bluuebunny/crossref_metadata_2025 huggingface dataset:
Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas.
Authors: Katz Matthew H. G. , Shi Qian , Meyers Jeffrey P. , Herman Joseph M. , Choung Michael , Wolpin Brian M. , Ahmad Syed , Marsh Robert de Wilton , Schwartz Lawrence Howard , Behr Spencer , Frankel Wendy L. , Collisson Eric Andrew , Leenstra James Lewis , Williams Terence Marques , Vaccaro Gina M. , Venook Alan P. , Meyerhardt Jeffrey A , O'Reilly Eileen Mary
Published: January 2021

377

Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]
Treatment patterns and survival outcomes of older patients with advanced pancreatic cancer (APC): A Canadian real-world evidence study.
Authors: Batra Atul , Ramjeesingh Ravi , Meyers Brandon M. , Vickers Michael M. , Goodwin Rachel Anne , Armstrong Dawn Elizabeth , Cheung Winson Y. , Kim Christina ,   on behalf of Cancer Health Outcomes Research Database (CHORD) Consortium
Published: January 2021

385

Background: We aimed to compare chemotherapy regimens used and overall survival (OS) among geriatric patients (≥ 75 years) with APC as compared to old (65-74 years) and young (< 65 years) patients with APC. Methods: In this retrospective population-based analysis, we identified patients with APC (defined as inoperable/metastatic disease) from 5 large provinces in Canada who were diagnosed from 2011 to 2016. Kaplan-Meier curves were plotted to derive OS and multivariable Cox regression models were constructed to determine the associations of different age groups on OS. Results: We included 636 patients diagnosed with APC of whom 258 (40.6%), 247 (38.8%) and 131 (20.6%) were young, old and geriatric. Approximately half (45.7%) of all patients were women. Eastern Cooperative Oncology Group performance status (ECOG PS) was known in 508 patients at diagnosis among whom 62.2% were 0-1 and 37.8% were 2+. ECOG PS was more likely to be 2+ in the geriatric group (46.8% vs 41.1% vs 31.3%; P = 0.017). Most patients (95.8%) had metastatic disease while the remaining patients had inoperable locally advanced disease. Within the study cohort, 38.7% received chemotherapy. Treatment rates differed based on age: 41.9% in young patients, 40.9% in old patients and 28.2% in geriatric patients (P = 0.02). Choice of first-line chemotherapy varied and included FOLFIRINOX (F) in 99 (40.2%), gemcitabine and nab-paclitaxel (GN) in 91 (37.0%) and gemcitabine (G) in 56 (22.8%). F, GN and G were administered in 27.0%, 32.4% and 40.5% of geriatric patients, 40.6%, 32.7% and 26.7% of old patients, and 44.4%, 42.6% and 13.0% of young patients, respectively (P = 0.007). After adjusting for baseline factors, both geriatric (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.42-1.17; P = 0.175) and old patients were as likely to receive chemotherapy (OR, 1.04; 95% CI, 0.70-1.56; P = 0.815) as their young counterparts. The median OS was 7.1 (6.3-8.4), 6.7 (5.5-8.9) and 5.3 (4.3-6.8) months in young, old and geriatric patients, respectively. After adjusting for baseline variables, both geriatric (hazard ratio [HR], 1.25; 95% CI, 0.96-1.62; P = 0.101) and old patients (HR, 1.16; 95% CI, 0.94-1.42; P = 0.171) experienced similar OS as young patients. ECOG PS 2+ at presentation was associated with worse OS as was treatment with G. Conclusions: Overall treatment rates for APC are low in the real world. The poor OS in geriatric patients with APC is driven by poor PS and use of less intensive chemotherapy. Age alone should not be considered a contraindication for more intensive chemotherapy since treatment benefit is observed across all age groups. [Table: see text]
Reference values for EORTC QLQ-C30, for metastatic pancreatic cancer (mPC): Enhancing the interpretation of HRQoL scores in the POLO trial.
Authors: Kindler Hedy L. , Amin Suvina , Joo Seongjung , Patel Nikunj , Yoo Hyun Kyoo , Johnson Colin , Byrnes Hilary , Costa-Cabral Sara , Nolte Sandra
Published: January 2021

393

Background: Metastatic pancreatic cancer (mPC) and its treatments significantly impact patients’ (pts) health-related quality of life (HRQoL). POLO, a randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy of olaparib as maintenance therapy in mPC pts who had not progressed during ≥16 weeks of first-line platinum-based chemo. HRQoL was assessed in POLO using EORTC QLQ-C30. To enhance the interpretation of HRQoL scores in POLO, we derived EORTC QLQ-C30 reference (ref) values for mPC from the literature, as these had not been previously established. Methods: A systematic literature review was conducted to identify existing baseline values in published data. EORTC QLQ-C30 ref values were calculated by deriving mean scores based on studies meeting all inclusion criteria. EORTC QLQ-C30 mean values were calculated for POLO using pooled baseline data from both study arms (olaparib; placebo). Results: Out of 186 studies identified, 4 met all inclusion criteria. Depending on respective EORTC QLQ-C30 subscale, the final sample sizes ranged from n=466 to n=639. Compared to the newly derived EORTC QLQ-C30 ref values based on the literature, POLO pts reported markedly better HRQoL scores at baseline across most subscales, with eight subscales showing differences of >15 points (table). Conclusions: This is the first study to systematically derive EORTC QLQ-C30 ref values for mPC. We found that mPC pts enrolled in POLO had better HRQoL scores compared with those reported in the literature and often close to or better than general population norm data, possibly due to positive effects of prior platinum-based first-line treatment, resolution of chemotherapy-related symptoms, response shift, or a combination. These newly derived ref values enhance the interpretation of patients’ HRQoL trajectory within a maintenance treatment setting. [Table: see text]
Comparative efficacy of commonly used first-line chemotherapy regimens in advanced pancreatic cancer: A network meta-analysis.
Authors: Haddad Philip A. , Gallagher Kevin Michael , Hammoud Dalia
Published: January 2021

403

Background: Pancreatic adenocarcinoma is one of the deadliest cancers, ranking fourth in mortality and accounting for up to 7% of all cancer related deaths in the United States. For many years, Gemcitabine and its combinations have been the standard first-line treatments for patients with unresectable locally advanced or metastatic pancreatic cancer (aPC). Recently, FOLFIRINOX was shown to be associated with a survival advantage as well. These chemotherapy combinations have not been compared to each other. We conducted this network meta-analysis to evaluate the relative efficacy of the commonly used chemotherapy regimens in patients with aPC. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of aPC; treatment with Gemcitabine (GEM) combined with Capecitabine (CAPE), Erlotinib (ERLO), or nab-Paclitaxel (NABPAC) and treatments with FOLFIRINOX; and randomized studies reporting survival and response rates. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Six studies comprising a total of 2,717 participants were included. FOLFIRINOX demonstrated a significantly better relative risk (RR) of progression and death (P&D) followed by GEM+NABPAC, GEM+ERLO, GEM+CAPE, and GEM in a decreasing order. When compared to GEM-based combination as a group, FOLFIRINOX maintained its superior RR for P&D. Moreover, FOLFIRINOX and GEM+NABPAC had significantly better response rates than GEM+CAPE and GEM+ERLO. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates. Conclusions: This network meta-analysis is the first to compare and rank commonly used treatment regimens in aPC. It indicates that FOLFIRINOX combination seems to be superior to GEM-based combinations with respect to P&D as well as response rates. Nevertheless, among GEM-based combinations, GEM+NABPAC seems to have the best profile given its lower RR for P&D and higher response rates.
Efficacy and preclinical safety of ARB202, a potential first-in-class anti-CDH17/CD3 bispecific T-cell engager, for treatment of pancreatic and colorectal cancers.
Authors: Wong Dennis A , Luk Moon Ching , Wong Tony K , Staunton Donald E , Harlan John M
Published: January 2021

405

Background: Globally, gastrointestinal (GI) cancers, which account for around 28% of all cancers, has increased constantly at a CAGR of 2% (2014-2019), while the treatment options remain limited and often ineffective. This is largely due to late diagnosis and lack of new tumor associated antigens for most of the GI malignancies. Cadherin-17, CDH17 (aka CA17), is being evaluated as a potential therapeutic target and molecular marker for GI cancers, of which aberrant expression of CDH17 was reported in 50-90% in tumor samples (including stomach, pancreas, liver/bile duct and colon) by multiple groups. The present study aims to develop a humanized CDH17-CD3 bispecific T-cell engager antibody, ARB202, to treat advanced pancreatic and metastatic colon cancers. Methods: The ARB202 bispecific was generated from anti-CDH17 monoclonal ARB102 as previously described (Lum Y et al, Mol. Pharm. 2020) by linking a CD3-binding scFv in the format of IgG4-scFv. Biophysical properties, efficacy and safety were evaluated. Efficacy was addressed in cytotoxicity assays, IL2-release assays and subcutaneous xenograft models using multiple GI tumor target lines. Preclinical safety profiles include Tissue cross-reactivity assays and GLP repeat-dose toxicity studies in NHP. Results: The ARB202 bispecific antibody was efficiently produced (yield ~1 g/L) and remained stable for at least 3 months under accelerated stress tests. Binding affinity (Kd [M]) of ARB202 to CDH17 and CD3 was at 10-10 and 10-9 respectively, with cellular affinities of 10-9 and 10-8. In vitro cytotoxicity assays demonstrate that ARB202-mediated tumor cell killing is CDH17-dependent and requires immune synapse formation with effector T cells. By contrast, normal cells and CDH17-negative cancer cells are resistant. Pancreatic AsPC1 xenograft model revealed an ARB202 (co-inoculated with human PBMC) dose-dependent inhibition of tumor growth. Human IL-2 release in mice blood samples was consistent with functional CDH17 and CD3 engagement. ARB202 PK profile in rodents and NHP was found to be excellent relative to other bispecifics and GLP toxicity studies showed no significant findings nor adverse effects. Conclusions: ARB202 bispecific antibody promises to be a first-in-class biologic, which may tackle approximately 50% of GI cancers that which have been reported CDH17 positive. First-in-human clinical study with advanced GI cancers is scheduled to start in Q1 2021.
Evaluating the clinical utility of universal screening to identify Lynch syndrome in stage III/III colorectal cancer patients: A prospective observational study in Japan.
Authors: Yamamoto Yasuaki , Tsukada Yuichiro , Kuwata Takeshi , Kojima Motohiro , Hiraoka Yumie , Taniguchi Hiroya , Bando Hideaki , Yoshioka Takahiro , Sasaki Takeshi , Nishizawa Yuji , Ikeda Koji , Akagi Kiwamu , Yoshino Takayuki , Ito Masaaki
Published: January 2021

41

Background: Universal screening for Lynch syndrome (LS) by identifying deficient DNA mismatch repair (MMR) in the tumor tissue of all new colorectal cancer (CRC) patients is widely accepted. The population prevalence of LS is approximately 3% in Western countries, whereas it is approximately 0.7% in Japan. In addition, the number of relatives diagnosed per proband is 3.6 in Western countries, whereas there are even fewer diagnoses per proband in Japan. To address the issue of LS remaining largely underdiagnosed in Japan, we prospectively evaluated the clinical utility of universal screening of LS in CRC patients. Methods: From March 2016 to August 2019, all consecutive new cases of stage II/III CRC underwent immunohistochemistry (IHC) screening for MMR using MLH1, MSH2, MSH6, and PMS2 antibodies. The patients negative for both MLH1 and PMS2 (MLH1-/PMS2-) were subjected to reflex testing for BRAF V600E mutation. Patients with both MLH1-/PMS2- and BRAF negative (cohort A, n = 14) and those with other IHC patterns (cohort B, n = 13) were referred for genetic counseling (GC) and genetic testing (GT). Furthermore, relatives of probands with confirmed LS were referred for GC/GT if they were willing. Results: Overall, 591 pts were enrolled in this study. Patient background were as follows: > 70 y/o, 35%; right-sided/left-sided colon/rectum, 24%/24%/53%; and cStage II/III, 65%/35%. Of 591 patients, 40 (6.8%) had MMR deficiency. Of 27 patients with MLH1-/PMS2-, 24 underwent BRAF reflex testing; only 10 of these patients tested positive for mutation. Of 27 patients recommended for GC, 25 were referred for GC and 22 for GT, which revealed 12 LS cases (2%, mutation genes:MLH1/PMS2/MSH2; 4/2/6). The frequency of LS diagnosis with respect to patient background was as follows: > 70/≤70 y, 1.0/2.6%; right-sided/left-sided colon/rectum, 5.8/0/1.3%; and cStage II/III, 2.6/1.0%. Interestingly, only 3 (25%) of 12 patients who underwent GC/GT in cohort A had LS compared with 9 (90%) of 10 patients in cohort B ( p= 0.004). Moreover, among 11 relatives of 5 families who were willing to undergo GC/GT, six (55%) had LS, of whom two were first-degree relatives (33%), one was a second-degree relative (50%), and three were third-degree relatives (100%). Conclusions: This study showed that universal screening of LS in CRC patients is significantly useful in Japan. Furthermore, implementing a reflex testing strategy demonstrated high adherence to guidelines and the appropriateness of our referrals for GC/GT.
Early outcomes of irreversible electroporation after stereotactic body radiation therapy for the treatment of locally advanced pancreatic adenocarcinoma (LAPC): A matched pair analysis.
Authors: Boyer Emanuel , Palm Russell , Frakes Jessica M. , Hoffe Sarah E. , Malafa Mokenge Peter
Published: January 2021

410

Background: Outcomes remain poor for those diagnosed with unresectable pancreatic cancer. SBRT and IRE have independently demonstrated high rates of local control and minimal toxicity for patients with locally advanced pancreatic cancer (LAPC). Data is limited regarding safety and efficacy in the sequential use of both therapies. Materials and Methods: A single institution retrospective matched cohort analysis was performed for patients with non-metastatic pancreatic cancer treated with induction chemotherapy and SBRT followed by IRE, compared with patients of the same cohort who did not receive IRE. Patients were paired based on age, tumor stage, GTV D95, CA19-9 prior to SBRT, and chemotherapy type to mitigate selection bias in surgical candidates. Overall survival (OS), progression free survival (PFS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were the primary outcomes compared via Kaplan-Meier survival analysis with log-rank methods. Results: From July, 2014 to February, 2020 17 patients received SBRT followed by IRE. These patients were matched with 17 patients who received SBRT from January, 2012 to March, 2019. Most patients received neoadjuvant FOLFIRINOX (82.4%) and were AJCC 8 stage III (79.4%). Median age of the overall cohort was 65.5 years and 50% were male. Median dose delivered to 95% of gross tumor volume was 32.61 Gy, and median pre SBRT CA19-9 value was 70.5 U/mL. There were no statistically significant differences in matched characteristics between the two cohorts. Among the SBRT+IRE, the median time between IRE and SBRT was 66 days (range:49-467 days). The median OS, PFS, FFLF, and FFDF for IRE+SBRT vs. SBRT alone from SBRT was 10.8 vs 15.1 months, 9.6 vs. 15.3 months, 15.7 vs. 15.3 months, 15.9 vs. 14.4 months respectively (all P > .10). 11 patients in the entire cohort experienced toxicity as a result of their radiation therapy (35%), with one G3 GIB and one patient experiencing G3 abdominal pain. Among the 17 patients who underwent IRE, nine patients experienced toxicity (53%). Most of these events were G3, with two G4 intestinal bleeds. There was zero mortality in the 90 day period post operatively. Conclusions: In a retrospective cohort,non-selective delivery ofIRE afterSBRT demonstrated no oncological benefit for patients with unresectable pancreatic adenocarcinoma compared to only SBRT. Compared to historical experiences of IRE alone, there was no increase in overall toxicity with the combination of SBRT and IRE. The optimal timing, sequencing, and indications for IRE and SBRT in LAPC remain unknown and are best assessed prospectively. [Table: see text]
Prognostic value of KRAS and PI3K pathway mutations for advanced pancreatic ductal adenocarcinoma (PDAC) patients (pts).
Authors: Diehl Adam , Hannan Lindsay Marie , Chiorean Elena Gabriela
Published: January 2021

424

Background: KRAS mutation (MUT) variants (var) have been associated with differential clinical outcomes in advanced PDAC pts (Hendifar, 2020). Recent data from PDAC cell lines suggests that, unlike KRAS G12D/V, the KRAS G12R var is unable to interact with p110α PI3Kα and relies on KRAS-independent p110γ PI3K activity to support macropinocytosis, a nutrient uptake process necessary for tumor growth (Hobbs, 2020). Methods: We retrospectively reviewed advanced PDAC pts who received at least first-line (1L) systemic therapy and underwent next generation sequencing (NGS) at University of Washington between 2013 and 2020. We analyzed, using Fisher’s exact test, whether KRAS var were associated with PI3K pathway mutations (PI3K MUT). Using multivariate (Cox proportional hazards) analysis, we compared overall survival (OS) and progression-free survival (PFS) from start of 1L therapy for pts whose tumors harbored any KRAS var with and without stratification by PI3K MUT status. Results: 127 pts had NGS (96% tissue, 4% ctDNA). Median OS (mOS) and PFS were 16.8 months (mos) and 8.6 mos, respectively. 111 PDAC were KRAS MUT (87%): 43 (39%) G12D, 35 (32%) G12V, 23 (21%) G12R, 1 (0.9%) G12C, 6 (5%) Q61. 15 PDAC (12%) had 16 PI3K MUT, including 7 PIK3CA, 3 AKT2, 3 RICTOR, 1 PTEN, 1 PIK3C2B, and 1 PIK3R1. PI3K MUT occurred in 26% of tumors with KRAS G12R vs 8% in other KRAS var (p=0.0265). In multivariate analysis controlling for age, performance status, stage at diagnosis, type of 1L chemotherapy, TP53 MUT and GATA6 amplification status, pts with KRAS G12R var PDAC vs other variants had longer mOS (20.4 vs 14.5 mos, HR 0.67 (95% CI 0.47 – 0.93), p=0.0215) and mPFS on 1L therapy (12.2 vs 6.8mos, HR 0.60 (95% CI 0.40 – 0.85), p=0.0040). In pts with KRAS G12R var PDAC, concurrent PI3K MUT vs PI3K WT associated with shorter mOS (19.4 vs 24.2mos, HR 2.79 (95% CI 0.97 – 10.6), p=0.0570). In pts with non-G12R KRAS var tumors, PI3K MUT vs WT did not confer shorter OS (mOS 17.6 vs 14.5 mos, HR 1.20 (95% CI 0.72 – 2.0), p=0.55). Conclusions: KRAS G12R PDAC have a higher incidence of PI3K MUT than other KRAS var. KRAS G12R status may confer improved prognosis vs other KRAS variants, albeit this benefit is offset by the presence of concurrent PI3K MUT.
The clinical and molecular characteristics of patients with personal or family history of gastrointestinal malignancies/polyposis and checkpoint kinase 2 (CHEK2) mutations.
Authors: Ozair Sana , Gurganus Cassandra , Krishnan Veena , Dosunmu Gideon T , Montoya Motino Delmer Alfredo , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Khushman Moh'd M.
Published: January 2021

44

Background: Checkpoint Kinase 2 (CHEK 2) encodes the protein CHK2, a serine/threonine kinase involved in pathways that conduct DNA repair as well as apoptosis in response to initial DNA damage. Germline mutations in the CHEK2 gene are associated with several malignancies such as colon, breast, stomach, prostate, kidney, thyroid and soft tissue cancers. Here, we describe the clinical and molecular characteristics of patients with personal or family history of gastrointestinal (GI) malignancies/polyposis and CHEK2 gene mutations. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a germline CHEK2 mutation were identified (N = 16). Patients with a CHEK2 mutation and personal and family history of GI malignancies/polyposis were further explored and their clinical and molecualr characteristics are summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services in patients with pathogenic CHEK2 mutations were personal history of colon cancer (N = 3) and family history of colon cancer (N = 4). One patient with the CHEK2 c.1100delC mutation had a personal history of juvenile polyposis syndrome and a family history of colon cancer. In our cohort, 11 out of 16 (69%) patients had a CHEK2 mutation and personal or family history of GI malignancies/polyposis. The median age was 57 years old (25-80). Six (55%) patients were males. All (100%) patients were Caucasians. Seven (64%) patients had a pathogenic germline CHEK2 mutation and 4 (36%) patients had a variant of unknown significance (VUS). Among patients with pathogenic germline CHEK2 mutations (N = 7), 5 (72%) patients had CHEK2 c.1100delC mutation, 1 (14%) patient had CHEK2 c.190G > A mutation and 1 (14%) patient had CHEK2 c.470T > C mutation. The CHEK2 VUS mutations seen in our cohort were CHEK2 c.539G > A, CHEK2 p.V395L, CHEK2 gain of exons 3-15 and CHEK2 c.1421G > A mutations. Conclusions: All patients in our cohort with CHEK2 mutations were Caucasians. The majority of our patients (69%) had an underlying personal or family history of GI malignancies/polyposis. In patients with personal or family history of GI malignancies/polyposis and CHEK2 mutation, 64% were found to have pathogenic CHEK2 mutations. The most common diagnosed CHEK2 mutation in our cohort was CHEK2 c.1100delC mutation.
Cost efficiency and budget-neutral expanded access to antineoplastic therapy from cost-savings derived from conversion to biosimilar pegfilgrastim-cbqv for the prophylaxis of chemotherapy-induced (febrile) neutropenia (CIN/FN):Simulation modeling in metastatic pancreatic cancer.
Authors: McBride Ali , MacDonald Karen , Abraham Ivo
Published: January 2021

441

Background: Biosimilars have contributed to the reduction in the cost of prophylaxis of CIN/FN in recent years. Savings generated from conversion to biosimilars could be reallocated on a budget-neutral basis to provide expanded access to additional prophylaxis or to anti-neoplastic treatment. To demonstrate this, we simulated: 1) the savings that could be realized from CIN/FN prophylaxis with biosimilar pegfilgrastim-cbqv (BIOSIM-PEG) over reference pegfilgrastim with or without on-body injector (PEG/PEG-OBI), 2) a model of expanded access to BIOSIM-PEG from cost-savings achieved from conversion from PEG/PEG-OBI, 3) a model of expanded access to chemotherapy with oxaliplatin, leucovorin, irinotecan, and fluorouracil (FOLFIRINOX) for metastatic pancreatic cancer (mPC), 4) the number-needed-to-convert (NNC) to BIOSIM-PEG to purchase one additional treatment of BIOSIM-PEG, and 5) the NNC to purchase one cycle of FOLFIRINOX. Methods: This simulation modeling from the US payer perspective utilized: 1) a blended rate of average selling price (ASP; derived from CMS Q4 2020 reimbursement) and wholesale acquisition cost (WAC; Redbook) for PEG/PEG-OBI, BIOSIM-PEG, and all FOLFIRINOX agents proportionate to the estimated 2020 incident pancreatic cancer age distribution per Surveillance, Epidemiology, and End Results Program (67.6% Medicare-insured patients ≥65 years of age; 32.4% commercially insured patients <65 years); 2) between one and twelve cycles of prophylaxis in a panel of 2,500 mPC patients treated with FOLFIRINOX; and 3) conversion rates from PEG/PEG-OBI to BIOSIM-PEG ranging from 10%—100%. Results: Using a current blended ASP/WAC rate, cost-savings of BIOSIM-PEG over PEG/PEG-OBI in a panel of 2,500 mPC patients range from $188,780 (for 1 cycle of prophylaxis at 10% conversion) to $22,653,609 (12 cycles at 100%). In a single cycle of chemotherapy, these savings translate into expanded access to additional BIOSIM-PEG prophylaxis ranging from 53 cycles at 10% conversion from PEG/PEG-OBI to 528 cycles at 100% or to between 321 to 3,214 cycles of FOLFIRINOX, respectively. The savings over twelve cycles could provide up to 6,330 additional cycles of BIOSIM-PEG or 38,571 cycles of FOLFIRINOX (at 100% conversion). The NNC from PEG/PEG-OBI to purchase one additional cycle of BIOSIM-PEG is 4.74; the NNC to purchase once cycle of FOLFIRINOX is 0.78. Conclusions: These simulated models demonstrate the magnitude of the cost savings for CIN/FN prophylaxis that can be generated by conversion to biosimilar pegfilgrastim-cbqv. Further, these savings could be reallocated to provide access to anti-neoplastic treatment on a budget-neutral basis, thus enhancing the value of cancer care to both payers and patients.
The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.
Authors: Krishnan Veena , Gurganus Cassandra , Montoya Motino Delmer Alfredo , Dosunmu Gideon T , Ozair Sana , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Rich Jamie , Khushman Moh'd M.
Published: January 2021

46

Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G > A, MSH2 c. 1687dupT, MSH2 c.1861C > T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A > T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T > C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G > A and MUTYH c.536A > G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T > C, POLE c.5480C > T, c.2999G > A, MLH1 c.1628A > G, CTNNA1 c.503G > A, MSH2 c.128A > G, NBN c.16C > T, ATM c.6537T > G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.
Comparison of clinical characteristics and survival outcomes in patients with malignant peritoneal and pleural mesothelioma.
Authors: Katiyar Vatsala , Kumar Rohit , Vohra Ishaan , Rojan Adam
Published: January 2021

460

Background: Malignant peritoneal mesothelioma (MPeM) is an aggressive tumor strongly associated with asbestos exposure. We analyzed a large nationwide database to better understand the differences in the demographic and clinical patterns of MPeM and pleural mesothelioma (MPlM). Methods: The National Cancer Database (NCDB) 2010-15 was queried to identify all patients diagnosed with MpeM and MPlM. The demographic and clinical characteristics were compared using Pearson’s chi-square test. Kaplan-Meier method and associated log-rank test were used to compare the unadjusted overall survival of the two malignant mesothelioma (MM) sites. A multivariate Cox regression analysis was done to determine survival difference between the 2 groups. Results: Of the 8,668 patients included in the study, 1,081 (12.5%) had MPeM and 7,587 (87.5%) had MPlM. The MPeM cohort was younger (median age at diagnosis 61 vs 73 years), predominantly females (45.7% vs 23.5%), had a lower Charlson Deyo Comorbidity Score ( > = 1: 24.5% vs 32.1%), had higher percentage of uninsured patients (4% vs 2.2%), was less likely to be treated at a community or comprehensive community center (36.1% vs 47.3%) and had lower proportion of sarcomatous or biphasic histology (9.3% vs 22.4%) compared to MPlM cohort. The MPeM cohort was more likely to receive surgery (56.5% vs 28%) and chemotherapy (68.4% vs 54.5%) but less likely to receive radiation (0.8% vs 11%). The p-value was < 0.001 for all comparisons. The median OS was 19.7 and 9.7 months for patients with MPeM and MPlM, respectively (log-rank p value < 0.001). On multivariate Cox proportional hazards analysis, OS was significantly worse for MPlP compared to MPeP [HR adj: 1.19, 95% confidence interval (CI): 1.09-1.30 (p < 0.001)]. Conclusions: There is paucity of data about clinical characteristics and outcomes of MPeM. Much of our current knowledge about MPeM is extrapolated from MPlM. Our study suggests significant differences in prognostic factors and survival outcomes between the two sites.
Stage IV gastrointestinal stromal tumors: Epidemiology, treatment and outcomes in adult US patients.
Authors: Uhlig Johannes , Stein Stacey , Lacy Jill , Cecchini Michael , Kim Kevin
Published: January 2021

462

Background: To evaluate epidemiology, treatment and outcomes of stage 4 gastrointestinal stromal tumors (GIST). Methods: The 2010-2016 United States National Cancer Database was queried for adult patients diagnosed with invasive GIST (ICD code 8936) at AJCC stage 4, without prior malignant disease. Overall survival (OS) was evaluated using Cox proportional hazards regression, accounting for potential confounders in multivariable models. Results: A total of 1,578 stage 4 GIST were included (13.3% of all GIST) with a male:female ratio of 1.38:1. The most common cancer site was the stomach (55.4%) and small intestine (40% of stage 4 GIST). At diagnosis, median age was 62 years and median tumor diameter 10 cm. Distant organ metastases were reported in 58.7%, the most frequent being hepatic (n = 801, 50.8% of stage 4 GIST). The majority of stage 4 GIST patients received systemic therapy (78.6%), either alone (35.4%) or combined surgery+systemic therapy (43.3%). Systemic therapy was administered neoadjuvant in 6.9%, adjuvant in 32%, and neoadjuvant+adjuvant in 5.1% of surgically resected patients. Another n = 204 patients (12.9% of all stage 4 GIST) were treated with surgical resection alone. GIST overall survival rates were 88%, 77%, 67% and 51% at 1, 2, 3, and 5 years, respectively. On multivariable Cox proportional hazard models, primary GIST treatment independently affected OS: compared to combined surgery+systemic therapy, OS was shorter for patients receiving systemic therapy alone (HR = 2.77 (95% CI: 2.12-3.61, p < 0.001)) and no treatment (HR = 4.2 (95% CI: 2.75-6.43, p < 0.001)). No significant OS difference was evident comparing surgery+systemic therapy and surgery alone (HR = 1.23 (95% CI: 0.88-1.72, p = 0.227)). In subgroup analyses of patients undergoing surgical resection, no statistically significant OS difference was evident comparing neoadjuvant, adjuvant and combined neoadjuvant+adjuvant systemic therapy on multivariable analyses. Treatment at non-academic vs. academic centers was associated with shorter OS (multivariable HR = 1.36 (95% CI: 1.1-1.69, p = 0.005)). Further independent OS predictors were male sex (vs. female HR = 1.28 (95% CI: 1.03-1.59, p = 0.023)), older age, higher comorbidities, higher cancer grade, and larger cancer diameter. Conclusions: Stage 4 GIST is a rare gastrointestinal malignancy that most commonly manifests in the stomach and small intestine in male patients, with frequent hepatic metastases and excellent 5-year OS rates of up to 51%. Combined surgery+systemic therapy demonstrates best outcomes, although surgical resection alone might yield comparable results in selected patients.
Germline testing of patients with personal history of colorectal polyposis by cancer genetics counseling services.
Authors: Dosunmu Gideon T , Gurganus Cassandra , Krishnan Veena , Montoya Motino Delmer Alfredo , Ozair Sana , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Rich Jamie , Khushman Mohd
Published: January 2021

47

Background: National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals with >10 adenomatous polyps, ≥2 hamartomatous polyps, or ≥5 serrated polyps proximal to the sigmoid colon have detailed risk assessment and potential genetic testing to rule out polyposis syndrome. Here, we describe germline testing of patients with a personal history of colorectal polyposis by Cancer Genetics Counseling Services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of colorectal polyposis were identified (N=20) and their germline testing results were summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services were personal history of >10 adenomatous polyps (N=13), personal and family history of colorectal polyposis (N=3), personal history of juvenile colorectal polyps (N=3) or personal history of ≥2 hamartomatous polyps (N=1). The median age is 58 years-old (1-84). Ten (50%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 80%, 10% and 10% respectively. In our cohort, 6 out of 20 (30%) patients had a pathogenic germline mutation, 5 (25%) patients had variant of unknown significance (VUS) and 9 (45%) patients had negative testing. Among patients with pathogenic germline mutations, 3 patients had a pathogenic APC mutation (APC c.1659G>A, APC c.2802C>A and APC c.1643dupT) and were diagnosed with Familial Adenomatous Polyposis (FAP). One patient had 2 pathogenic MUTYH mutations (MUTYH c.536A>G and MUTYH c.1187G>A) and was diagnosed with One patient had a pathogenic PTEN c.634+5G>A mutation and was diagnosed with PTEN Hamartoma Tumor Syndrome. Among the 3 patients with a personal history of juvenile colorectal polyps, one patient had a CHEK2 c.190G>A mutation while the other two had negative genetic test results. The VUS mutations in our cohort were MRE11A c.826C>T, BLM c.3478T>C, BRCA2 c.2519T>C, CHEK2 p.V395L and CTNNA1 c.392dupT. Conclusions: In our cohort of patients with personal history of colorectal polyposis, the majority of patients (45%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 30% and 25% of the patients, respectively. FAP Syndrome was the most commonly diagnosed hereditary polyposis syndrome with 3 patients found to have APC germline mutations. Other pathogenic mutations were identified in the MUTYH, PTEN and CHEK2 genes. Patients with MUTYH and PTEN mutations were diagnosed with MAP and PTEN Hamartoma Tumor Syndromes respectively.
Adjuvant therapy in the treatment of resected nonmetastatic gallbladder cancer of stage II-IV: A generalized propensity score analysis.
Authors: Wan Wenze , Zheng Bohao , Sun Wentao , Wang Jiwen , Shen Sheng , Liu Han , Ni Xiaojian , Liu Houbao
Published: January 2021

471

Background: The benefit of adjuvant therapy for gallbladder cancer (GBC) remains controversial due to the limited evidence. The current study was aimed to explore the efficacy of adjuvant therapy in patients with resected non-metastatic GBC and to establish a prognosis model to predict the survival benefit of GCB patients with different adjuvant therapies. Methods: Patients with resected non-metastatic GBC of stage II-IV were selected from the Surveillance, Epidemiology, and End Results database and divided into non-radiotherapy and chemotherapy (NCRT) group, chemotherapy (CT) group, and chemoradiotherapy (CRT) group. Generalized propensity score (GPS) and inverse probability of treatment weighting (IPTW) was used to reduce the imbalances between groups. Nomogram was constructed based on Cox proportional hazard model, and the model was validated for discrimination and calibration. Results: Among the 2689 enrolled patients, 1193 (44.4%) patients were classified as stage II, 1371 (51.0%) as stage III, and 125 (4.6%) as stage IV according to the 8th American Joint Commotion Cancer staging manual. Patients in NCRT, CT, and CRT groups were 1703, 444, and 542 respectively. After the IPTW, absolute standardized differences of baseline characteristics were less than 0.1 both in patients with stage II tumors and with stage III-IV tumors. In patients with GBC of stage II, no significant difference in OS was observed between the three treatment groups (P > 0.05). In patients with GBC of stage III-IV, CT group has a superior OS compared with the NCRT group (P < 0.001), and CRT group has a superior OS compared with the CT(P < 0.001) and NCRT (P < 0.001) group. Sensitivity analysis showed consistent results. A nomogram was constructed for patients with stage III-IV tumors to predict the survival benefit of adjuvant therapies. The C-index was 0.673 (95% CI: 0.654-0.692) in the validation using the training set (diagnosed at 2004-2012) and was 0.707 (95% CI: 0.677-0·739) in the internal validation using the validation set (diagnosed at 2013-2015). The calibration curves indicated that the predicted probability closely corresponded to the actual observation OS. Conclusions: Patients with GBC of stage II could not benefit from adjuvant therapy. Patients with GBC of stage III-IV could benefit from chemotherapy and chemoradiotherapy while chemoradiotherapy provide a superior OS. A nomogram was built to predict the survival benefit of different adjuvant therapies in patients with GBC of stage III-IV.
Patient characteristics and survival outcomes in gastrointestinal cancers harboring RNF43 mutations or RSPO3 fusions: a retrospective analysis.
Authors: Sackstein Paul , Buechner Garrett , Weinberg Benjamin Adam
Published: January 2021

473

Background: The growth of intestinal epithelium is dependent on the Wnt/β-catenin signaling pathway. The R-Spondin (RSPO) family of proteins form complexes with Wnt ligand and RNF43 protein, which promote ubiquitination and degradation of Wnt receptors. Patients with gastrointestinal cancers harboring RSPO3 gene fusions or RNF43 gene mutations may benefit from Wnt pathway inhibitors. Methods: We retrospectively studied 51 patients at our institution diagnosed with gastrointestinal cancers with RSPO3 gene fusions or RNF43 gene mutations identified using Caris Life Sciences next-generation sequencing (NGS). Microsatellite-instability (MSI) was evaluated using NGS. Tumor mutational burden (TMB) was estimated from 592 genes by counting all nonsynonymous missense mutations not previously defined as germline mutations, expressed as mutations per megabase. First-line median progression-free survival (PFS) and median overall survival (mOS) were estimated using the Kaplan-Meier method. Results: Of the 51 patients in our study, 44 (86.3%) had RNF43 mutations and 7 (13.7%) had RSPO3 fusions, 6 of whom had colorectal cancer (CRC) and had PTPRK as the fusion partner, 1 case of small bowel cancer had a RSPO3: IFNGR1 fusion. Median age at diagnosis was 64.0 ± 12.0 years. The most common primary tumors were CRC in 23 patients (45.1%) and pancreas in 12 patients (23.5%). Co-occurring mutations in CRC patients with RSPO3 fusions included KRAS (50%, Q61H, G12C, and G12V), BRAF V600E (50%), and TP53 (100%), none were MSI-H, median TMB (mTMB) was 9.5 (range 7-11). Sixty-seven percent of RNF43-mutated CRC patients had the G659fs mutation. Co-occurring findings in RNF43-mutated CRC patients included 67% MSI-H, median TMB 27 (range 6-123), KRAS (28%), BRAF V600E (28%), and TP53 mutations (33%). Twenty-two patients (43.1%) had stage IV disease, 18 (35.3%) had stage III disease and 11 (21.6%) had stage II disease. Thirty RNF43-mutated patients (58.8%) underwent definitive surgical resection, with a mean time to recurrence of 22.2 months and mOS of 43.0 months (95% CI, 15.6-70.4). Among RNF43-mutated stage IV CRC (mCRC) patients, median PFS was 8.0 months (95% CI, 5.9-10.1). Stratified by stage, mOS was 111.0 months for stage II disease, 72.0 months for stage III disease, and 37.0 months for stage IV disease (95% CI, 14.7-59.3). Conclusions: RNF43 correlates with overall favorable mOS in patients with mCRC. mOS in RNF43-mutated mCRC is similar to those of RAS and BRAF wild-type subgroups as reported in the TRIBE study (Cremolini et al. 2015). Therefore, RNF43 mutational status appears to be useful in predicting clinical outcomes for patients with stage IV CRC and overlaps significantly with MSI-H. RSPO3 fusions are rare events and the clinical outcomes of this subset of patients with tumors with RSPO3 fusions remains largely unknown.
Role of DNA polymerases family members in cancer: The pan-cancer perspective.
Authors: Luo Zhiwen , Bi Xinyu , Bi Xingang
Published: January 2021

475

Background: DNA polymerases family (DNA pols) has a lengthy reported significant influence on the initiation, development, and progress of cancer. However, the pan-cancer value of whole family members was poorly done. Our study intends to demonstrate the expression pattern and clinical cancer value of DNA pols members as prognostic biomarkers and a therapeutic target of pan-cancer. Methods: Comprehensive bioinformatics analyses were done using data from TCGA and CCLE. MultiCox regression was done to select tumor prognosis-related members. Nomogram was constructed to predict the overall survival (OS) across cancer patients. Transcription factor, GO, IPA, and GSEA enrichments were done to explore regulatory mechanisms and functions. Results: A total of 22 DNA pols were identified to have a potential to diagnostic value, and 10 DNA pols have a pan-cancer prognostic value under various stages, and cancer type, among which overexpression of 6 DNA-pols (POLA2, POLD1, POLD2, POLE2, POLE4, and POLQ) was found to be significantly related to worse outcomes regarding OS, while 4 DNA-pols (POLH, POLL, POLN, and REV1) significantly related to better outcomes. A 5-DNA pols based risk score (POLQ, POLD2, POLL, POLH, and REV1) was generated by MultiCox regression with a nomogram validated an accurate predictive efficacy. MYB Proto-Oncogene Like 2 (MYBL2) was identified as transcription factors of prognostic DNA pols in pan-cancer, and IPA mimic experiment reveals inhibiting MYBL2 could be a drug target to recover and balance the dysregulated expression pattern of DNA pols in pan-cancer. GO, IPA, and GSEA enrichments revealed functions and pathways altered by DNA pols in cancer, and the results were supported by pan-cancer cell sequencing data. Conclusions: DNA pols have a pan-cancer clinical value and can work as potential prognostic biomarkers. Furthermore, MYBL2 could be a drug target for pan-cancer.