bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of routine image follow-up in nonmetastatic colorectal cancer after curative surgical resection.
Authors: Diniz Lara Azevedo , Karani Amanda , De Brito Sales Diogo , Machado Larissa , Barros Milton Jose
Published: January 2019

524

Background: Follow-up surveillance is performed after primary treatment in colorectal cancer (CRC), but it is controversial in the literature the real benefit of an intensive examination in terms of outcomes and resources. Intensive follow-up after surgery for colorectal cancer has been challenged by some new published data (CEA watch trial and FACS trial). These new data suggest that a less intensive follow-up program based on carcinoembryonic antigen (CEA) measurements or CEA-Triggered imaging would be enough to detected most of the recurrences. We believe that there is a high percentage of patients with recurrence disease and normal CEA value, for whom image screening would be necessary to detect early disease recurrence suitable to metastasectomy with curative intention. Methods: This is a retrospective study that included 372 patients from a tertiary cancer center in São-Paulo (Brazil) diagnosed with colorectal adenocarcinoma stages I to III. We observed, after primary treatment, a pattern of recurrence detected either by CT (computed tomography) imaging only or CEA elevation and CT image in combination. Results: Out of the 372 patients analyzed, 110 (29,5%) had recurrent disease with a median follow-up time of 34 months. Of the 110 recurrences detected, 75 (68,18%) were detected by CEA elevation in combination with CT image, 33 (30%) were detected only by CT image and 2 (1,81%) neither by CT nor by CEA alteration. There was no clinic feature that would predict pattern of recurrence when analyzed by qui square test. Metastasectomy rate from this analysis 53,6% and it was similar among both groups. Recurrence rate after metastasectomy was 59,3%. There is a 5-year overall survival difference between patients that underwent or not metastasectomy (79,4% vs. 54%, p 0,01). Conclusions: CEA-based follow-up program and CEA-triggered imaging failed to detect early recurrence in almost 30% of cases. We believe that this number is high enough to allow us to continue to perform image test during CRC follow-up.
The incidence of infusion reactions associated with monoclonal antibody drugs targeting the epidermal growth factor receptor in metastatic colorectal cancer patients: A systematic literature review and meta-analysis.
Authors: Lowe Kimberly , Bylsma Lauren C , Dean Rebecca , Gillezeau Christina , Sangaré Laura , Alexander Dominik D , Fryzek Jon
Published: January 2019

526

Background: Infusion reactions have been reported in studies of metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies, including cetuximab and panitumumab, with incidences ranging from 0-33%. A systematic literature review and meta-analysis were conducted to estimate the incidence of infusion reactions in this population and identify variations in this incidence by patient and study characteristics. Methods: Multiple scientific databases were searched to identify observational studies or clinical trials of mCRC patients treated with anti-EGFR therapies that reported rates of infusion reactions, hypersensitivity, or allergy/anaphylaxis. Random effects models were used to meta-analyze the incidence of infusion reactions overall and stratified by therapy, study design, geographic location, KRAS mutation status, and grade of reaction severity. Results: Among 48 studies included in this meta-analysis, the pooled estimate for infusion reaction incidence was 0.049 (95% CI: 0.036 – 0.065), or nearly 5%. Reactions of grades 1 or 2 were more common than reactions of grades 3-5 (0.089 vs. 0.028) No significant variations in infusion reaction incidence were observed by study design, KRAS status, or study location. Conclusions: Infusion reactions occur in approximately 5% of mCRC patients treated with anti-EGFR therapies and the incidence varies significantly by grade and severity. Future studies should consider investigating survival outcomes for only those patients with infusion reactions to determine its prognostic relevance.
Genomic and immune infiltration differences between MSI and MSS GI tumors.
Authors: Newton Yulia , Golovato Justin , Tan Iain Beehuat , Lam Justina Yick Ching , Yu Guo , Koo Si-Lin , Chua Clarinda , Yeong Joe Poh Sheng , Ping Christine , Skanderup Anders , Göke Jonathan , Johnson Mark , Rabizadeh Shahrooz , Sanborn J Zachary , Benz Stephen Charles , Vaske Charles Joseph , Szeto Christopher
Published: January 2019

528

Background: Dysregulation of DNA mismatch repair pathway can lead to microsatellite instability in many GI tumors, and microsatellite instability is an important diagnostic and prognostic marker. Microsatellite instable (MSI) tumors comprise about 15% of colorectal malignancies and can be found in other gastrointestinal (GI) tumor types. We present results of analysis of genomic and immune infiltration differences between MSI and microsatellite stable (MSS) GI tumors spanning multiple cancer types. Methods: A total of 521 GI patients with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200M reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: Gene expression and pathway analysis found significantly higher immune signaling in MSI cohort and higher metabolic signaling in MSS cohort. We also found upregulation of structural cellular integrity pathways in MSI tumors. Per-sample deconvolution of immune infiltration using cell type gene markers shows some MSI samples with high CD8 T-cells. Co-expression analysis of checkpoint and TME genes shows higher correlation of FOXP3 and CTLA4 in the MSS cohort compared to the MSI samples, whereas correlation between FOXP3 and PDL1 is decreased. TIM3, LAG3, and OX40 are significantly more expressed in MSI samples than MSS samples. Within the subset of colorectal tumors, additional checkpoints are significantly differentially overexpressed in MSI malignancies. 50 somatic variants are significantly differential in MSI tumors. Conclusions: MSI tumors demonstrably exhibit higher immune signaling, with many immune and checkpoint markers expressed at higher levels in MSI tumors. Some cellular integrity pathways also appear to be up in MSI cohort. A number of potentially important somatic variants are associated with MSI samples.
Assessment of systemic and metastatic neutrophilic inflammation in synchronously resected colorectal cancer and liver metastases.
Authors: Steele Colin William , Roxburgh Campbell SD , McMillan Donald C , Horgan Paul G. , Samson Owen J
Published: January 2019

534

Background: Immunotherapy has proven a largely ineffective treatment for MMR proficient colorectal cancer (CRC). Resistance to immunotherapy is due to the immunosuppressive microenvironment of colorectal cancer, with CMS4 disease proving most aggressive. Using a cohort of synchronously resected CRC and metastases we examine the relationships between common immune cells in the circulation and microenvironment of primary and secondary CRC to assess microenvironmental determinants of outcome in metastatic CRC. Methods: 46 patients that had synchronous resection of primary CRC and liver metastasis at Glasgow Royal Infirmary were included. The relationships between Neutrophil lymphocyte ratios (NLR), tissue MPO and CXCR2 positive neutrophils, CD68 positive macrophages, and CD8 positive effector T cells and Klintrup-Makinen (KM) scores were quantified. Results: There was correlation between MPO and CXCR2 positive neutrophils (r = 0.668, P = 0.014) within metastases and both of these factors were independently associated with poor outcome ( P < 0.001, P = 0.002 respectively). High CD8+ T cells numbers and KM grade in both primary and metastatic niches were independently associated with better outcome following synchronous resection (P < 0.01). High systemic neutrophil counts (NLR) were associated with poor outcome in patients having synchronous resection (P = 0.001) and correlated with neutrophil numbers in metastases (r = 0.329, P = 0.05). MPO (P < 0.001) and CXCR2 (P = 0.004) positive neutrophils within the metastatic niche and KM grade of the primary tumour (P = 0.002) remained negative prognostic indicators on multivariate analysis. Conclusions: While CD8+ T cells impact positively on prognosis, the negative impact of neutrophils within the metastatic niche is the strongest determinant of outcome in synchronously resected CRC. This study raises questions as to the heterogeneity of neutrophils within primary and metastatic colorectal cancer and whether negatively prognostic neutrophils can be phenotyped and therapeutically targeted.
CEA expression patterns determine response and resistance to the CEA-TCB bispecific immunotherapy antibody in colorectal cancer patient derived organoids.
Authors: Gonzalez Exposito Reyes , Semmianikova Maria , Griffiths Beatrice , Khan Khurum Hayat , Barber Louise J , Woolston Andrew , Spain Georgia , von Loga Katharina , Swain Amanda , Thomas Janet , Bryant Annette , Mansfield David , Rao Sheela , Watkins David J. , Chau Ian , Starling Naureen , Matthews Nik , Wallberg Fredrik , Cunningham David , Gerlinger Marco
Published: January 2019

535

Background: The bispecific antibody CEA-TCB binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells. This triggers T cell killing of colorectal cancer cell lines expressing moderate to high levels of CEA at the cell surface (Bacac, Clin Cancer Res 2016). Patient derived organoids (PDOs) may more accurately represent patient tumors than established cell lines. Yet, determinants of CEA-TCB resistance have not been studied in PDOs. Methods: PDOs were established from biopsies of eight multidrug-resistant metastatic CRCs, GFP labelled and adapted to 2D culture. Allogenic CD8 T cells and CEA-TCB or a non-targeting control antibody were added and cancer cell killing and growth were monitored for 10 days. CEA expression of PDOs was determined by FACS. Results: CRC PDOs could be categorized into three groups based on CEA cell-surface expression: CEAhigh (n = 3), CEAlow (n = 2), and CEA heterogeneous PDOs (n = 3) that stably maintained populations of both CEAhigh and CEAlow cells, which has not previously been described in CRC cell lines. Heterogeneity of cell-surface CEA expression is common in CRC cells in patients, supporting that PDOs may better represent these tumors than established cell lines. CEAhigh cells were sensitive whereas CEAlow cells showed resistance to CEA-TCB. All PDOs with heterogeneous CEA expression were resistant to CEA-TCB, suggesting that CEA-negative cells maintain cancer cell growth. Culture of FACS sorted CEAhigh and CEAlow cells from PDOs with heterogeneous CEA expression demonstrated high plasticity of CEA expression which may contribute to rapid resistance acquisition through CEA antigen loss. Conclusions: These results suggest that cell-surface CEA expression is a major determinant of CEA-TCB sensitivity and resistance in PDOs. In addition, we identified heterogeneous CEA expression in several PDOs and demonstrated that this could confer CEA-TCB resistance in vitro. These PDO models are likely to provide insights into the mechanism of CEA loss and may inform therapeutic opportunities to counter CEA-TCB resistance. RNA-sequencing and functional experiments are ongoing to investigate this and will be presented.
Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.
Authors: Ohmura Hirofumi , Yamaguchi Kyoko , Hanamura Fumiyasu , Ito Mamoru , Makiyama Akitaka , Uchino Keita , Shimokawa Hozumi , Esaki Taito , Mitsugi Kenji , Shibata Yoshihiro , Oda Hisanobu , Tsuchihashi Kenji , Ariyama Hiroshi , Kusaba Hitoshi , Akashi Koichi , Baba Eishi
Published: January 2019

54

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.
Pretreatment metabolomic markers associated with therapeutic responses to FOLFOX with bevacizumab in chemotherapy-naive patients with colorectal cancer.
Authors: Tanigawara Yusuke , Sugimoto Shinji , Muro Kei
Published: January 2019

540

Background: FOLFOX with bevacizumab (BV) is a standard treatment for metastatic colorectal cancer (mCRC); however, its clinical response is around 50% and there is no way to predict responders prior to therapy. In this study, we attempted to identify new biomarkers associated with positive therapeutic responses by means of a comprehensive metabolomic analysis of patient serum. Methods: Serum collected from 68 mCRC patients, who were registered in a phase II study of first-line FOLFOX with BV treatment (Nishina, JJCO 2013) was used to conduct a comprehensive metabolomic quantification analysis using a capillary electrophoresis time-of-flight mass spectrometry. Responders (Rs: n = 37) and non-responders (NRs: n = 31) were defined as those achieving a status of CR/PR and SD/PD, respectively, which were assessed by an extramural review board using RECIST. Statistical analyses were performed using a logistic regression model for treatment response and Cox proportional hazard analysis for overall survival (OS). Results: Among 470 annotated endogenous metabolites, cysteine-glutathione disulphide (CSG), gamma-glutamyl cysteine (gGC) and hypoxanthine (HPX) were identified as significant (p < 0.05) metabolites associated with positive therapeutic responses by both response and survival analyses. Patients were divided into two groups according to cutoff values of pretreatment serum levels of these metabolites. The actual response rate in the high CSG, gGC and HPX group were 86, 69 and 8% whereas those in the low group were 40, 26 and 64%, respectively. The hazard ratio (HR) for OS in CSG, gGC and HPX were 0.28 (p < 0.01), 0.37 (p < 0.01) and 2.39 (p < 0.05), respectively. Using CSG, gGC and HPX, we have developed a multivariate logistic regression model to predict Rs/NRs and survival benefit based on the three metabolite levels in pretreatment serum. Sensitivity, specificity, ROC AUC and HR of OS between Rs and NRs were 89%, 65%, 0.83 and 0.36 (p = 0.002), respectively. Conclusions: We identified three novel pretreatment serum metabolomic markers that are associated with treatment response to FOLFOX with BV in chemotherapy-naive mCRC patients. Clinical trial information: UMIN000001490.
The parametric estimation procedure to predict long-term efficacy on survival from publication data of clinical trials for metastatic colorectal cancer (mCRC).
Authors: Pak Kyongsun , Sunakawa Yu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi
Published: January 2019

541

Background: In comparative clinical trials with time-to-event outcomes, the long-term treatment effect profile is clinically crucial. The conventional non-parametric measures, i.e., the median survival times and the t-year survival rates are informative but sometimes cannot be observed due to the limited study follow-up. For example, in the PEAK trial (Schwartzberg LS et al. J Clin Oncol 2014), the group contrast over 3 years could not be adequately confirmed due to the short follow-up. To predict the subsequent survival prognosis with the limited outcome data, one may estimate the survival curve using a parametric model. Here, we illustrate the parametric estimation procedure to predict long-term efficacy using the results of two randomized controlled trials for the patients with wild-type KRAS mCRC, i.e., PRIME (Douillard JY et al. J Clin Oncol 2010, Douillard JY et al. Ann Oncol 2014) and PEAK trials. Methods: We considered both the primary and updated results for the PRIME to assess the validity of the procedure, and then estimated the long-term efficacy in the two trials. We used the reconstructed overall survival (OS) data obtained by scanning the Kaplan-Meier curves in the literature. Fitting the data to the Weibull distribution, we estimated the parametric group contrast measures including the difference in the 3- and 5-years restricted mean survival times and mean survival times. Results: The extrapolated parametric OS curves from the primary PRIME results fitted well with the observed Kaplan-Meier curves for OS in the updated results. The parametric estimations demonstrated that, in the PRIME trial, panitumumab plus FOLFOX arm increased 2.0 (95% CI: 0.1-4.0), 4.0 (0.5-7.5), and 5.4 (0.3-10.5) months in survival on average over 3-, 5-years and the entire time, respectively, compared to FOLFOX arm. In PEAK trial, compared to bevacizumab plus FOLFOX arm, panitumumab plus FOLFOX arm increased 3.6 (0.7-6.5), 7.9 (2.1-13.7), and 12.8 (0.5-25.1) months in survival on average, respectively. Conclusions: The estimators for parametric survival curve would provide the informative summaries for long-term survival profile to the clinicians and patients.
Prospective analysis of microRNA 31-3p (miR31-3p) as a predictive biomarker of response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mABs) in patients with metastatic colorectal cancer (mCRC).
Authors: Anandappa Gayathri , Lampis Andrea , Cunningham David , Kouvelakis Kyriakos , Khan Khurum , Vlachogiannis George , Tunariu Nina , Rao Sheela , Watkins David , Starling Naureen , Braconi Chiara , Peckitt Clare , Thomas Janet , Rana Isma , Begum Ruwaida , Bryant Annette , Hahne Jens , Chau Ian , Fassan Matteo , Valeri Nicola ,   Julie Duncan, The Royal Marsden Hospital NHS Foundation Trust
Published: January 2019

548

Background: RAS status in tissue and/or liquid biopsies and tumour location (sidedness) are predictive markers of patients’ response to anti-EGFR mABs. MiR-31-3p expression has been correlated with clinical benefit from anti-EGFR mABs with chemotherapy. We aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs in the PROSPECT-C trial (NCT02994888). Methods: MiR-31-3p was tested by in-situ hybridization in 91 pre-treatment (PT) core biopsies from 45 mCRC patients. Sequential tissue biopsies obtained PT, at time of best response and at disease progression were tested to monitor changes in miR-31-3p expression over treatment. In 34 patients miR-31-3p, gender, sidedness, previous lines of treatment and RAS status in PT cell free (cf) DNA were evaluated in multivariate Cox and logistic regression models. Results: Patients with low miR-31-3p expression in PT biopsies showed better overall response rate (ORR: 58.3% vs 22.2%), median progression free survival (mPFS: 4.21 vs 2.27 months) and overall survival (mOS: 4.21 vs 2.27 mo) compared to those with high miR-31-3p expression (Hazard Ratio for PFS high vs low: 1.96; 95% CI: 0.98-3.88; p: 0.06 and HR for OS high vs low: 2.14; 95% CI: 1.04- 4.40; p: 0.04) adjusting for age, gender and sidedness. There was significant association between ORR and miR-31-3p expression (χ2 test p: 0.029). MiR-31-3p expression was an independent predictor of response, adjusting for gender, previous treatment lines and RAS (odds ratio: 0.14; 95% CI: 0.02-1.00, p: 0.048). A trend towards improved mPFS (5.10 vs 2.27 mo) and mOS (15.23 vs 4.67 mo) was noted in miR31-3p low vs high group in cfDNA RAS wild-type patients. No significant change in miR-31-3p expression were observed in archival tissue and sequential tissue biopsies. Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mABs. Further studies are needed to test if miR-31-3p combined with cfDNA RAS test can identify best responders in specific clinical niches.
Patient-derived colorectal cancer spheroids for single cell characterization of intratumor heterogenity in response to EGFR inhibition.
Authors: Kratz Jeremy D. , Sprackling Carley M. , Favreau Peter F. , Karim Mohammad R. , Pasch Cheri , Clipson Linda , Skala Melissa C , Deming Dustin A.
Published: January 2019

569

Background: Epidermal growth factor receptor inhibitors (EGFRi) have improved clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC). Molecular profiling and primary tumor sidedness are used to predict population benefit. Our group has recently demonstrated that patient-derived organotypic cancer spheroids (PDOCS) and optical metabolic imaging (OMI) can predict in vivo chemotherapy response. Translational tools are needed to characterize targeted therapeutic response to predict clinical outcomes. Methods: PDOCS were generated from patients with mCRC at time of molecular profiling. Following culture maturation, PDOCS were treated with physiologic doses of EGFRi panitumumab. Response was evaluated by change in sphere diameter and OMI to exploit intrinsic autofluorescence of NAD(P)H and FAD at spheroid and single-cell level. Effect size was calculated using Glass’s delta (GΔ) defined as differences in means between treatment groups normalized to control standard deviation with comparison to predetermined sensitivity thresholds. Results: PDOCS from pts with mCRC were generated from tissue biopsies, surgical specimens, and malignant effusions (n = 38). Mutational profiles were stratified by RAS status from next-generation sequencing. Six PDOCS were evaluable for experimental and clinical response. KRAS mutation predicted primary resistance to EGFRi with no difference in diameter (GΔ = -0.01) or single cell response by OMI (GΔ = 0.02). RAS wild-type PDOCS had significant response with decreased diameter with EGFRi (P < 0.001). Gaussian fit of single-cell analyses revealed heterogeneity in EGFRi sensitivity. Differential sensitivity to EGFRi in RAS wild-type population correlated with clinical response. Conclusions: PDOCS predict response to panitumumab in these preliminary investigations. Diameter and OMI analyses provide complementary information of line-specific sensitivity. Further studies are warranted to characterize the molecular profiles underlying intratumor heterogenity. Prospective investigations are needed to understand the predictive role of this technique in targeted therapeutic response.
Comprehensive profiling of immune landscape in gastrointestinal (GI) and head and neck (HN) cancers via computational deconvolution.
Authors: Szeto Christopher , Veerapaneni Saihitha , Kazmierczak Kevin , Benz Stephen Charles , Reddy Sandeep K. , Yan Dongyao
Published: January 2019

579

Background: Immune contexture shapes oncogenesis, tumor progression and response to therapy. Traditional techniques for studying the microenvironment, such as flow cytometry, are limited by low throughput. Recently, computational methods using transcriptomic data have enabled deconvolution of tumor immune landscape, particularly in colorectal cancer (CRC). However, the immune profiles of other GI and HN cancers remain unclear. We proposed that elucidating the immune compositions in those cancers would reveal biological insights and potentially therapeutic targets. Methods: 464 GI tumors with RNA-Seq data (∼200x106reads per tumor) from a commercial database were available for analysis. Tumors were categorized into CRC, gastroesophageal (GE), HN, and biliary cancer. A curated panel of 122 genes that discriminate between 28 immune subsets was identified. For each of these immune signatures, a database containing 1880 unselected tumors was used to define a distribution of expression. The study samples were then scored for their deviances within such distributions.In addition to immune deconvolution, each of the 464 tumors were assigned to one of the colorectal Consensus Molecular subtypes (CMS). Significant enrichment for immune subsets between locations and CMS was analyzed. Results: Unsupervised clustering revealed 2 clusters with distinct immune profiles, which largely separated CRC from HN/GE tumors (silhouette coefficient = 0.14). Eosinophils are more abundant in GI cancers than others. HN/GE tumors were characterized by abundant NK and Tregs (adj. p < 0.001), and were predominantly classified as the immune-active CMS1 (adj. p < 0.001). CRC was significantly associated with high eosinophils and fibroblasts (adj. p < 0.0001). Biliary tumors spanned both immune-type clusters, and were frequently classified as the stromal-rich CMS4 (adj. p < 0.0001). Immature dendritic cells were sparse in GI tumors, especially GE. Conclusions: Upper and lower GI tumors have distinct immune contextures, which may differentially impact the efficacy of immunotherapy. Comprehensive immune profiling may facilitate the identification of targetable immune subsets.
Liquid biopsy for optimizing the rechallenge of cetuximab in metastatic colorectal cancer: Additional study of E-Rechallenge Trial.
Authors: Ohhara Yoshihito , Shinozaki Eiji , Osawa Hiroshi , Nakamura Masato , Shindo Yoshiaki , Shiozawa Manabu , Uetake Hiroyuki , Matsumoto Hiroshi , Ureshino Norio , Satake Hironaga , Kobayashi Takaaki , Suto Takeshi , Kitano Shiro , Ohashi Yasuo , Uemura Kohei , Yamaguchi Kensei
Published: January 2019

585

Background: Several previous reports indicated that cetuximab (Cmab) rechallenge may be efficacious in some patients for whom Cmab was previously effective. Liquid biopsy can detect the some emerging mutations for resistance with Cmab. Considering the plasticity and elasticity of sensitive clone, we assumed we could identify the patients with benefit from Cmab rechallenge by liquid biopsy. This current study investigates the predictability of efficacy for Cmab rechallenge by liquid biopsy in the E-Rechallenge Trial. Methods: The E-Rechallenge Trial is a multicenter phase II study in mCRC patients who have become refractory to fluoropyrimidines, L-OHP, CPT-11, Cmab, and bevacizumab, and in whom previous treatment with Cmab was effective in any earlier line (achieving CR, PR, or SD that persisted for ≥ 6 months). The other main eligibility criteria are; RAS wild type, measurable disease, aEFI ≥ 16 weeks between the last dose of Cmab during previous treatment and the start of Cmab rechallenge. Protocol treatment is the combination of weekly Cmab with biweekly CPT-11. Additional research of ctDNA was conducted optionally. Baseline plasma samples were analyzed for KRAS, NRAS, BRAF and EGFR S492R mutations using digital PCR (LBx probe, RIKEN GENESIS). A cut-off of the mutation allele frequency was > 0.1%. Results: Between Dec. 2014 and Oct. 2017, 33 patients were enrolled. The primary endpoint; the rates of PR/SD/PD were PR 15.6%/SD 40.6%/PD 43.8%. Twenty-four of 33 patients participated in the additional research. In the additional cohort, the rates of PR/SD/PD were PR 12.5%/SD 50.0%/PD 37.5%. The mutations were detected at the baseline of Cmab rechallenge as followings; KRAS exon 2 29.2%, exon 3,4 33.3%, BRAF V600E 12.5%, EGFR S492R 12.5%. In wild type of these genes the PR and SD rate increased to 25% and 50%, respectively. Conclusions: Cmab rechallenge showed some activity in the salvage setting, in patients for whom Cmab was previously effective. KRAS, BRAF, and EGFR S492R screening by liquid biopsy may contribute to identify patients with benefit from Cmab rechallenge. The additional data of ctDNA may be provided in the conference. Clinical trial information: UMIN 000016439.
Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer.
Authors: Johnson Benny , Loree Jonathan M. , Morris Van K. , Dasari Arvind , Pant Shubham , Raghav Kanwal Pratap Singh , Kopetz Scott
Published: January 2019

596

Background: Atypical BRAF mutations (a BRAF) represent a rare molecular subtype of metastatic colorectal cancer (mCRC), distinct from BRAFV600E (class I). Preclinical data categorizes a BRAF into class II (intermediate-high kinase activity without RAS dependency) and III (low kinase activity, RAS dependent), however the clinical impact regarding these functional classes is unknown. Methods: We retrospectively analyzed 2,084 mCRC patients (pts) at MD Anderson Cancer Center (MDACC) to identify a BRAF and BRAFV600E. Clinicopathologic features were compared by chi-square or fisher’s exact test. Overall survival (OS) calculated utilizing Kaplan-Meier method and log-rank test. Statistical tests were two-sided. Results: a BRAF occurred in 36 mCRC pts (1.7%; 95% CI 1.2-2.4): 22 class III, 10 class II, 4 unclassified. The most common class II and class III BRAF codons were 469 (60%) and 594 (59%), respectively . Median OS (mOS) for a BRAF mCRC was 39.4 months (mo), without difference between class III and II. 19/36 (53%) were left sided primary tumors and 24/36 (67%) were microsatellite stable. BRAFV600E occurred in 221 mCRC pts (10.6%; 95% CI 9.3-12.0) with a mOS of 21.0 mo. In contrast to BRAFV600E which is mutually exclusive with RAS mutations, 12 pts with a BRAF were RAS mutants (class III, 7/21 [33%], class II 5/10 [50%]). Among a BRAF RAS wt pts, 11 (50%) received anti-EGFR monoclonal antibodies (mAb) (class III 7/14 [50%], class II 3/5 [60%]). There were no responses, and only three pts (all class III) achieved stable disease as best response. Median time on therapy was 4 months. Class II RAS wt pts treated with anti-EGFR mAb had mOS of 31.7 mo versus 46.8 mo for those not exposed (HR 2.0; 95% CI 0.3-15.9). Class III RAS wt pts treated with anti-EGFR mAB had mOS of 44.2 mo versus 45.7 mo for those not treated (HR 0.80; 95% CI 0.2-2.6). Conclusions: a BRAF mCRC appear to manifest improved clinical outcomes as previously reported. Despite this, the efficacy of anti-EGFR therapy appears limited in class II and III patients. Future efforts are needed to establish the predictive impact of functional classes on anti-EGFR efficacy and to design novel therapeutic strategies for a BRAF mCRC.
FOLFOX versus POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel plus FOLFOX) as a first-line treatment in advanced gastric cancer (AGC): A multicenter, randomized phase II trial, FNF-004 trial.
Authors: Lin Rongbo , Li Hui , Chen Yigui , Zhu Jinfeng , Lin Peicheng , Chen Wujin , Fang Wenzheng , Liu Jie , Zhao Shen , Fan Nanfeng
Published: January 2019

6

Background: Double regimens are commonly accepted for AGC in East Asia. However, triple regimens are recommended in west countries. POF regimen (reported in 2007, 2008, 2009, 2010 ASCO) appeared to be of good efficacy and was well tolerated in patients with AGC. Intraperitoneal paclitaxel showed high local concentration in abdominal cavity and low systemic toxicity. The aims of this study were to find out if the POF and IP PAC was more effective with manageable side effects than FOLFOX in AGC (reported in 2017 ASCO-GI for feasibility analysis). Methods: The patients with AGC were randomized to three groups. The POF consisted of a 3-hour infusion of paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-Fu bolus. The IP PAC consisted of paclitaxel 80 mg/m2 intraperitoneally plus FOLFOX. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression. The primary endpoint was PFS. Results: Between Nov 2015 and May 2018, 89 pts (30 POF, 29 IP PAC, 30 FOLFOX) were randomly allocated. PFS, OS and RR were seen in the table below. POF was better in PFS and RR than FOLFOX, although no statistically significant difference in RR. IP PAC was trend to be better in PFS than FOLFOX, but not in RR. OS was unmatured. The most common adverse events of grade 3 or 4 were neutropenia and neuropathy, but no significant difference among three groups. Conclusions: Both POF and IP PAC improved survival compared to FOLFOX. Only POF, not IP PAC, improved response rate compared to FOLFOX. Clinical trial information: NCT02845908. [Table: see text]
Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: A National Cancer Database (NCDB) analysis.
Authors: Hasan Shaakir , Renz Paul , Wegner Rodney E , Finley Gene Grant , Raj Moses S. , Monga Dulabh K. , McCormick James , Kirichenko Alexander V.
Published: January 2019

616

Background: The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. We therefore utilized the national cancer database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. Methods: We analyzed 5,086 patients between 2010-2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4,450 MSI-negative(-) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional hazard ratios were used for survival. Results: All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher grade tumors (P < 0.05). The overall pCR rate was 8.6%, including 8.9% for MSI(-) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (OR = 0.65, 95% CI 0.43 – 0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared to 73% without it (< 0.001). Conclusions: Microsatellite instability was independently associated with a reduction in pathologic complete response for locally advanced rectal cancer following neoadjuvant chemoradiation in this NCDB-based analysis.[Table: see text]
Distribution of neuroendocrine marker-positive cells in colorectal cancer tissue and adjacent mucosa.
Authors: Ogimi Takashi , Sadahiro Sotaro , Miyakita Hiroshi , Saito Gota , Chan Lin Fung , Okada Kazutake , Tanaka Akira , Suzuki Toshiyuki , Kajiwara Hiroshi
Published: January 2019

617

Background: Neuroendocrine carcinoma (NEC) is a rare disease and has been reported to most frequently arise in the right side of the colon. In the 2010 WHO classification, mixed adenoneuroendocrine carcinoma (MANEC) was defined as a neoplasm consisting of NEC and adenocarcinoma components. To clarify the histogenesis of NEC, we attempted to detect neuroendocrine marker-positive cells in cancer tissue and in the adjacent mucosa in patients with adenocarcinoma. Methods: The study group comprised 390 patients with Stage II or III colorectal adenocarcinoma between 2007 and 2012. Immunostaining was performed with anti chromogranin A, synaptophysin, and CD56 antibodies. Cases with positively stained cells in cancer tissue were defined as positive. In the adjacent mucosa, at least 5 cm from the tumor, the numbers of positive cells per 15 HPF were measured. Results: Tumor location was right side in 181 patients, left side in 173, and the rectum in 36 patients. Positive rates of Chromogranin A in cancer tissues were 23.7% in the right colon, 13.2% in the left colon, and 19.4% in the rectum. Those of synaptopysin were 35.3%, 21.9%, and 30.6%, respectively. Those of CD56 were 22.6%, 8.0%, and 16.7%, respectively. Positive rates of these three markers in right colon were significantly higher than those in left colon and rectum. (p = 0.0115, p = 0.0054, p = 0.0062). In the adjacent mucosa, the mean numbers of positive cells for chromogranin A were 62.2 ± 20.5 in the right colon, 131.9 ± 44.7 in the left colon, and 243.7 ± 60.2 in the rectum (p < 0.001). Those for synaptophysin were 47.7 ± 23.5, 95.3 ± 35.1, and 156.9 ± 56.8, respectively. (p < 0.001). There were no significant differences in the number of positive cells for CD56 among the sites (p = 0.295). Conclusions: In cancer tissue, the rate of positive staining for neuroendocrine marker-positive cells was higher in the right side of the colon, whereas in normal mucosa the rates of positive staining for these cells were higher in the sigmoid colon and the rectum. These results suggest that neuroendocrine marker-positive cells are an acquired characteristic of cancer tissue.
The prognostic value of systemic inflammatory factors in BRAF (V600E) mutant metastatic colorectal cancer (mCRC).
Authors: Martinez Lago Nieves , Covela Rúa Marta , Brozos Vazquez Elena , Fernandez Montes Ana Fernandez , de la Cámara Gómez Juan Cruz , Méndez Méndez Carlos , Jorge Fernández Mónica , Cousillas Castiñeira Antia , Suárez Begoña Graña , Quintero Aldana Guillermo Alfonso , Candamio Folgar Sonia , Salgado Fernandez Mercedes , Pellon Augusto Maria Luz , Gonzalez Villarroel Paula , Gallardo Martin Elena , Carmona Campos Marta , Vazquez Rivera Francisca , Grande Ventura Carlos , Carral Maseda Alberto , Reboredo Lopez Margarita
Published: January 2019

622

Background: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLT) and albumin levels including patients with early and advanced metastatic colorectal cancer. However, it is unknown the prognostic impact in patients with BRAF (V600E) mutant metastatic colorectal cancer (mCRC). Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university Spanish hospitals belonging to GITuD (Galician Research Group on Digestive Tumors). Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively analyzed. Results: Data from 65 pts. treated between November 2010 to June 2018 were recorded. Median age was 62.8 years (range 30-83), 55.4 % female, 75.4% ECOG PS0-1, 49.2% right-sided, 35.2% high grade, 69.2% synchronous presentation, 66.2% primary tumor resection and median metastatic locations was 2 (range 1-5). With a median follow up of 64.6 months, median OS was 12.9 months (95% CI, 9.8-16.0) and first line PFS was 4.1 months (95% CI, 2.7-5.5). NLR (HR 2.294; p = 0.004), PLR (HR 6.329; p = 0.028) and albumin levels (HR 2.575, p = 0.011) were independent prognostic factors for OS. Patients with higher NLR (> 3 vs. < 3): had a significantly lower OS 6.8 versus 17.5 months (HR 2.294; 95% CI 1.3-4.1, p = 0.004), which was also true for patients with higher PLR (> 200 vs. < 200): with OS 6.3 versus 14.5 months (HR 1.879; 95% CI 1.1-3.3, p = 0.028), while patients with low albumin had lower OS 6.8 versus 13.4 months (HR 2.575; 95% CI 1.2-5.5, p = 0.011). NLR was positively associated with PLR (p < 0.001). Neither NLR (p = 0.190) or PLR (p = 0.327) were associated with low albumin levels. A Systemic Inflammation Score (assigning one point for each factor) was predictive of survival: OS 0/1/2/3 factors were 17.7 versus 8.7 versus 9.7 versus 5.0 months (p < 0.001). Patients with Systemic Inflamation Score = 0 had significantly higher OS: 17.7 versus 8.2 months (HR 0.357; 95% CI 0.2-0.7, p = 0.001). Conclusions: NLR, PLR and albumin levels are significant prognostic factors in patients with BRAF V600E-mt mCRC.
Comprehensive molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon.
Authors: Puccini Alberto , Poorman Kelsey , Salem Mohamed E. , Goldberg Richard M. , Shields Anthony Frank , Berger Martin D , Battaglin Francesca , Tokunaga Ryuma , Naseem Madiha , Zhang Wu , Soni Shivani , Korn W. Michael , Philip Philip Agop , Marshall John , Lenz Heinz-Josef
Published: January 2019

63

Background: Signet ring cell carcinoma (SRCC) is a rare variant of adenocarcinoma, accounting for about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however little is known about the underlying molecular characteristics. Herein, we aimed to characterize the molecular features of SRCCs, and to compare the molecular profile of SRCC to adenocarcinoma; further, we assessed the impact of tumor location on the molecular profile of SRCC. Methods: SRCCs were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry, and in-situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Chi-square and t-tests were used for comparative analyses. Results: A total of 8,500 CRC and 1,100 GC were screened for SRCC histology. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%), KRAS (22%), RFN43 (16%), KMT2D (12%), KMT2C (11%), SMAD4 (10%) and BRAF (10%), while in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%), BAP1 (7%), PIK3CA (7%), ERBB2 (5%). When compared to non-SRCC histology (N=3522), CRC-SRCC (N=37) showed more frequently mutation in BRCA1 (11% vs 1%, P < .001) and less mutation in APC (19% vs 78%, P < .001), KRAS (22% vs 51%, P = .001) and TP53 (47% vs 73%, P = .001). Among GC cohort, SRCC (N=54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, and higher rate of amplification MYB compared to non-SRCC (N=540), although none of these differences were statistically significance. When we compared GC-SRCC vs. CRC-SRCC, only the mutation rate in APC (0% vs 25%) and KRAS (2% vs 22%) genes were significantly different (P < .001). Conclusions: Our research is the first to comprehensively characterize the molecular features of SRCC. Our data suggest that SRCCs harbor similar molecular profile, regardless the tumor location. On the other hand, significant differences were observed between SRCCs and non-SRCC tumors, therefore tailored therapy should be provided to these patients.
A phase I study of TAS-102 in combination with oxaliplatin (TAS-OX) for refractory metastatic colorectal cancer (mCRC).
Authors: Cecchini Michael , Kortmansky Jeremy S. , Lacy Jill , Fischbach Neal A. , Thumar Jaykumar Ranchodbhai , Sabbath Kert D. , Gomez Christina M. , Sporn Jonathan , Stein Stacey , Hochster Howard S.
Published: January 2019

630

Background: TAS-102 is an oral combination of the anti-metabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI), preventing the degradation of FTD. It is approved as mCRC monotherapy with improved survival. Oxaliplatin is often reintroduced in mCRC after progressive disease (PD) on maintenance 5-FU although response is poor. The decreased efficacy may be related to acquired 5-FU resistance. We therefore explored the safety and efficacy of oxaliplatin in combination with an alternative and non cross-resistant anti-metabolite, TAS-102. Methods: Phase 1 of TAS-OX is a 3+3 dose-escalating study at a starting dose of TAS-102 25 mg/m2 and oxaliplatin 85 mg/m2 with three dose levels (table). TAS-102 is administered days 1-5 and oxaliplatin day 1, every 2 weeks. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. The primary objective was to determine the recommended phase II dose (RP2D). Results: Twelve patients were evaluable for dose limiting toxicity (DLT). No DLTs were observed. Treatment related grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 (59%) SD and 4 (33%) PD. Conclusions: The RP2D of TAS-102 is 35 mg/m2 in combination with oxaliplatin 85 mg/m2. No DLTs were observed and no unexpected AEs were seen. The DCR in this heavily pretreated patient population is encouraging. Phase II is now enrolling at this dose (NCT 02848079). Clinical trial information: NCT02848079. [Table: see text]
Lung metastasis as predictor for prognosis in metastatic colorectal cancer with mutated KRAS.
Authors: Boursi Ben , shacham-Shmueli Einat , Lawrence Yaacov Richard , Yang Yu-Xiao , Reiss Kim Anna , Golan Talia , Mamtani Raashi , Halpern Naama , Aderka Dan , Giantonio Bruce , Margalit Ofer
Published: January 2019

636

Background: Previous studies have shown that prognosis in metastatic colorectal cancer (mCRC) may vary according to sites of metastasis. We evaluated prognosis in individuals with single site metastasis, according to several clinical and genetic variables. Methods: Using the National Cancer Database we identified 58,044 mCRC patients with a synchronous single site of metastasis. We first examined the effect of metastasis site on prognosis. In a secondary analysis, among individuals who had not undergone surgery or received radiotherapy, we examined the prognostic value of chemotherapy intensity, KRAS status, primary tumor location and CEA levels. Results: Individuals with lung metastasis had the best prognosis (HR = 0.80, 0.77-0.83), followed by those with liver metastasis (HR = 1.11, 1.07-1.15), while those with bone or brain metastasis had the worse prognosis. In a subgroup analysis, we assessed prognosis among individuals who received multi-agent chemotherapy and had not undergone surgery or received radiotherapy. Individuals with lung metastasis and mutant KRAS had better prognosis compared with those with liver metastasis, (HR = 0.69, 0.54-0.88), regardless of primary tumor location or CEA levels. Conclusions: Single site metastasis to the lungs is associated with better prognosis in mCRC, specifically among KRAS mutant tumors. This survival advantage should be taken into consideration in clinical decision-making.