bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with FOLFIRI +/- bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Bendell Johanna C. , Hubbard Joleen Marie , O'Neil Bert H. , Jonker Derek J. , Starodub Alexander , Peyton James D. , Pitot Henry C. , Halfdanarson Thorvardur Ragnar , Nadeau Benjamin Rolland , Zubkus John D. , Adesunloye Bamidele , Edenfield William Jeffery , Li Youzhi , Li Wei , Grothey Axel , Borodyansky Laura , Li Chiang 
Published: September 2018

3529 Background: Cancer stem cells are considered to be fundamentally important for resistance, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mCRC pts was done to confirm the RP2D and signs of anti-cancer activity of napabucasin in combination with FOLFIRI +/- Bev. Pts received napabucasin 240 mg PO BID with bi-weekly FOLFIRI IV +/- Bev 5 mg/kg until disease progression or other discontinuation criterion. Results: 82 pretreated mCRC pts were enrolled (ITT); including 32 (39%) previously treated with FOLFIRI +/- bev. Of the 82 pts, 48 received FOLFIRI and 34 FOLFIRI plus bev in combination with napabucasin. There was no dose-limiting or unexpected toxicity or significant PK interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, cramping, nausea, vomiting, fatigue and anorexia with grade 4 diarrhea in 1 pt and 27 pts with grade 3 AEs including: diarrhea (15), fatigue (5), dehydration (1), electrolyte imbalance (4), abdominal pain (1), vomiting (1) and weight loss (1), which resolved with dose reduction and supportive care. Disease control (CR+PR+SD) was observed in 55 of 66 pts who received RECIST evaluation (83%), with 1 CR (1.5%), 13 PR (20%) (33-100% regression) and 27 SD with tumor regression (41%). Conclusions: This phase Ib/II study confirmed that napabucasin can be safely combined with FOLFIRI +/- bev, and shows encouraging signs of efficacy in pretreated mCRC pts, including pts previously treated with FOLFIRI +/- bev. Clinical trial information: NCT02024607. [Table: see text]
A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer.
Authors: Shahda Safi , Noonan Anne M. , Bekaii-Saab Tanios S. , O'Neil Bert H. , Sehdev Amikar , Shaib Walid Labib , Helft Paul R. , Loehrer Patrick J. , Tong Yan , Liu Ziyue , El-Rayes Bassel F. 
Published: September 2018

3541 Background: Pembrolizumab (PEM) has activity in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC). Oxaliplatin (OX) and 5FU lead to immunogenic cell death and increased antigen presentation. We hypothesized that combining mFOLFOX6 and PEM may enhance immunogenic cell death and improve outcome in patients with CRC irrespective of MMR status. Methods: Subjects ≥18 years old with untreated, unresectable CRC were assigned to a single arm study. The study had a safety run in cohort of six patients (OX 85 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2, 5FU infusion 2400 mg/m2over 46 hours) and PEM 200 mg Q 3 weeks, followed by a phase II cohort. The primary objective was median progression free survival (mPFS), with secondary objectives: safety and toxicity per CTCAE V4.03, median overall survival, response rate, immune related response, disease control rate, and molecular correlates. Results: Between 4/2015 and 9/2016, 30 subjects were enrolled with following characteristics: 11 female, 26 Caucasian, median age: 45 years (25-75), 3 with dMMR, 22 MMR-proficient, and 5 with no available data. During the safety run in, 2 patients had G3 febrile neutropenia (FN) and 1 G4 neutropenia. The data safety monitoring committee recommended dose reduction of mFOLFOX6 to OX 68 mg/m2, leucovorin 400 mg/m2, 5FU of 320 mg/m2, 5FU infusion of 1920 mg/m2over 46 hours and PEM 200 mg Q 3 weeks. At the data cut off (12/29/16), median follow up was 24 weeks (10-66) and 27 patients remained on study. Rate of G3/4 toxicity associated with FOLFOX/PEM and PEM alone was 36.7% and 13.2%, respectively. No further FN was observed. No grade 5 toxicity was seen on study. Best response was recorded as: 1 complete response, 15 partial response (CR +PR = 53%), and 14 stable disease, with 100% DCR at 8 weeks. One patient with dMMR had resection after 2 months of therapy with complete pathologic response. MPFS has not been reached (95% CI: 5.5 months, NR). Conclusions: Based on these preliminary results, PEM/mFOLFOX6 has acceptable toxicity though demonstrated a suggestion of increased neutropenia in the initial cohort. Clinical activity was seen in patients with untreated advanced CRC including those with proficient MMR. Clinical trial information: NCT02375672.
Bevacizumab combined with first-line chemotherapy in elderly patients (≥75 years old) with metastatic colorectal cancer: Final results of the noninterventional CASSIOPEE study.
Authors: Francois Eric , Smith Denis Michel , Gourgou Sophie , Gandon Sophie , Rollot Florence , Mineur Laurent 
Published: September 2018

3547 Background: Approximately half of the patients (pts) with metastatic colorectal cancer (mCRC) are elderly (≥65 years). Although few elderly pts are included in clinical studies, results in mCRC have shown similar treatment benefits in terms of progression-free survival and overall survival in young and elderly pts. This study was conducted in pts ≥75 years-old with mCRC treated in real life 1st line bevacizumab + chemotherapy in order to improve the knowledge on this population and to contribute in optimizing treatment strategy. Methods: CASSIOPEE is a prospective, multicenter, non-interventional study evaluating 1st line combination of bev + chemotherapy over 24 months in pts aged ≥75 years with mCRC. The primary endpoint was to describe progression-free survival (PFS). Secondary endpoints included the description of pts characteristics, overall survival, bev and chemotherapy regimen, safety and autonomy criteria (Lawton Instrumental Activities of Daily Living Scale; Balducci score). Results: A total of 402 pts were included between March 2012 and July 2016. In the efficacy population (n = 358), 52% were men, mean age 81 (±4); 54% were≥ 80 years old and 19% were ECOG ≥2; 80% had primary tumor located in the colon; main metastatic sites: liver (66%) and lung (30%). Bev was mainly combined with Folfox (36%) and Folfiri (29%). Median PFS was 9.1 months [8.3;10.2] in the efficacy population and 9.3 months for pts aged < 80, 9.5 months for pts aged ≥ 80 or ≤ 85 and 8.3 months for pts aged > 85. The PFS rate at 24 months was 11.8%. Median OS was 19.0 months [16.5;21.5] in the efficacy population and 20.6 months for pts aged < 80, 17.8 months for pts aged ≥ 80 or ≤ 85 and 13.0 months for pts aged > 85. The OS rate at 24 months was 42.0%. Autonomy and ECOG status remained stable from baseline to 24 months. In the safety population (n = 383), grade ≥ 3 adverse events occurred in 40% pts including 10% pts with bev related AEs. Overall, 4% pts died of an AE and 0.5% were bev related. Conclusions: These results suggest that mCRC patients aged ≥75 years-old, can benefit from 1st line bev plus chemotherapy in daily practice in this population. The safety profile is acceptable. Clinical trial information: NCT01555762.
An open-label expanded-access study of trifluridine/tipiracil for metastatic colorectal cancer.
Authors: Mayer Robert J. , Grothey Axel , Hochster Howard S. , Cohen Steven J. , Vukovic Vojislav M. , Makris Lukas 
Published: September 2018

3559 Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) treated with standard chemotherapy and targeted-therapy drugs (Mayer et al. N Engl J Med 2015;372:1909-19). An expanded-access program (EAP) was started to provide access to FTD/TPI for patients with mCRC with similar eligibility and to further assess the safety of FTD/TPI in a “real-world” setting in US patients. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy with appropriate biologics and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m2twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. Sites reported duration of therapy, discontinuation due to disease progression, and adverse events (AEs) for each patient. Results: 549 patients were enrolled; 53.2% were male. Median duration of FTD/TPI therapy was 9.7 weeks, which was similar to US patients from RECOURSE (8.9). 10.2% of patients died during the study period, 9.7% due to disease progression. 76.1% of patients discontinued treatment due to disease progression and 4% discontinued due to AEs. Drug-related clinically significant AEs (all grades) are summarized in the table. Conclusions: Patients with refractory mCRC in this EAP had a similar exposure duration to that reported in US patients from RECOURSE, with no unexpected safety concerns. While gastrointestinal toxicity was lower in this population, this may be due to reporting of “significant” events. The clinical profile of FTD/TPI is confirmed in this larger, non-randomized “real-world” experience. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion. Clinical trial information: NCT02286492. [Table: see text]
The outcome of patients (pts) with metastatic colorectal cancer (mCRC) based on site of metastases (mets) and the impact of molecular markers and site of primary cancer on metastatic pattern.
Authors: Prasanna Thiruvarudsothy , Craft Paul Stanley , Chua Yu Jo , Karapetis Christos Stelios , Gibbs Peter , Wong Rachel , Tie Jeanne , Roder David , Price Timothy Jay , Padbury Rob , Piantadosi Cynthia , Yip Desmond 
Published: September 2018

3560 Background: Although liver is the commonest site of mets in pts with CRC, pattern of spread is variable and may reflect different biology in different subsets of pts. Methods: This is a retrospective analysis to explore the outcome of pts with mCRC based on their site of mets at diagnosis and to identify tumor characteristics which could predict the site of mets. Pts from 2 Australian databases, BioGrid (BG) and South Australian Cancer Registry (SA), from 01/2006 to 12/2015 were grouped into 5 cohorts; lung only, liver only or any pts with brain, bone or peritoneal mets. Overall survival (OS) for each group was compared with the rest of the sample using Kaplan Meier analysis and the log rank test separately in each dataset. Mantel-Haenszel Chi-squared test was performed in pooled data to assess the association between KRAS, BRAF, Micro satellite instability (MSI), site of primary and site of mets. Results: 5967 pts were included. In both datasets median OS was significantly higher when mets were limited to lung or liver and shorter for those with brain, bone or peritoneal mets. BRAF, KRAS and MSI data were available for 20%, 37% and 21% of the sample. In the pooled analysis BRAF mutation was associated with brain (Relative Risk=5.2) and peritoneal mets (RR=1.8) with lower incidence of lung (RR=0.3) and liver (RR=0.7) limited mets. KRAS mutation was associated with lung only mets(RR=1.4). Left colon tumors were associated with bone (RR=1.6) and lung only mets (RR=2.3) while peritoneal spread was less frequent compared with right colon tumors(RR=0.6). Rectal cancer was strongly associated with brain, bone and lung mets (RR=1.7, 1.7, 2.0). MSI status was not associated with site of mets though liver only mets was less frequent in MSI high tumors. Conclusions: Survival duration with mCRC is related to the site of mets. OS was significantly better when mets were confined to either lung or liver. BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites like brain and bone. [Table: see text]
Rapid in vitro evaluation of immune responses to tumor-derived organoids as an adjunct to immunotherapy trials.
Authors: Ramsay Robert George 
Published: September 2018

3573 Background: Cancer immunotherapy has made rapid advances with the development of agents that subvert the negative arm of the immune system. This has been important because patients can mount anti-tumor immune responses. In the case of colorectal cancer (CRC), the presence of tumour infiltrating lymphocytes (TILs) appears to have predictive power regarding outcome. Nevertheless, assays that directly evaluate the quality, phenotype and anti-tumor activity of TILs are lacking. Here a novel immune assay platform is presented that measures the kinetics of TIL killing which correlates with pathological tumour response after treatment. Methods: Treatment naïve fresh cancer biopsies were processed to generate organoids and TILs from patients (n = 12) with pathological complete response (pCR) verses non-responding tumours (NRT). These were co-cultured with TILs to organoid ratios of 1:1, 5:1 and 10:1 for 48 hs and TILs function were measured by cytokine release and mean fluorescence intensity (MFI) based upon activated caspase activity. Additionally, TILs from patients with metastatic CRC (n = 20) have also been evaluated. Results: Ten thousand+ organoids are routinely cultured while millions of TILs are retrieved and expanded from biopsies. TIL-mediated killing of patient-matched tumor organoid confirm CD8+ve specific killing. At 24hrs MFI was significantly higher in pCR organoid indicative of immune-mediated cell death compared to NRT organoids at a ratio of 1:1. The efficiency of TIL killing was further enhanced as the ratio increased to 5:1 and 10:1. Gamma interferon production by cytotoxic (CD8+) T-cell is a robust measure of TIL activation state and was also significantly higher by pCR TILs compared to NRT TILs. Substantive differences in TIL subsets were also found in mCRC-derived samples compared to primary CRC. Conclusions: This is a novel functional immune assay and the first of its kind that successfully demonstrated the differences in patient-matched TIL killing between non-responding and responding CRC. This assay can be performed within in two weeks and thus it has translational potential that may change clinical management in the future and immunotherapy strategy design.
Extraordinary survivorship after colorectal liver metastasis resection to identify a distinct molecular profile associated with survival in an independent cohort of 965 patients.
Authors: Smith Jesse Joshua , Kandoth Cyriac , McAuliffe John Christopher , Vakiani Efsevia , Frankel Timothy , Wasserman Isaac , Chatila Walid , Lipsyc Marla , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Kingham T. Peter , Jarnagin William R. , Schultz Nikolaus , Kemeny Nancy E. , Garcia-Aguilar Julio , Taylor Barry S. , Solit David B. , Yaeger Rona , D'Angelica Michael Ian ,   MSK Collaborators: Agnes Viale, PhD, Karuna Ganesh MD, PhD, Garrett M. Nash MD, MPH, Jose G. Guillem MD, Philip B. Paty MD, Martin R. Weiser MD, Leonard Saltz MD, Michael Berger PhD and Charles L. Sawyers MD
Published: September 2018

3581 Background: Half of patients diagnosed with colorectal cancer (CRC) develop metastases and most are CRC liver metastasis (CRLM). A mere 20% of these patients undergo complete resection of their liver disease and 5-year overall survival (OS) is only 50%. We hypothesized that we could identify a specific molecular profile associated with extraordinary survivorship in CRLM patients that would more precisely inform underlying tumor biology beyond standard clinical and pathologic features. Methods: Tumor samples were identified from patients who underwent curative resection. Patients with disease-specific survival (DSS) ≥10 years following resection were compared to those with ≤2-year survival (10yr vs. 2yr). Evaluable DNA was obtained from 36 cases (2yr, n = 17; 10yr, n = 19) then sequenced and analyzed with MSK-IMPACT (MSK-I), a hybridization capture, next generation sequencing platform. Differentially altered genes in 10yr vs. 2yr cohorts were identified (Fisher’s exact). Findings in the extraordinary survivors group were validated using MSK-I in an independent cohort of 965 metastatic CRCs (metCRCs). Kaplan-Meier estimates and log-rank test were used. Results: In the 2yr group, we noted higher clinical risk scores and more complex chemotherapy regimens vs. the 10yr group. Molecularly, mutually exclusive KRAS and TP53 mutations were noted in the 10yr group, whereas significant co-occurrence of KRAS and TP53 mutations was seen in the 2yr group. Further, we noted significant enrichment of VEGF copy number gains in the 2yr group vs. the 10yr group. APC mutation was equally common. In the validation cohort, KRASmut/TP53wt and TP53mut/KRASwt patients (median OS of 10 and 15 years respectively) had significantly better OS than the co-occurring KRASmut / TP53mutpatients (median OS of 4.9 years; (P = 0.0001)). Conclusions: Single mutation of either KRAS or TP53 is associated with better outcomes than co-occurring KRAS/TP53 mutations in metCRC. These data demonstrate use of an extraordinary survivor cohort to identify a molecular profile associated with significant survival differences in an independent cohort of metCRC patients.
Factors contributing to the black/white colorectal cancer survival disparity in nonelderly patients.
Authors: Sineshaw Helmneh M. , Ng Kimmie , Flanders W. Dana , Brawley Otis W. , Jemal Ahmedin 
Published: September 2018

3587 Background: Previous studies reported that black/white survival disparities among elderly colorectal cancer (CRC) patients largely reflect differences in tumor presentation rather than differences in treatment. We sought to determine the contribution of differences in tumor presentation and receipt of treatment to the black/white survival disparity among nonelderly CRC patients. Methods: We selected non-Hispanic black (black) and Non-Hispanic white (white) patients aged 18-64 years, and diagnosed between 2004-2012 with single or first primary invasive stage I-IV CRC in the National Cancer Data Base. Blacks were sequentially matched with three white comparison cohorts, using propensity score and greedy matching algorithm, by demographics (age, sex, diagnosis year, region), tumor presentation (stage, grade, margin, tumor location, node status, comorbidity score), and treatment (surgery, chemotherapy, radiotherapy, metastatectomy) characteristics. We used Kaplan-Meier method to estimate 5-year survival for blacks compared with whites in the entire cohort and in the three sequentially matched cohorts. Results: In the entire cohort, 5-year survival was 9.2% lower in nonelderly blacks than whites (57.3% vs 66.5%). The survival difference remained unchanged after demographic matching, but it decreased to 3.3% (5.9% absolute and 64% relative reductions) after tumor presentation matching, and to 2.6% (0.7% absolute and 7.6% relative reductions) after treatment matching. By anatomic subsite, treatment matching reduced the black/white 5-year survival difference by 26% (3%/11.5%) for rectal cancer, only by 5.6% (0.5%/9%) for left colon cancer, and no change for right colon cancer. Conclusions: Differences in tumor presentation characteristics explained about two-thirds of the black/white survival disparity in nonelderly CRC patients, while treatment explained less than ten percent of the disparity. Future research should explore the biological mechanisms underlying these observed differences in tumor presentation and implications for treatment.
Genetic polymorphisms of CCL5 and CCR5 to predict efficacy of cetuximab-based treatment in metastatic colorectal cancer patients depending on primary tumor location.
Authors: Suenaga Mitsukuni , Cao Shu , Stintzing Sebastian , Zhang Wu , Yang Dongyun , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Schirripa Marta , Gopez Roel , Melendez Elizabeth , Soni Shivani , Barzi Afsaneh , Yamaguchi Toshiharu , Heinemann Volker , Lenz Heinz-Josef 
Published: September 2018

3594 Background: EGFR signaling blockade increases CCL5 expression, which attracts with tumor-infiltrating leukocytes regulating either the host-derived anti-tumor immunity or tumor progression. We tested whether genetic polymorphisms in the CCL5/CCR5 axis could predict efficacy of cetuximab (CET)-based first-line treatment in metastatic colorectal cancer (mCRC) patients (pts). Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC in the FIRE-3 study: an evaluation cohort of 244 pts receiving CET plus FOLFIRI (median age 64 yrs; median follow-up 34.1 mos); and a control cohort of 247 pts receiving bevacizumab plus FOLFIRI (median age 65 yrs; median follow-up 39.4 mos); Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. Results: Pts in the evaluation cohort with any CCL5 rs2280789 G allele had shorter OS compared to those with the A/A variant (19.9 vs. 33.4 mos, HR 1.56, 95%CI: 1.05–2.30, P= 0.024), which was confirmed in multivariable analysis (HR 1.64, P= 0.015). Pts carrying any CCR5 rs1799988 T allele had a trend lower response rate than those with the C/C variant (68 vs. 81%, P= 0.078). Statistically significant differences in efficacy were shown between the groups consisting SNPs and tumor location (Table). The findings were not confirmed in the control cohort. Conclusions: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC pts receiving CET-based first-line treatment depending on tumor location. [Table: see text]