bluuebunny/crossref_metadata_2025 huggingface dataset:
Health economic analysis of doublet chemotherapy with and without bevacizumab for first-line treatment of RAS mutant metastatic colorectal cancer based on real-world data.
Authors: Degeling Koen , Wong Hui-Li , Pereira-Salgado Amanda , Kosmider Suzanne , Wong Rachel , Tie Jeanne , Stefanou Greg , Nott Louise M. , Shapiro Jeremy David , Richardson Gary Edward , Gibbs Peter , IJzerman Maarten J. ,   TRACC Collaboration
Published: May 2020

e16048

Background: Bevacizumab remains the dominant biologic treatment option for RAS mutant (RASmt) metastatic colorectal cancer (mCRC). While the health economic impact of bevacizumab in the RASmt subpopulation may deviate from its use in the general mCRC population, this has never been investigated. This study uses the power of real-world data to assess the cost-effectiveness of doublet chemotherapy with compared to without bevacizumab (ChemBev and ChemOnly, respectively) for first-line treatment of RASmt mCRC, while accounting for subsequent treatment in second and third line. Methods: Data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was analyzed to populate a discrete event simulation of three treatment lines, surgery of primary tumor and metastases, hospitalizations following serious adverse events, and best supportive care. Imbalance in baseline patient and disease characteristics was corrected for in all analyses using inverse probability weights. Costs were included from an Australian public payer perspective in Australian dollars (AUD). All health and economic outcomes were discounted at 5% per year. Results: Of the 507 included RASmt mCRC patients that started first-line treatment in the 2010 – 2017 time period, 345 received ChemBev and 162 ChemOnly. The corrected median time on first-line treatment was 7.1 months (95% confidence interval: 6.4 – 8.0) for ChemBev and 4.1 months (3.5 – 5.1) for ChemOnly. Time on second- and third-line treatment was comparable between the groups. Corrected overall survival was 22.6 months (21.7 – 24.0) for ChemBev and 14.3 months (12.1 – 21.7) for ChemOnly. In terms of the health economic impact, mean life years were 1.9 for ChemBev and 1.5 for ChemOnly, and mean costs were AUD 93,025 and AUD 44,929 per patient, respectively. The resulting incremental cost-effectiveness ratio (ICER) of ChemBev compared to ChemOnly was AUD 149,317 per life-year gained (LYG). Conclusions: In contrast to results from clinical trials, overall survival was substantially longer for patients who received bevacizumab, which can possibly be attributed to an imbalance between groups despite correction for known prognostic factors. At an ICER of AUD 149,317 per LYG, the economic burden of upfront treatment with bevacizumab was found to be substantial and consistent with estimates for the general mCRC population. This is mainly caused by the duration of first-line treatment, which was significantly longer for ChemBev.
Clinically relevant multi-omic analysis of colorectal cancer.
Authors: von der Heyde Silvia , Krawczyk Margarita , Bischof Julia , Corwin Thomas , Frommolt Peter , Woodsmith Jonathan , Juhl Hartmut
Published: May 2020

e16063

Background: Cancer is a highly heterogeneous disease, both intra- and inter-individually consisting of complex phenotypes and systems biology. Although genomic data has contributed greatly towards the identification of cancer-specific mutations and the progress of precision medicine, genomic alterations are only one of several important biological drivers of cancer. Furthermore, single-layer omics represent only a small piece of the cancer biology puzzle and provide only partial clues to connecting genotype with clinically relevant phenotypic data. A more integrated approach is urgently needed to unravel the underpinnings of molecular signatures and the phenotypic manifestation of cancer hallmarks. Methods: Here we characterize a colorectal cancer (CRC) cohort of 500 patients across multiple distinct omic data types. Across this CRC cohort, we defined clinically relevant whole genome sequencing based metrics such as micro-satellite-instability (MSI) status, and furthermore investigate gene expression at the transcript level using RNA-Seq, as well as at the proteomic level using tandem mass spectrometry. We further characterized a subgroup of 100 of these patients through 16s rRNA sequencing to identify associated microbiome profiles. Results: We combined these analyses with comprehensive clinical data to observe the impact of ascertained molecular signatures on the CRC patient cohort. Here, we report how patient survival correlates both with specific molecular events across individual omic data types, as well as with combined multi-omic analyses. Conclusions: This project highlights the utility of integrating multiple distinct data types to obtain a more comprehensive overview of the molecular mechanisms underpinning colo-rectal cancer. Furthermore, through combining identified aberrant molecular mechanisms with clinical reports, multi-omic data can be prioritized through their impact on patient cohort survival.
A new CRISPR mediated intestinal tumor mouse model targeting four canonical tumor suppressor genes.
Authors: Kashima Hajime , Veronese-Paniagua Daniel , Fischer Anthony , Madison Blair , Rubin Deborah
Published: May 2020

e16064

Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]
Assessing real-world outcomes in metastatic colorectal cancer with KRASG12C mutation.
Authors: Wong Hui-Li , Cui Wanyuan , Loft Matthew , Lee Margaret , Wong Rachel , Shapiro Jeremy David , Tie Jeanne , Lee Belinda , Cooray Prasad , Zimet Allan Solomon , Gibbs Peter , Solomon Benjamin J. , Desai Jayesh ,   TRACC Collaboration
Published: May 2020

e16072

Background: The KRASG12C mutation is present in 3% of colorectal cancer and is of particular interest given the recent development of specific targeting drugs. Previous data suggest KRAS (all) mutations may impact prognosis. Here we assess the clinical features and outcomes of real world patients with KRASG12C mutant metastatic colorectal cancer (mCRC) to explore any clinicopathologic associations and prognostic impact. Methods: Patients diagnosed with mCRC between January 2011 and December 2018 were included in this prospective mCRC registry. Patients with BRAF mutations, unknown or unspecified KRAS variants were excluded. Clinicopathologic features, treatment and overall survival (OS) were compared for RAS wildtype (RASWT) and KRASG12C mutant patients, and between KRASG12C and other (RASother) mutations. Results: Of 1308 patients analysed, 674 (52%) were RASmut, of whom 56 (8.3%) were KRASG12C. More patients with KRASG12C were female compared to RASother and RASWT (Table). No differences were observed in primary tumor location, number of metastatic sites and distribution of metastases. The proportion of patients undergoing metastasectomy was similar between KRASG12C and RASother, and KRASG12C and RASWT. There was no difference in the proportion of patients receiving systemic therapy. RASWT patients received more lines of therapy. Median OS was similar between KRASG12C, RASother, and RASWT: 31.7 vs 29.2 vs 31.8 months respectively (P = 0.545). Conclusions: KRASG12C mutations were observed in 4.3% of mCRC patients and in 8.3% of RAS mutant cases. Patients with KRASG12C have comparable clinical features to RASWT or RASother mCRC. Treatment and survival were also similar between groups. KRASG12C does not appear to be prognostic, but may be an important predictive biomarker as promising targeted therapies continue to be developed. [Table: see text]
Trends in colorectal cancer incidence in India.
Authors: Mathew Thomas Vinay , Baby Basil , Wang Kevin , Lei Feitong , Chen Quan , Huang Bin , Mathew Aju
Published: May 2020

e16084

Background: Colorectal cancer (CRC) accounts for 10% of global cancer deaths yearly. It is postulated that the incidence rates are rising in developing countries like India. We present a comprehensive overview of colorectal cancer incidence in India from various regions from 2004 to 2014. Methods: We obtained data on CRC incidence from the Population Based Cancer Registries (PBCR) of the National Cancer Registry Program. We calculated age-standardized incidence rates (to WHO World Standard Population 2000) for five-year age groups for period of diagnosis (2004-05, 2006-08, 2009-11, and 2012-14). Results: From 2004 to 2014, CRC incidence rates in India increased by 20%. During 2004-2005, the incidence rate of CRC was 5.8 per 100,000 persons. It increased to 6.9 during 2012-2014. Conclusions: CRC rates are rising in India. Even though the absolute rates are low in the Indian population, the rising rates pose a problem in rising cancer morbidity in India. The rising rates can be attributed to changing lifestyles that include consumption of calorie-rich and low fibre diet, excessive use of red meat and processed foods, and physical inactivity. There is a need for cost-effective strategies to enable early diagnosis for colorectal cancer in India. Affordable and equitable treatment will help increase the 5-year survival rates of colorectal cancers. [Table: see text]
Predictive and prognostic factors of apatinib in metastatic colorectal cancer.
Authors: Wang Fen , Wang Shubin , Yuan Xia , Jia Jun , Bi Xiaoxia , Zhou Zeqiang , Zhou Qiming , Li Xia , Luo Changguo , Deng Minghui , Yi Liangjie , Li Yong , Lu Jianxin , Su Wenzhi , Chen Hanbin , Zhu Yu
Published: May 2020

e16092

Background: It has been extremely challenging to identify suitable predictive or prognostic factors of anti-VEGF agents. Apatinib, a vascular endothelial growth factor receptor 2(VEGFR-2) inhibitor, showed promising efficacy in chemo-refractory metastatic colorectal cancer (mCRC) patients in a phase II trial. The aim of current study was to identify the potential predictive and prognostic factors of apatinib in this phase II trial. Methods: A total of 48 patients with mCRC who had failed from standard fluorouracil-containing chemotherapies were recruited in this prospective single-arm study. Apatinib at a 500mg dose was administered daily continuously. Clinical parameters, including patients background, biochemical parameters at baseline, tumor markers at baseline and day 28, and adverse events in initial 28 days were evaluated to identify predictive and prognostic factors. The median neutrophil/lymphocyte ratio (NLR) was adopted as a cutoff value to discriminate patients with low versus high NLR. Early tumor marker decrease was defined as an abnormal parameter with a decrease of > 10% by day 28. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR1900020503. Results: Patients characteristics were not associated with differences in PFS and OS. Seven (14.6%) and 11 (22.9%) patients had initial normal CEA and CA19-9, respectively, and were excluded from the analysis of tumor markers. The median NLR were 4.1. In univariate analysis, low baseline NLR, early CA19-9 decrease, and the hand-foot syndrome (HFS) were associated with good progression-free survival (PFS) [NLR, HR 0.38 (95% CI 0.16–0.89), P = 0.027; CA19-9, HR 0.37 (95% CI 0.16-0.83), P = 0.016; HFS HR 0.23 (95% CI 0.08-0.68, P = 0.007); respectively]. Low baseline NLR and early CA19-9 decrease were also associated with good overall survival (OS) [NLR, HR 0.34 (95% CI 0.17–0.67), P = 0.002; CA19-9, HR 0.46 (95% CI 0.23-0.95), P = 0.035; respectively]. NLR and HFS retained a significant association with PFS [NLR, HR 0.36 (95% CI 0.15–0.84), P = 0.019; HFS, HR 0.25 (95% CI 0.08–0.77), P = 0.016; respectively] while only NLR retained a significant association with OS [NLR, HR 0.35 (95% CI 0.17–0.70), P = 0.019] in the multivariate analysis using the aforementioned factors. Conclusions: Clinical parameters including low baseline NLR, early CA19-9 decrease and HFS could be positive predictive factors of the efficacy of apatinib in mCRC. NLR could be the independent prognostic factor of OS in mCRC. Additional studies are warranted for further validation.
Deviation from the precisely timed phenomic ageotypes can assist in early CRC screening and reveal underlying pathophysiology.
Authors: Thyparambil Sheeno P. , You Jin , Liu Kang , Sun Hui , Peng Junjie , Cai Sanjun , Li Yaqi , Fu Chen , Bao Pingping , Li Qing , Hao Shiying , Zhang Yani , Li Zhen , Yang Jingzhi , Yin Ziyu , Yao Xiaoming , Zhu Xiurui , Schilling James , Sylvester Karl G. , Ling Xuefeng B.
Published: May 2020

e16098

Background: Human serum proteome and metabolome profiles have been analyzed to explore the molecular changes that occur with aging. We hypothesized that deep phenomic profiling of longitudinal sera would allow the identification of distinct phenomic chronologic patterns as a normal biological clock baseline to study personal aging. We further hypothesized that molecular assessment of this chronologic deviation, due to advance adenoma and early CRC, from the normal reference ageotypes would be instrumental as potential early diagnostics and reveal underlying pathophysiology. Methods: A cohort of 7673 normal, 746 advanced adenoma, 1177 stage I, 103 stage II and 119 stage III blood samples were assembled. Innovative multi-omics approaches, with global and targeted LCMS data production (metabolomics, lipidomics, and 2D proteomics), were applied to deep profile these subjects. Identification of the age-associated molecular patterns in normal subjects, modeled with an elastic net algorithm, established the reference baseline to mirror a biological clock. CRC associated deviation from this chronologically paced multi-omics clock was quantified to screen for early CRCs and explore the underlying pathophysiology. Results: Multiple mProbe aging indices of proteins and metabolites were identified, strongly predicting chronologic age ( P < 0.001, R > 0.90). Significant disruptions from normal molecular patterns were observed in advanced adenoma and early CRCs patients (R < 0.7). Pathway analysis of the proteins/metabolites with deviating patterns revealed both known and new pathways underlying CRC. Unsupervised cluster analysis identified unique aging subgroups among advanced adenoma and different stage CRC patients, indicating unique underlying biology relating to aging with different severities of cancer burdens. Conclusions: Deviations from the meticulously timed phenomic aging patterns may provide utility to allow future early CRC screening. Close examination of the underlying pathophysiology associated with early CRC, relating to ageotypes, not only may improve the sensitivity and specificity of prognostic and diagnostic tests of early CRCs, but also shed new insights into CRC therapeutics.
Copy number variation and expression of CT-genes in patients with colorectal cancer.
Authors: Gevorkyan Yuriy A. , Kutilin Denis S. , Kit Oleg I. , Soldatkina Natalya V. , Kharagezov Dmitry A. , Dashkov Andrey V. , Kaymakchi Dmitry O. , Poluektov Sergey I. , Kolesnikov Vladimir E. , Dontsov Vladimir A. , Tolmakh Roman E. , Ilchenko Sergei A. , Stateshny Oleg N. , Petrov Dmitry S. , Grechkin Fedor N. , Oganyan Nairi B. , Mirzoyan Ellada , Fomenko Yuriy A.
Published: May 2020

e16104

Background: Cancer-testis antigens (CTAs) can be used for immunotherapeutic approaches and early detection of malignant tumors. Despite numerous studies of CTA expression in various tumors, including colon tumors, the mechanisms of transcriptional activity regulation in colorectal cancer (CRC) remain poorly studied. One of the possible mechanisms of regulation of gene expression is a change in their copy number (CNV). The aim of the study was to analyze the changes in the copy number and expression of CT-genes in patients with CRC. Methods: Tumor and normal colon tissues of 81 patients were used in the study. DNA was isolated by phenol-chloroform extraction. RNA was isolated by the Chomczynski&Sacchi method (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Determination of expression and copy number of 16 CT genes ( MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) was performed using the Real-Time qPCR method (reference genes - GAPDH and GUSB). Differences were evaluated using the Mann-Whitney test, correlation analysis - using Spearman's rank correlation coefficient (r). Results: An analysis of CT-gene expression and CNV in tumor and normal colon tissues (n = 81) revealed a statistically significant (p < 0.05) difference between these parameters in tumor tissue relative to normal one: for MAGEB1 an increase of 2.0 and 2.7 times, GAGE3 an increase of 2.0 and 2.5 times, GAGE4 decreased by 5.0 and 6.8 times, BAGE decreased by 2.4 and 1.7 times, SSX2 increased by 1.8 and 2.1 times, SCP1 increased copy number by 4.4 times and PRAME1 increased expression and copy number by 2.9 and 2.3 times, respectively. When comparing CNV and expression of 16 CT genes, a positive correlation was observed (r = 0.875). Conclusions: Thus, the aberrant expression of MAGEB1, GAGE3, GAGE4, BAGE, SSX2 and PRAME1 found in the tumor tissue of CRC patients depends on the copy number of these CT-genes.
Treatment modalities and outcomes in patients with rectal cancer (RC) in a referral center in Mexico.
Authors: Camargo Vanessa Rosas , Buerba Hector , Martinez Cruz Perla Lizeth , Anaya Sánchez Luis Guillermo , Cedro-Tanda Alberto , Caballero Rosa , Nieto Garcia Zuleyma , Meneses Medina Mónica Isabel , Flores Balcázar Christian Haydeé , Gamboa Dominguez Armando , Salgado Nesme Noel , Huitzil Melendez Fidel David
Published: May 2020

e16105

Background: Regarding cancer care, health system in Mexico is characterized by heterogeneous medical and technical infrastructure among institutions. Limited access to specialized surgeons, radiation therapy and medications may differ and affect survival. Our institution has surgeons, medical oncologists and radiation therapy for the treatment of uninsured low-income patients with RC. The institution does not provide chemotherapy or biologic therapy. Our aim was to describe treatment modalities and outcomes in patients (pts) with RC treated in a referral center in Mexico. Methods: A retrospective database of all consecutive pts with histological diagnosis of rectal adenocarcinoma evaluated at our institution from January 2010 to December 2016 was created. Clinical and pathological variables at diagnosis and treatment modalities were recorded. Overall survival (OS) was estimated using Kaplan-Meier method and compared by log rank test. Results: 99 pts were included, 61.6% male gender. Median age was 61 y/o (range 19 – 97). EGOG PS 0 – 1: 86%. 69% were moderately differentiated. Tumor location: lower (25%), middle (57%), and upper third (18%). Clinical stage (CS) was localized (T1-2, N0 M0) 5%, locally advanced (T3-4, or N+) 71% and advanced (M1) 24%. Treatment modalities (TM) by stage are presented in the Table. For those with advanced disease, 58% had metastasis in one site. RAS and BRAF mutation determination was performed in 21%. 5-year survival rate: 56%. Median OS (months): 25.3 for localized, 103.1 for locally advanced and 18.6 for advanced disease (P = 0.001). Conclusions: In our center, pts with local and regional RC had treatment according to international guidelines and survival was not compromised. On the contrary, limited access to systemic therapy affected patients with advanced disease and decreased survival was documented. To improve survival in patients with advanced disease, health policy adjustments to incorporate systemic treatment coverage are required. [Table: see text]
A novel xenonucleic acid mediated molecular clamping technology for early colorectal cancer diagnostics.
Authors: Sun Qing , Pastor Larry , Du Jinwei , Powell Michael Joseph , Zhang Aiguo , Bodmer Walter , Sha Michael Y.
Published: May 2020

e16106

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Early detection is critical to reduce CRC morbidity and mortality. In order to meet this need, we developed a molecular clamping assay called ColoScape for early colorectal cancer diagnostics. Methods: Nineteen mutations in four genes APC, KRAS, BRAF and CTNNB1 associated with early events in CRC pathogenesis are targeted in the ColoScape assay. Xenonucleic Acid (XNA) mediated qPCR clamping technology was applied to minimize the wild-type background amplification in order to improve assay sensitivity of CRC mutation detection. The assay analytical performance was verified and validated, cfDNA and FFPE CRC patient samples were assessed for clinical performance, and a ROC curve was applied to evaluate its performance. Results: The data showed that the assay analytical sensitivity is 0.5% Variant Allele Frequency, corresponding to ~7-8 copies of mutant DNA with 5ng total DNA input per test. This assay is highly reproducible with intra-assay CV < 3% and inter-assay CV < 5%. We have investigated 380 clinical samples including plasma cfDNA and FFPE samples from patients with different stages of CRC. The preliminary assay clinical specificity and sensitivity for cfDNA were 100% (95% CI, 80.3-97.5%) and 92.2% (95% CI, 94.7-100%) respectively with AUC being about 0.96; and 96% (95% CI, 77.6-99.7%) specificity and 92% (95% CI, 86.1-95.6%) sensitivity with AUC 0.94 for FFPE. Conclusions: XNA mediated molecular clamping assay is a rapid, precise, and sensitive assay for the detection of CRC mutations in cfDNA or FFPE samples.
Circulating tumor DNA to monitor treatment response and investigate resistance mechanism in BRAF inhibitor treated colorectal cancer patients.
Authors: Wang De-Shen , Li Yu-Hong , Bao Hua , Chen Xiaoxi , Hu Ming-Tao , Li Ting , Yang Hui , Ju Huai-Qiang , Wu Xue , Shao Yang , Xu Rui-hua
Published: May 2020

e16112

Background: BRAF mutations are found in about 10% of colorectal cancer (CRC) patients and is a poor prognosis factor in standard chemotherapy. Combination of BRAF and EGFR inhibition exerts a better therapeutic effective, whereas the resistance develops through undefined mechanisms. Circulating tumor DNA (ctDNA) is a non-invasive approach to assess the genetic evolution of tumors and prognosis in response to therapy, which would help better understanding the treatment response and resistance mechanism in BRAF inhibitor treated colorectal cancer patients. Methods: We performed panel next-generation sequencing of 425 cancer-related genes in 39 serial plasma samples collect from 19 patients who have BRAF V600E mutation CRC to track the resistance during the Vemurafenib treatment in combination with Irinotecan and Cetuximab (VIC) and evaluate the treatment response. Tumor responses were assessed radiologically every two months and are used to determine patients with innate or acquired resistance Results: A total of 19 patients were enrolled into the vemurafenib treatment with irinotecan and cetuximab. By January 20, 2020, treatment had been discontinued in 12 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. Among them, four patients with innate resistance (n = 4, 21.1%) were defined as those with PFS of less than 2 months, while patients (n = 15, 78.9%) with acquired resistance were defined as those with PFS of greater than 2 months. The VIC regimen demonstrated efficacy in patients with BRAF-mutant mCRC, with overall response rates was 63.2% (n = 12). Changes in levels of ctDNA at 4 weeks predicts therapeutic responses. CBLB, TP53 and APC baseline mutations were enriched in baseline samples of innate resistant patients. In contrast, MYC and Cell-cycle pathway alterations were enriched in baseline samples of patients with acquired resistance. Acquired RAS and MAPK mutations, known to confer resistance to BRAF inhibitors, were identified in 60% of acquired resistance patients. Moreover, acquired TGFBR2 and SMAD4 loss-of-function mutations were identified as novel resistant mechanism to the combination of BRAF and EGFR inhibition. Experimental validation is ongoing. Conclusions: Longitudinal analysis of ctDNA in BRAF CRC patients provides insights of molecular difference between innate and acquired resistance and gene alternation during resistance requiring. Serial ctDNA monitoring provides early indication of response to BRAF inhibitor in CRC patients.
Identifying education, knowledge and communication gaps in biomarker testing between YO-CRC patients, caregivers, and their medical team.
Authors: Newcomer Kim Lynn , Peterson Danielle , Yarden Ronit ,   N2Young Advisory Board
Published: May 2020

e16115

Background: The proportion of new young-onset colorectal cancer (YO-CRC) cases diagnosed in young people (20-49) had doubled over the past 3 decades, and it is becoming an alarming public health issue. YO-CRC patients face unique clinical challenges, as many are diagnosed at advanced stages of the disease and subjected to aggressive treatments. With the increase of targeted therapies and precision medicine available, NCCN and ASCO guidelines recommend that all stage IV, metastatic CRC patients be tested for 4 biomarkers in addition to MSI-H. However, not all eligible patients benefit from biomarker testing and biomarker-driven therapies. Methods: We conducted an online survey to assess patients, survivors and caregivers’ knowledge and understanding of biomarker testing and whether they feel empowered to discuss with their doctor different treatment options based on their unique tumor characteristics and their preferences. Results: The cross-sectional study was completed by patients and survivors (N = 885) and unrelated caregivers of YO-CRC patients (N = 203). The median age of patients and survivors was 42, and the median age of caregivers was also 42. The majority of the participants were college graduates. Although 82% of stage IV, YO-CRC patients felt informed before treatment began, only 70% indicated their tumor was tested for biomarkers, and 54% of them received biomarker testing before treatment initiation. Only 33% of patients reported they became aware of biomarkers by their medical team while others indicated resources such as internet searches, family and friends, or patient navigators. Many of the caregivers who reported that they served as a liaison between patients and medical information retrieval felt that they did not fully understand the critical aspects of the patients' medical treatment plan. Conclusions: Multiple studies have shown that patient-centered care improves patients’ outcomes. Our organization encourages patients and their families to use medical information to navigate their journey. Our patient-reported study suggests that there are gaps in patients’ and caregiver’s understanding of biomarker testing that may hinder patient's empowerment for reaching evidence-based shared-decision treatment plan together with their physicians.
Genomic biomarkers to determine survival in Multicenter Study of RAS mutations (MURAS) in patients with colorectal liver metastases receiving Y90 radioembolization treatment.
Authors: Dendy Case Meaghan , Ghodadra Anish , Novelli Paula M. , Wu Vincent , Ganguli Suvranu , Wildgruber Moritz , Kohler Michael , Robinson Charles , Kim Charles , Wang David S. , Sze Daniel Y. , Kolbeck Kenneth , Russell Lori , Ludwig Johannes M. , Uhlig Johannes , Kim Kevin
Published: May 2020

e16119

Background: Assessment of the clinical outcomes and prognostic value of genomic mutations in colorectal liver metastases treated with Y90 radioembolization. Methods: Multi-institution retrospective study of patients who underwent Y-90 radioembolization treatment after tumor genotyping was completed for CRLM. Patients treated between 2008 and 2019 were included from 7 institutions within the United States and Europe. Patient demographics, tumor characteristics, pre- and post- treatment regimens, serum laboratory evaluation and overall survival were analyzed between patients with differing histopathologic and genomic status. Tumor genotyping was obtained for KRAS, BRAF, PIK3CA, AKT, MEK, NRAS and MMR genes. Kaplan-Meier survival estimation and multivariate Cox regression were analyzed. Results: 434 patients treated with Y90 radioembolization fulfilled the inclusion criteria. Of the total cohort, 399 patients were available who had sufficient documented tumor profiling data. Average age at diagnosis was found to be 58.8 years for all patients (60.1% male, 39.9% female). Decreased survival post Y-90 treatment was shown in those patients with increased number of documented tumor mutations (n = 0,1 or ≥2 mutations: median OS 9.63 mos vs. 6.2 mos vs. 5.3 mos; p < 0.0001). Additionally, the median survival in patients with mutated BRAF was 5.0 months, as compared to 9.4 months in those patients with wild-type BRAF (p = 0.0009). Primary colon cancer sidedness was also shown to demonstrate significant difference in survival post-Y90 treatment with left sided primaries showing improved median overall survival (left = 7.5 mos vs. right = 6.3 mos; p = 0.04.) Patient demographics including gender, age and race were not shown to be significant in overall survival post-Y90 treatment (p-values > 0.05). Number of tumor mutations (p < 0.0001, HR = 1.69 CI: 1.39-2.05), BRAF status (p = 0.02, HR = 2.6 CI:1.20-4.9), primary sidedness (p = 0.01, HR = 0.65 CI:0.47-0.90), pre-treatment neutrophil-lymphocyte ratio (p = 0.04, HR = 1.42 CI: 1.02-1.98) and KRAS mutation status (p < 0.0001, HR = 1.81 CI: 1.45-2.26) all persisted as significant predictors of survival on multivariate analysis. Conclusions: Number of tumor mutations, BRAF mutation status, primary tumor sidedness, neutrophil-lymphocyte ratio and KRAS mutation status are all shown to be significant prognostic factors in patients with colorectal liver metastases receiving Y90 radioembolization.
The prognosis valve of tumor regression grade in the same ypStage patients after neoadjuvant treatment in locally advanced rectal cancer: Post-hoc analysis of a prospective trial.
Authors: Zhang Jianwei , Cai Yue , Hu Huabin , Wu Zehua , Xie Xiaoyu , Ling Jiayu , Deng Yanhong
Published: May 2020

e16129

Background: The ypStage after neoadjuvant treatment was an important prognosis factor in locally advanced rectal cancer (LARC). pCR or ypStage 0 showed best prognosis, while ypStage II-III showed poor prognosis and further adjuvant chemotherapy with FOLFOX was recommended. Tumor regression grade (TRG) was another factor to evaluate the response to neoadjuvant treatment. Even in the same ypStage, the TRG could be different. Here, we tried to analyze the prognosis valve of TRG in the same ypStage after neoadjuvant treatment in LARC from a prospective trial (FOWARC study). Methods: Patients with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil plus radiotherapy followed by surgery and seven cycles of infusional fluorouracil as adjuvant treatment, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). Survival analysis was performed on different ypStage and TRG (WHO classification) group. Results: In total, 495 patients were randomly assigned to different neoadjuvant treatment. 444 patients received surgery with a median follow-up of 45.2 months. The 3-year disease free survival (DFS) in ypStage 0, ypStage I, ypStage II and ypStage III was 95.8%, 89.2%, 71.7% and 55.1%, respectively (P < 0.0001). In TRG 0, 1, 2 and 3, the 3-year DFS was 93.3%, 83.2%, 68.4% and 63.6%, respectively (P < 0.0001). In ypStage I subgroup, TRG was not an independent prognosis factor, the 3-year DFS for TRG 1, 2 and 3 was 90.0%, 90.7% and 76.2%, respectively (P = 0.277). In ypStage II population, the 3-year DFS for TRG 1, 2 and 3 was 78.6%, 70.3% and 64.7%, respectively (P = 0.184). The ypStage III group showed great heterogeneity, the 3-year DFS for TRG 0-3 was 60.0%, 70.0%, 41.8% and 59.5%, respectively (P = 0.067). Conclusions: Both ypStage and TRG was strong prognosis factor for rectal cancer after neoadjuvant treatment. However, TRG was not an independent prognosis factor in the same ypStage after neoadjuvant treatment. Clinical trial information: NCT01211210 .
Clinical study on the tunnel approach in laparoscopic radical right hemicolectomy.
Authors: Zhang Xijie , Zhang Junli , Zhao Yuzhou
Published: May 2020

e16135

Background: The medial to lateral approach Laparoscopic right hemicolectomy complies with the “no-touch” principle, but need a demanding procedure with a steep learning curve. This study was designed to assess the superiority of the tunnel approach compared to traditional medial-to-lateral approach in laparoscopic right hemicolectomy for patients with right-sided colon cancer. Methods: The new method was called Tunnel Approach: The tunnel was formed with Toldt's gap was dissociated upward from the attachment of ileocecal part and retroperitoneum, then the right mesocolon was lifted to expose and divide the superior mesenteric blood vessel. We analyzed retrospectively the patients with resectable right-sided colon cancer confirmed by colonoscope and imaging who received the laparoscopic radical right hemicolectomy. The patients were divided into the tunnel approach (group A) and the traditional medial-to-lateral approach (group B) according to the surgical maneuver performed. Results: A total of 84 patients who received laparoscopic radical right hemicolectomy were assigned to group A (n = 42) or group B (n = 42) between January 2016 to June 2017. There was no difference in baseline characteristics including demographics, body mass index (BMI), tumor stage, tumor location and differentiation. The operation time and intraoperative blood loss in group A were significantly better than group B (137.74±22.7 vs. 153.1±28.8min, p < 0.05; 49.0±40.7 vs. 142.9±87.4ml, p < 0.05, respectively).There was no difference in tumor size(5.7±2.1 vs. 5.7±2.1cm, p>0.05), conversion to laparotomy rate(0 vs. 3, p>0.05), lymph node yield(30.5±14.4 vs. 27.9±12.7, p>0.05), time to first flatus(3.4±1.3 vs. 4.0±1.3d, p>0.05), postoperative hospital stays(10.0±2.2 vs. 12.3±3.0d, p>0.05) and complications(2 vs. 3, p>0.05) between two groups. There was no treatment-related death in both groups. Conclusions: The characteristic of “tunnel” approach is to convert the anatomy from a two-dimensional to a three-dimensional view, it showed the benefits of both speed and safety with low intraoperative conversion to laparotomy rate and mortality. This new tunnel approach right hemicolectomy is worth recommended.
Safety and feasibility of systemic anticancer therapy in gastrointestinal (GI) cancer patients on hemodialysis (HD): The largest retrospective study.
Authors: Park Jennifer , McGovern Kerri , Ledbetter Leslie , Kaley Kristin , Rodriguez Teresa , Maloney Antonia , Saif Wasif M.
Published: May 2020

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Background: There is an increasing incidence of malignancies in patients with chronic kidney disease including patients on HD. Minimal reports exist in the literature regarding optimal management of chemotherapy in HD patients. This study investigates the feasibility of chemotherapy for patients with GI malignancies who were on HD. Methods: We collected retrospective data on 37 patients on HD who were treated for a GI malignancy from 2002-2018. Data points collected included demographics, cancer type, treatment regimens, toxicity and treatment outcomes. Results: Of the 37 patients, 28 patients were male and 9 female. Ethnicity consisted of White (25), African American (7), Hispanic (2) and other (4). Diagnoses included colorectal cancer (11), gastric cancer (7), pancreatic cancer (5), carcinoma of unknown primary (3), esophageal cancer (2), gallbladder cancer (2), peritoneal cancer (2), cholangiocarcinoma (2) and others (3). 7 patients received neoadjuvant chemotherapy with 4 undergoing successful resection of tumor. The following chemotherapies were administered post-HD: 5-FU, capecitabine, carboplatin, cisplatin, epirubicin, irinotecan, oxaliplatin and navelbine. Gemcitabine, docetaxel, paclitaxel and etoposide was given prior to HD. Grade > 3 toxicities included anemia, nausea, vomiting and fatigue. Etiology of anemia was partly attributed to renal etiology. Response rate of treatments for HD patients were comparable to that of treatments for patients with normal renal function. 32 patients (86%) completed treatment as planned. Conclusions: Our data constitutes the largest set of patients with GI malignancies who received chemotherapy while on HD. Chemotherapy was feasible and needed a multi-modality approach. Our data calls for larger studies to further investigate pharmacokinetic parameters of cytotoxic drugs in hemodialysis patients to provide strong evidence based guidelines.
Patient-initiated approach to prevent oxaliplatin induced peripheral neuropathy: A social media experiment.
Authors: Cardinas Dana , George Manju , Norton Amber , Gentzel Renee
Published: May 2020

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Background: Oxaliplatin continues to be the standard of care in the adjuvant and palliative setting in colorectal cancer (CRC). Although effective in CRC treatment, it is associated with a high risk of chemotherapy induced peripheral neuropathy (CIPN), which can debilitate the patient, prevent completion of care, and deteriorate their quality of life. Methods: Colontown is a Facebook-based CRC patient and caregiver support, education and advocacy group. Live Wire, a Colontown neighborhood that was formed in 2018 to help members manage CIPN, consists of over 700 CRC patients. One member of this group applied ice on hands and feet (‘icing’) during oxaliplatin infusion to limit exposure to chemotherapy via cold-induced vasoconstriction. The member was able to prevent CIPN, gaining the attention of the entire group. Results: Subsequently, popularization of icing occurred, as administrators communicated patient experiences and relayed published results on the effect of oral icing to patients. Several Colontown members voluntarily tried it during their chemotherapy, and reported successful outcomes. Live Wire created an “icing protocol” and distributed it to patients, oncologists, and care teams, both in-person and on social media (sm). Conclusions: This real-world example highlights the role of educated patient advocates on sm. Working with these groups directly can provide insights for the medical community on measures patients can do to prevent chemotherapy-associated side effects. The limited publications on icing to prevent CIPN, although promising, have not been enough to make it a recommended standard practice. Meanwhile, voluntary participation using icing for CIPN is growing in Colontown. At this time, Colontown is discussing with oncologists and cancer centers the potential of creating a clinical trial to verify the efficacy icing has during oxaliplatin infusion as a strategy to counter CIPN. Our hope is that this patient-informed icing protocol will be able to guide the design of a clinical trial on icing. Furthermore, with this “experiment”, we hope to illustrate the advantages of serious engagement with a large patient population through the modern use of social media.
A novel XNA-based NGS panel for cancer diagnostics.
Authors: Gan Qiang , Cui Zhen , Tang Simin , Powell Michael Joseph , Zhang Aiguo , Sha Michael Y.
Published: May 2020

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Background: Identification of genetic variants with low allelic frequency using NGS method is confounded by the complexity of the human genome sequence and by bias and errors that arise during library preparation, sequencing and analysis. To overcome this, we developed a novel NGS approach employing a modified backbone nucleic acid molecule, Xenonucleic Acid (XNA) to enrich the target mutant before the sequencing. XNA enables to efficiently and selectively suppress wild type targeted DNA amplification but amplify targeted mutant alleles. Methods: We developed this XNA-based NGS for detection of mutations in lung and colorectal cancer which includes 8 genes (KRAS, NRAS, EGFR, BRAF, PIK3CA, APC, CTNNB1 and TP53) and 19 hotspots. Results: With as low as 10 ng input DNA, low allelic frequency mutant analysis powered by the XNAs in the library preparation increased the sensitivity of detection dramatically. There were, on average, 32, 24, 25 and 18-fold enrichment in variant allele frequency (VAF) for samples with original 0.10%, 0.25%, 0.50% and 1.25% VAF mutants, respectively. The analytical specificity is about 92% and analytical sensitivity (LOD) can be down to 0.10% VAF with 1000-2000X on Illumina MiSeq. The reproducibility results were obtained for intra-assays, inter-assays and inter-operator assays, and the CVs of detected VAF% were investigated. These 19 actionable mutants were validated by testing cfDNA and FFPE. Preliminary clinical sensitivity for FFPE sample is about 100% for lung cancer and colorectal cancer samples respectively, comparing to without XNA NGS about 85.7% for lung cancer and 70% for colon cancer. For cfDNA sample its clinical sensitivity is about 100% for lung and colon cancer, but without XNA mediated enrichment NGS is only about 70% for lung cancer and undetectable for early colon cancer. Conclusions: The result demonstrated that XNA can selectively block amplification of wild type alleles and leads to enrich of mutants read, and significantly increases the assay sensitivity without the requirement for NGS deeper sequencing.
Phase II expansion cohort in colorectal cancer to evaluate the safety and tolerability of RRx-001 blood mix.
Authors: Fisher George A. , Caroen Scott , Oronsky Bryan , Williams Jeannie , Reid Tony R.
Published: May 2020

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Background: In a 34 patient randomized Phase 2 trial in 3rd/4th line colorectal cancer called ROCKET (NCT02096354) of RRx-001 + irinotecan versus regorafenib + irinotecan, RRx-001 + irinotecan demonstrated improved overall survival (OS) (8.6 vs 4.7 months) and progression free survival 2 (PFS2) (7.5 vs. 1.7 months) compared to the regorafenib control arm. The main adverse event attributed to RRx-001 treatment, which involved once weekly peripheral or central infusion, was a painful infusion-related superficial phlebitis in 80% of patients. Following the randomized portion of the ROCKET trial, another 18 colorectal patients were enrolled in an expansion cohort to evaluate the safety and tolerability of an RRx-001 “blood mix”, the objective of which was mitigation of the phlebitic complications of direct RRx-001 infusion. Methods: Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly via blood mix until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle. Results: The median OS and PFS2 were 6.3 and 5.2 months, respectively, which was similar to that of RRx-001 administered by direct infusion in the randomized part of the trial. No patients experienced phlebitis. The adverse event profile was otherwise unchanged compared with direct IV infusion of RRx-001. Conclusions: The results of this expansion cohort demonstrate similar activity of RRx-001 given by blood mix followed by irinotecan to RRx-001 given by direct IV infusion followed by irinotecan.RRx-001 alleviated the pain that had been observed in the direct IV infusion and therefore allowed for a shorter infusion time without any apparent compromise in activity (based on OS/PFS2 comparability to earlier results). Finally, since phlebitis in theory may progress to deep venous thrombosis or suppurative thrombophlebitis in hypercoagulable and immunosuppressed cancer patients, blood mix RRx-001 is the preferred method of infusion. Clinical trial information: NCT02096354 .
Survival among colorectal cancer patients with a history of previous cancer.
Authors: Pruitt Sandi , Gerber David E. , Zhu Hong , Heitjan Daniel , Maddineni Bhumika , Singal Amit G , Xiong Danyi , Tavakkoli Anna , Halm Ethan , Murphy Caitlin C.
Published: May 2020

e16146

Background: A growing number of patients with colorectal cancer (CRC) have survived a previous cancer. Although little is known about their prognosis, this population is frequently excluded from clinical trials. We examined the impact of previous cancer on overall and cancer-specific survival in a population-based cohort of patients diagnosed with incident CRC. Methods: We identified patients aged ≥66 years and diagnosed with CRC between 2005-2015 in linked SEER-Medicare data. For patients with and without previous cancer, we estimated overall survival using Cox regression and cause-specific survival using competing risk regression, separately by CRC stage, while adjusting for numerous covariates and competing risk of death from previous cancer, other causes, or the incident CRC. Results: Of 112,769 CRC patients diagnosed with incident CRC, 15,935 (14.1%) had a previous cancer – most commonly prostate (32.9%) or breast (19.4%) cancer, with many 7505 (47.1%) diagnosed ≤5 years of CRC. For all CRC stages except IV in which there was no significant difference in survival, patients with previous cancer had modestly worse overall survival (hazard ratios from fully adjusted models range from 1.11-1.28 across stages; see Table). This survival disadvantage was driven by deaths due to previous cancer and other causes. Notably, most patients with previous cancer had improved CRC-specific survival. Conclusions: CRC patients who have survived a previous cancer have generally worse overall survival but superior CRC-specific survival. This evidence should be considered concurrently with concerns about trial generalizability, low accrual, and heterogeneity of participants when determining exclusion criteria. [Table: see text]