bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC).
Authors: Parikh Aparna Raj , Clark Jeffrey William , Wo Jennifer Yon-Li , Yeap Beow Y , Allen Jill N. , Blaszkowsky Lawrence Scott , Ryan David P. , Giantonio Bruce J. , Weekes Colin D. , Zhu Andrew X. , Van Seventer Emily E. , Matlack Lauren , Foreman Bronwen , Ly Leilana , Drapek Lorraine C. , Ting David Tsai , Corcoran Ryan Bruce , Hong Theodore S.
Published: May 2019

3514

Background: mCRC remains a lethal cancer and immunotherapy in MSS mCRC has yet to show significant activity. In preclinical models, radiation induced cellular damage may increase responsiveness to immunotherapy via the abscopal effect, with evidence for synergy between radiation therapy (RT) and dual checkpoint blockade. In this study, we assessed dual blockade of CTLA-4 and PD-1 combined with RT as a strategy to stimulate an immune response for patients with MSS mCRC. Methods: In this open-label, single arm phase-2 study, we enrolled 40 MSS mCRC patients (pts). Eligible pts had histologically-confirmed MSS mCRC, ECOG PS 0-1, and progression on at least two lines of therapy. Treatment (Tx) consisted of ipilimumab (1mg/kg q6 weeks), nivolumab (240 mg q2 weeks) and 3 fractions of 8 Gy of RT at cycle 2 every other day. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was Disease Control Rate (DCR), with radiological evaluations every 3 months. Exploratory endpoints included ORR, PFS, OS and safety. Response was defined as disease control outside the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone (cycle 1) and 2 weeks after initiation of radiation. Intention-to-treat analysis (ITT) includes all pts receiving at least one dose of study agent. Results: 40 pts (median age 59 years (26-83), 58% male) enrolled and started treatment from 7/2017 to 12/2018. DCR was 17.5% (7/40) with a 7.5% (3/40) ORR by ITT. Median duration of disease control was 77 days in the ITT; 252 days for those with disease control (n=7) based on the first re-staging scans at 3 months or censored (n=3) and 70.5 days for pts with PD (n=17) or who did not receive RT due to clinical progression (n=13). In the modified ITT (all pts receiving RT and restaged), N=24 pts, excluding 1 pt pending 1st scans post-RT, DCR was 29.2% (7/24) and ORR 12.5% (3/24). Median duration of disease control in mITT was 77.5 days: 252 days for those with disease control and 77 days for those with PD. TRAEs were reported in 22/40 (55%). 20/40 (50%) with grade ≥3 toxicities, with fatigue, nausea, vomiting, diarrhea, infusion-related reaction and dyspnea being the most common. 1(2%) pt died of respiratory failure possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with RT is feasible and demonstrates durable activity in pts with MSS mCRC. There are 3 pts who have not completed RT or had their post-RT re-staging. We will report updated efficacy data and outcomes from correlative serial tumor biopsies upon trial completion. Clinical trial information: NCT03104439.
Tumor dynamics with fluorouracil/folinic acid, irinotecan, and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (mCRC): Central radiologic review of VOLFI—A randomized, open label, phase-2 study (AIO KRK0109).
Authors: Modest Dominik Paul , Noerenberg Dominik , Seidensticker Max , Ricke Jens , Martens Uwe Marc , Riera-Knorrenschild Jorge , Greeve Jobst , Florschütz Axel , Wessendorf Swen , Ettrich Thomas Jens , Kanzler Stephan , Held Swantje , Buechner-Steudel Petra , Atzpodien Jens , Heinemann Volker , Tannapfel Andrea , Reinacher-Schick Anke C. , Geissler Michael
Published: May 2019

3530

Background: The VOLFI trial demonstrated improved objective response rate (ORR) with the addition of pmab to modified triplet chemotherapy with FOLFOXIRI in a 2:1 (63 patients FOLFOXIRI plus pmab; 33 patients FOLFOXIRI) randomized, controlled, phase II trial in patients with untreated RAS wildtype mCRC. Methods: Radiologic images from the study were centrally examined according to RECIST 1.1. We further assessed early tumor shrinkage (=ETS: 20% shrinkage of tumor diameter at first re-assessment) and depth of response (=DpR= maximum shrinkage of lesions defined as relation of smallest tumor diameter to baseline). Moreover, time to depth of response was calculated (randomisation to depth of response image). Results: Images were available for 88 of 96 patients (91.7%), 86 patients (89.6%) had at least one follow-up image and were included in the central review. According to central review, objective response rates were 89.2% vs 66.7% with FOLFOXIRI plus pmab vs FOLFOXIRI alone (P=0.02). ETS was also significantly more frequent (Fisher’s exact test; P=0.01)) and DPR (Wilcoxon test; P= 0.004) significantly greater with pmab as compared to chemotherapy alone. See table for details. Time to DpR was similar in the panitumumab- vs chemotherapy alone arm (3.9 (95% confidence interval 2.8-4.7) vs. 4.2 (95% CI 3.6-5.7) months, respectively. P=0.63). Conclusions: In this central review, pmab significantly improves ORR, the rate of ETS and also DpR when added to a mFOLFOXIRI regimen. Our findings underline the potential of this highly active regimen in patients with RAS wildtype mCRC that need to achieve early and profound shrinkage of the tumor. Additional analysis including molecular subgroups and tumor sidedness will be shown at the meeting. Clinical trial information: NCT01328171. [Table: see text]
cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.
Authors: Harle Alexandre , Gavoille Celine , Bouche Olivier , Ben Abdelghani Meher , Plaza Jérôme Edouard , Lambert Aurélien , Spaeth Dominique , Boudrant Axelle , Ghiringhelli François , Villing Anne-Laure , Borg Christophe , Rouyer Marie , Husson Marie , Gilson Pauline , Polet Fabienne , Jones Frederick S. , Edelstein Dan , Baumard Florian , Salleron Julia , Merlin Jean-Louis
Published: May 2019

3542

Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.
ctDNA as a potential prognostic marker for locally advanced rectal cancer patients with ‘watch and wait’ approach.
Authors: Yang Lifeng , Wang Yaqi , Bao Hua , Wan Juefeng , Fan Xiaojun , Bao Hairong , Shen Lijun , Guan Yun , Wu Xue , Shao Yang , Zhu Ji , Zhang Zhen
Published: May 2019

3544

Background: ‘Watch and Wait’ policy has currently led to growing interest for organ-preservation after neoadjuvant chemoradiation (nCRT) to improve quality of life. However, how to predict and select patients who may achieve clinical complete response is still an unsolved issue. We conducted a pilot study to evaluate the potential role of ctDNA as a biomarker to predict treatment outcome and improve risk stratification in locally advanced rectal cancer (LARC). Methods: In this study, we recruited 119 patients with LARC receiving nCRT. 595 serial plasma samples were collected at d0, d15, d25 of radiotherapy as well before and 7 days post surgery. The level of ctDNA was calculated by dynamic monitoring the mutant allele frequency of somatic mutations in plasma. Plasma and tissue samples were subjected to targeted-NGS using a 422 cancer-related genes panel. We followed up patients with concomitant CT until disease progression or death. Results: Detected mutation of TP53 and APC gene in pre-treatment samples was negatively correlated with patients’ response to nCRT. Alterations in homologous recombination and adherens junction pathways were associated with a better response (P < 0.05). Detection of pre-treatment mutations in any time points during nCRT was significantly (P = 0.03) decreased from TRG3 to TRG0 group (33%, 29%, 22% and 4%, respectively); while detection of acquired mutations showed an opposite trend (P = 0.04). A predictive model based on support vector machine was developed for prediction of pCR achieving a mean AUC of 0.85 assessed by repeated cross validation. Further, detection of pre-treatment mutations after completion of nCRT was significantly associated with worse disease-free survival (DFS) (P < 0.05). Through tracking clonal extinction, persistence and emergence, patients were grouped into four evolutionary subtypes with distinct TRG and DFS. Conclusions: Our data showed the prognostic value of ctDNA on DFS. Dynamic monitoring of ctDNA can be used to predict TRG and prognosis in LARC patients receiving nCRT. ctDNA sequencing depicts the evolutionary trajectories of sensitive and resistant clones during nCRT in LARC. CtDNA could potentially be used to guide patient selection for W&W strategy.
Randomized phase II trial of adjuvant hepatic arterial infusion (HAI) + systemic FOLFIRI +/- panitumumab (Pmab) in patients with resected RAS wild type colorectal cancer hepatic metastases (CRLM).
Authors: Kemeny Nancy E. , Hauser Haley , Capanu Marinela , Kingham T. Peter , Jarnagin William R. , DeMatteo Ronald P. , Cercek Andrea , Balachandran Vinod P. , Drebin Jeffery A. , D'Angelica Michael Ian
Published: May 2019

3555

Background: HAI therapy has improved recurrence free (RF) survival in several randomized trials after resection of CRLM. The purpose of this trial was to determine whether systemic Pmab added to adjuvant HAI + FOLFIRI in RAS WT pts increases 15 months RF survival (RFS) after liver resection. Secondary endpoints are evaluation of overall survival, toxicity, and predictive biomarkers. Methods: RAS WT pts with resected liver mets were randomized to HAI + SYS (+/-) Pmab after stratification by clinical risk score (≥ 3 or < 3) and previous chemotherapy (Y/N). For a particular arm, if 24 or more patients (pts) were alive and RF at 15 months, the regimen in that arm would be considered worthy of further investigation. The initial dose of HAI FUDR 0.12mg/Kg + dexamethasone was infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 (irinotecan 125 mg/m2, LV 400 mg/ m2, 5FU 1000 mg/m2 48-hour continuous infusion and +/- Pmab 6mg/kg). Patient characteristics were compared between arms using Fisher’s exact test and Wilcoxon rank-sum test. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: After randomization of 75 pts, the arm receiving + Pmab met the decision rule of having ≥ 24 patients alive and RF at 15 months. The two arms had similar pt characteristics and toxicity, with the exception of Pmab related rash (Table). The 15-month RFS is 79% and 67% in +/- Pmab arms, respectively. With a median follow-up of 45 months, 3-year RFS is 65% [CL 0.45-0.78] and 42% [CL 0.24-0.57], and 3-year survival is 96% and 90% in +/-Pmab arms, respectively. Conclusions: In this trial, the addition of Pmab to HAI and SYS showed promising activity without increase in biliary toxicity and should be further investigated in a larger study. Predictive biomarkers will be presented. Clinical trial information: NCT01312857. [Table: see text]
A phase I study of PolyPEPI1018 vaccine plus maintenance therapy in patients with metastatic colorectal cancer with a predictive biomarker (OBERTO).
Authors: Hubbard Joleen Marie , Cremolini Chiara , Graham Rondell P , Moretto Roberto , Mitchelll Jessica L , Wessling Jaclynn , Toke Eniko Rita , Csiszovszki Zsolt , Lőrincz Orsolya , Molnar Levente , Somogyi Eszter , Megyesi Mónika , Pantya Kata , Tóth József , Miklós István , Lisziewicz Julianna , Lori Franco , Falcone Alfredo
Published: May 2019

3557

Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequently expressed in mCRC. These epitopes were designed to be Personal EPItopes (PEPIs), i.e. predicted by our novel PEPI test to bind to at least three autologous HLA alleles and more likely to induce T-cell responses than epitopes presented by a single HLA. Methods: mCRC patients in the first line setting received the vaccine (dose: 0.2 mg/peptide) just after the transition to maintenance therapy with a fluoropyrimidine and bevacizumab. Vaccine-specific T-cell responses were first predicted by the PEPI test (using the patient’s complete HLA genotype and antigen expression rate) and then measured by ELISpot after one cycle of vaccination. Results: Eleven patients were vaccinated with PolyPEPI1018. The most common adverse events were transient skin reactions (local inflammation at the site of the injections, e.g. erythema, redness and itchiness) and flu-like syndrome. No grade 3 or higher adverse events related to the vaccine occurred. Initial analysis on 4 patients demonstrated that T-cell responses were elicited by 96% of vaccine peptides. The overall percentage agreement between PEPI test-predicted and Elispot-measured CD8+ T cell responses was 71%, consistent with our retrospective analysis on 64 vaccine clinical trials involving 1,790 patients. Two of these 4 patients had unexpected tumor size reduction. Based on these encouraging results, the trial was amended to administer 3 doses of PolyPEPI1018 given 12 weeks apart. Conclusions: PolyPEPI1018 combined with maintenance therapy was safe and well-tolerated in mCRC patients. Unprecedented immune responses were induced after single dose, with broad CRC-specific T cell responses and high accuracy prediction of CD8+ T cell responses. This promising activity in mCRC patients led to a trial amendment to administer 3 doses of PolyPEPI1018 in combination with systemic therapy. Clinical trial information: NCT03391232.
Feasibility of a national expert panel to determine resectability in patients with initially unresectable colorectal cancer liver metastases (CRLM).
Authors: Bolhuis Karen , Huiskens Joost , Dejong Cornelis H.C. , Engelbrecht Marc R.W. , Gerhards Michael F. , Grunhagen Dirk J. , de Jong Koert P. , Kazemier Geert , Klaase Joost M. , Liem Mike S.L. , van Lienden Krijn P , Molenaar I. Quintus , Patijn Gijs A. , Rijken Arjen M. , Ruers Theo M. , Swijnenburg Rutger-Jan , Verhoef Cornelis , de Wilt Johannes H.W. , Punt Cornelis J. A. , van Gulik Thomas M
Published: May 2019

3562

Background: Decision on optimal treatment strategy for CRLM remains complex because uniform (un)resectability criteria are lacking. We hypothesize that the use of an expert panel can improve the identification of patients with potentially resectable CRLM. The Dutch Colorectal Cancer Group (DCCG) Expert Panel was established in conjunction with the CAIRO5 study (Huiskens J et al. BMC Cancer 2015), a multicenter, randomized, phase-3 trial, investigating optimal systemic induction treatment in patients with initially unresectable CRLM. Here, we present the feasibility of this panel. Methods: The DCCG Expert Panel consists of 13 liver surgeons and 4 radiologists. Consensus was reached on predefined (un)resectability criteria at baseline. An online platform allowed resectability-assessment by 3 surgeons in case of inter-surgeon agreement, and 5 surgeons if they disagreed. CRLM were assessed as 1) resectable 2) potentially resectable, or 3) permanently unresectable. Patients with initially unresectable CRLM were evaluated at baseline and subsequently every 2 months as long as CRLM were considered potentially resectable. Results: Overall, 397 panel evaluations in 183 patients were analyzed. Median time to panel conclusion was 7 days (IQR 5-11 days) and 204 (51%) evaluations showed inter-surgeon disagreement, with major disagreement (resectable versus permanently unresectable) in 24 (14%) and 12 (29%) evaluations after 2 and 4 months of systemic treatment. Ultimately, 84 (79%) patients with resectable CRLM underwent resection and 23 (27%) resections included portal vein embolization or 2-stage procedures. In resectable CRLM with inter-surgeon agreement versus disagreement, R0 resection was achieved in 39 (75%) versus 28 (52%) patients, p = 0.013. Median time to recurrence was similar between resections with panel agreement versus disagreement, 8 versus 6 months, p = 0.447. Conclusions: This study shows the feasibility of a national Liver Expert Panel for prospective resectability assessment of patients with initially unresectable CRLM. High inter-surgeon disagreement supports the use of a panel. We aim to further validate the panel with outcome parameters. Clinical trial information: NCT02162563.
Factors affecting differential outcomes in the definitive treatment of anal cancer between HIV+ and HIV- patients.
Authors: Susko Matthew , Kim Stephanie , Lazar Ann , Laffan Angela , Feng Mary Uan-Sian , Venook Alan P. , Atreya Chloe Evelyn , Van Loon Katherine , Anwar Mekhail
Published: May 2019

3572

Background: Anal cancer is an uncommon malignancy with numerous factors that influence treatment outcomes. Historically, HIV+ patients were restricted from entering clinical trials, limiting data on their outcomes to small retrospective reports. This study seeks to understand the factors related to anal cancer outcomes, specifically the differences between HIV+ and HIV- patients. Methods: Inclusion criteria was non-metastatic anal squamous cell carcinoma treated with a definitive course of chemotherapy and radiation between 2005 and 2018 at a single institution. Clinical data related to baseline characteristics, treatment parameters, and post-treatment follow-up were extracted for calculation of freedom from local recurrence (FFLR) and overall survival (OS). Univariate analysis (UVA) and multivariate analysis (MVA) were done using cox proportional hazard model, and FFLR and OS were calculated using the Kaplan-Meier method. Results: During the study period, 111 patient initiated definitive treatment for anal cancer. Median age was 56.7 years (IQR: 51.4-63.5), and 47% (N = 52) were HIV+. At median follow-up of 28 months, 12 and 24-month FFLR was 84.1% and 78.2% respectively, with 24-month OS of 87.3%. MVA demonstrated significant association between FFLR and T-stage HR 4.02 (95% CI: 2.14-7.55) p < 0.001, elapsed treatment time (median of 50 days) 1.08 (95% CI: 1.04-1.12) p < 0.001, and diagnosis to treatment start (median time of 15 weeks) 1.05 (95% CI: 1.01-1.08) p = 0.005. Additional analysis with log-rank test for FFLR demonstrated significant difference between patients taking < 50 days to complete treatment (p = 0.03), and < 15 weeks from diagnosis to treatment completion (p = 0.006). In HIV+ patients, post-treatment CD4 < 150 was significantly associated with worse OS on log-rank test (p = 0.016), with pretreatment CD4 values being non-significant. Conclusions: This study represents the largest single institution report of HIV positive patients treated for anal cancer. No difference in local recurrence or overall survival between HIV+ and HIV- patients was elucidated; however, HIV+ patients with lower post-treatment CD4 counts had worse OS. The most significant predictors of local recurrence were advanced T-stage, increased time from diagnosis to treatment initiation, and prolonged treatment time.
Combination of tissues analysis and immune infiltrate in localized colon cancer using artificial intelligence in PETACC8 study.
Authors: Reichling Cynthia , Taieb Julien , Derangere Valentin , Le Malicot Karine , Emile Jean Francois , Gornet Jean Marc , Becheur Hakim , Fein Francine , Cojocarasu Oana , Kaminsky Marie-Christine , Lagasse Jean-Paul , Luet Dominique , Nguyen Suzanne , Etienne Pierre-Luc , Gasmi Mohamed , Vanoli Andr , Perrier Herve , Klopfenstein Quentin , Lepage Come , Ghiringhelli Francois
Published: May 2019

3574

Background: We used artificial intelligence to perform tissue classification and count CD3 and CD8 in each subclass and determined their role in outcome prediction in PETACC8 cohort of stage III colon cancer treated with FOLFOX or FOLFOX plus cetuximab. Methods: We developed artificial intelligence aimed to detect tumor, healthy mucosa, stroma and immune cells on whole slide of CD3 and CD8 staining. The invasive margin (IM) was also automatically determined. Using a lasso algorithm, the software was able to detect digital parameters within the tumor core (TC) which were related to patients’ outcome (variable called DGMate for DiGital tuMor pArameTErs). CD3 and CD8 lymphocytes density were also quantified automatically by the software in TC and at IM. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for age, T/N stage, sidedness, KRAS/BRAF, DNA mismatch repair (MMR). Results: On 1220 samples collected, data could be generated for 1018 patients. We observed that a high IM stromal area and a high DGMate were associated with a poorer DFS [HR 5.65 (95% CI, 2.34, 13.67), p < 0.0001; HR 2.72 (95% IC, 1.92, 3.85), p<0.001 respectively for the continuous variable]. A higher density of CD3+ TC, CD3+ IM and CD8+ TC were significantly associated with a longer DFS (HR 0.75 (95% IC, .66, .87), p<0.0001; HR 0.78 (95% IC, .68, .88), p<0.0001; HR 0.83 (95% IC, .71, .96), p=0.01). All these immune variables were significantly correlated with each other. ANOVA test demonstrated that CD3+ TC gave a similar prognostic value compared to the classical CD3/CD8 immunoscore (p=0.44). The combination of IM stromal area, DGMate and CD3 outperformed the classical CD3/CD8 immunoscore to estimate patients’ prognosis (C-index= 0.601 vs 0.578, p-value=0.04). Adding this new variable to classical clinical prognostic parameters we generated a nomogram which predicted the risk of relapse of stage III colon cancer with a stronger predictive value compared to clinical parameters or the immunoscore. Conclusions: We propose a new fully automated method of whole slide analysis using a software based on artificial intelligence which classify tissue and determine tumor and immune parameters on one single slide stained with CD3 antibody. This valuable strategy outperforms immunoscore and clinical outcome prediction models.
Dissection of the lateral lymph nodes with short axis of ≥ 5 mm affects the prognosis in rectal cancer patients: A central review of 738 lower rectal cancer magnetic resonance images.
Authors: Hida Koya , Nishizaki Daisuke , Sumii Atsuhiko , Sakai Yoshiharu , Konishi Tsuyoshi , Akagi Tomonori , Yamaguchi Tomohiro , Akiyoshi Takashi , Fukuda Meiki , Yamamoto Seiichiro , Uemura Mamoru , Hasegawa Hirotoshi , Okamura Ryosuke , Yamamoto Michio , Kawada Kenji , Morita Satoshi , Watanabe Masahiko
Published: May 2019

3578

Background: The usefulness of lateral lymph node dissection (LLND) for lower rectal cancer has been discussed. Concerning relapse-free survival (RFS), in the JCOG0212 trial, the non-inferiority of avoiding LLND for rectal cancer without LLN enlargement of ≥10 mm was not shown; however, the superiority of LLND was also not demonstrated. Methods: To examine whether the difference in dissection effect could be demonstrated by the size of LLN, magnetic resonance imaging (MRI) for the central review of pre-registered patients with stages II/III lower rectal cancer below the peritoneal reflection was performed, and the prognosis of the patients were prospectively investigated as a cohort. The relationship between LLND and RFS was also evaluated. Results: MR images of 738 cases (mean distance from anal verge: 4.5 cm) were evaluated. Twenty patients with LLN enlargement of ≥10 mm were excluded from the analysis. Overall, of 718 patients, 310 did not undergo LLND (non-LLND group), whereas the other 408 underwent LLND (LLND group). The lymph node sizes of ≥5 mm were observed in 10.0% and 21.1% of patients in the non-LLND and LLND groups, respectively. Although there was some bias in the background characteristics of the two groups (non-LLND vs. LLND; median age 66 vs. 61 years; laparoscopic surgery 64.2% vs. 17.9%; preoperative treatment 39.4% vs. 27.9%; circumferential resection margin evaluated by MRI 37.3% vs. 49.9%; and postoperative complications 33.2% vs. 44.4%), almost no difference in the 5-year RFS was observed (63.4% vs. 67.5%).The LLND group had significantly more favorable with ≥5 mm LLN (non-LLND 51.6% vs. LLND 69.0% P = 0.023) than with < 5 mm LLN (non-LLND 64.7%; LLND 67.0%). Conclusions: Oncological benefit of LLND was suggested in patients with enlarged lateral nodes on MRI using a large cohort of clinical stage II/III lower rectal cancer.
Population-based screening for BRAF V600E in metastatic colorectal cancer (mCRC) to reveal true prognosis.
Authors: Chu Jenny E. , Johnson Benny , Morris Van K. , Raghav Kanwal Pratap Singh , Swanson Lucas , Lim Howard John , Renouf Daniel John , Gill Sharlene , Wolber Robert , Karsan Aly , Schaeffer David F. , Kopetz Scott , Loree Jonathan M.
Published: May 2019

3579

Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text]
Identifying anti-EGFR (EGFRi) response subgroups using evidence of ctDNA selective pressure.
Authors: Parseghian Christine Megerdichian , Willis Jason , Morris Van K. , Raghav Kanwal Pratap Singh , Dasari Arvind , Raymond Victoria M. , Lanman Richard B. , Overman Michael J. , Kopetz Scott
Published: May 2019

3587

Background: Metastatic colorectal cancers (mCRC) that respond to EGFRi display a robust circulating tumor DNA (ctDNA) signature that reflects selective pressure and clonal evolution. Conversely, non-responding tumors do not exhibit this signature. On this basis, we developed a novel method that defines EGFRi sensitivity with improved biological confidence with fewer patients (pts), and does not rely on clinical trial outcomes where responses may be confounded by concurrent chemotherapy. We used this method to further elucidate the association of several features that have been previously reported to be associated with EGFRi resistance, namely tumor sidedness, BRAF, PIK3CA, or ERBB2 ( HER2) MTs, and the absence of APC/ TP53MT. Methods: We analyzed 112 pts with baseline tissue based RASWT mCRC who had progressed following EGFRi, and with plasma samples available for ctDNA sequencing using a blood based NGS assay. Using our previously validated EGFRi exposure signature, we identified pts with evidence of selective pressure. Results: Post EGFRi ctDNA found 37% and 33% of pts with left sided and transverse tumors displayed evidence of selective pressure, respectively. 0 pts with right sided tumors displayed evidence of selective pressure; p= 0.01. Similarly, BRAFV600EMT displayed no evidence of selective pressure vs 30% of WT pts; in contrast, selective pressure was evident in pts with PIK3CAMT, ERBB2MT and pts with absence of APC/TP53MT (42% vs 28%, 67% vs 28%, 24% vs 43%, respectively for MT vs WT, p= NS for all). BRAF, PIK3CA, ERBB2, and APC/TP53 MT were present in 4/117, 12/108, 3/118 and 30/91 pts, respectively. ctDNA shedding was similar for all subgroups, as was time from previous EGFRi, indicating that these factors were not confounders. Conclusions: Consistent with prior large randomized studies, no pts with right sided tumors or BRAFMT had evidence of biologic benefit as assessed by presence of selective pressure. In contrast a number of pts with transverse tumors, ERBB2MT, PIK3CAMT or absence of APC/TP53MT had evidence of EGFR selective pressure, confirming that these are not absolute predictors of EGFR resistance and suggesting a subset of these pts were deriving benefit from EGFR inhibition. This biology based approach has the potential to more efficiently evaluate biomarkers of targeted therapy in the future without reliance on large randomized datasets.
Association of microRNA-21 with efficacy of cetuximab in RAS wild-type patients in the FIRE-3 study (AIO KRK-0306) and microRNA-21’s influence on gene expression in the EGFR signaling pathway.
Authors: Miller-Phillips Lisa , Heinemann Volker , Stahler Arndt , Fischer von Weikersthal Ludwig , Kaiser Florian , Al-Batran Salah-Eddin , Neureiter Daniel , Kahl Christoph , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Vazart Celine , Fontaine Karine , Held Swantje , Modest Dominik Paul , Neumann Jens , Jung Andreas , Kirchner Thomas , Stintzing Sebastian
Published: May 2019

3593

Background: FIRE-3 compared first-line therapy with FOLFIRI plus cetuximab (cet) or bevacizumab (bev) in KRAS exon 2 wild-type (wt) patients with metastatic colorectal cancer. Recent analyses showed mircoRNA-21 (miR-21) expression level may be a predictive biomarker for anti-EGFR-therapy raising the question whether miR-21 influences gene expression in the EGFR signaling pathway. Methods: Reverse-transcription quantitative polymerase chain reaction assay identified quantitative miR-21 expression. Median expression was defined as a threshold value to discriminate FIRE-3 population into miR-21 low and high groups. Differential gene expression based on additional mRNA microarray data (Almac Inc, Xcel Array) was calculated by linear models adjusted for multiple testing followed by single sample gene set enrichment analysis (ssGSEA) to compare differentially enriched hallmarks of cancer gene sets. Overall response rate (ORR) was compared using Fisher´s exact test. Median progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimation and log-rank test. Results: 333 RAS wt patients provided material for miR-21 expression analysis. In these patients, low miR-21 expression was associated with higher ORR (80.0% vs. 57.9%; p = 0.005) and longer OS (35.8 months (mo) vs. 25.9 mo; p = 0.005) when cet vs bev was added to FOLFIRI. High miR-21 expression was associated with comparable ORR (74.6% vs. 64.0%; p = 0.21) and OS (24.5 mo vs. 23.8 mo; p = 0.4). There was no significant difference in PFS in either group. By comparing miR-21 low and high groups using normalized mRNA microarray data, 538 genes were found to be significantly differentially expressed in RAS wt patients after adjustment for multiple testing. Including data from the two groups into ssGSEA yielded 23 hallmark of cancer gene sets that were significantly differentially enriched; among them, KRAS-signaling showed higher enrichment in the miR-21 high group (adjusted p = 2.09 E-13). Conclusions: MiR-21 expression level might be a predictive biomarker for anti-EGFR-therapy by modulating KRAS signaling in FIRE-3 patients.
Prognostic stromal and immune response expression patterns in early-stage colorectal cancer predicted by genes intrinsically expressed by tumor epithelial cells.
Authors: Wirapati Pratyaksha , Qu Xueping , Huw Ling , Etlioglu Emre , Tejpar Sabine , Kabbarah Omar
Published: May 2019

3601

Background: High stromal content (CMS4) and immune infiltration (CMS1) are important features of the tumor micro-environment (TME) in early stage colorectal cancer, with poor and good RFS prognosis, respectively. However, it remains unclear how these TME features are influenced by intrinsic tumor epithelial expression profiles. We examined how the former can be predicted by the latter, and assessed their respective prognostic contributions. Methods: Eighteen public gene-expression datasets (n=3511) were used for discovery, and an adjuvant trial dataset (PETACC3 n=688) was used for validation. Whole-transcriptome hierarchical clustering was applied to identify intrinsic versus extrinsic co-expression modules, corroborated by single-cell profiling data. The epithelial gene subset were used to predict previously assigned CMS labels, producing new CRC classifier that we refer to as epithelial-CMS (eCMS). Results: Despite lacking stromal and immune response genes, eCMS predicted CMS with an accuracy of 82% [CI 78-85%] in the test dataset. Not only were the RFS prognostic values retained (eCMS1 vs non-eCMS1: HR=0.59 [CI 0.35–0.95, p=0.029], and eCMS4 vs non-e-CMS4: HR=1.82 [CI 1.38–2.41, p=0.0003]), but they were also significantly improved when compared to the original CMS classification (CMS1 vs non-CMS1: HR=0.76 [CI 0.49–1.16, p=0.2] and CMS4 vs non-CMS4: HR=1.43 [CI 1.07–1.91, p=0.017]. In a multivariable regression comparison, eCMS was superior to CMS (p=0.001 vs p=0.36). Each eCMS group was associated with specific combinations of up- and down-regulation of CRC-relevant pathways, such as CDX2, map-kinase, mucin secretion, DNA damage repair and cell proliferation. Conclusions: Stromal and immune infiltration patterns in the TME are strongly associated with tumor epithelial expression profiles, as captured by eCMS. This finding sheds new light on the interplay between intrinsic molecular features of CRCs and their TME, and illuminates new paths for potential combination therapies.
A plasma-only integrated genomic and epigenomic circulating tumor DNA (ctDNA) assay to inform recurrence risk in colorectal cancer (CRC).
Authors: Parikh Aparna Raj , Van Seventer Emily E. , Boland Genevieve Marie , Hartwig Anna , Jaimovich Ariel , Raymond Victoria M. , Talasaz AmirAli , Corcoran Ryan Bruce
Published: May 2019

3602

Background: ctDNA identifies patients (pts) at high risk for disease recurrence post CRC resection (post-op). Current ctDNA residual disease detection approaches assess only genomic alterations (alts) and rely on tissue sequencing to identify tumor-derived alts. We evaluated a plasma-only ctDNA assay to identify high risk pts. Methods: 72 CRC pts (surgery only = 42; adjuvant therapy (adj) = 30) had post-op and/or post-adj plasma samples (3-4mL). Extracted cfDNA (median 27 ng) was analyzed using a single-sample NGS test validated in early stage CRC that integrates assessment of genomic alts with epigenomic cancer signature (Guardant Health, CA). A variant classifier was applied to differentiate tumor-derived from non-tumor derived alts in a tumor tissue-uninformed approach. Results: In the surgery cohort, samples were collected a median of 31 days (d) post-op. 7/8 pts with post-op ctDNA detected (ctDNA+) recurred (PPV 88%; median time to recurrence (mTTR) 248d). The recurrence-free pt has < 180d follow-up. 7/34 pts without ctDNA detected (ctDNA-) recurred (NPV 79%; mTTR 333d). 1/1 Stage 0-II ctDNA+ pt recurred (PPV 100%; TTR 440d) while 1/20 ctDNA- recurred (NPV 95%; TTR 440d). 27 pts in the adj cohort had samples collected a median of 37d post-adj. 6/6 ctDNA+ pts recurred (PPV 100%, mTTR 239d). 4/21 ctDNA- pts recurred (NPV 81%, mTTR 466d). 2/2 ctDNA+ and 0/11 ctDNA- Stage III pts recurred (PPV, NPV 100%, mTTR 420d). All 3 post-op ctDNA+/post-adj ctDNA+ (ctDNA persistence) pts recurred. 1/2 post-op ctDNA+/post-adj ctDNA- (ctDNA clearance) pts is recurrence free (306d). 2 post-op ctDNA-/post-adj ctDNA+ pts recurred. In the entire cohort, ctDNA+ after standard therapy completion had a recurrence PPV 93%, NPV 80%, HR 11.29 (p < 0.0001). Conclusions: In post-op CRC, ctDNA detection utilizing a tumor-uninformed integrated genomic and epigenomic assay has high recurrence PPV and NPV following standard therapy completion. ctDNA identifies pts who may benefit from post-op adj therapy or additional/modified post-adj therapy. These findings demonstrate that ctDNA detection from a single post-op/post-adj plasma sample stratifies high/low risk pts and informs therapy decision making.
Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.
Authors: Yoshino Takayuki , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Yuki Satoshi , Komatsu Yoshito , Homma Shigenori , Uemura Mamoru , Kato Takeshi , Kotani Daisuke , Fukuoka Shota , Sasaki Takeshi , Nishizawa Yuji , Nakamura Naoki , Wakabayashi Masashi , Kojima Motohiro , Togashi Yosuke , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki
Published: May 2019

3606

Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.
Effect of neoadjuvant treatment on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma: A post-hoc analysis from 3 prospective studies.
Authors: Zhang Jianwei , Deng Yanhong , Cai Yue , Hu Huabin , Wu Zehua , Ling Jiayu
Published: May 2019

3608

Background: Mucinous adenocarcinoma and signet-ring cell carcinoma were uncommon in locally advanced rectal cancer. And it has been reported that both mucinous adenocarcinoma and signet-ring cell carcinoma showed poor response to standard neoadjuvant chemoradiotherapy. Here, we tried to compare the efficacy of different neoadjuvant treatment regimen on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma (M/S). Methods: We enrolled patients with locally advanced rectal cancer from 3 prospective clinical trials (NCT01211210, NCT02217020 and NCT02887313), including FOWARC study (N = 309), mFOLFOXIRI neoadjuvant chemotherapy trial (N = 103) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). Among the 541 patients, 41 (7.6%) patients were M/S and 500 were non-M/S. Totally, 7 M/S patients and 84 non-M/S patients received 5FU concurrent with radiotherapy (Group A), 20 M/S patients and 208 non-M/S underwent FOLFOX concurrent with radiation or total neoadjuvant treatment (Group B), 11 M/S patients and 92 non-M/S patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (Group C). Other 3 M/S patients and 116 non-M/S patients received FOLFOX neoadjuvant chemotherapy alone (Group D). Results: Among M/S patients, only 4 (9.7%) achieved pathologic complete response (pCR), and 6 (14.6%) patients had tumor downstaging to ypstage 0-I. In group A, the pCR rate was 14.3% and 11.9% (p = 0.85), and the tumor downstaging rate was 14.3% and 36.9% (p = 0.22) in M/S and non-M/S patients, respectively. In group B, the pCR rate was 15.0% and 34.6% (p = 0.07), and the tumor downstaging rate was 25.0% and 60.1% (p = 0.002) in M/S and non-M/S patients, respectively. However, in group C and group D with chemotherapy alone as neoadjuvant treatment, no M/S patients showed pCR or tumor downstaging; while in non-M/S patients higher tumor downstaging rate was observed. Conclusions: M/S showed resistance to neoadjuvant chemotherapy along regimens. Even with chemoradiotherapy, M/S patients showed poorer response than that of non/M/S patients. Further study was warranted to explore the new regimen for M/S patients. [Table: see text]
Simultaneous versus staged resection for synchronous colorectal cancer liver metastases: A population-based cohort study.
Authors: Serrano Aybar Pablo Emilio , Bogach Jessica , Wang Julian , Parpia Sameer , Hallet Julie , Simunovic Marko
Published: May 2019

3612

Background: Simultaneous resection of colorectal cancer primary and liver metastases is not performed routinely due to concerns about safety. We hypothesized that simultaneous resection has steadily increased overtime and that the outcomes are similar. Methods: Population-based cohort study of patients undergoing resection for synchronous (resection of the primary colorectal cancer and liver metastases within six months) liver metastases from 2006-2015 by linking administrative datasets in Ontario, Canada. Outcomes: post-operative complications, length of hospital stay, and overall survival. Survival for the staged group was measured from the last surgical resection to death and estimated using Kaplan Meier and compared with the log-rank test. Cox proportional hazard models were used to calculate risks for death. We aimed to identify practice patterns, outcomes of simultaneous vs. staged resections for these patients. Results: Of 2,738 patients undergoing colorectal and liver resection for colorectal cancer, 1,168 were synchronous, of which, 442 underwent simultaneous resection. Rate of synchronous disease presentation increased on average by 3% per year (p = 0.02). Median length of stay was shorter (8 vs. 11 days, p < 0.001); rate of major liver resections were lower (17% vs. 65%, p < 0.001), and 90-day post-operative mortality was higher (6% vs. 1%) for simultaneous resections. Major postoperative complications were higher in the simultaneous group (28% vs. 23%, p = 0.067), mostly due to a higher reoperation rate (6% vs. 3%, p = 0.034). Median overall survival was worse with simultaneous resection (40 months, 95%CI 35-46 vs. 78 months, 95%CI 59-86). Risks factors for worse survival were comorbidities, rurality, right-sided primary and simultaneous resection. There is selection bias that favours survival in the staged group, as patients must have survived the first operation and have stable disease in order to undergo the second operation. Conclusions: Simultaneous resection is associated with worse postoperative outcomes. Considering selection bias, randomized studies would be necessary to determine the role of simultaneous.