bluuebunny/crossref_metadata_2025 huggingface dataset:
Extranodal extension influences prognosis in pancreatic head cancer.
Authors: Sung Min Kyu , Park Guisuk , Park Seo Young , Lee Woohyung , Song Ki Byung , Lee Jae Hoon , Kim Song Cheol , Hwang Dae Wook , Hong Seung Mo
Published: January 2022

593

Background: Extranodal extension (ENE) is an established prognostic factor of several gastrointestinal cancers; furthermore, ENE is already included as one component of nodal category of oral cavity, penis, and vulvar cancers. However, the prognostic impact of ENE in pancreatic cancer remains unclear. In this study, we aimed to investigate prognostic implication of ENE in patients with surgically resected pancreatic cancer. Methods: We retrospectively reviewed electronic medical records and pathologic slides of 503 surgically resected pancreatic head cancer patients, who consecutively underwent pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. Patients were categorized into subgroups according to ENE status and AJCC 8th pancreatic cancer staging system. We compared the disease-free survival rates of the patients according to ENE status. Cox proportional hazard analysis was performed to evaluate prognostic factors for the disease-free survival of pancreatic head cancer. Results: ENE-positive patient group showed a larger tumor size, a higher rate of lymph node metastasis, and a tendency to be positive for lymphovascular invasion, perineural invasion, and resection margin (p < 0.001). Patients with ENE had lower overall survival (OS) and disease-free survival (DFS) rates compared with those without ENE (N0, 30 months; LN+/ENE-, 20 months; LN+/ENE+, 16 months; p < 0.001), (N0, 13 months; LN+/ENE-, 8 months; LN+/ENE+, 5 months; p < 0.001). Patients with higher N categories had lower OS and DFS rates. In addition, even in the same N stage, patients with ENE showed lower OS and DFS rates than those without ENE (p < 0.001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer. Conclusions: ENE significantly influenced adverse prognosis among patients with pancreatic head cancer especially for those with nodal metastasis. Therefore, ENE should be considered as a prognostic factor in the future editions of the AJCC staging system.
Targeted therapy (TT) in patients with KRAS wildtype (WT) pancreatic ductal adenocarcinoma (PDAC) produces durable response.
Authors: Mehdi Maahum , Annunzio Kaitlin , Taylor Bradley W. , Szabo Aniko , Shreenivas Aditya V. , Chakrabarti Sakti , Thomas James P. , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Clarke Callisia , Hall William A. , Erickson Beth , Thapa Bicky , Ahmed Gulrayz , George Ben , Kamgar Mandana
Published: January 2022

596

Background: Genomic alterations (GA) that drive cancer development and predict therapeutic response remain elusive in patients (pts) with KRAS WT PDAC. We interrogated our institutional database to identify actionable GAs in pts with metastatic, KRAS WT PDAC and analyzed the therapeutic impact of matched TT. Methods: We reviewed electronic medical records of KRAS WT PDAC pts (n=24) who underwent comprehensive genomic profiling (CGP) utilizing Foundation One CDx (25.0%) or Tempus (75.0%) between 2015-2021. Duration of response (DOR) was calculated from date of treatment (Tx) initiation to Tx discontinuation. Overall survival (OS) was measured from the date of the diagnosis (Dx) of advanced disease (AD) to death or last follow-up. OS was estimated using the Kaplan-Meier method, with at-risk periods left-truncated at the time of CGP. The effect of covariates on survival was evaluated using Cox proportional hazards regression. Results: Of the 24 KRAS WT pts, 14 (58%) had AD: 8 (57%) pts had metastatic disease at or shortly after Dx, 6 (43%) pts developed metachronous recurrence. Median age at Dx for pts with AD was 65, and 57% were female. Seven of 14 pts with AD (50%) had highly actionable GA (HAGA), (Table). Pts with HAGA demonstrated durable responses to TT (Table) with manageable toxicities. Pts with HAGA had a median OS of 28 mo compared to 5.9 mo for those without (Hazard Ratio = 0.47, p = 0.33). Conclusions: The sustained therapeutic benefit noted with TT matched to HAGA in pts with KRAS WT PDAC underscores the need for systematic interrogation of the somatic genome in PDAC pts. Optimal sequencing of cytotoxic therapy with TT and its impact on modulating clonal selection pressure in pts with KRAS WT PDAC merits prospective evaluation.[Table: see text]
Outcomes of patients with small intestine adenocarcinoma (SIA) in a Canadian province: A population-based cohort study.
Authors: Yanko Emma , Le Duc , Mahmood Shazia , Ginther Nathan , Chalchal Haji I. , Kanthan Rani , Haider Kamal , Zaidi Adnan , Dorie-Anna Dueck , Ahmed Shahid
Published: January 2022

641

Background: SIA is a rare cancer. Limited data is available about clinicopathological factors and interventions that correlate with its outcomes. The current study aims to determine outcomes of patients with SIA who were diagnosed in a Canadian province. Methods: In this retrospective population-based cohort study patients with biopsy proven SIA diagnosed during 2008-2017 in the province of Saskatchewan were assessed. A Cox Proportional multivariate regression analysis was performed to determine correlation between survival and exploratory factors. Results: 112 eligible patients with median age of 73 yrs and M:W 53: 59 were identified. 75% had a comorbid illness, 34% had a secondary cancer and 45% had WHO performance status (PS) < 2. Of 112 patients, 51 (46%) had early-stage disease and 61 (54%) had advanced-stage disease. Median neutrophil: lymphocyte (NLR) was 4.5. The median overall survival (mOS) in relation to stage of the disease were as follow: stage 1, 59 months, stage 2, 30 months, stage 3, 20 months and stage 4, 3 months (P < 0.001). The patients with early-stage disease had mOS of 36.0 months (95% CI: 8.0-64.0) vs. 3.0 months (1.74-4.26) with advanced disease (P < 0.0001). Of 21 patients with stage 3 disease their median disease-free survival was 26 months (23.1-28.9) with chemotherapy vs. 4 months (0.0-9.1) with no chemotherapy, p = 0.04. Patients with stage 4 disease who had surgery and or chemotherapy had mOS of 18 months (13.70-23.32) vs. 4 months (2.20-5.82) with chemotherapy alone p = 0.03. On univariate analysis age ≥70 yrs, WHO PS > 1, stage 4 disease, low albumin, elevated creatinine, high alkaline phosphatase, duodenal cancer, lack of surgery, and NLR of > 4.50 were significantly correlated with inferior survival. On multivariate analysis stage 4 disease, HR, 3.20 (95%CI:1.84-5.40), WHO PS > 1, HR, 2.22 (1.42-3.45), no surgery, HR, 2.10 (1.25-3.50), and NLR > 4.5, HR, 1.72 (1.10-2.71) were significantly correlated with inferior survival. Conclusions: Most patients with SIA were diagnosed with advanced-stage. In addition to advanced-stage disease and poor PS, lack of surgery and baseline LNR of > 4.5 were significantly correlated with inferior survival.
Integration of molecular cancer classification and NGS to identify metastatic patients eligible for IDH inhibitors.
Authors: Kasi Pashtoon Murtaza , Ma Li , Treuner Kai , Wong Jenna , Schnabel Catherine A.
Published: January 2022

647

Background: Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2) often occur in hematologic malignancies and solid tumors. Ivosidenib was recently approved for IDH1-mutated cholangiocarcinoma based on improved progression-free survival (PFS) and overall survival (OS). Notably, cancers of uncertain diagnoses presenting as liver metastases are often cholangiocarcinoma. While several trials are ongoing to evaluate IDH1/2 inhibitor efficacy in other advanced solid tumor types, currently eligibility for IDH inhibitor therapy requires both tumor type identification and IDH mutation confirmation. The 92-gene assay (CancerTYPE ID) is a gene expression classifier of 50 tumor types and subtypes for metastatic patients with diagnostic ambiguity. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. Here, a database of metastatic cases that integrates tumor type with biomarker analysis was used to identify those eligible for IDH inhibitor treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tumor type-guided multimodal biomarker testing by NGS (Neogenomics). In this study, metastatic cancers classified as pancreaticobiliary and other solid tumor types with IDH1/2 mutations were identified. Results: CancerTYPE ID determined 27 different tumor types in 2377 of 2572 cases (92.4%). The most common tumor type identified was pancreaticobiliary with 644 cases; subtypes with IDH1/2 mutation status are shown in the table. An IDH1 mutation was identified in 23 out of 78 (29.5%) cholangiocarcinoma cases which are eligible for ivosidenib treatment. IDH1/2 mutations were also detected in 11 other tumor types. For patients with IDH1 mutations, 28.2% were identified in tumor types with no FDA-approved IDH therapy, whereas 50.0% of IDH2 mutations overlapped with tumor types that have ongoing trials to determine the clinical benefit of targeting IDH2. Conclusions: These findings support the clinical utility of molecular tumor type classification combined with biomarker profiling to identify approved or investigational treatment options. The MOSAIC analysis identified metastatic patients with actionable aberrations ( IDH1) eligible for FDA-approved therapy, as well as those who may be eligible for investigational IDH inhibitor therapies based on tumor type and IDH1/2 mutation status. As new and approved IDH inhibitors are evaluated for efficacy, increased patient selection may be afforded through this approach in additional tumor types.[Table: see text]
Feasibility of acupressure intervention to improve chemotherapy-related symptoms and functioning among gastrointestinal cancer patients.
Authors: Armstrong Samantha Ann , Wang Judy Huei-yu , Liu Geng-Hao , Arieta Carla , Thomas Maya , Geng Stephanie , Fritz Zach , He Aiwu Ruth , Noel Marcus Smith , Weinberg Benjamin Adam , Marshall John
Published: January 2022

657

Background: Chemotherapy-related symptoms, including fatigue, pain, insomnia, nausea, and vomiting, affect cancer patients’ (pt) physical and mental functioning. Acupressure (AP), which uses fingers to stimulate acupoints in the body per traditional Chinese medicine, has shown beneficial effects in improving chemotherapy-related symptoms. Yet, AP has been understudied in gastrointestinal cancer (GI) pts’ symptom management. Methods: This single-arm pilot trial enrolled 24 patients with stage I-IV GI cancers undergoing chemotherapy. They were trained to self-administer AP to 4 acupoints (Li4, PC6, ST36, SP6) on each side of the body, then practice one minute per acupoint for 8 minutes every day and fill daily logs through an 8-week intervention period. The primary endpoint examined the feasibility (interest, retention, and adherence rates) of delivering self-administered AP. Chemotherapy-related symptoms and functional status at baseline and 8-week post-intervention follow-up were assessed using NIH patient-reported outcome assessments (PRO-CTCAE and PROMIS short forms). Paired t-tests were run to examine change scores in symptom outcomes before and after intervention. Results: Pt demographics were 50% male, 21% African American, 67% Caucasian and 12% other (mean age = 56). They included 38% colorectal cancer, 25% pancreatic cancer, 17% cholangiocarcinoma, and 20% upper GI cancers. Feasibility outcomes showed that 83% of approached pts were interested in participation; 24 of 31 eligible pts (77%) were enrolled; retention rate was 71% (N = 17). Seven pts did not complete the trial due to two with infections, three concerning time to fill daily logs, and two with unspecified reasons. Approximately 65% of pts adhered to performing AP for over 80% of the time and filling daily logs every week. No adverse events were attributed to AP. Data from PRO-CTCAE showed that over 93% of pts reported no or mild nausea and vomiting through the intervention period except one reporting a moderate level of vomiting. Data from PROMIS surveys showed that after the 8-week intervention, patient-reported pain interference with daily activities and physical functioning remained similar to the baseline level. Yet, pts had reduced fatigue (-4.4 points), sleep disturbance (-3.1), depression (-3.3), anxiety (-2.7), and increased cognitive function (2.6) after AP intervention. These improvements were not statistically significant due to the small sample size, but a 3-point change in the PROMIS symptom scores is clinically meaningful. Conclusions: This trial shows that self-administered AP proves to be a feasible, safe, and low-cost approach and may be beneficial for GI cancer pts to relieve treatment-related symptoms. Future randomized trials are needed to determine efficacy.
Medications to manage cancer-associated anorexia/cachexia syndrome (CACS) in patients with advanced gastrointestinal (GI) cancer.
Authors: Arora Nivedita , Ramesh Vidhyalakshmi , Virnig Beth A. , Blaes Anne Hudson , Gupta Arjun
Published: January 2022

658

Background: Patients with advanced GI cancer have a high prevalence of CACS. Medications used for CACS have limited efficacy, unwanted side effects, and high costs. We sought to describe the prescribing patterns of medications for CACS in patients with advanced GI cancer. Methods: We identified patients with advanced GI cancer (primary pancreatic, gastric, colorectal, and hepatobiliary) treated at the UM Fairview Medical Center, Minneapolis, MN from 2011-2019. We extracted sociodemographics, clinicopathological data (e.g. body mass index [BMI]), other treatments (e.g. nutrition referral), and prescriber specialty (e.g. oncology). The primary outcome was medication use for CACS: outpatient oral prescription of ≥7 days of megestrol, dronabinol, mirtazapine, olanzapine, or cyproheptadine as any formulation (e.g., tablet, solution) on a scheduled basis. Since medications can have overlapping indications, we clarified prescription indication through chart review if needed. We excluded dexamethasone given extremely non-specific use. Results: We identified 974 patients with advanced GI cancer (45.9 % women, 84.2% White, 4.7% Black, median age 65 years, 36.8% pancreatic cancer, median overall survival 212 days). Of these, 265 (27.2%) patients received at least 1 prescription for CACS (Table). There were 736 unique prescriptions (41.8% dronabinol, 26.9% mirtazapine, 22.4% olanzapine, 8.4% megestrol and 0.4% cyproheptadine). Brand-name formulations comprised 2.7% prescriptions. Most prescriptions were provided by oncologists (67.1%), followed by primary care practitioners (20.3%), and palliative care (6.0%). The median times from advanced cancer diagnosis to first prescription, and from last prescription to death were 73 and 50 days respectively. The median BMI (kg/m2) and serum albumin (g/dL) at time of first prescription were 24.3 (range 11.8-51.1) and 2.5 (range 0.7-4.5) respectively. Conclusions: Almost 1/3rd of patients with advanced GI cancers received medications for CACS. Prescribing was primarily driven by oncologists, and was common in the last weeks of life. Our findings can guide interventions to optimize CACS care by reducing reflexive medication prescribing for CACS, while underscoring the need to develop better pharmacologic and non-pharmacologic CACS treatments.[Table: see text]
Core homologous recombination mutations and improved survival in nonpancreatic GI cancers.
Authors: Tan Elaine , Whiting Junmin , Walko Christine Marie , Knepper Todd C , Xie Hao , Imanirad Iman , Carballido Estrella M. , Felder Seth , Frakes Jessica M. , Mo Qianxing , Permuth Jennifer , Kim Richard D. , Anaya Daniel A. , Fleming Jason B. , Sahin Ibrahim Halil Halil
Published: January 2022

663

Background: GI malignancies continue to be a major cause of cancer related deaths, despite advances in therapy options. In pancreatic cancer, the presence of homologous recombination mutations (HRM) has been shown to confer increased sensitivity to platinum chemotherapy. However, the role of HRM mutations in other GI cancers remains to be determined. The focus of this study is to evaluate the prognostic nature of core and noncore HRM in nonpancreatic GI cancers. Additionally, we aim to understand the predictive nature of these mutations related to platinum exposure. Methods: This was a retrospective review of patients at Moffitt Cancer Center with a primary stage IV nonpancreatic GI cancer treated with platinum therapy. All patients had next generation sequencing and were in the Clinical Genomics Action Committee database between 1/1/2013 and 11/1/2020. All patients had either a core HRM (BRCA1, BRCA2, PALB2) or noncore HRM (such as ATM, ATR, BARD1, BRIP1, FANCA, NBN, and RAD51). Patients were grouped into core HRM vs. noncore HRM. Response was stratified between responders (complete response and partial response) vs. non responders (stable disease and progressive disease), based on RECIST criteria. Progression free survival and overall survival were estimated using Kaplan-Meier method, and the log-rank test was used to assess the difference in progression free survival (PFS) and overall survival (OS) by HRM status and type of platinum therapy used. Results: There were 72 patients included in the study: the majority of patients were male (65.3%) and Caucasian (87.5%). Twenty-one (29.2%) patients had a core HRM and 51 (70.8%) had a noncore HRM. There was no significant difference in response rate between patients with core HRM and patients with noncore HRM for evaluable patients (n = 66): 20.0% of patients with core HRM vs. 21.7% of patients with noncore HRM demonstrated a response to platinum therapy (p = 0.41). An improved OS was noted for patients with core HRM vs. those with noncore HRM at 68.9 vs. 24.3 months (p = 0.019). An improved PFS was also seen in patients with core HRM at 10.4 months vs. 6.3 months with noncore HRM (p = 0.027). There was no difference in PFS based on type of platinum therapy used (oxaliplatin vs. carboplatin vs. cisplatin), while an improved OS was noted for patients treated with oxaliplatin vs. carboplatin vs. cisplatin at 43.1 vs. 28.2 vs. 16.0 months (p = 0.011). Conclusions: Our study demonstrated that in stage IV nonpancreatic GI malignancies treated with platinum therapy, patients with core HRM had a greater OS and PFS compared to those with noncore HRM, suggesting a potential prognostic and predictive role of these mutations. Further studies are needed to confirm our findings.
Phase II trial of moderate dose omega-3 acid ethyl esters for colorectal cancer prevention in patients with lynch syndrome (COLYNE).
Authors: Choucair Khalil , Dixon Dan , Bansal Ajay , Klemp Jennifer R. , Abdulateef Yazan , Chalise Prabhakar , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Saeed Anwaar
Published: January 2022

TPS209

Background: Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome and is responsible for about 3% of newly diagnosed CRC. It is caused by germline mutations in one of the DNA mismatch repair (MMR) genes, and patients with LS carry a lifetime risk of CRC ranging between 10% and 70%. The role of inflammation in driving this malignant transformation is now well established and retrospective studies have revealed a potential chemo-preventative role for omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), possibly via inhibition of inflammatory pathways associated with the development of defective MMR CRC tumors. While patients with LS have the highest risk of developing CRC, the majority of chemoprevention trials are focused on sporadic CRC. Effective interventions to reduce the risk of developing CRC in this population are limited to close surveillance and surgical prophylaxis. There is an unmet need for safe, effective, and non-invasive chemo-preventive interventions in patients with LS. Methods: This pilot study is a single-arm, open-label, phase 2 clinical trial of omega-3 acid ethyl esters (generic Lovasa; 2 grams orally once daily) for adult patients (≥ 18 years of age) with confirmed LS (based on germline testing of the MMR genes panel: MLH1, MSH2, MSHS6, PMS2 or deletion in EPCAM gene). Patients who are not candidate for elective endoscopy and/or with prior history of right sided or pan-colectomy are excluded. Thirty-four patients are expected to enroll, with a primary objective to determine the feasibility (defined as 80% retention rate) of 12 months of treatment with 2 grams capsules of omega-3 acid ethyl esters daily. Secondary endpoints include safety and tolerability of the intervention. Correlative aims include pre and post treatment assessment of colon mucosal tissue proliferation (right sided colon specimens will be evaluated for markers of proliferation (Ki-67) and apoptosis (Caspase-3)), the effect of omega-3 acid ethyl esters on inflammatory markers in serum, urine and feces (PGE-2, COX-2, β-catenin levels, and EPA:AA ratios), and gene expression related to proliferation, apoptosis and cell survival in colon tissue (NF-κB/Wnt pathways). The impact of omega-3 acid ethyl esters on intestinal microbiota will also be assessed (16S rRNA-based profiling). Correlative Colon tissue, serum, urine and feces samples are collected at baseline and at 12 months. The study is actively enrolling with 20 patients enrolled at the time of submission. Clinical trial information: NCT03831698.
NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US).
Authors: Dasari Arvind , Lin Yan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Wolmark Norman , Yothers Greg , George Thomas J. , Lieu Christopher Hanyoung
Published: January 2022

TPS212

Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in CC patients (pts) and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using Natera’s Signatera assay, those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP + Ox vs more intensive AC with addition of irinotecan (I) for 6 mos. The primary objectives for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs delayed AC arms. The primary objective for Cohort B is DFS in the FP + Ox vs FP + Ox + I arms for both phase II and phase III portions of the trial. Secondary objectives include prevalence of detectable ctDNA post-operatively, time-to event outcomes (overall survival & time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/ normal blood samples will be collected for exploratory correlative research. Study will activate in early 2022 across the NCTN. NCT#: Pending. Support: U10-CA-180868, -180822; UG1CA-189867; Natera.
A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in advanced colorectal cancer (CRC) and other solid tumors (CodeBreaK 101).
Authors: Hong David S. , Yaeger Rona , Kuboki Yasutoshi , Masuishi Toshiki , Barve Minal A. , Falchook Gerald Steven , Govindan Ramaswamy , Sohal Davendra , Kasi Pashtoon Murtaza , Burns Timothy F. , Langer Corey J. , Puri Sonam , Chan Emily , Jafarinasabian Pegah , Ngarmchamnanrith Gataree , Rehn Marko , Tran Qui , Gandara David R. , Strickler John H. , Fakih Marwan
Published: January 2022

TPS214

Background: Approximately 3% of patients (pts) with CRC have the oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation. Sotorasib, a small molecule that specifically and irreversibly inhibits the KRAS G12C mutant protein, has demonstrated modest clinical activity and no dose-limiting toxicities as a single agent in heavily pretreated pts with KRAS p.G12C-mutated CRC. The combination of sotorasib with other anticancer therapies, such as EGFR or MEK inhibitors, may enhance antitumor efficacy and counteract potential escape mechanisms. Other attractive partners for sotorasib in CRC include biologics and chemotherapy combinations. The CodeBreaK 101 master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib-based combinations in pts with KRAS p.G12C mutated solid tumors. Key subprotocols with CRC combination treatment arms are highlighted here. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens in pts with advanced KRAS p.G12C mutated CRC, NSCLC, and other solid tumors. Key regimens being explored in CRC include (1) Subprotocol A: Sotorasib + trametinib (MEK inhibitor) +/- panitumumab (EGFR inhibitor), (2) Subprotocol H: Sotorasib + panitumumab and sotorasib + panitumumab + FOLFIRI, and (3) Subprotocol M: Sotorasib + bevacizumab-awwb + FOLFIRI or FOLFOX. Key eligibility criteria include advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in treatment-naïve and pretreated patients depending on cohort. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (objective response, disease control, duration of response, time to response, and progression-free survival assessed per RECIST 1.1, and overall survival). Enrollment is ongoing. Contact Amgen Medical Information for more information: medinfo@amgen.com (NCT04185883). Abbreviations: EGFR = epidermal growth factor receptor; FOLFIRI = 5-fluorouracil + leucovorin + irinotecan; FOLFOX = 5-fluorouracil + leucovorin + oxaliplatin; MEK = mitogen-activated protein kinase. Clinical trial information: NCT04185883.
Anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pretreated with bevacizumab plus standard chemotherapy: A single-arm, phase IB/II study.
Authors: Qu Xin , Chen Xian , Li Yong , Liu Li-rong , Qu Yan-chun , Hou Fang-fang , Li Wen-zhu , Liu Yi-hong , Zhu Yan-juan , Zhang Haibo
Published: January 2022

TPS220

Background: For advanced colorectal cancer (CRC), fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin) with VEGF inhibitors (bevacizumab) is standard first-line treatment. However, once this treatment had been used, the second line treatment is limited. Although continuation of bevacizumab after first progression can improve PFS and OS, the benefit of bevacizumab may be reduced compared with who never pre-treated with bevacizumab (the ML18147 study). Anlotinib is an oral small molecule tyrosine kinases inhibitor, targeting VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α/β and c-kit. mXELIRI is a chemotherapy regimen consisting of irinotecan and capecitabine. The trial is to investigate the efficacy and safety of anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pre-treated with bevacizumab plus standard chemotherapy. Methods: This is a multi-center, prospective, single-arm, 2-part, phase Ib/II study. Eligible pts are aged 18-75 years with histologically and radiographically confirmed mCRC who had progressed or intolerant with bevacizumab plus FOLFOX or CAPEOX regimen chemotherapy treatment. ECOG performance status 0 - 1, and adequate organ function. Treatment: anlotinib (8mg, 10mg or 12mg), po, qd, on days 1-14 every 3 weeks; irinotecan 180-200 mg/m2, iv, on day 1 every 3 weeks; capecitabine, 800 mg/m2, po, bid, on days 1-14 every 3 weeks. For the phase 1b segment, a standard 3+3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of anlotinib. 3 patients are enrolled and treated per dose level (8mg,10mg,12mg). If no DLT, dose is escalated for the next cohort of 3 patients; If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs；If ≥ 2 DLTs, prior dose level is defined as MTD. MTD decided when 6 patients are treated at a dose level with < 2 DLTs. Primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and quality of life (QoL). Based on a one-sided one sample log-rank test with 2.5% Type I error, 80% power to detect an improvement in ORR from 5.4% to 15%, there will be 94 patients consider 20% of patients fall off. Research Sponsor: Guangdong Provincial Hospital of Chinese Medicine Clinical trial information: NCT05035914.
An open-label, single-center, phase II study of exploration on optimizing the administration time of fruquintinib combined with camrelizumab in the third-line treatment of MSS advanced colorectal cancer.
Authors: He Yifu
Published: January 2022

TPS225

Background: Immune checkpoint inhibitors monotherapy has limited clinical benefits in patients with MSS or pMMR metastatic colorectal cancer (CRC), which may be attributed to low level of tumor-infiltrating lymphocytes in MSS advanced CRC. Combination immunotherapy is changing the landscape of cancer treatment, especially combination of immunotherapy with small molecule angiogenesis inhibitors. Preclinical studies have shown that there is a time window from anti-angiogenesis to vascular normalization and this has been initially demonstrated in the clinical study of breast cancer. However, the time window is rarely considered in clinical practice. It is necessary to explore the optimal administration timing of angiogenesis inhibitors when combined with immunotherapy. Here, we conduct an open-label, single-center, phase II study to explore the issue. Methods: Patients eligible for the trial are included: 1) pathologically confirmed advanced colon or rectal adenocarcinoma, MSS or pMMR; 2) previously received only 2 standard regimens after recurrence or metastasis; 3) aged 18-70 years (boundary value included); 4) ECOG performance status of 0 or 1; 5) at least 3 months of survival expectations; 6) patient must present with measurable lesions according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST version 1.1; 7) patients with asymptomatic central nervous system metastases or asymptomatic brain metastases after treatment, with stable disease for at least 3 months, and need not be treated with steroids for at least 4 weeks; 8) had adequate organ function before the enrollment; 9) patients of reproductive age should agree to use effective contraceptive measures from the time of signing the informed form until 3 months after the last dose; 10) sign an informed consent form voluntarily, and be willing to and be able to follow and complete all experimental procedures. The patients enrolled were given oral fruquintinib (3 mg, qd, for 2 consecutive weeks, and then discontinued for 1 week, in 3 weeks [21 days] cycle); on the day 5, administered with intravenous camrelizumab (200mg, once every 3 weeks). The treatment was administered continuously until disease progression, unacceptable toxicity, or required withdrawal from patients. The primary endpoint is progression free survival (PFS), and the secondary endpoints are overall survival (OS), objective response rate (ORR), disease control rate (DCR) and drug safety. As of September 23, 2021, a total of 21 patients have been enrolled. Clinical trial information: ChiCTR2100048528.
mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS mutant unresectable colorectal liver-limited metastases: A study protocol of a multicenter randomized controlled phase 3 (BECOME2) trial.
Authors: Tang Wentao , Wei Ye , Ren Li , Ye Qing-Hai , Liu Tianshu , Xu Jianmin
Published: January 2022

TPS228

Background: Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined. Methods: BECOME2 is a multicenter, randomized, phase 3 clinical study. RAS mutant and BRAF wild type colorectal cancer patients with initially unresectable liver-limited metastases are eligible. The (un)resectability status is prospectively assessed by a central multidisciplinary team (MDT) consisting of at least one radiologist and three liver surgeons, according to predefined criteria. RAS and BRAF mutation status were evaluated according to primary tumor. Patients with RAS mutant and BRAF wild type will be randomized between modified FOLFOXIRI (IRI, 165mg/m2; Oxa, 85mg/m2; LV, 400mg/m2; 5-FU 2400mg/m2) plus bevacizumab (5mg/kg) and modified FOLFOX6 (mFOLFOX6) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central MDT every eight weeks. The primary study endpoint is conversion resection rate. Secondary endpoints are the ETS, DpR, ORR, PFS, OS, toxicity, perioperative complication, and the proportion of no evidence of disease. Clinical trial information: NCT04781270.
Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomized phase II trial (PRIME-RT).
Authors: Hanna Catherine Ruth , O'Cathail Sean Michael , Graham Janet , Saunders Mark P. , Samuel Leslie M. , Devlin Lynsey , Edwards Joanne , Maka Noori , Kelly Caroline , Dempsey Laura , Jones Leia , Lewsley Liz-Anne , Morrison Paula , Atherton Peter , Dillon Susan , Gourlay Jacqueline , Platt Jonathan , Tiplady Ellie , Adams Richard , Roxburgh Campbell SD
Published: January 2022

TPS231

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. The PRIME-RT trial tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in (n≥6) which is recruiting patients with metastatic disease. After opening in January 2021, three patients have been treated within the safety run-in; 2 in Arm A and 1 in Arm B. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Funding information Core funding (Glasgow CRUK CTU) and trial specific funding (Astrazeneca). Trial registration Clinicaltrials.gov NCT04621370 (Registered 9 Nov 2020) ISRCTN18138369 (Registered 27 October 2020) Clinical trial information: NCT04621370.
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Hong Theodore S. , Wolmark Norman , George Thomas J.
Published: January 2022

TPS233

Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N = 1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the Guardant Reveal assay, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Enrollment continues across North America to the 540-patient phase II endpoint. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.
Examination of the functional and diagnostic potential of methylation-sensitive enhancers in metastatic colorectal cancer.
Authors: Carroll Hailey Kathryn , Harrold Emily , Greally Megan , Aird John , O'Donoghue Niamh , Finnegan Ellen , Shields Conor J , Brannigan Ann E , Mulsow Jurgen , Cahill Ronan , Toomey Des , Das Sudipto , McCaffrey John
Published: January 2022

TPS237

Background: Molecular characterisation of colorectal cancer (CRC) has demonstrated the regulatory role of epigenetic alterations, such as DNA methylation, in CRC tumorigenesis(1). Robust molecular profiling of CRC has the potential to provide critical diagnostic and prognostic information. The establishment of 4 consensus molecular subtypes (CMSs), developed initially for primary CRC tumours, resulted in the evolving framework for molecularly targeted interventions; the molecular genetic profile characterising mCRC is less well defined(3, 4). Previous pilot work identified a unique tumour-specific methylation sequence, at 376 sites within the DNA of mCRC cells(5). This study will assess whether this methylation sequence drives mCRC pathogenesis and underpins disease phenotype. The primary aim of this study is validation of the diagnostic utility of this novel enhancer signature and identification of key enhancers with the potential to direct targeted treatment development. Secondary aims include CRISPR knockdown library development targeting the enhancers in CRC cells in vitro, evaluating the impact of the knockdown on phenotype in vitro, and identifying the mechanisms by which methylation-sensitive enhancers regulate the mCRC phenotype. Methods: This is a retrospective, non-interventional, single-centre clinical study, including patients > 18 years, with (group A) de novo mCRC (n = 100), (group B) stage III colorectal cancer that subsequently relapsed (n = 100) or (group C) stage III colorectal cancer without radiological evidence of relapse at study enrolment (n = 100). Formalin-fixed, paraffin-embedded ( FFPE) tissue obtained at diagnosis will be analysed. Additionally, 50 stage III patients who have relapsed (group B) will have blood samples collected prospectively at time of consent to enable assessment for the presence of the methylation signature on ctDNA. The presence or absence of the novel methylation signature will be evaluated via the application of a targeted bisulfite sequencing panel consisting of the previously identified differentially methylated enhancer (DME) signature to both tissue and plasma samples; results will be correlated with conventional histological parameters, systemic therapy, and overall survival. Quantitative statistical analysis will be performed using SPSS with linear regression analysis for survival data. Ethical approval was obtained from the MMUH Institutional Review Board; reference 1/378/2188. This study is open and recruiting. Clinical trial information: 1/378/2188.
Assessment of changes in chest wall mechanics in esophageal cancer survivors using a 3D-motion capture system.
Authors: Tukanova Karina , Banger Matthew , Hanna George , McGregor Alison , Markar Sheraz
Published: January 2022

TPS360

Background: Surgical resection remains the mainstay of treatment for loco-regional esophageal cancer. Traditional open esophagectomy is associated with considerable morbidity, with postoperative pulmonary complications (PPC) being the most frequently observed morbidity. There are several peri- and postoperative factors that are known to affect the respiratory mechanics, including an open surgical approach, administration of sedatives, rib spreading with subsequent fracture or nerve injury, presence of PPC and neuropathic pain leading to post-thoracotomy syndrome. Enhanced recovery programmes with early mobilization protocols and chest physiotherapy have been shown to reduce pulmonary complication rates. However, no data is currently available regarding the long-term respiratory function, quality of life and chest wall function in esophageal cancer survivors. Quantification of chest wall movements provides an objective measurement of function for the long term assessment of chest wall mechanics and could be used to develop tailored physiotherapy for patients undergoing esophagectomy. The aim of this study is to develop a method to objectively quantify changes in breathing mechanics in esophageal cancer survivors using a biomechanical approach. Methods: In the initial phase, an 89-marker protocol will be validated against a 3D-printed chest wall model that can produced simulate of normal and abnormal motions. Retroreflective markers will be placed non-invasively on the anterior, posterior, and lateral parts of the thorax and abdomen. A working protocol of breathing mechanics will be assessed in healthy control volunteers with the subject seated in upright position. Subjects will perform the respiratory function tests, the spirometer and the respiratory pressure meter. Further to this clinical assessment, the impact of thoracic movements and treadmill exercise will be assessed on the parameters obtained from changes in breathing movements. Following this, an optimization phase will refine markers placement and identify parameters that are most likely to be clinically relevant in the assessment of breathing mechanics. A finalized protocol will be trialled in esophageal cancer survivors, to identify changes in thoracoabdominal motion after surgery and to assess whether these changes are associated with impairment in health-related quality of life. This information will aid the development of evidenced based physiotherapy regimens tailored to the needs of this patient population. Clinical trial information: NCT03835273.
A prospective, multicenter, dose-escalation, and dose-expansion study evaluating apatinib plus chemotherapy in second-line therapy of patients with postoperatively gastric cancer (ACHIEVE).
Authors: Han Junyi , Pang Tao , Zhang Zhan , Lu Zhengmao , Dong Ping , Wu Jianguo , Yin Kai , Chang Xusheng , Luo Tianhang
Published: January 2022

TPS362

Background: Apatinib, a highly selective small-molecule tyrosinase inhibitor of VEGFR2, is the third-line standard therapy for patients (pts) with advanced gastric cancer. Many previous studies have preliminarily demonstrated the efficacy and safety of apatinib combined with chemotherapy in the second-line treatment of gastric cancer. Comparing with pts who have not undergone surgery, previous pharmacological study has found that pts who have undergone gastric cancer surgery have lower bioavailability and can tolerate higher doses of apatinib (Clin Pharmacokinet. 2017 Jan; 56(1):65-76). However, there is no prospective evidence of apatinib plus chemotherapy for second line treatment in pts with postoperatively gastric cancer. Methods: To explore the efficacy, safety and the maximum tolerated dose (MTD) of apatinib from apatinib+chemotherapy for second line treatment in pts with postoperatively gastric cancer. We designed ACHIEVE as a multicenter, dose-escalation, and dose-expansion trial in pts with gastric or gastroesophageal junction cancer who had prior undergone gastrectomy. In part 1 (dose escalation), pts who had received previously first-line treatment will be assigned to 1 of 3 three dose groups: (1) apatinib (250mg qd) + chemotherapy drug; (2) apatinib (500mg qd) + chemotherapy drug; (3) apatinib (750mg qd) + chemotherapy drug. The therapeutic drugs for second-line chemotherapy are determined by the investigator, it’s recommended to use docetaxel or albumin-bound paclitaxel, and chemotherapeutics are used for up to 6 cycles. In part 2 (dose expansion), pts will be treated with apatinib (MTD determined by dose escalation, qd) + chemotherapy drug. Whether PD-1 or PD-L1 inhibitors have been used in the first-line treatment will be analyzed as a subgroup analysis factor. Primary endpoints are progression-free survival (PFS) and MTD. Secondary endpoints include confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Tumor response will be assessed by RECIST v1.1 every 6 weeks in the first 18 weeks, and every 9 weeks thereafter. Clinical trial information: ChiCTR2100048288.