bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients.
Authors: Giannakis Marios , Li Haoxin , Jin Chelsea , Gopal Shuba , Desai Kaushal , Horak Christine , Wind-Rotolo Megan , Van Allen Eliezer Mendel , Clish Clary , Hodi F. Stephen , Garraway Levi A. , Choueiri Toni K. 
Published: September 2018

3036 Background: Immune-checkpoint inhibition has been shown to be effective in a variety of cancers, including renal cell carcinoma (RCC) and melanoma. However, only a subset of patients with RCC and melanoma respond to anti-PD1 therapy. Given the importance of metabolism in the tumor immune microenvironment, we performed serum metabolomics in nivolumab-treated patients towards identifying novel non-invasive correlates of response and progression-free survival in immunotherapy-treated patients. Methods: We performed liquid chromatography-mass spectrometry on pre- and on-treatment serum samples from 79 patients with advanced melanoma (CA209-038 study) and 82 patients with metastatic RCC (CA209-009 study) receiving nivolumab. We precisely measured more than one-hundred named metabolites at baseline (prior to starting nivolumab), at 4 weeks and at 6 (melanoma) or 9 weeks (RCC) after initiation of treatment and correlated these with best overall response as well as progression-free survival (PFS). Results: In melanoma patients treated with nivolumab, the difference in mean levels of kynurenine (the product of IDO / TDO activity in tryptophan catabolism) between weeks 4 and 6 compared to baseline was significantly different between responders and non-responders (t-test with unequal variance p-value = 0.043 and p-value = 0.044 respectively). In RCC patients, we observed that patients with no response to nivolumab had significantly higher adenosine levels, than those who responded, at baseline and at 4 weeks after initiation of treatment (158% and 138% higher, t-test p-value = 0.0019 and p-value = 0.0011 respectively). RCC nivolumab-treated patients with higher (top quartile) baseline adenosine levels also had a significantly worse PFS (log rank test p-value = 0.004). Conclusions: In this first-of-its kind metabolomic analysis of peripheral blood from nivolumab-treated patients, we find that the change in kynurenine levels in melanoma patients correlates to response. In addition, higher baseline levels of adenosine in RCC patients are associated with worse PFS and lack of response to nivolumab. These results suggest a possible role for serum metabolites as biomarkers of benefit to PD1 inhibition.
CD133-redirected chimeric antigen receptor engineered autologous T-cell treatment in patients with advanced and metastatic malignancies.
Authors: Wang Yao , Chen Meixia , Wu Zhiqiang , Tong Chuan , Huang Jianhua , Lv Haiyan , Dai Hanren , Feng Kaichao , Guo Yelei , Liu Yang , Yang Qingming , Han WeiDong 
Published: September 2018

3042 Background: Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T cells directed CD133 (CART-133) were firstly tested in this clinical trial. We aimed to determine the safety dosage, toxicity and biological activity of CART-133 in epithelium-derived solid tumors. Methods: The initially enrolled 8 patients with sorafenib-refractory hepatocellular carcinoma (HCC), treated by CART-133 monotherapy, were assigned into 3 dose cohorts (1, 0.5-1.5×105/kg; 2, 5-10×105/kg; 3, 1-2×106/kg). For the additional 16 patients (6 HCCs, 7 pancreatic carcinomas, 2 colorectal carcinomas, and 1 cholangiocarcinoma), all non-HCCs were conditioned by regimen (Nab-pacitaxel/cyclophosphamide or anti-PD1 antibody) before cell infusions. Results: For the initial 8 HCCs, 1 from cohort 2 occurred hemoglobin/platelet decline and direct hyperbilirubinemia (Grade 3), 4 from cohort 2/3 reported delayed low fever, nausea accompanied with elevation of CRP and serum cytokines. The 4-6 week persistence of relatively higher CAR copy numbers and its reverse relationship with the count of CD133+ cells harboring pro-metastatic epithelial progenitor cells in peripheral blood led to the determination of acceptable cell infusion dose from 0.5 to 2×106/kg and reinfusion cycle in 24 patients. Similar toxicities ( ≤ Grade 3) were observed in 15 cases. The cholangiocarcinoma patient who uniquely received 1 cycle of CART-133 infusion after anti-PD1, developed Grade 3 skin/mucosal vasculature damage, blood three-lineage decline and cytokine release syndrome, whereas, obtained a 4.5 month-lasting partial remission. Although no marked reduction of tumor volume was observed in most patients, 21 out of 23 patients had an 8-22 week progression-free survival, 2 patients without bulky tumor burden attained 8/10-month ongoing stable disease by the cut-off data (Jan 1, 2017). Conclusions: This trial showed the feasibility, controllable toxicities and effective biological activity of CART-133 transfer for the treatment of late-stage tumor patients. Clinical trial information: NCT02541370.
Efficacy of single administration of tumor-infiltrating lymphocytes (TIL) in heavily pretreated patients with metastatic melanoma following checkpoint therapy.
Authors: Sarnaik Amod , Kluger Harriet M. , Chesney Jason Alan , Sethuraman Jyothi , Veerapathran Anandharamen , Simpson-Abelson Michelle , Lotze Michael T. , Larsen Bente , Fischkoff Steven A. , Suzuki Sam , Wang Lei , Mirgoli Mariam , Fardis Maria , Curti Brendan D. 
Published: September 2018

3045 Background: Adoptive cell therapy with TIL involves collection of autologous lymphocytes from the tumor via surgical resection, ex vivo expansion of TIL, lymphodepletion of the patient prior to infusion of TIL using Fludarabine and Cyclophosphamide, followed by infusion of TIL. Up to 6 doses of IL-2 (600,000 IU/kg) is administered to support multiplication of TIL and engraftment. Here, we present the preliminary results from an ongoing, multi-site Phase 2 study of TIL for advanced metastatic melanoma. Methods: Patients with advanced metastatic melanoma who have failed at least one prior systemic therapy were enrolled. Primary objective of the study was to characterize safety profile of LN-144. At baseline, patients had a median age of 56 (41-72) years; 44% were ≥ 60 years old. Median sum of tumor diameters for the target lesions was 10.4 cm, and median of 3 prior therapies. All enlisted patients had prior anti-PD1 as well as anti-CTLA4 and 67% had received ≥ 3 prior therapies. Responses were assessed by RECIST 1.1. TIL products were centrally manufactured. No complications arose from shipment of tumors or TIL. Results: Results are presented through 31 Jan 2017 for the first 9 infused patients evaluable by two assessments. Eight of 9 patients received all 6 doses of IL-2 per protocol. The most common (≥3 patients) non-hematologic grade 3-4 TEAE was hypophosphatemia. No neurotoxicity of grade ≥ 3 was reported. There were no deaths or discontinuations due to SAEs related to study treatment. ORR was 33% (CR = 11%, PR = 22%, SD = 22%, PD = 33%, NE = 11%). Mean time to best response was 3.0 months and median duration of follow up was 3.6 months (1.1+, 12.1). Responses were observed in patients with tumors carrying wild type or BRAF mutations. All patients demonstrated persistence of TIL on day 14 post-infusion. Conclusions: Cell therapy with TIL is an effective treatment with acceptable safety profile for advanced metastatic melanoma patients who are refractory to anti-PD1. TIL products can be centrally manufactured for broad clinical application. This study will be expanded to enroll patients with a shorter manufacturing process as well as offering retreatment for study patients. Clinical trial information: NCT02360579.
Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Sullivan Ryan J. , Gonzalez Rene , Lewis Karl D. , Hamid Omid , Infante Jeffrey R. , Patel Manish R. , Hodi F. Stephen , Wallin Jeffrey , Pitcher Bethany , Cha Edward , Roberts Louise , Ballinger Marcus , Hwu Patrick 
Published: September 2018

3063 Background: Targeted inhibition of MEK with C and BRAF with V in BRAFV600-mutant mel can lead to both anticancer immune activation and direct tumor cell death. A, an anti–PD-L1 monoclonal antibody, inhibits PD-L1/PD-1 signaling. Combining C + V with A may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from this phase Ib study (NCT01656642) showed that A + C + V had a manageable safety profile and promising antitumor activity in patients (pts) with untreated BRAFV600-mutant unresectable/metastatic mel, with increases in CD8-positive T-cell infiltration observed after C + V (Sullivan et al SMR 2016). We present updated safety and efficacy data. Methods: Pts received A + C + V after a 28-day run-in with C + V. A was given at 800 mg q2w, C at 60 mg qd for the first 21 days of each 28-day cycle, and V at 960 mg bid during day 1–21 of run-in and 720 mg thereafter. Safety was evaluated in pts who had ≥1 dose of A; efficacy, in pts who had ≥1 dose of A by the data cutoff date and received ≥1 dose of A, C, or V by the dosed-by date. Results: Thirty-four patients were treated and evaluated for both safety and efficacy. Median survival follow-up was 7.1 months (range 2.5–19.9). Elevated AST/ALT, diarrhea, arthralgia, fatigue, photosensitivity, pyrexia, nausea, flu-like symptoms, maculopapular rash, and pruritus were reported as A- and/or C- and/or V-related in > 20% of pts at any grade (G). A/C/V-related G3–4 adverse events (AEs) were seen in 15 pts (44.1%) with the triple combination (none G5). Three serious AEs were A-related. All AEs were manageable and reversible. Elevated ALT/AST (three pts each) and rash (one pt) led to discontinuation of any drug. Unconfirmed RECIST V1.1 responses were observed in 29 pts (85.3%; six complete, 23 partial). Three pts with confirmed partial responses had resolution of target lesions. Twenty of the 29 responding patients continue to respond at the time of the data cutoff. Conclusions: Updated results confirm preliminary findings that A + C + V has a manageable safety profile and promising antitumor activity in pts with BRAFV600-mutant metastatic mel. Continued exploration of A + C + V is warranted. Clinical trial information: NCT01656642.
Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer.
Authors: Iveson Timothy , Kerr Rachel , Saunders Mark P. , Hollander Niels Henrik , Tabernero Josep , Haydon Andrew Mark , Glimelius Bengt , Harkin Andrea , Scudder Claire , Boyd Kathleen , Waterston Ashita Marie , Medley Louise C. , Wilson Charles , Ellis Richard , Essapen Sharadah , Dhadda Amandeep Singh , Harrison Mark , Falk Stephen , Raouf Sherif , Paul James 
Published: September 2018

3502 Background: Six months of oxaliplatin-based treatment has been the mainstay of adjuvant chemotherapy for colorectal cancer for the last 13 years. Neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. A shorter duration of treatment would save patients significant toxicity/time and substantially reduce the costs of the drug, its administration, and treatment of adverse effects. Methods: SCOT is a non-inferiority randomised study designed to determine whether 3 months of adjuvant chemotherapy with OxMdG or Xelox (physician/patient choice) in Stage III/high risk Stage II colorectal cancer is as effective as 6 months treatment. Non-inferiority was determined to be a maximum 2.5% fall in 3-year disease-free survival (DFS) on the 3 month arm (from 78% on the 6 month arm) corresponding to a hazard ratio upper limit of 1.13. The study was designed with 90% power at the 2.5% 1-sided level of statistical significance and aimed to recruit 9500 patients to observe 2,750 DFS events (relapses/deaths/new colorectal cancers). Analysis used a Cox model adjusted for study minimisation factors. Results: 6088 patients (60% male, median age 65) with Stage III/high risk Stage II cancers of the colon or rectum were randomised between 27th March 2008 and 29th November 2013. The arms were balanced for clinical and pathological factors. Intended treatment was OxMdG for 1981 and Xelox for 4107 patients. There were 1469 DFS events (734 in 3 month arm and 735 in 6 month arm) giving the study 66% power. 3 year DFS was 76.8% (se = .8%) for the 3 month arm and 77.4% (se = .8%) for the 6 month arm (HR 1.008, 95% CI 0.910-1.117, test for non-inferiority p = 0.014). Non-inferiority appeared stronger for Xelox than OxMdG (test for heterogeneity, p = .059). Results will be shown broken down by stage, site, age, gender and achieved duration of treatment. Conclusions: The SCOT study has shown that 3 months adjuvant treatment is not inferior to 6 months treatment. However the SCOT study is part of the IDEA consortium and the results from the 6 studies in the IDEA consortium addressing the same duration question will also be presented at ASCO 2017. Clinical trial information: ISRCTN59757862.
Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort.
Authors: Marisa Laetitia , Ayadi Mira , Balogoun Ralyath , Pilati Camilla , Le Malicot Karine , Lepage Come , Emile Jean-François , Salazar Ramon , Aust Daniela Ellen , Duval Alex , Selves Janick , Guenot Dominique Esperance , Milano Gerard A. , Seitz Jean-François , Taieb Julien , Boige Valerie , De Reynies Aurelien , Laurent-Puig Pierre 
Published: September 2018

3509 Background: The molecular subtyping of colon cancers (CC) has been the subject of several recent publications, leading to an international consensus. The clinical relevance of these molecular classifications remains to be evaluated on large prospective patient cohorts using a tool that can be widely used on formalin-fixed paraffin-embedded (FFPE) samples. Methods: We aimed to evaluate the clinical relevance of two molecular subtyping systems, CMS (Guinney et al. 2015) and CCMST (Marisa et al. 2013), on the PETACC-8 cohort, a randomized phase III trial comparing adjuvant FOLFOX with or without cetuximab in patients with stage III CC. For each of these two classification systems, a predictor tool was developed and adapted to FFPE samples. The NanoString nCounter platform was used to screen 196 genes. Predictors were built from 249 frozen tumor samples previously used to build our classification system and 61 new paired FFPE/frozen samples. Both predictors were then applied to 1781 PETACC-8 FFPE samples. Subtypes associations to clinical and molecular features were analyzed. Results: The CMS predictor assigned 297 samples to CMS1 (17%), 585 to CMS2 (34%), 68 to CMS3 (4%) and 770 to CMS4 (45%). CMS were significantly associated with several molecular and clinical features, including MSI status (49% in CMS1, p < 0.001), CIMP status (47% in CMS1, p < 0.001), KRAS mutation (75% in CMS3, p < 0.001), BRAF mutation (34% in CMS1, p < 0.001), tumor location (less proximal tumors in CMS2, p < 0.001), validating the predictor tool developed. The classification was significantly associated to prognosis in multivariate analysis, CMS4 subtype having a shorter overall survival (hazard ratio = 1.7, p= 0.021). A deleterious effect of cetuximab was observed in CMS1 (p < 0.05). Similar results were obtained with the CCMST classification. Conclusions: We validated molecular CC subtyping predictors for both CMS and CCMST classifications on PETACC-8 FFPE samples. The prognostic value of CMS and CCMST classifications was confirmed, stem-like tumors being associated with a poor prognosis. These results pave the avenue for widely use of the CC molecular classification in clinical routine.
Analysis of serum vitamin D levels and prognosis in stage III colon carcinoma patients treated with adjuvant FOLFOX+/- cetuximab chemotherapy: NCCTG N0147 (Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Smyrk Thomas C. , Goldberg Richard M. , Heying Erica N , Cohen Steven J. , Gill Sharlene , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Sargent Daniel J. , Jahagirdar Balkrishna N. , Pollak Michael N. , Alberts Steven R. 
Published: September 2018

3516 Background: Epidemiological data suggest a protective effect of vitamin D on CC risk. However, association of serum vitamin D level with clinical outcome in pts with surgically resected CC remains unknown. We analyzed total circulating 25-hydroxyvitamin D [25(OH)D)] with clinical outcome in pts with resected stage III CC treated with FOLFOX +/- cetuximab in a phase III trial. Methods: Association of pre-treatment level of plasma 25(OH)D with disease-free survival (DFS) and time-to-recurrence (TTR) was analyzed with 25(OH)D as a continuous variable by a relative risk model with splines and as a binary variable (vitamin D deficient [<30 ng/mL]) using multivariable Cox regression. Results: Overall, 49% (291/600) of pts were vitamin D deficient. Prevalence of vitamin D deficiency was significantly higher in women vs men (52% vs. 48%, p=0.030) and in blacks vs whites (74% vs. 45%, p=0.0003). The continuous 25(OH)D level and pt sex were associated by the interaction test (pinteraction=0.044). There were no statistically significant associations with DFS/TTR for either continuous 25(OH)D level (DFS, p=0.22; TTR, p=0.26) nor for vitamin D deficiency (DFS, adjusted hazard ratio [HRadj]=1.01, 95% CI, 0.74-1.38; padj=0.94; TTR, HRadj=1.00; CI, 0.72-1.38; padj=0.99. A comparison of the highest vs lowest tertile showed a significant association between the highest 25(OH)D level and better outcomes in men (DFS, HRadj.=0.18, CI, 0.04-0.76, padj=0.020; TTR, HRadj.=0.12, CI, 0.02-0.64, padj=0.014), but not in women (DFS, pinteraction=0.039; TTR, pinteraction=0.033). Conclusions: Nearly one-half of pts in the clinical trial cohort were vitamin D deficient with lowest 25(OH)D levels found in women and blacks. While vitamin D deficiency was not associated with adverse outcome, high levels of vitamin D in men, but not women, were associated with longer survival. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, U10CA077202, CCSRI 021039. ClinicalTrials.gov Identifier: NCT00079274.
Nut consumption and survival in stage III colon cancer patients: Results from CALGB 89803 (Alliance).
Authors: Fadelu Temidayo , Niedzwiecki Donna , Zhang Sui , Ye Xing , Saltz Leonard , Mayer Robert J. , Mowat Rex B. , Whittom Renaud , Hantel Alexander , Benson Al Bowen , Atienza Daniel M. , Messino Michael J. , Kindler Hedy L. , Venook Alan P. , Ogino Shuji , Ng Kimmie , Giovannucci Edward L. , Meyerhardt Jeffrey A. , Bao Ying , Fuchs Charles S. 
Published: September 2018

3517 Background: Recent prospective cohort studies suggest states of energy excess and hyperinsulinemia, including type 2 diabetes (T2D), obesity, sedentary lifestyle, Western pattern diet, increased dietary glycemic load, high intake of sugar-sweetened beverages, and elevated plasma C-peptide are each associated with an increased risk of colon cancer (CC) recurrence and mortality. Conversely, observational studies indicate that increasing nut intake is associated with lower risk of T2D, metabolic syndrome and insulin resistance. However, the effect of nut intake on CC recurrence and survival is unknown. Methods: We conducted a prospective, observational study of 826 patients with stage III CC who reported dietary intake with food frequency questionnaires while enrolled in a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. The primary endpoint was disease-free survival (DFS) defined as time from completion of dietary questionnaire following adjuvant therapy to cancer recurrence, death or last follow-up. Results: Compared to patients who abstained from nuts, those who consumed ≥ 2 servings of nuts per week had an adjusted hazard ratio (HR) of 0.58 (95% CI, 0.37 to 0.92; Ptrend = 0.03) for DFS and 0.43 (95% CI, 0.25 to 0.74; Ptrend = 0.01) for overall survival (OS). On subgroup analysis, the significant association was confined to tree-nut intake: HR = 0.54 (95% CI, 0.34 to 0.85; Ptrend = 0.04) for DFS and HR = 0.47 (95% CI, 0.27 to 0.82; Ptrend= 0.04) for OS. There was no significant association between intake of peanut or peanut butter and patient outcome. Association of total nut intake with improved outcomes was maintained across other known or suspected predictors of recurrence and mortality, including across common genomic alterations (microsatellite instability, KRAS mutation, BRAF mutation, and PIK3CA mutation). Conclusions: Higher consumption of nuts may be associated with significantly reduced cancer recurrence and death in patients with stage III CC. Support: U10CA180821, U10CA180882, Pfizer. Clinical trial information: NCT00003835.
Profiling circulating tumor (ct)DNA mutations after panitumumab treatment in patients with refractory metastatic colorectal cancer (mCRC) from the phase III ASPECCT study.
Authors: Boedigheimer Michael , Ang Agnes , Price Timothy Jay , Peeters Marc , Kim Tae Won , Gibbs Peter , Thomas Anne L. , Hool Kristina , Bach Bruce A. 
Published: September 2018

3523 Background: ASPECCT was a clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This biomarker analysis explores the mutational landscape in panitumumab monotherapy subjects. Analysis of plasma ctDNA at baseline and post-treatment (PT) by next-generation sequencing provides a snapshot of the main changes in key genes before and after therapy. Methods: CtDNA collected at baseline and PT was analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). Gain or loss of mutation was defined at the amino acid level. Net change is the sum of mutations gained minus the sum of mutations lost. A single individual could have both net gain and/or net loss of mutations within a single gene. Results: Significant tumor clonal diversification was observed during therapy. In 238 subjects with paired plasma samples,29% of subjects had multiple mutations in the same gene at baseline and 41% of subjects had multiple mutations in the same gene PT. At least 10% of subjects demonstrated an on-therapy acquired mutation in at least one of the following genes: APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT (ordered by frequency). New mutations were noted both inside and outside the EGFR pathway. Unexpectedly, patients with a large decrease in mutant DNA burden after anti-EGFR treatment were also seen. EGFR pathway genes with significant net gain were: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1. Non-EGFR pathway mutations gained included: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1. Conclusions: This 63-gene plasma analysis suggests that there are significant dynamic changes in clonal mutational fraction under anti-EGFR selection. Our analysis reveals that increasing global tumor heterogeneity is associated with poorer overall survival. A subset of patients demonstrated an overall decrease in tumor heterogeneity on panitumumab therapy (28%), indicating that under anti-EGFR selective pressure mutational heterogeneity can also decrease. Clinical trial information: NCT01001377.