ALK gene fusions were found in about 5% and 2% of lung adenocarcinomas and are highly sensitive to specific tyrosine kinase inhibitors. This study aimed at identifying the presence of ROS1 and ALKrearrangements in CRC using FISH technology. Methods: Arrayed specimens of metastatic CRC (mCRC) patients were tested with a 4-target, 4-color break-apart FISH probe set (Abbott Molecular) designed to simultaneously evaluate the genomic status of ROS1 and ALK. Fused 3’/5’ signals of each gene were considered negative for rearrangement; single 3’/single 5’ (for ROS1) and split 3’-5’ or single 3’ (for ALK) were considered positive for rearrangement. Results: Among 236 mCRC patients tested, two were positive for ROS1 (single 3’ROS1 signals in 39% and 61% of tumor cells) and one was positive for ALK rearrangement (single 3’ALK in 41% of tumor cells). The upper cut-off for positive FISH patterns in the negative specimens was identified as <15% both for ROS1 and ALK. Interestingly, the ALK+ patient displayed intra-tumoral heterogeneity, detected in the tissue cores and confirmed in two resection blocks. The fusion partner for ALK was identified as EML4 by PCR-based tests and sequencing. The fusion partner(s) for ROS1 remains to be identified by other technologies. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. Conclusions: The novel FISH probe set was effective to identify the first cases of ROS1 rearrangements in CRC and re-confirm the occurrence of ALK rearrangements. This supports further evaluation of mCRC cases for ROS1 and ALK gene fusions as these may represent new targets for evaluation in clinical trials. Tumor heterogeneity in the ALK rearrangement must be addressed for screening tests. (Partially supported by research grant from Abbott Molecular and the Colorado CCSG P30CA046934).
Cochrane systematic review and meta-analysis of adjuvant chemotherapy for stage II colon cancer.
Authors: Meyers Brandon Matthew , Al-Shamsi Humaid Obaid , Figueredo Alvaro Tell
Published: March 2020

3548

Background: Colon cancer is potentially curable by surgery in the early stages of the disease. Adjuvant chemotherapy improves disease-free and overall survival in patients with stage III disease, but the magnitude of benefit in stage II colon cancer is less clear. A previous Cochrane systematic review and meta-analysis (SR/MA) found improved disease-free, but not overall survival (Figueredo et al., 2008). An updated SR/MA was performed to determine the effects of adjuvant chemotherapy on disease-free and overall survival in patients with stage II colon cancer. Methods: Relevant databases (MEDLINE, EMBASE, and Cochrane) were independently searched by all authors, using the same search strategy employed in the original study (1/1988 to 9/2012). Randomized trials containing data on stage II colon cancer patients undergoing adjuvant 5-fluorouracil (5FU) chemotherapy versus observation were included. Pooled results were expressed as hazard ratios (HR) whenever possible, or risk ratios (RR), with 95% confidence intervals (95%CI) using a random effects model. Results: Seven studies were identified, and included in the final SR/MA. Six of the 7 studies were included in the disease-free survival analysis (n=4587). Adjuvant 5FU was associated with better disease-free survival (RR 0.84 (95%CI 0.75-0.94)). All 7 studies (n=5353) were included in the overall survival analysis showing an improvement with adjuvant 5FU (HR 0.87 (95%CI 0.78-0.97)). There was no evidence of heterogeneity across the studies (I2 = 0% for all analyses). Conclusions: In stage II colon cancer, adjuvant 5FU chemotherapy statistically improves both disease-free and overall survival. Our SR/MA demonstrates, for the first time, an overall survival advantage with adjuvant chemotherapy in stage II colon cancer.
The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer.
Authors: Abdul Jalil Khairun Izlinda , Sheehan Katherine M , Toomey Sinead , Schmid Jasmin , O'grady Anthony , Cummins Robert , O'Neill Brian , McNamara Deborah A , Deasy Joseph , Grogan William , Breathnach Oscar S. , Rogers Ailin , Doherty Glen , Winter Des C , Gibbons David , Ryan John , Sheahan Kieran , Gillen Peter , Kay Elaine , Hennessy Bryan
Published: March 2020

3549

Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP-kinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic variations in these pathways and clinical outcomes in LARC. Methods: We genotyped a total of 234 Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations in 33 cancer related genes including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET and NRAS using the Sequenom platform. DNA samples utilized herein were extracted from pre-treatment rectal cancer biopsies of 201 patients who were then treated with long-course pCRT followed by surgical resection. Results: 62 different mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (n=93, 47%), PIK3CA (n=29, 14%), MET (n=27, 13%), STK11 (n=13, 6.3%), CTNNB1 (n=12, 6%), BRAF (n=8, 4%) and NRAS (n=7, 3.5%). Mutations were also detected in AKT, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK and TNK2, but at frequencies of less than 2%. Pathologic complete response (pCR) was associated with excellent (97%) 5-year Recurrence-Free Survival (RFS) (Hazard ratio [HR], 0.076; 95% CI, 0.01-0.50, P=0.001). We found: 1) Mutations in PI3K pathway-related genes (PIK3CA, AKT, STK11) were significantly associated with absence of pCR (odd ratio [OR], 5.40; 95% CI, 1.24-23.54, P=0.024). However, mutations in MAPK pathway-related genes (KRAS, BRAF, NRAS, MEK) was not found to be significantly associated with pCR (P=0.805). 2) In contrast, in patients who did not achieve pCR (non-pCR), mutations in PI3K pathway-related genes were not associated with RFS. However, in these patients, codon 12 (G12D/G12V/G12S) and 13 mutations in KRAS were associated with poor RFS (HR, 0.336; 95% CI, 0.115-0.981, P=0.046). Conclusions: These results suggest that mutations in kinase signaling pathways may modulate treatment responsiveness and clinical outcomes in locally advanced rectal cancer and thus may constitute rational targets for novel therapies.