bluuebunny/crossref_metadata_2025 huggingface dataset:
Boosting pazopanib exposure by splitting intake moments: A prospective pharmacokinetic study in cancer patients.
Authors: Groenland Stefanie L. , van Eerden Ruben A.G. , Verheijen Remy B , Huitema Alwin , Mathijssen Ron H.J. , Steeghs Neeltje
Published: May 2019

3119

Background: Pazopanib is approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). Due to high (40-70%) interpatient variability in pharmacokinetic (PK) exposure, 16-20% of patients do not reach the 20 mg/L exposure threshold related to prolonged progression free survival (20 weeks versus 52 weeks, respectively) with the currently used fixed dose of 800 mg QD (Suttle, 2014; Verheijen, 2017). PK simulations showed that, due to non-linear absorption of pazopanib, splitting the intake (400 mg BID) leads to an increase in Cmin and AUC0-24h of 75% and 59%, respectively (Yu, 2017). This study aimed to show whether switching patients from an 800 mg QD to a 400 mg BID dose schedule will lead to a significant increase in PK exposure. Methods: We performed a prospective PK trial (NL6137) in which PK sampling at the 800 mg QD dose schedule occurred at day 1, after which the intake moments were split into 400 mg BID during one week, followed by PK sampling at day 8. Paired samples t-tests were used to assess differences in Cmin, Cmax and AUC0-24h between these two dose schedules. To detect an increase in PK exposure of 50% (2-sided α = 0.05 and β = 0.20), 10 evaluable patients were needed. Results: Eleven patients (6 RCC and 5 STS) have been included, of whom ten were evaluable for PK analyses. Using the 800 mg QD dose schedule mean Cmin, Cmax and AUC0-24h were 26.7 mg/L (coefficient of variation (CV%) 44.7), 46.1 mg/L (CV% 37.1) and 809 mg h/L (CV% 42.1), respectively. Switching to 400 mg BID resulted in an increase of both Cmin and AUC0-24h to 40.7 mg/L (CV% 37.0, p = 0.013) and 1059 mg h/L (CV% 33.1, p = 0.068), respectively, while Cmax did not significantly change (56.5 mg/L, CV% 33.2, p = 0.185). One patient (9%) experienced grade 3 diarrhea after splitting intake moments, leading to treatment interruption. This strategy could potentially save up to 2000 USD/patient/month compared to conventional dose increments. Conclusions: This study demonstrates that boosting pazopanib exposure by splitting intake moments leads to a significant increase in Cmin, of 52%, with acceptable tolerability. Therefore, this new dose schedule offers a safe and cost-neutral opportunity to optimize treatment for patients with low PK exposure. Clinical trial information: NL6137.
Phase 1b study of selinexor, a first-in-class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).
Authors: Malone Eoghan Ruadh , Lewin Jeremy Howard , Al-Ezzi Esmail Mutahar , Gupta Abha A. , Pedersen Pernille , Ng Michelle , Wang Lisa , Rodriguez Angela , Abdul Razak Albiruni Ryan
Published: May 2019

3123

Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination with doxorubicin in pts with incurable STS. Methods: This phase 1b study was conducted using a bayesian model (modified toxicity probability index). Patients with locally advanced or metastatic STS received selinexor at either 60 or 80mg weekly PO plus doxorubicin (75mg/m2 IV q21 days, max 6 cycles). Pts with stable disease (SD) or better (per RECIST 1.1 criteria) after 6 cycles of combination treatment received selinexor monotherapy until disease progression or unacceptable toxicity. Disease assessments were made with standard imaging after every 2 cycles. Results: 24 pts (19F/5M, ECOG 0/1: 12/12, median age 58.5 years [range 34-74]) were enrolled. Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumor (n = 3) and other sarcomas (n = 15). Three pts at 60mg selinexor and 21 pts at 80mg selinexor were treated. The most common G3 drug related adverse events were hematological, neutropenia n = 13 (54%), anemia n = 6 (25%). There were 4 dose-limiting toxicities (2 febrile neutropenia, 1 vomiting and 1 unresolved fatigue) all at the 80mg dose level, but does not satisfy criteria for maximum tolerated dose. Two patients had clinically significant and relevant drop in ejection fraction, presenting with cardiac symptoms. Of the 24 evaluable pts 4 (17%) had a partial response, 16 (67%) had SD as best response and SD > 16 weeks was seen in 13 pts (54%). PK analysis of selinexor did not demonstrate changes compared to single agent profile. The estimated median PFS and OS are 5.5 (95% CI:4.1-7.0) and 9.4 (6.6-13.8) months. Conclusions: Our initial data demonstrate that the combination of selinexor at 80mg with doxorubicin is tolerable and is associated with clinical benefit. Longer term follow up of available patients will be needed to understand toxicity profile. Clinical trial information: NCT03042819.
Measuring phospho-MET by multiplex immunofluorescence to aid in selection of patients with MET activation in tumors.
Authors: Navas Tony , Srivastava Apurva K. , Govindharajulu Jeevan P , Evrard Yvonne A. , Borgel Susanne , Carter John , Chen Li , Das Biswajit , Divelbiss Raymond , Karlovich Chris , Patidar Rajesh , Radzyminski Marianne , Stottlemyer Jesse , Williams Paul M. , Hollingshead Melinda G. , Bottaro Donald , Doroshow James H. , Parchment Ralph E.
Published: May 2019

3131

Background: Currently, patient selection criteria for clinical testing of MET inhibitors are limited. Robust studies selecting patients based on MET protein expression, MET gene amplification, or mutations have not met their efficacy goals. Development of microscopy-based assays to quantify levels of phospho-MET (pMET) in tumors has been hampered by poor antibody specificity. Here, we present the development and validation of a robust, highly specific multiplex immunofluorescence assay (IFA) that measures pY1235-MET and total MET in tumor tissue. Methods: This assay utilizes antibodies to pY1235-MET (NCI-23111), total MET (D1C2), and plasma membrane (PM) marker Na+/K+-ATPase, each conjugated to a different Alexa Fluor dye. We used tumor tissue from crizotinib-treated SNU5 xenograft models to demonstrate pY1235-MET assay fitness-for-purpose and cross-platform assay concordance with our validated pMET ELISA. In addition, this IFA was validated by phospho-peptide competition using custom tissue microarrays (TMA) derived from patients with colorectal carcinoma (CRC). Finally, we developed quantitative algorithms to assess pY1235 MET levels in the plasma membrane and nucleus using PM and DAPI masks, respectively. Patient-derived xenograft models (PDX) were obtained from NCI’s Patient-Derived Models Repository (www.pdmr.cancer.gov). Results: The prevalence of high pY1235-MET expression in CRC patient specimens was greater than expected; of the 64 TMA cores evaluated, 29 (45%) and 19 (29%) had high pY1235-MET and total MET levels, respectively, as defined by mean marker area of ≥ 30 μm2/cell. To address the potential utility of pY1235-MET as a diagnostic biomarker, we examined 15 CRC PDX models by pMET ELISA and IFA. Two CRC tumor models were positive for pY1235-MET expression in both assays. The pY1235-MET IFA results and gene expression data were used to select PDX models for ongoing preclinical trials of potent MET inhibitors. Conclusions: This novel pY1235-MET IFA will enable clinicians to address the utility of activated MET as a biomarker for patient selection and/or prediction of response in clinical trials of MET inhibitors. Funded by NCI Contract No. HHSN261200800001E.
Machine learning methods with salivary metabolomics for breast cancer detection.
Authors: Murata Takeshi , Yanagisawa Takako , Kurihara Toshiaki , Kaneko Miku , Ota Sana , Enomoto Ayame , Tomita Masaru , Sugimoto Masahiro , Sunamura Makoto , Hayashida Tetsu , Kitagawa Yuko , Jinno Hiromitsu
Published: May 2019

3135

Background: Saliva is non-invasively accessible and informative biological fluid which has high potential for the early diagnosis of various diseases. The aim of this study is to develop machine learning methods and to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls. Methods: We conducted a comprehensive metabolite analysis of saliva samples obtained from 101 patients with invasive carcinoma (IC), 23 patients with ductal carcinoma in situ (DCIS) and 42 healthy controls, using capillary electrophoresis and liquid chromatography with mass spectrometry to quantify hundreds of hydrophilic metabolites. Saliva samples were collected under 9h fasting and were split into training and validation data. Conventional statistical analyses and artificial intelligence-based methods were used to access the discrimination abilities of the quantified metabolite. Multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning methods were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods. Results: Among quantified 260 metabolites, amino acids and polyamines showed significantly elevated in saliva from breast cancer patients, e.g. spermine showed the highest area under the receiver operating characteristic curves (AUC) to discriminate IC from C; 0.766 (95% confidence interval [CI]; 0.671 – 0.840, P < 0.0001). These metabolites showed no significant difference between C and DICS, i.e., these metabolites were elevated only in the samples of IC. The MLR yielded higher AUC to discriminate IC from C; 0.790 (95% CI; 0.699 – 0.859, P < 0.0001). The ADTree with ensemble approach showed the best AUC; 0.912 (95% CI; 0.838 – 0.961, P < 0.0001). In the comparison of these metabolites in the analysis of each subtype, seven metabolites were significantly different between Luminal A-like and Luminal B-like while, but few metabolites were significantly different among the other subtypes. Conclusions: These data indicated the combination of salivary metabolomic profiles including polyamines showed potential ability to screening breast cancer in a non-invasive way.
The whole genome landscape of adult metastatic sarcoma.
Authors: Zhao Eric Yang , Feng Xiaolan , Pleasance Erin D. , Ng Tony L. , Grewal Jasleen , Mohammad Nissreen , Taylor Sara Kristina , Simmons Christine E. , Srikanthan Amirrtha , Rassekh Shahrad Rod , Deyell Rebecca , Shen Yaoqing , Titmuss Emma , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Yip Stephen , Jones Steven J. M. , Marra Marco A. , Laskin Janessa J.
Published: May 2019

3137

Background: Metastatic sarcomas represent a heterogeneous, difficult to treat family of cancers with poor median overall survival of 18 months. While global sequencing initiatives have catalogued genomic variation among primary sarcomas, metastatic sarcoma is less well understood. Genome-guided targeted therapy has made promising advances but is difficult to study in sarcomas due to heterogeneity and low prevalence. Whole genome and transcriptome analysis (WGTA) can help elucidate sarcoma oncogenesis, metastasis, and potential therapeutic targets. Methods: Using whole genome (80X) and transcriptome (200M read) sequencing of 43 metastatic sarcomas across 19 subtypes, we analyzed structural variants (SV), copy-number variants (CNV), mutation signatures, gene expression, and the immune microenvironment. All prior treatments were retrieved through chart review. Results: 17 patients (40%) attempted WGTA-informed therapy, of which 8 (47%) were classified as responders. Metastatic sarcomas demonstrated recurrent CNVs, with 17p11-p12 amplification in 42% of cases. Some recurrent expression outliers were associated with potential targets (e.g. MYOCD, PMP22, COPS3) while others (e.g. ADORA2B) have not been previously observed in sarcoma. Discovery of oncogenic fusions refined diagnoses in two cases with atypical histology. Clustering by mutation signatures distinguished histological subtypes, and two signatures were novel in sarcoma: (1) a strong base excision repair signature associated with NTHL1 loss and (2) a cisplatin-associated signature exclusive to platinum-treated cases. Frequent homologous recombination deficiency was observed and was associated with response to ifosfamide in three leiomyosarcomas. Of four immunotherapy-treated cases, the only responder demonstrated outlier CIBERSORT immune infiltration score, which did not correlate with PD-L1 expression. Conclusions: This is the first in-depth WGTA of metastatic sarcoma. We found recurrent and potentially targetable CNVs, expression outliers, mutation signatures, and immune markers. Our results suggest that clinical translation is promising using actionable insights obtained through WGTA.
Prediction of biomarker status, diagnosis and outcome from histology slides using deep learning-based hypothesis free feature extraction.
Authors: Klaiman Eldad , Gildenblat Jacob , Ben-Shaul Ido , Heller Astrid , Korski Konstanty , Kiermaier Astrid Christina , Gaire Fabien
Published: May 2019

3140

Background: Recently, histological pattern signatures obtained from diagnostic H&E images have been found to predict mutation, biomarker status or outcome. We report here on a novel deep learning based framework designed to identify and extract predictive histological signatures. We have applied this framework in 3 experiments, predicting specifically the microsatellite status (MSS) of colorectal cancer (CRC), breast cancer (BC) micrometastasis in Lymph nodes (LN) and Pathologic Complete Response (pCR) in BC diagnostic biopsies. Methods: Our deep learning based algorithm was trained on histology images at 20X magnification. Algorithms were trained for binary classification for each of the three cohorts. We used 75% of the images for training and test our algorithm on the remaining 25% of the images. Cohort details are as follows: MSS for CRC: 94 patients’ H&E stained tissue images from the Roche internal CRC80 dataset (MSS n =24; MSI n = 70) were used. BC LN: 270 patients’ H&E stained tissue images from the CAMELYON16 dataset ( LN(+) n = 110 ; LN(-), n =160) were used. pCR for BC: 225 patients’ H&E stained tissue images from the Tryphaena Study BO22280, neoadjuvant, Trastuzumab/Pertuzumab chemotherapy combination trial. (pCR=111, non-pCR n=114). Results: We report and assess algorithm performance on each of the cohorts by Area Under the Curve (AUC). Prediction of MSS in the CRC80 status yielded AUC 0.9. Prediction of LN invasion on CAMELYON16 dataset yielded AUC 0.85. Prediction of pCR on the Tryphaena cohort yielded an AUC of 0.8. Conclusions: We present a new approach to generate predictive signatures based on conventional diagnostic H&E images and a novel machine learning framework. The CRC80 and CAMELYON16 cohorts served as a confidence building experiments with predictive features well known by clinicians and visually confirmed. The predictive algorithm for pCR in the Tryphaena cohort yielded both response prediction and the high predictive value FOVs. These included tissue patterns which have not until now been considered to influence on the prediction of pCR.
Reassignment of HER2 status for subgroups of breast cancer according to the 2018 updated American Society of Clinical Oncology and College of American Pathologists guidelines: The impact of combined immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) reflex testing in a large national reference laboratory.
Authors: Geiersbach Katherine , Meyer Reid G. , Kloft-Nelson Sara M. , Knutson Darlene L. , Knudson Ryan A. , Sukov William R. , Ketterling Rhett P. , Greipp Patricia T. , Jenkins Robert B.
Published: May 2019

3144

Background: Updated ASCO/CAP Guidelines for HER2 testing in breast cancer have been most impactful on the resolution of certain challenging groups of FISH results. We review the change in assignment of HER2 status in a large series of breast cancers referred to a large national reference laboratory for FISH testing since the introduction of the 2018 updated guidelines. Methods: Patient samples submitted to the Mayo Clinic Cytogenetics Laboratory (N = 2208) were analyzed by FISH. Samples with Group 2, Group 3, or Group 4 FISH results were reflexed to immunohistochemistry (IHC) in our central laboratory; FISH slides for those cases with equivocal 2+ IHC results were re-scored in the regions of invasive cancer showing more intense membranous staining. A subset of 202 samples with Group 4 FISH results were also reflexed to the previously employed reflex FISH assay (HER2/D17S122), and these were also re-analyzed according to the new reflex IHC/FISH process. Results: 382 of 2208 breast cancer samples tested (17.3%) had FISH results categorized as Group 2 (N = 17, 0.8%), Group 3 (N = 34, 1.5%), or Group 4 (N = 331, 15%) and required reflex IHC testing, and of those, 75% were 2+ equivocal and required targeted re-analysis of the FISH slide according to the 2018 updated guidelines. Re-analysis of the FISH slide resulted in switching between Groups 1-5 in 19.4% of cases, but HER2 status was changed by FISH re-scoring in only 7.7% of cases re-scored (1.0% of all samples), generally due to only minor shifts in HER2 copy number and HER2/control ratios between the initial and IHC-guided reflex FISH scores. In the subset of 202 cases tested by both reflex methods, the previously employed HER2/D17S122 reflex probe set was positive in 123 cases (60.9%), whereas reflex IHC/FISH was positive in only 10 cases (7.9%). Including positive reflex IHC (0.4%) and positive reflex FISH results (2.1%), the overall assignment of positive HER2 status on our series of 2208 cases was 11.5%. Conclusions: Overall rates of HER2 positive FISH results have declined under the most recent ASCO/CAP guideline update as a consequence of new recommendations for reflex testing for Groups 2-4. This change is largely due to reassignment of Group 2 and Group 4 results as negative in the absence of positive IHC.
BRCA1 genetic variant to predict survival in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI/bevacizumab (bev): Results from phase III TRIBE and FIRE-3 trials.
Authors: Naseem Madiha , Cao Shu , Stintzing Sebastian , Loupakis Fotios , Berger Martin D. , Puccini Alberto , Tokunaga Ryuma , Battaglin Francesca , Barzi Afsaneh , Soni Shivani , Millstein Joshua , Salem Mohamed E. , Cremolini Chiara , Zhang Wu , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef
Published: May 2019

3145

Background: BRCA muts in CRC are associated with a higher tumor mutation burden irrespective of microsatellite instability, which highlights the possibility of using PARP-inhibitors(i) in CRC in the future. Early phase studies have shown that combination of PARP-i with oxaliplatin or irinotecan enhances tumor lysis in CRC. In this study, we investigated the influence of mutations in the Homologous Repair Pathway genes on survival outcomes among mCRC pts treated with oxaliplatin or irinotecan-based regimens. Methods: The impact of selected SNPs within 4 genes (BRCA1, BRCA2, RAD51, BARD1) on OS/PFS was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 431 pts enrolled in 2 randomized trials. TRIBE FOLFIRI/bev arm (n = 215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n = 107, mPFS/OS: 11.5/31.4 mo) as validation and TRIBE FOLFOX/bev arm (n = 109, mPFS/OS: 10.8/26 mo) as control. Results: Significant associations were found among carriers of BRCA1 rs8176318 SNP, where C > A base change is known to reduce BRCA1 expression among CRC cells. In the discovery cohort, pts with A/A had shorter OS (22.4 vs 27.3 mo, P = .009) and PFS (7.5 vs 10.5 mo, P = .0006) compared to carriers of any C allele in both univariate and multivariate analysis. Same results were observed in pts with left-sided CRCs (PFS-7.5 vs 11 mo, P = .005; OS- 25.6 vs 32.3, P = .034) and among males (PFS- 7.5 vs 10.3 mo, P = .008; OS- 25.7 vs 31.3 mo, P = .008) in both uni and multivariate analysis. These results were also seen in the validation cohort: A/A carriers in left-sided CRCs had poor OS (26.1 vs 36.0 mo, P = .027) and PFS (9.5 vs 11.7 mo, P = .002. Males with A/A genotype also had poor OS (24.7 vs 32.5 mo, P = .028) and PFS 96.9 vs 12.2 mo; P = .0002). In the control cohort, A/A genotype carriers had poor tumor response in overall (P = .011) and left-sided disease (P = .034). These outcomes were independent of KRAS mutation status. No significant relationship was observed among females with mCRC. Conclusions: This is the first study to report that BRCA1 mut influence survival outcomes among mCRC pts, particularly among males and those with left-sided disease. Prospective trials are warranted to assess the utility of routine BRCA mut testing and the role of PARP-i in improving survival outcomes in this pt population.
Randomized phase III study comparing FOLFOX + bevacizumab versus folfoxiri + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥3 baseline circulating tumor cells (bCTCs).
Authors: Sastre Javier , Vieitez Jose María , Gomez-España Maria Auxilidora , Gil Calle Silvia , Salud Salvia Antonieta , Suárez Begoña Graña , Garcia-Alfonso Pilar , Martinez de Castro Eva , Quintero Aldana Guillermo Alfonso , Reina-Zoilo Juan José , González Flores Encarnación , Fernández Mercedes Salgado , Guillen Carmen , Garcia-Carbonero Rocio , Safont Maria Jose , La Casta Munoa Adelaida , García de Paredes Beatriz , Lopez Rafael , Aranda Enrique , Díaz-Rubio Eduardo ,   Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
Published: May 2019

3507

Background: FOLFOXIRI+BEV has demonstrated a survival benefit compared with FOLFIRI plus BEV (TRIBE Lancet Oncol 2015) in first-line mCRC. Nevertheless, due to its safety profile, this schedule is not recommended for all pts. In addition, we have showed that the detection of ≥3 bCTCs is a poor prognostic factor for survival (MACRO The Oncologist 2012). The VISNU-1 trial compares FOLFOX + BEV vs FOLFOXIRI + BEV in pts with mCRC and ≥3 bCTCs. Progression-free survival (PFS) is the primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Methods: This is an open, multicentric, randomized phase III trial. Patients with mCRC younger than 70 years, ECOG 0-1 were randomized to FOLFOX+BEV (arm A) or FOLFOXIRI+BEV (arm B), stratified per KRAS mutation (mutated vs WT) and number of involved organs (1 vs >1). Results: 349 pts were included in the ITT population; 177 in group A and 172 in group B. Characteristics of the pts, molecular profiling and safety analysis have been previously presented at ASCO 2018 and showed that this schedule had an acceptable toxicity profile. Efficacy analysis in the ITT population is shown in the table. Conclusions: In this population with very bad prognosis, our study met its primary endpoint. Pts who received FOLFOXIRI + Bev benefit for a statistically significative PFS and ORR. OS showed a trend of benefit in the experimental arm. According to these results, FOLFOXIRI-Bev could be considered an adequate treatment option for pts with mCRC and ≥3 bCTCs. Clinical trial information: 2012-000846-37. [Table: see text]
A randomized controlled trial of the conventional technique versus the no-touch isolation technique for primary tumor resection in patients with colon cancer: Primary analysis of Japan Clinical Oncology Group study JCOG1006.
Authors: Takii Yasumasa , Mizusawa Junki , Kanemitsu Yukihide , Komori Koji , Shiozawa Manabu , Ohue Masayuki , Nishimura Yoji , Ikeda Satoshi , Takiguchi Nobuhiro , Kobatake Takaya , Ike Hideyuki , Sato Toshihiko , Tomita Naohiro , Ota Mitsuyoshi , Masaki Tadahiko
Published: May 2019

3515

Background: The no-touch isolation technique (NTIT) aims to reduce cancer cells flowing from the primary tumor site to the liver and other organs by first ligation of blood vessels that feed the primary tumor. The efficacy of NTIT has not been proved in previous studies. To acquire the answer of an unsolved problem more than 60 years, we conducted a phase III trial to confirm the superiority of NTIT in patients with cT3/T4 colon cancer. This is the primary analysis of the disease-free survival (DFS) as the primary endpoint. Methods: Eligibility criteria included histologically proven colon cancer; tumor located in the cecum, ascending, transverse, descending, sigmoid or rectosigmoid colon; clinical T3 or T4, N0-2, M0; patients age 20-80 years. Patients were randomized preoperatively to either conventional technique (CoT) arm or NTIT arm. Operation was performed in open surgery. Patients with pathological stage III received adjuvant chemotherapy with capecitabine. The primary endpoint was DFS. Planned sample size was 850 to detect a hazard ratio (HR) of 0.732 in DFS with one-sided alpha of 5% and power of 80%. Results: A total of 853 patients were randomized (CoT: 427, NTIT: 426) between January 2011 and November 2015. The 3-year DFS were 77.3% and 76.2% in the CoT arm and NTIT arm,respectively. The HR was 1.029(95% CI 0.800-1.324); thus the superiority of NTIT was not confirmed (p = 0.59). The 3-year overall survival (OS), 3-year recurrence-free survival (RFS) and 3-year liver-recurrence-free survival (LRFS) are shown in the Table. Conclusions: The superiority of NTIT to CoT was not confirmed. NTIT does not improve the DFS or OS, RFS, LRFS in the patents with stage II and III colon cancer. Clinical trial information: UMIN000004957. [Table: see text]
A pooled analysis of multicenter cohort studies of post-surgery circulating tumor DNA (ctDNA) in early stage colorectal cancer (CRC).
Authors: Tie Jeanne , Cohen Joshua , Wang Yuxuan , Li Lu , Lee Margaret , Wong Rachel , Kosmider Suzanne , Wong Hui-Li , Lee Belinda , Burge Matthew E. , Yip Desmond , Karapetis Christos Stelios , Price Timothy Jay , Tebbutt Niall C. , Haydon Andrew Mark , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter
Published: May 2019

3518

Background: Studies in multiple tumor types have demonstrated the prognostic impact of ctDNA analysis after curative intent surgery. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. Further review of existing study data could increase the precision of ctDNA guided adjuvant therapy decision making. Methods: We combined individual patient (pt) data from three independent prospective cohort studies that enrolled 485 pts with stage II or III CRC. Clinicians were blinded to ctDNA results. We evaluated pt outcomes over a 5-year follow-up period (median, 47.2 months). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using Safe-SeqS. Results: ctDNA was detected after surgery in 59 (12%) pts overall (11.0%, 12.5% and 13.8% respectively for samples taken at 4-6, 6-8 and 8-10 weeks; P = 0.740). ctDNA detection was associated with nodal status; 8.7%, 16.7% and 32.4% in N0, N1 and N2 disease (P < 0.001), but remained an independent adverse prognostic factor in multivariable analysis. ctDNA detection was associated with poor overall survival for pts treated (mortality ratio, 3.0; P = 0.026) or not treated with adjuvant chemotherapy (mortality ratio, 5.17; P < 0.001). The median MAF (mutant allele frequency) in pts with detectable ctDNA was 0.046%. For pts not treated with adjuvant chemotherapy, 3 year recurrence free survival (RFS) was 9% in pts with a MAF > 0.046% vs 33% with a MAF ≤ 0.046% (HR, 2.7; P = 0.032). For chemotherapy treated pts, 3 year RFS was 25% in pts with a MAF > 0.046% vs 70% with a MAF ≤ 0.046 (HR, 3.1; P = 0.025). In 90 pts with recurrence, ctDNA had been detected post surgery in 3 of 20 (15%) with locoregional recurrence, 27 of 60 (45%) with distant recurrence and 5 of 10 (50%) with both (P = 0.044). Conclusions: Where samples for ctDNA analysis were collected 4 to 10 weeks post surgery, sampling timing may not significantly impact detection rates. The prognostic significance of ctDNA detection can be further stratified by MAF level, but MAF level may not impact adjuvant treatment benefit. ctDNA analysis is most sensitive for detecting minimal residual disease at distant sites.
Recent changes in overall survival of real-life stage IV colorectal cancer patients.
Authors: Hamers Patricia , Bos Amanda C.R.K. , May Anne Maria , Punt Cornelis J. A. , Koopman Miriam , Vink Geraldine R.
Published: May 2019

3522

Background: In the past decade, the reported median overall survival (mOS) in phase 3 trials of metastatic colorectal cancer (mCRC) patients increased from approximately 16 to over 36 months. However, only 2.5-20% of cancer patients participate in clinical studies and these are often patients with favourable prognostic factors. Therefore, we explored for which proportion of real-life stage IV CRC patients OS improved in recent years. Methods: Nationwide population-based data of all stage IV (synchronous metastatic) CRC patients diagnosed between 2008-2016 in the Netherlands who received local and/or systemic antitumor therapy were obtained from the Netherlands Cancer Registry (NCR). Initial treatment was registered in the NCR. Vital status was recorded until January 31st 2018. OS per incidence year was determined for various percentiles, which represent the number of months after which 10-30-50-70-80-90% of the patients had died. For some percentiles survival time exceeded follow-up duration. Results: The total study population comprised 21,047 patients. mOS remained unchanged in the period 2008-2016 at around 15 months. OS of p10 and p30 increased by 1,5 months to 3,6 and 10,0 respectively. For the ‘best’ (longest-living) patients (p70-p80) OS improved in the period 2008-2016 by 4 and 6 months to 30 and 43 months, respectively. Follow-up duration is insufficient to analyse change over time for the 10% ‘best’ patients. mOS did not change for any of the treatment subgroups except for the patients who received exclusively non-systemic therapy (e.g. metastasectomy, radiotherapy) in which mOS improved by 11 months to almost 20 months. Conclusions: mOS of real-life stage IV CRC patients has not improved since 2008. We observed a clinically relevant survival improvement in only 30% of all treated patients and in all patients who received exclusively non-systemic therapy. These data illustrate the different outcomes between trial patients and total patient population, which emphasizes that trial patients represent a selection of patients with favourable prognosis. Our results highlight the value of real-life data to determine efficacy of innovations in daily clinical practice.
A regulatory program that promotes metastasis in colorectal cancer (CRC) through modulation of mRNA stability.
Authors: Goodarzi Hani , Warren Robert S. , Yu Johnny , Fish Lisa
Published: May 2019

3523

Background: CRC progression accompanies dysregulations in pathways of gene expression control. Regulatory pathways that govern RNA decay have emerged as key mechanisms coopted by cancer cells. Here, we have described a novel regulatory program that acts as a suppressor of metastasis in CRC. Methods: We have developed a computational approach called PRADA that identifies master regulators of aberrant mRNA stability. By applying this tool to a compendium of gene expression data collected from patient samples and colon cancer cell lines, we have identified a novel regulatory program involved in CRC metastasis. We have used xenograft models and genomic technologies to functionally dissect this pathway. We have also performed multivariate analysis in public datasets, as well as qPCR-based measurements in tumor samples to establish its clinical relevance. Results: PRADA identified the RNA-binding protein RBMS1 as a key factor in CRC metastasis. RBMS1, which is silenced in highly metastatic cells, binds and stabilizes a large regulon of mRNAs. Silencing RBMS1 in established lines resulted in increased liver colonization in xenograft models and its over-expression reduced metastasis. We also identified the set of genes that are directly bound and regulated by RBMS1 and function downstream. Loss of RBMS1 and its regulon provide a signature predictive of RFS in localized CRC (n = 574, HR = 0.48, p = 0.038) even when controlled for known prognostic factors in a multivariate analysis (Table). We also observed a 4-fold reduction (P<1e-3) in the expression of RBMS1 in stage IV tumors relative to earlier stage disease. Conclusions: In sum, we have discovered a previously unknown regulatory pathway of RNA stability that acts as a suppressor of metastasis in CRC which may inform new therapeutic targets among the RBMS1 regulon for adjuvant therapy.[Table: see text]
ROCKET: A randomized, multicenter phase 2 study of RRx-001 + irinotecan versus regorafenib in 3rd/4th line colorectal cancer.
Authors: Reid Tony R. , Fisher George A.
Published: May 2019

3526

Background: The purpose of this study was to assess the efficacy of combination therapy with RRx-001, an aerospace-derived macrophage repolarizing agent with epigenetic and vascular normalization properties, plus irinotecan vs. regorafenib plus irinotecan in 3rd/4th line metastatic colorectal cancer that previously received treatment with irinotecan. Methods: Between June 2014 and August 2015, 34 patients were enrolled. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. Results: The survival follow up for RRx-001 + irinotecan range was approximately 14.5 months (mean 6.0 months, median 5.0 months, standard deviation 4.5 months). The survival follow up for regorafenib range was approximately 10.8 months (mean 4.5 months, median 4.0 months, standard deviation 3.9 months). The median survival time was 8.6 months for RRx-001 + irinotecan and 4.7 months for regorafenib. The median progression free survival was 7.5 months for RRx-001 + irinotecan vs. 1.7 months for regorafenib. In addition, the toxicity profile of RRx-001 + irinotecan was dramatically improved compared with regorafenib. The regorafenib arm was terminated for futility at interim analysis, after which any enrolled patients only received RRx-001 co-infused with an aliquot of autologous blood to evaluate the safety of that method of administration. Conclusions: The results of this trial demonstrate improved efficacy and efficacy of RRx-001 + irinotecan compared with regorafenib in patients with metastatic colorectal cancer. Clinical trial information: NCT02096354.
Metastasectomy and BRAF mutation: An analysis of survival outcome in metastatic colorectal cancer.
Authors: Prasanna Thiru , Wong Rachel , Price Timothy Jay , Shapiro Jeremy David , Tie Jeanne , Wong Hui-Li , Nott Louise M. , Roder David , Lee Margaret , Kosmider Suzanne , Jalali Azim , Burge Matthew E. , Padbury Robert , Maddern Guy , Moore James , Carruthers Scott , Sorich Michael , Karapetis Christos Stelios , Gibbs Peter , Yip Desmond
Published: May 2019

3531

Background: Surgical resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether such benefit is consistently observed for BRAF V600E mutant (MT) and wild type (WT) mCRC. We conducted a retrospective analysis to explore the influence of BRAF mutation status on survival outcomes after metastasectomy. Methods: Data collected from two large prospective population databases in Australia (Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and South Australian cancer registry). Overall survival (OS) and recurrence free survival (RFS) for BRAF MT and WT mCRC were evaluated by Kaplan-Meier method and compared by log-rank test. Results: 513 patients who had undergone metastasectomy were identified, 6% were BRAF MT. Median age 63. Metastasectomy rate was lower in BRAF MT (13 v 27%). In BRAF WT, 4% underwent resection of metastases (mets) in >1 organ at diagnosis and 5% had 3 or 4 metastasectomies versus none in BRAF MT. Median OS in BRAF MT v WT: 25.7 v 48.5 months (HR 1.95; 1.18-3.22). In a multivariate model adjusting for variables which were significant on univariate analysis, OS differences were not statistically significant. Right primary tumor, intact primary, >1 metastatic sites at diagnosis, non R0 resection, peritoneal mets and synchronous mets were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 v 19 months, p=0.09). Rate of downsizing was higher with triplet chemo than doublet +/- bevacizumab or doublet/EGFR in BRAF WT (50 v 30%) as well as MT (33 v 11%). Conclusions: Median OS was > 2 years in BRAF MT V600E after metastasectomy in this study consistent with an OS benefit. OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Presence of BRAF MT should not impact patient selection for metastasectomy.[Table: see text]
Comprehensive transcriptome analysis reveals link between epigenetic dysregulation, endogenous retrovirus expression and immunogenicity in metastatic colorectal carcinoma.
Authors: Mendis Shehara Ramyalini , Topham James Thomas , Titmuss Emma , Williamson Laura , Pleasance Erin D. , Culibrk Luka , Karasinska Joanna , Liu Shiru Lucy , Lee Michael , Aird John , Moore Richard A , Mungall Andrew J. , Laskin Janessa J. , Jones Steven J. M. , Marra Marco A. , Schaeffer David F. , Renouf Daniel John , Loree Jonathan M.
Published: May 2019

3535

Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated increases in ERV mRNA as a result of DNA hypomethylation, and ERV transcription has been associated with increased immunogenicity in metastatic renal cell carcinoma. We performed comprehensive bioinformatics analysis of ERV transcription in metastatic colorectal carcinoma (mCRC), to identify novel links between ERV transcription, epigenetic dysregulation and immunogenicity in metastatic colorectal carcinoma (mCRC). Methods: Tumour samples from 63 patients with mCRC were subjected to RNA sequencing as part of the Personalized OncoGenomics program (POG; NCT02155621) at BC Cancer. Patients were enrolled between 07/2012-07/2017. ERV transcription was quantified across 702,533 distinct loci. Tumors were classified ERV-hi if their total ERV expression (RPKM) was greater than the mean across all samples. High antiviral gene expression tumors (AVG-hi) were designated as having a mean expression of IFIH1, DDX58, TLR3, TANK, TBKBP1, TBK1, IRF3 and IRF7 that was greater than the mean across all samples. All pairwise comparisons of gene expression were subjected to multiple hypothesis correction. Results: Median age was 59 years, with 34 (54%) male and 1 tumor microsatellite unstable. ERV-hi tumors showed increased expression of DNA demethylators TET2 ( q=0.0045) and TET3 ( q<0.0001). Significant overlap existed between ERV-hi and AVG-hi tumors (18/27, p=0.016). Tumors both ERV-hi and AVG-hi trended towards increased PD-L1 expression (p=0.055) and showed a significant increase in survival compared to tumors with high antiviral expression in the absence of high ERV transcription (p=0.0043). Conclusions: Our results suggest DNA demethylation drives increased ERV transcription and ERV-associated immunogenicity in mCRC. Moreover, we provide novel insight into the impact of ERV transcription on the biology of mCRC, highlighting ERV transcription as a potential biomarker and target for precision immunotherapy. Clinical trial information: NCT02155621.
A phase II study of lenvatinib in patients with metastatic colorectal cancer refractory to standard chemotherapy: LEMON study (NCCH1503).
Authors: Shoji Hirokazu , Iwasa Satoru , Kuchiba Aya , Ogawa Gakuto , Kawasaki Mamiko , Nakamura Kenichi , Mori Mikio , Honma Yoshitaka , Takashima Atsuo , Kato Ken , Boku Narikazu , Okita Natsuko , Yamada Yasuhide
Published: May 2019

3538

Background: Although regorafenib significantly improved overall survival compared with placebo for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies in the global phase III CORRECT trial, regorafenib is often discontinued due to toxicity. Lenvatinib is an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptors α, RET, and KIT, showing receptor inhibition profile and kinetics different from regorafenib. This phase II study was conducted to evaluate the efficacy and safety of lenvatinib in patients with mCRC refractory to standard chemotherapies. Methods: mCRC patients with measurable lesions, PS 0-1, and refractory to standard chemotherapies including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab (if RAS wild-type), and TAS-102 (trifluridine/tipiracil) were eligible. Prior treatment with regorafenib was not allowed. Patients received lenvatinib orally at a dose of 24 mg once daily in 28-day cycles until unacceptable toxicity or disease progression. The primary endpoint was disease control rate (DCR) assessed by independent central review. Secondary endpoints included safety, response rate, progression-free survival (PFS), and overall survival. The planned sample size was 30 patients to expect a DCR of 60% with a threshold DCR of 35%, one-sided alpha of 5% and power of 80%. Results: Between October 2016 to January 2018, 30 patients were enrolled. All had received prior chemotherapy; 14 (47%) and 16 (53%) had received 3 or ≥ 4 prior lines for advanced disease, respectively. The median number of lenvatinib cycles was 4 (range 1-13). Two patients achieved partial response and 19 patients had stable disease, resulting in a response rate of 6.7% and DCR of 70.0% (95% CI: 50.6-85.3%). Median PFS was 3.6 months (95% CI: 2.6-3.7). The most common grade ≥ 3 adverse events were hypertension (53%), elevated serum aspartate aminotransferase (13%), thrombocytopenia (10%), and anorexia (7%) without unexpected safety signals. Conclusions: Lenvatinib showed promising antitumor activity with acceptable toxicity for patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000023446.
Effect of patient age on efficacy of FOLFIRI plus cetuximab vs bevacizumab in 1st-line treatment of metastatic colorectal cancer: An analysis of FIRE-3 (AIO KRK 0306).
Authors: Heinemann Volker , Modest Dominik Paul , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Kaiser Florian , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Jung Andreas , Kirchner Thomas , Stintzing Sebastian
Published: May 2019

3541

Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. The subgroup of extended RASwt patients consisted of 400 patients. The median age of patients treated in FIRE-3 was 64 years. Analyses of efficacy of doublet-chemotherapy in patients >70 years have shown inconsistent results. Methods: In this exploratory analysis, patients were grouped into cohorts with 65 years and 70 years as a cut-off for age-related analysis of the FIRE-3 study population. ORR was compared using Fisher´s exact test, Survival analyses were done using Kaplan-Meier estimation and median survival times were compared using log-rank testing. Results: Within the RAS wt population, patients older than 70 years had a significantly shorter OS when compared to patients ≤70 years of age in both arms (p= 0.02 for cetuximab arm, p= 0.02 for bevacizumab arm). Patients ≤65 years and ≤70 years had a significantly longer OS when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab (p= 0.01 and 0.02 respectively). The OS benefit of cetuximab treated patients compared to bevacizumab treated patients was consistent for patients ≤65 years (p=0.005) and patients ≤70 years (p= 0.009) of age. In patients older than 70 years, however, comparable efficacy of bevacizumab and cetuximab was observed. This effect of age on outcome appears to be affected by sidedness. RAS wt population (n=400). Conclusions: In the overall RAS wt population, younger patients have a significant OS benefit when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab, while this was not the case in patients older than 70 years.[Table: see text]
Blood-based genomic profiling of cell-free DNA (cfDNA) to identify microsatellite instability (MSI-H), tumor mutational burden (TMB) and Wnt/B-Catenin pathway alterations in patients with gastrointestinal (GI) tract cancers.
Authors: Isaacs James , Nixon Andrew B. , Bolch Emily , Quinn Katie , Banks Kimberly , Hanks Brent Allen , Strickler John H.
Published: May 2019

3552

Background: MSI-H cancers are responsive to immune checkpoint blockade (ICB), but nearly half of all patients experience primary or early treatment resistance. Activation of the WNT/B-Catenin pathway can lead to immune exclusion and may drive resistance to ICB. Methods: 12 patients had stage III (N = 1) or IV (N = 11) MSI-H GI tract (small bowl, colon, or rectal) cancers. Blood samples were obtained after (N = 5) or during (N = 5) ICB. 2 patients did not receive ICB. Blood samples from 8 patients with microsatellite stable (MSS) metastatic colorectal cancer were included as controls. The Guardant Health (Redwood City, CA) Omni 2.0 mb panel was used to analyze cfDNA. We analyzed MSI-H status, TMB, and mutations within the WNT/B-Catenin pathway, including APC, RNF43 and CTNNB1. Results: Of 12 patients with MSI-H GI cancers, 1 sample failed enrichment due to hemolysis. MSI-H was not detected in 2 patients with a history of MSI-H in tissue; however these patients had a complete response to ICB at the time of blood collection. The Omni panel identified MSI-H in the remaining 9 patients with MSI-H disease in tissue. Among 8 control patients with MSS disease in tissue, MSI-H was not detected. Median TMB (mutations/Mb) was greater for MSI-H specimens (109; range 30-807) than for MSS specimens (13; range 6-24). All 8 patients with MSS GI cancers were identified to have APC mutations, and none were found to have CTNNB1 or RNF43 mutations. Of 9 evaluable MSI-H GI cancers, 2 had APC mutations alone. The remaining 7 carried RNF43 mutations (G659fs). All patients with RNF43 mutations were found to have disease progression while on ICB. Among these 7 patients with RNF43 mutations, 6 had additional mutations in APC or CTNNB1. Conclusions: Blood based genomic profiling can identify MSI-H cancers. Patients with MSI-H cancers resistant to ICB in this cohort have mutations in RNF43 as well as additional mutations in APC or CTNNB1, suggesting that co-activation of the WNT/B-Catenin pathway may be biologically important. Further study of the role of WNT/B-Catenin pathway activation in ICB resistance will be pursued using tumor tissue from this cohort.