bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA dynamics, serial testing and evolution on treatment in 322 colorectal cancer patients.
Authors: Kasi Pashtoon Murtaza , Kamatham Saivaishnavi , Colibaseanu Dorin , Merchea Amit , Shahjehan Faisal , Starr Jason Scott , Mody Kabir
Published: May 2019

3566

Background: According to the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint review on circulating tumor DNA (ctDNA) issued in March 2018, widespread use of ctDNA assays in most patients with advanced cancer is still an area of ongoing research. However, multiple studies thereafter published and/or presented support its use in patients with metastatic colorectal cancer (CRC). This has led to several institutions adopting it as ‘clinical practice’. The aim of this study is to report on our institution’s adoption of ctDNA testing for every patient at the time of diagnosis and/or time of progression. Methods: We report on results of 322 CRC patients with 607 ctDNA tests at our center from January 2017 to February 2019 using a commercially available platform (Guardant360). Results: Among 322 patients of our cohort, a total of 607 ctDNA tests were done (Table). 127 (39.4%) of these tests were serial analyses. In the CRC patients who had serial testing, at progression, mechanisms of resistance included acquisition of KRAS, NRAS, EGFR mutations; and HER2- and MET-amplifications. The subclonal mutations were noted to disappear when the selective inhibition was stopped. This was seen in patients on targeted therapies/biologics rather than chemotherapy. This was of value in treatment modification, clinical trial selection and/or monitoring of disease progression in these patients. Conclusions: While ctDNA testing may not be ready for primetime in all advanced cancers, it is increasingly being adopted in practice for especially metastatic CRC. Of particular value is the serial ctDNA testing in the RAS/RAF wildtype subset and now BRAF V600E mutant CRC on anti-EGFR based therapies. [Table: see text]
Association between pretreatment Fusobacterium nucleatum and cancer pain at six months postsurgery in newly diagnosed colorectal cancer patients: Results from the ColoCare Study.
Authors: Peoples Anita Roselyn , Gigic Biljana , Ose Jennifer , Holowatyj Andreana Natalie , Mallea Patrick M. , Warby Christy A. , Stephens W. Zac , Hardikar Sheetal , Schrotz-King Petra , Ryan-Wolf Julie , Ulrich Alexis B. , Swanson Eric A. , Schneider Martin , Li Christopher I. , Shibata David , Siegel Erin M. , Figueiredo Jane C. , Toriola Adetunji T. , Round June , Ulrich Cornelia M.
Published: May 2019

3581

Background: Pain is a prevalent, debilitating symptom in more than half of cancer patients. Accumulating evidence suggests a bi-directional relationship between gut microbiota and pain, potentially via inflammation and oxidative stress. Fusobacterium nucleatum (Fn), a pro-inflammatory anaerobic bacterium, is frequently detected in colorectal cancer (CRC) patients. To date, no study has identified a relationship between Fn and cancer pain in CRC patients. We investigated the associations between pre-treatment Fn and cancer pain at 6 months post-surgery in CRC patients. Methods: We utilized pre-surgery stool samples collected from 80 prospectively followed, newly diagnosed CRC patients recruited from the German site of the international ColoCare Study. Eligible patients were neo-adjuvant treatment naïve and did not use antibiotics for at least 1 month before stool collection. Fn DNA was assessed via quantitative real-time polymerase chain reaction. Patients were median split into Fn-high (>17.27; n=40) or Fn-low (≤17.27; n=40). Cancer pain was assessed using the 2 pain symptom items from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core-30 (lower score=lower pain) at pre- and 6 months post-surgery. Results: Before surgery, 48% of all patients reported any pain. At 6 months post-surgery, we observed a decrease in cancer pain by 33% for Fn-low, while there was an increase in cancer pain by 41% for Fn-high. After controlling for pre-surgery cancer pain in ANCOVA model, we observed significantly higher mean cancer pain at 6 months post-surgery in the Fn-high group vs. the Fn-low group (24.07 vs. 13.44; effect size, ES=0.45; p=0.04). These results were maintained even after controlling for age, sex, tumor stage and site, adjuvant chemotherapy, BMI, physical activity, and any pain medications (29.11 vs. 16.55; ES=0.53; p=0.03). Conclusions: These findings suggest that high Fn is an independent predictor of cancer pain at 6 months post-surgery in colorectal cancer patients. Further research is needed to confirm and understand the mechanisms of these results. Funding: NCI U01 CA206110.
Association of PIK3CA mutations (mut) with immune engagement and clinical benefit from immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC) patients (pts).
Authors: Nusrat Maliha , Roszik Jason , Katkhuda Riham , Menter David , Raghav Kanwal Pratap Singh , Morris Van K. , Sharma Padmanee , Allison James Patrick , Blando Jorge M. , Maru Dipen M. , Lizee Gregory , Janku Filip , Overman Michael J. , Kopetz Scott
Published: May 2019

3604

Background: PI3K pathway alterations, PIK3CA mut or PTEN loss, are known to modulate anti-tumor immune microenvironment. MSS CRC pts respond infrequently to immunotherapy, suggesting the presence of a rare MSS immunogenic subset. We investigated the immune repertoire and outcomes on immunotherapy trials in PIK3CA mut MSS CRC pts. Methods: Immune infiltrates and checkpoints were evaluated using quantitative immuno-histochemistry (IHC) on primary CRC. Mutations were assessed by next generation sequencing. PIK3CA mut neoepitopes and HLA allele affinities were predicted using NetMHC 4.0 Server. Outcomes of MSS CRC pts enrolled in 7 immunotherapy trials were assessed. Clinical benefit (CB) was defined as CR, PR or SD of 24 weeks. Time to progression (TTP) was calculated using Kaplan-Meier Method. PIK3CA mut vs wild type (wt) groups were compared using Mann-Whitney U, Fisher’s exact, or Log-Rank tests as appropriate. Results: PI3K alterations were present in 14/40 MSS CRC pts in IHC cohort (7 PIK3CA mut, 33 wt; 7 PTEN loss, 33 intact). The center of PIK3CA mut MSS CRC had higher median densities of CD3+ cells [1112 (IQ range 865-1421) vs 435 (300-744) cells/mm3; P=0.037] and CD8+ cells [554 (331-1200) vs 185 (60-473) cells/mm3; P=0.037] as compared to PIK3CA wt tumors. Intratumoral immune infiltrates did not differ by PTEN IHC staining in MSS CRC. PD-L1 H-scores were also higher in PIK3CA mut MSS CRC [85 (34-114) vs 29 (11-60); P=0.01]. Several activating PIK3CA mut (E542K, E545K, H1047R) were predicted to generate true neoepitopes with high binding affinity to common HLA types. Indeed, among MSS CRC pts enrolled in 7 immunotherapy trials, half (4/8) of PIK3CA mut pts derived CB as compared to 3/35 (8.6%) PIK3CA wt pts (P=0.015). PIK3CA mut pts had trend towards longer TTP (3.8 months in mut vs 2.1 months in wt; P=0.08). CB or TTP did not differ by colon sidedness, monotherapy / combination therapy, number of mut, or mut in other key genes ( APC, SMAD4, TP53, KRAS, NRAS or BRAF). Conclusions: PIK3CA mut MSS CRC are associated with increased cytotoxic T cell infiltration, higher PD-L1 expression, and greater clinical benefit from immunotherapy. Further investigation of immunotherapy outcomes in the context of neoepitope-HLA allele interaction may help identify a subset of PIK3CA mut MSS CRC pts who are likely to benefit from immunotherapy.
Stage-based variation in the impact of colon cancer surveillance.
Authors: Gately Lucy , Semira Christine , Jalali Azim , Faragher Ian , Ananda Sumitra , Kosmider Suzanne , Field Kathryn M. , Lok Sheau Wen , Steel Malcolm , Lee Margaret , Wong Rachel , Wong Hui-Li , Gibbs Peter
Published: May 2019

3609

Background: Multiple meta-analyses have demonstrated that routine surveillance following curative intent colorectal cancer surgery improves overall survival. This benefit is largely driven by early detection and curative intent resection of oligometastatic disease. Intuitively, any surveillance benefit should be proportional to recurrence risk, leading some to question the value of surveillance for stage I patients where recurrence rates are low. However, the survival benefit of surveillance has not previously been reported by stage. Methods: We explored data from a multi-site cohort of colorectal cancer patients (pts) diagnosed from 1 January 2001 to 31 December 2016. Pts were followed according to standard protocols with a standardized comprehensive outcome data captured prospectively. Pts with a rectal primary or metastatic disease at presentation were excluded from the analysis. We examined the correlation of stage at diagnosis with tumor recurrence and subsequent outcomes. Results: Of 3608 colon cancer pts, 690 (19%) had stage 1, 1580 (44%) had stage 2, and 1338 (37%) had stage 3 disease. Median follow-up was 7.8 years. Stage at diagnosis impacted recurrence rate (4% stage I vs 12% stage II vs 28% stage III, p < .0001) but not median time to recurrence. Recurrence patterns varied with stage (e.g. distant nodal disease 5% vs 7% vs 16%, p = .003; liver metastases 90% vs 53% vs 42%, p = 0.001). In pts with recurrence, resection of oligometastatic disease varied significantly by stage (58% vs 42% vs 30%, p < .0001) as did post-resection 5 year survival (91% vs 66% vs 43%, p < 0.001). In pts with recurrence treated with palliative intent, stage at diagnosis also impacted post-recurrence 5 year survival (11% vs 7% vs 5%, p < 0.03). Conclusions: Colon cancer stage at diagnosis substantially impacts the proportion of pts able to undergo curative intent surgery for surveillance detected recurrent disease, potentially driven by stage specific metastatic patterns. Stage at diagnosis also has a significant impact on post-resection survival outcomes potentially driven by stage specific biology. Our data indicate a far greater survival impact of surveillance for stage I colon cancer than would be anticipated based on recurrence rate alone.
Long-term outcomes after high-dose chemoradiotherapy for non-surgical management of distal rectal cancer.
Authors: Dizdarevic Edina , Appelt Ane L , Hansen Torben , Ploeen John , Jensen Henrik , Lindebjerg Jan , Rafaelsen Soeren Rafael , Jakobsen Anders Kristian Moeller
Published: May 2019

3611

Background: Surgery is standard treatment for rectal cancer, but neoadjuvant chemoradiotherapy (CRT) may result in clinical complete response (cCR) in selected patients, allowing for non-surgical management (NSM). Prospective studies of NSM strategies are sparse however, and long-term data on quality of life (QoL) are limited. We conducted a single-arm phase II trial of high-dose CRT for NSM of distal rectal cancer; we report secondary long-term patient-reported outcomes (PROs), local regrowth and overall survival (OS) in patients managed non-surgically. Methods: Fifty-one patients with resectable, T2 or T3, N0–N1, low adenocarcinoma received 65Gy (IMRT, brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, MRI, biopsy) were referred for observation, and followed closely with clinical examinations, endoscopies, PET-CTs, and PROs for 5 years. Overall colorectal cancer specific QoL and specific symptom scores were compared between timepoints using paired Wilcoxon tests. Local regrowth was estimated using cumulative incidence; overall survival using Kaplan-Meier estimates. Results: Forty patients achieved cCR after treatment; 28 were in follow-up at 24m, 21 at 36m, 18 at 60m. Patients left the trial due to local tumor regrowth (n=12), distant metastases (n=3), new primary cancers (n=6) and loss to follow-up (n=1). Average QoL score did not differ between baseline (median 11.1) and 24m (13.7), 48m (11.1,) or 60m (6.9). See Table for individual scores; only rectal bleeding deteriorated from baseline (significantly worse at 24m). At median follow-up of 5.0 years, local regrowth rate and OS were 31% (95 CI 15%-47%) and 85% (95 CI 75%-97%), respectively. Conclusions: Long term follow-up after NSM of early rectal cancer showed excellent general colorectal cancer QoL and local symptom scores. (NCT00952926). EORTC QLQ – CR 29. Proportion reporting ‘quite a bit’ or ‘very much’ on symptom scales. Clinical trial information: NCT00952926. [Table: see text]
S-1 plus oxaliplatin versus S-1 plus cisplatin as first-line treatment for advanced diffuse-type or mixed-type gastric/gastroesophageal junction adenocarcinoma: A randomized, phase 3 trial.
Authors: Xu Rui-hua , Wang Zhi-Qiang , Shen Lin , Wang Wei , Lu Jian-Wei , Dai Guanghai , Xu Jian-Ming , Zhang Yan-Qiao , Chen Xiao-Bing , Deng Yan-Hong , Zhao Yun-Bo , Fan Nan-Feng , Yu Gengsheng , Liao Wangjun , Yuan Xia , Lin You-En , Liu Guo-Long , Zou Qing-Feng
Published: May 2019

4017

Background: Diffuse-type or mixed-type gastric adenocarcinoma is associated with poor prognosis, and more effective treatment is needed. In Asia, S-1 plus cisplatin (SP) is the standard first-line chemotherapy regimen for advanced gastric cancer. Nevertheless, some clinical data suggested that oxaliplatin-based chemotherapy might be more efficacious and more tolerant than cisplatin-based chemotherapy. Methods: This trial is a multicenter, randomized, parallel-group, open-label, phase 3 trial in China. Patients aged 18-75 years, with PS 0-2, adequate organ function, histology confirmed, unresectable, advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA were randomized 1:1 to S-1 plus oxaliplatin group (SOX) (S-1: 40-60mg bid on d1-14, q3w; oxaliplatin: 130 mg/m2 on d1, q3w) or SP group (S-1: 40-60mg bid on d1-14, q3w; cisplatin: 60 mg/m2 d1, q3w). The primary endpoint was overall survival (OS) in the full analysis set (FAS). The secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF) and safety. Results: Between Jul 2013 and Jul 2018, 576 patients were randomized and 558 initiated treatment (279 patients/group). The median number of chemotherapy cycles was four in each group. In the FAS, the SOX group showed improved OS (13.0 vs. 11.8 months, HR = 0.764, 95% CI: 0.636-0.918), PFS (5.7 vs. 4.9 months, HR = 0.752, 95%CI: 0.632-0.895), and TTF (5.2 vs. 4.7 months, HR = 0.763, 95%CI: 0.641-0.909) compared with the SP group. In terms of grade≥3 adverse events, SOX showed lower occurrences of neutropenia (10.0% vs. 22.9%), leukopenia (9.7% vs. 21.9%), anemia (4.3% vs. 14.3%),vomiting (3.9% vs. 10.4%), nausea (2.2% vs. 10.4%), anorexia (2.2% vs. 6.8%), and febrile neutropenia (2.5% vs. 6.8%) than SP (all P < 0.05). The occurrence of grade≤2 sensory neuropathy(41.6% vs. 12.2%, P < 0.001)was higher with SOX than with SP. Conclusion: Compared with SP, SOX was more effective and less toxic (except neurosensory toxicity ) in patients with previously untreated advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA. Clinical trial information: NCT01824459.
Adjuvant chemotherapy versus perioperative chemotherapy (CTx) for resectable gastric signet ring cell (SRC) gastric cancer: A multicenter, randomized phase II study (PRODIGE 19).
Authors: Eveno Clarisse , Adenis Antoine , Bouche Olivier , Le Malicot Karine , Hautefeuille Vincent , Faroux Roger , Thirot Bidault Anne , Egreteau Joëlle , Meunier Bernard , Mabro May , Carrere Nicolas , Barriere Nicolas , Ben Abdelghani Meher , Mauvais François , Di Fiore Frédéric , Malka David , Manfredi Sylvain , Piessen Guillaume
Published: May 2019

4019

Background: The incidence of SRC gastric cancers is markedly increasing in Western countries. SRC cancers may harbor intrinsic resistance to chemotherapy (CTx) leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach. The primary objective of this study was to assess whether upfront surgery plus adjuvant CTx would provide enough survival benefit for study in a phase III trial when compared to perioperative CTx. Methods: Patients with stage IB-III SRC gastric cancer were randomly assigned to receive upfront surgery plus adjuvant CTx (epirubicin, cisplatin and 5-fluorouracil [ECF regimen], 6 cycles; experimental arm [SurgFirst]) or perioperative CTx (ECF, 3 cycles before and 3 cycles after surgery; control arm [CTxFirst]). Randomization (1:1) was stratified by tumor stage, tumor location, performance status and center. The primary endpoint was overall survival (OS) at 2 years (OS2; target (H1): OS2 > 26%). Results: 83 eligible patients were included in 27 centers from 11/12 to 09/16 (median age, 61 years (range: 32-80 years); male, 59%; ECOG PS 0-1, 99%). Results were (CTxFirst/SurgFirst): full completion of CTx, 87%/77%; surgical resection, 82.5%/90%; major postoperative complications (Clavien Dindo III-IV), 24%/23%; R0 resection rate, 88%/78%; OS2, 60%/53.5%; and median OS, 39/28 months (exploratory hazard ratio, 0.71 [95%CI: 0.40-2.64]). Conclusions: This trial met its primary endpoint (OS2 > 26% in the experimental arm). With OS2 rates > 50%, both CTx modalities deserve further evaluation in Phase III studies in stage IB-III SRC gastric cancer. Clinical trial information: NCT01717924.
Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.
Authors: Wang Feng , Ren Chao , Zhao Qi , Xu Nong , Shen Lin , Dai Guanghai , Yuan Xianglin , Chen Ye , Yang Shujun , Shi Jianhua , Hu Xichun , Lin Xiaoyan , Zhang Qingyuan , Feng Jifeng , Ba Yi , Liu Yunpeng , Li Wei , Shu Yongqian , Wang Fenghua , Xu Rui-hua ,   Shanghai Junshi Biosciences Co., LTD
Published: May 2019

4036

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.
Safety of neoadjuvant chemoradiation (CRT) in combination with avelumab (A) in the treatment of resectable esophageal and gastroesophageal junction (E/GEJ) cancer.
Authors: Uboha Nataliya Volodymyrivna , Maloney James D. , McCarthy Daniel , Deming Dustin A. , LoConte Noelle K. , Matkowskyj Kristina , Eickhoff Jens C. , Emmerich Philip , DeCamp Malcolm M. , Lubner Sam Joseph , Turk Anita Ahmed , Bassetti Michael Frederick
Published: May 2019

4041

Background: Neoadjuvant CRT followed by surgery is the standard of care (SOC) for patients (pts) with stage II/III E/GEJ cancer. However, recurrence rates are high. Immunotherapy has demonstrated promising activity in advanced E/GEJ cancer. This trial evaluates safety and efficacy of perioperative A with CRT in resectable E/GEJ cancer. Methods: This is a 2-part phase I/II trial. Part 1 is a run-in phase with 6 pts for safety evaluation. Part 2 will enroll additional 18 pts in the expansion cohort. Pts with E/GEJ cancer of any histology receive CRT (41.4 Gy in 23 fractions) with carboplatin and paclitaxel as per SOC. Three doses of A (10 mg/kg, q14 days) are administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Surgery is performed ~8 weeks after CRT completion. Pts receive 6 doses of A after resection. Dose-limiting toxicity (DLT) evaluations are completed on the first post-operative clinic visit, 2-4 weeks post resection. Results: Between 6/2018 and 2/2019, 6 pts (all male, median age 62) enrolled in part 1: 6 adenocarcinoma (100%); 1 E, 3 Siewert 1, 2 Siewert 2; 1 cT2N0, 2 cT3N0, 3 cT3N1. All pts underwent successful resection with negative surgical margins. 1/6 pts had R1 resection due to tumor extension to inked adventitial surface without invasion of surrounding structures. There were no unexpected surgical complications. At resection, 2 pts had ypT0N0, 2 ypT1N0, 1 ypT2N0, and 1 ypT3N1 disease. Combination of CRT and A had an acceptable toxicity profile. No DLTs were seen in the first 5 pts, so expansion cohort is open to enrollment. No grade ≥3 immune-related AEs were observed. Immune-related hypothyroidism was seen in 1 patient (grade 2). 6/6 pts had reversible grade 3 or 4 lymphopenia; 1/6 had grade 3 neutropenia. Correlative studies are ongoing and will be presented at the meeting. Conclusions: Perioperative CRT with A is well tolerated with no unexpected toxicities. Additional safety and correlative data will be presented at the meeting. This study is actively enrolling pts to an expansion cohort at University of Wisconsin. Clinical trial information: NCT03490292.
Perioperative (P) UGT1A1 genotype guided irinotecan (iri) dosing ‘gFOLFIRINOX’ for gastroesophageal adenocarcinoma (GEA).
Authors: Catenacci Daniel V.T. , Chase Leah , Lomnicki Samantha , Karrison Theodore , Marsh Robert de Wilton , Rampurwala Murtuza M. , Narula Sunil , Alpert Lindsay , Setia Namrata , Xiao Shu-Yuan , Hart John , Siddiqui Uzma , Liao Chih-Yi , Polite Blase N. , Kindler Hedy L. , Turaga Kiran , Prachand Vivek N. , Roggin Kevin K. , Ferguson Mark K. , Posner Mitchell C.
Published: May 2019

4050

Background: Complete resection (R0) and pathologic response grade (PRG) correlate with long-term GEA outcome. FOLFIRINOX demonstrated efficacy in advanced GEA; gFOLFIRINOX improved tolerability. We evaluated R0, PRG and tolerability in this pilot P study. Methods: Gastric body (GB) + esophagogastric (EGJ) GEA patients (pts) with ≥T3Nx or TxN+ were enrolled & treated with 4 pre + 4 postoperative biweekly cycles of gFOLFIRINOX (5-FU 2400mg/m2 over 46 hrs; oxaliplatin 85mg/m2; iri: 180mg/m2 for UGT1A1 genotype 6/6, 135mg/m2 for 6/7, 90mg/m2 for 7/7) (+ trastuzumab (T) 6mg/kg then 4mg/kg for HER2+) with prophylactic peg-filgastrim. 1°endpoint R0 resection required 36 pts to assess for a 90% R0 rate (intention to treat (ITT)) with 90% power + 0.05 alpha; ≥30/36 R0 considered positive. Co-1°endpoint was PRG (Becker); 36 pts provided 85% power with 0.05 alpha for a complete (pCR G1a) rate of 16%. 2°endpoints were safety/toxicity, PET response, & R0/PRG by tumor site, histologic subtype, HER2 status, & UGT1A1 genotype. We report efficacy and toxicity data from the neoadjuvant (Neo) portion of the study; postop data & survival outcomes will be presented at the meeting. Results: 4 sites enrolled 36 ITT pts between 2/2014-8/2018; 75% male, median age 66 (range 27-85). All pts completed all 4 cycles of Neo therapy: 10% had any dose reduction of iri (16%/0%/25% by genotype 6/6, 6/7, 7/7); any G3+ toxicity occurred in 35% of pts (32% 6/6, 29% 6/7, 75% 7/7). G3+ toxicity in ≥5% of pts: diarrhea (17.5%; 6/6 21%, 6/7 11%, 7/7 25%), anemia (5%), vomiting (5%). Efficacy is shown in the Table. Of pts going to surgery, both R1 resections were GB linitus. PRG1(a+b) was achieved in 36% of ITT pts, 46% of intestinal type histology. Conclusions: Neo gFOLFIRINOX was tolerable with surrogate efficacy comparable to FLOT. Clinical trial information: NCT02366819. [Table: see text]
The quality of life in neoadjuvant versus adjuvant therapy of esophageal cancer treatment trial (QUINTETT).
Authors: Malthaner Richard , Yu Edward , Sanatani Michael Susmoy , Lewis Debra , Warner Andrew , Dar A. Rashid , Yaremko Brian P , Bierer Joel , Palma David A. , Rodrigues George , Fortin Dalilah , Inculet Richard , Frechette Eric , Raphael Jacques , Gaede Steward , Kuruvilla Sarah , Younus Jawaid , Vincent Mark David
Published: May 2019

4052

Background: We compared the health-related quality-of-life (HRQOL) of standard neoadjuvant cisplatin and 5-FU chemotherapy plus radiotherapy (N) followed by surgical resection to adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy (A) following surgical resection for resectable esophageal carcinoma. Methods: 96 patients with stage I to III resectable cancer of the esophagus were enrolled into a prospective randomized trial (NCT00907543) from April 2009 to November 2016. Patients were randomized into 2 groups: N (47 cases) and A (49 cases). The primary end point was HRQOL using the FACT-E at one year. The secondary endpoints included other HRQOL measures, overall survival (OS), disease-free survival (DFS), and adverse events. Results: The median follow-up was 5.0 years [95% CI :4.6 to 5.5]. The majority of patients had adenocarcinomas of the distal esophagus/gastroesophageal junction (80.9% vs 87.8%). The stage distribution was: I 9%; II 22%; III 58%; TxN0-1 10%. Using an intention-to-treat analysis there was no significant difference in the FACT-E total scores between arms at one year (p = 0.759), with 35.5% vs. 41.2% respectively showing an increase of ≥ 15 points ( a priori minimal clinical difference) compared to pre-treatment (p = 0.638). The HRQOL was temporarily significantly inferior at 2 months in the N arm for FACT-E, EORTC OG25, and EQ-5D-3L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). There were no 30-day mortalities but 2.1% vs. 10.2% 90-day mortalities (p = 0.204). There were no significant differences in either 5-year OS (37.9% vs 28.9%, p = 0.321) or DFS (34.0% vs 25.5%, p = 0.551. 48.9% of patients required chemotherapy to be modified or stopped in the N arm compared to 57.1% in the A arm (p = 0.421). 51.1% of patients were able to complete the prescribed N arm chemotherapy without modification compared to only 14.3% in the A arm (p < 0.001). Chemotherapy related adverse events significantly more frequent in the neoadjuvant arm (p < 0.05). Surgery related adverse events were significantly more frequent in the neoadjuvant arm (p < 0.05). Conclusions: Trimodality therapy is challenging for patients with resectable esophageal cancer regardless if it is given before or after surgery. Less toxic protocols are needed. Clinical trial information: 00907543.
Safety results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma (ESO-Shanghai 2).
Authors: Ai Dashan , Chen Yun , Liu Qi , Zheng Xiangpeng , Li Yunhai , Wei Shihong , Ye Jinjun , Zhou Jialiang , Lin Qin , Luo Hui , Cao Jianzhong , Li Jiancheng , Huang Guang , Wu Kailiang , Fan Min , Yang Huanjun , Zhu Zhengfei , Zhao Weixin , Li Ling , Zhao Kuaile
Published: May 2019

4055

Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC) . Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. TP group had a significant higher incidence of acute grade 3/4 neutropenia (59.7% vs. 16.8%(TF) or 32.4%(TC)), thrombocytopenia (12.7% vs. 3.5%(TF) or 6.2%(TC)), anemia (6.4% vs. 4.4%(TF) or 4.4%(TC)), fatigue (10.0% vs. 0.9%(TF) or 0.9%(TC)) and vomiting (5.5% vs. 0%(TF) or 0.9%(TC)) than other two groups ( P < 0.05). TF group had a significant higher incidence of grade 3/4/5 esophagitis (13.1% vs. 1.8%(TP) or 5.3%(TC)) and pneumonitis (4.4% vs. 0%(TP) or 1.8%(TC)) than other two groups ( P < 0.05). One patient in TF group died of acute pneumonitis. One patient in TF group and one in TC group died of acute esophagitis. Conclusions: TP and TF regimen showed different severe AEs in CCR in ESCC patients and TC showed mild AEs. Clinical trial information: NCT02459457.
Landscape of innate and adaptive immunity targets in oesophagogastric adenocarcinoma (OGA).
Authors: Smyth Elizabeth Catherine , Linossi Constanza , Jammula Sriganesh , Devonshire Ginny , Fitzgerald Rebecca C.
Published: May 2019

4063

Background: Anti-PD-1 therapy modestly improves survival in chemorefractory OGA. Combining PD-1 blockade with novel checkpoint inhibitors, T-cell co-stimulatory molecules, or myeloid suppressors could enhance PD-1 inhibition. Herein, we explore the landscape of known targetable immune markers in non-Asian OGA. Methods: OGA patient biopsies were prospectively collected and clinically annotated from 19 UK cancer centres (Oesophageal Cancer Clinical and Molecular Stratification – OCCAMs network). Genomic (WGS) and transcriptomic (bulk-RNA seq) data were generated using Illumina and processed using a validated in-house pipeline (Frankell, Nat Genetics 2019). Gene expression was computed in transcripts per kilobase. Using unsupervised clustering patient clusters were selected according to the expression of gene targets for immune therapy - PD-L1, LAG3, TIM3, TIGIT, ICOS, CCR2, CCR5, CXCR4, and CSF1R. Immune cell infiltration was extrapolated using GSVA gene set enrichment analysis. Results: RNAseq data were available for 251 patients; 96% had operable tumours (Stage I: 6%, II: 63%, III: 22%, IV: 4%). In untreated patients (n = 156) 3 subgroups were identified: immune low (83, 53%) with low level expression of all 9 markers, immune high (14, 9%) with high expression of all or majority of markers and intermediate (59, 38%) with heterogenous marker expression. Clinicopathological variables (sex, age, smoking, tumour location (gastric/GEJ/esophagus) and tumour regression grade) were similarly distributed across subgroups. In a cohort of 114 patients with matched WGS and RNAseq data tumour mutation burden was not different between subgroups. In post-chemotherapy biopsies (n = 95) a similar co-expression pattern was observed. Gene enrichment analysis supported infiltration by cells of innate and adaptive immune system in immune high patients. Neoantigen results, phenotypic immunohistochemistry and optimised survival outcomes according to lymphoid and myeloid target expression will be presented. Conclusions: High level co-expression of immune regulatory targets in OGA patients may limit the efficacy of anti-PD-1 monotherapy. Combination immune directed therapies may be required in this patient group.
Comprehensive molecular characterization of clinical response in ramucirumab-treated gastric cancer patients: Phase II trial with integrated genomic profiling.
Authors: Kim Seung , Oh Sung Yong , Park Se Hoon , Kim Kyung , Park Joon Oh , Park Young Suk , Kang Won Ki , Lee Jeeyun
Published: May 2019

4064

Background: The absence of tumor cells enables an enriched stromal environment to generate RNA signatures and through assembling genes involved in tumor stroma, four distinct stromal signatures that reflected biological processes such as signature vascular mature (VM), vascular mature/inflammatory (VMI), vascular immature/noninflammatory (VINI) and inflammatory alone (I) depending on mature of vasculature. We hypothesized that these stromal specific signatures may provide additional information to the pre-existing TCGA/ACRG subtypes when predicting response to anti-angiogenesis agent such as ramucirumab. Methods: We conducted a single-center phase II trial in which we treated 61 unselected patients with metastatic GC with ramucirumab plus paclitaxel as second line therapy and performed pre-planned integrated genomic profiling. Results: Sixty-two patients were enrolled in this study between May 2014 and June 2017. The cut-off date for treatment outcome analysis was January 2, 2019, at which time response evaluations were available for 57 patients with a median follow-up of 30.2months. In an intent-to-treat analysis cohort, there was no CR and 22 patients achieved confirmed PRs resulting in an ORR of 35.5% (95% CI: 23.6 – 47.4). The response rate to ramucirumab was considerably enriched in VM/VMI group (29.2%) (P = 0.0003) when compared to I ( < 10%) or VINI group ( < 10%). The strongest response defined by maximal response to ramucirumab was shown in GC patients with VM/VMI signatures. Of note, VM/VMI patients had prolonged duration of response to ramucirumab/paclitaxel demonstrating that these patients not only respond to ramucirumab but also had durable response. Conclusions: This is the first study to demonstrate a clinically robust correlation between stromal-based signature and response to anti-angiogenesis inhibitor in GC. Clinical trial information: 02628951.
Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies.
Authors: Bang Yung-Jue , Ueno Makoto , Malka David , Chung Hyun Cheol , Nagrial Adnan , Kelley Robin Kate , Piha-Paul Sarina Anne , Ros Willeke , Italiano Antoine , Nakagawa Kazuhiko , Rugo Hope S. , De Braud Filippo G. , Varga Andrea I. , Hansen Aaron Richard , Gao Chao , Krishnan Suba , Norwood Kevin , Doi Toshihiko
Published: May 2019

4079

Background: Antitumor activity with pembro, an anti–PD-1 antibody, has been observed in patients (pts) with advanced/metastatic biliary tract cancers (BTC), who have limited treatment options. We present follow-up data from pts with advanced BTC treated with pembro in the KN158 (NCT02628067; phase 2) and KN028 (NCT02054806; phase 1) studies. Methods: Eligible pts ≥18 y in the KN158/KN028 BTC cohorts had histologically/cytologically confirmed incurable advanced BTC that progressed after/failed any number of prior standard treatment regimens, measurable disease per RECIST v1.1, ECOG PS of 0/1, and no prior immunotherapy. PD-L1–positivity (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma) was required for eligibility in KN028, but not KN158. Pts received pembro 200 mg Q3W (KN158) or 10 mg/kg Q2W (KN028) for up to 2 y. Radiographic imaging occurred Q9W for 12 mo (KN158) or Q8W for 6 mo (KN028) and Q12W thereafter. Primary efficacy endpoint in both studies was ORR by RECIST 1.1. Response assessed by independent central review is reported. Results: Median (range) follow-up was 7.5 (0.6–29.5) mo in the 104 pts from KN158 and 6.5 (0.6–33.1) mo in the 24 pts from KN028 with BTC. All pts in KN028 and 61 in KN158 had PD-L1–positive tumors. No pt had MSI-H tumors (not assessed in KN028). In KN158, ORR was 5.8% (6/104, all PR [including 1 pt with PD-L1–negative tumor]; 95% CI, 2.1%–12.1%) and median duration of response (DOR) was not reached (NR; range, 6.2 to 23.2+ mo). Median OS and PFS were 7.4 mo (95% CI, 5.5–9.6) and 2.0 mo (95% CI, 1.9–2.1). 12-mo OS rate was 32.7%. In KN028, ORR was 13.0% (3/23, all PR; 95% CI, 2.8%‒33.6%) and median DOR was NR (range, 21.5 to 29.4+ mo). Median OS and PFS were 6.2 mo (95% CI, 3.8‒10.3) and 1.8 mo (95% CI, 1.4‒3.7), respectively. 12-mo OS rate was 27.6%. Grade 3–5 treatment-related AEs occurred in 13.5% in KN158 (1 pt had grade 5 renal failure) and 16.7% of pts in KN028 (no grade 5). 18.3% in KN158 and 20.8% of pts in KN028 had an immune-mediated AE or infusion reaction. Conclusions: Pembro provides durable antitumor activity, regardless of PD-L1 expression, and manageable toxicity in a subset of pts with advanced BTC. Clinical trial information: NCT02054806 and NCT02628067.
Neoadjuvant FOLFIRINOX versus adjuvant gemcitabine in pancreatic cancer.
Authors: Wolfe Adam R , Miller Eric David , Abushahin Laith I. , Cloyd Jordan , Manilchuck Adrei , Dillhoff Mary , Diaz Pardo Dayssy Alexandra , Noonan Anne M. , Williams Terence M
Published: May 2019

4123

Background: In the metastatic or adjuvant setting for pancreatic cancer, the combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in longer overall survival (OS) compared to gemcitabine therapy. We conducted an institutional study to compare the efficacy of neoadjuvant modified FOLFIRINOX (neo-mFOLFIRINOX) to adjuvant gemcitabine (adj-gem) for pancreatic cancer patients who completed resection. Methods: The study retrospectively enrolled patients from 2006 to 2017 from Ohio State University. While patients who received adjuvant gemcitabine were considered to be resectable upfront, patients who received neo-mFOLFIRINOX were either staged as borderline resectable (BR) or un-resectable (UR) by the institutional tumor board group. 111 patients received adj-gem (average cycles, 5.5) and 52 patients received neo-mFOLFIRINOX (average cycles, 3.5). The survival rates were determined by the Kaplan-Meier method and analyzed using Cox regression and log-rank test. Results: At a median follow up of 21.3 months, the median OS was 35.4 months in the neo-mFOLFIRINOX group and 21.8 months in the adj-gem group (hazard ratio, 0.56, 95% confidence interval (CI), 0.37-0.84 p = 0.005). The OS rate at 3 years was 46% in the neo-mFOLFIRINOX group and 22% in the adjuvant gemcitabine group (p = 0.001). The median disease free survival (DFS) was 18.6 months in the neo-mFOLFIRINOX group and 12.0 months in the adj-gem group (hazard ratio, 0.63, 95% CI, 0.43-0.93 p = 0.022). The DFS rate at 3 years was 17% in the neo-mFOLFIRINOX group and 11% in the adj-gem group (p = 0.02). On surgical pathological specimen review, the neo-mFOLFIRINOX group had statistically (p < 0.05) lower tumor grade, lower rates of perineural invasion and lymphovascular invasion, lower pathological T stage, lower pathological N stage, and lower number of nodes positive compared to the adj-gem group. Frequencies of obtaining R0 resections were higher in the neo-mFOLFIRINOX versus adj-gem groups but not statistically different (51.9% vs 40.4, p = 0.2). The average age and performance status were similar between the two groups. Conclusions: At our institution, BR and UR pancreatic cancer patients who received neo-mFOLFIRINOX and completed resection had longer OS, DFS, and more favorable pathological indicators compared to those patients who had upfront surgery and adjuvant gemcitabine. Randomized clinical trials comparing neoadjuvant versus adjuvant FOLFIRINOX are needed to validate these findings.
Elevated pretreatment serum IL-8 and PD-L1 and overall survival in a phase III randomized advanced pancreatic cancer clinical trial.
Authors: Maddukuri Ashok , Moku Prashanth Reddy , Polimera Hyma Vani , Nagabhairu Vinod , Ali Suhail M. , Leitzel Kim , Drabick Joseph J. , Halstead Scott , Umstead Todd , Mckeone Daniel , Ali Aamnah , Poulose Joyson , Pancholy Neha , Menon Harry , Spiegel Howard , Lipton Allan
Published: May 2019

4131

Background: We previously reported the prognostic and predictive utility of pretreatment serum PD-L1 in the CCTG MA.31 serum bank (SABCS 2018, abstr PD3-10). IL-8 (CXCL8) is a pro-inflammatory cytokine that binds to CXCR1 and CXCR2 and promotes tumor immune escape and progression. High serum IL-8 levels are associated with poor prognosis in many cancers, and have recently been reported to predict for reduced OS to nivolumab in lung cancer and melanoma (ASCO 2018, abstr #3025). In this study, we retrospectively evaluated combined pretreatment serum IL-8 and PD-L1 on overall survival (OS) from a phase III randomized pancreatic cancer trial of first-line therapy (octreotide + 5-FU vs. 5-FU) that had reported no significant OS difference between treatment arms. Methods: This study had 147 patients with serum available for this retrospective biomarker analysis from an advanced pancreatic cancer phase III clinical trial.TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was utilized to quantitate serum levels of IL-8 and PD-L1. Kaplan-Meier life table analysis was used to correlate serum biomarkers with overall survival (OS). Results: In univariate analysis, pretreatment serum IL-8 was a significant biomarker as a continuous variable (HR = 1.004; p = 0.012) and trended significant at the median cutpoint (HR = 1.379; p = 0.098) for OS, however serum PD-L1 was not significant at any cutpoint. When serum PD-L1 and IL-8 levels were analyzed as combined biomarkers (median cutpoints), the serum IL-8 high / PD-L1 high cohort had a significantly shorter OS vs the serum IL-8 low / PD-L1 low cohort (HR = 1.816; p = 0.017). Conclusions: In this phase III randomized clinical trial in advanced pancreatic cancer, pretreatment serum IL-8 was a significant biomarker for OS, but serum PD-L1 was not. Higher combined pretreatment serum levels of PD-L1 and IL-8 (both biomarkers high vs. both low) were prognostic for reduced OS in this phase III pancreatic cancer trial. Further study of circulating IL-8 and PD-L1 is warranted in pancreatic cancer for evaluation of targeted and investigational therapies, including the immune checkpoint inhibitors and anti-IL8 therapy.
Improved overall survival (OS) for advanced pancreatic cancer (PDAC) patients (pts) enrolled in the Know Your Tumor (KYT) program whose tumors harbored highly actionable molecular alterations and who received molecularly-matched therapies (tx).
Authors: Pishvaian Michael J. , Blais Edik Matthew , DeArbeloa Patricia , Brody Jonathan Robert , Rahib Lola , Hendifar Andrew Eugene , Mikhail Sameh , Chung Vincent , Sohal Davendra , Picozzi Vincent J. , Mason Kimberly , Tibbetts Lisa , Lyons Emily , Matrisian Lynn McCormick , Madhavan Subha , Petricoin Emanuel
Published: May 2019

4138

Background: Initial results from the KYT program demonstrated that 27% of PDACs harbor highly actionable molecular alterations (herein labelled “actionable biomarkers”), defined as biomarkers that predict for a high response rate to appropriately targeted tx, in any cancer type. Within this cohort, the median progression-free survival on molecularly-matched tx was 2 months longer than unmatched tx. Here, we present OS data emphasizing the 125 pts with “actionable biomarkers” who did or did not receive molecularly-matched tx. Methods: PanCAN and Perthera have coordinated tumor molecular profiling through commercial labs (NGS/IHC panels) for PDAC pts since 2014. Results are reviewed by a molecular tumor board, and tx options are prioritized based on the actionable biomarkers, in the context of the pt’s tx history. Pts are followed longitudinally to track physician tx choices and survival outcomes. Cox regression was used to assess differences in OS (measured from date of diagnosis until death). Results: Of 1053 pts who received a Perthera Report, 25% had “actionable biomarkers”. OS analyses across 454 pts with adequate tx history are shown in the Table below. Notably, pts with “actionable biomarkers” who received a molecularly-matched tx had a significantly increased OS compared to those with “actionable biomarkers” but who did not receive molecularly-matched tx. Subgroup analyses related to tx history and specific molecular pathways that warrant further investigation will be discussed. Conclusions: When the ~25% of PDAC pts whose tumors harbored “actionable biomarkers” received molecularly-matched tx, they had a better OS. These findings support the need to test all pts with PDAC, and just as importantly, to maximize access to molecularly-matched tx for appropriate pts, to achieve the best pt outcomes. [Table: see text]