bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of African ancestry on colorectal cancer disparity.
Authors: Joung Yoo Jin , Lee Michelle Jeung-Eun , Jain Sanjay R.
Published: June 2022

3621

Background: Colorectal cancer is the second leading cause of cancer deaths in the world to affect both men and women. Racial disparities have been known to affect the disease diagnosis and progression, and proliferative genomic studies have been undertaken to elucidate their relationship. In this study, we investigate the tumor mutation profile in colorectal adenocarcinoma (COAD) based on genetic ancestry using The Cancer Genetic Ancestry Atlas (TCGAA). Methods: 59 AA (African American) individuals in TCGAA COAD dataset were identified. To account for and eliminate the biases introduced by self-identification of races, we utilized TCGAA genomic analysis to accurately estimate the ancestral genomic composition of each individual. For each individual, percentages of European (EA), West African (WA), East Asian (EAA), and Native American (NA) ancestry were identified based on Local Ancestry in adMixed Populations (LAMP). Individuals were screened for dominant WA ancestry (≥50% based on LAMP) and assigned to three groups, ≥90%, 80-89%, and 50-79%. Differences in gene mutation frequency and overall survival were compared among the three subgroups of individuals with WA ancestry. Results: Based on genomic ancestry analysis, 58 individuals with dominant WA ancestry (Range 53%-100%) were identified. We classified them into three groups based on percentage of WA ancestry: ≥90% (n = 17), 80-89% (n = 26), and 50-79% (n = 15). APC was the most frequently mutated gene in all groups except ≥90% WA ancestry, which had the most mutation frequency in TP53. ≥90% WA ancestry showed the highest rate of mutation of 81.3% in TP53 compared to 70.8% (80-90% WA ancestry) and 40.0% (50-79% WA ancestry). Interestingly, ≥90% WA ancestry had the highest average rate of mutation (33%) for 7 tumor suppressor genes ( AMER1, APC, ARID1, FBXW7, TCF7L2, TGFBR2, and TP53), compared to 29% and 22% in 80-89% WA ancestry and 50-79% WA ancestry, respectively. In addition, ≥90% WA ancestry had a lower rate (19%) of mutation in 6 oncogenes ( BRAF, NRAS, KRAS, PIK3CA, SMAD4, and SOX9) compared to 24% in both 80-89% and 50-79% WA ancestry. Although not statistically significant, a higher percentage of WA ancestry in an individual was correlated with a downward trend in the overall survival rate (median survival 56.3 months in ≥90% WA ancestry vs 61.8 months in 80-89% WA ancestry). Conclusions: In this study, we analyzed different gene mutations correlated with African ancestry and their potential relationship to the etiology, progression, and prognosis of COAD. The mutation profile of these genes will allow us to investigate altered pathways associated with African ancestry and draw insight into colon cancer pathogenesis in various ancestry groups. Further studies are warranted to elucidate the role of genetic ancestry in tumorigenesis and disease progression and to identify potential therapeutic targets specific to groups disproportionately affected by cancer.
Radical versus local surgical excision for early rectal cancer: A systematic review and meta-analysis.
Authors: El-Nakeep Sarah , Madala Samragnyi , Chidharla Anusha , Martin Benjamin , Kasi Anup
Published: June 2022

3622

Background: Colorectal cancer is the third common cancer worldwide. Radical excision (RE) as total mesorectal excision for rectal cancer carries a higher risk of mortality and morbidity, while local excision (LE) could decrease these postoperative risks. However, the long-term oncologic outcomes of LE are still debatable. We aim to study the effect of LE versus RE in T1 and T2 rectal cancer. Methods: We conducted a systematic review and meta-analysis. We searched PubMed and CENTRAL databases, using an optimized search-strategy from inception until 15 June 2021, without restriction on publication date or status. We included only cohort and randomized controlled trials (RCTs). Two authors independently screened the title, abstracts, and full-text manuscripts for inclusion and data extraction. All included trials contained at least one of the primary outcomes. We used RevMan 5.4 tool for data analysis. We calculated both hazards ratio (HR) and risk ratio (RR) for the 5-years survival analyses, with their 95% confidence intervals (CI). We assessed both clinical and statistical heterogeneity of the studies; I2 >75% was considered highly heterogeneous. We used random effect model (REM). We used standardized mean difference (SMD) for hospitalization days. We conducted a subgroup analysis of patients with T1-only without adjuvant chemo/radiotherapy (CRT). Results: We retrieved from the search a total of 1243 reports. A total of 18 studies were included for final meta-analysis (4 RCTs and 14 retrospective cohorts). Nine studies were multi-central while ten were unicentral studies. We did not find any difference in risk ratio (RR) between overall survival (OVS) and disease-free survival (DFS). But there were higher HRs in OVS and DFS with LE as compared to RE. A higher recurrence rate was also seen with LE. Six studies showed absent 30-days postoperative mortality in both groups so we used peto-odds ratio. Postoperative mortality and morbidity were lower with LE rather than RE. Conclusions: LE for early stage rectal cancer has a higher risk of decreased 5-year OVS and DFS than RE, with higher local recurrence rate. However, LE is associated with lower early postoperative mortality, morbidity, and hospitalization days, as compared to RE. Patient selection is key to balance these risks for the optimal outcome. [Table: see text]
Adapted physical activity in patients (Pts) with advanced pancreatic cancer (APACaP): Results from a prospective national randomized GERCOR trial.
Authors: Neuzillet Cindy , Bouché Olivier , Tournigand Christophe , Chibaudel Benoist , Bouguion Lucile , Bengrine-Lefevre Leila , Lopez-Trabada Ataz Daniel , Mabro May , Metges Jean-Philippe , Péré-Vergé Denis , Conroy Thierry , Lievre Astrid , Andre Morgan , Desseigne Françoise , Goldwasser François , Henriques Julie , Anota Amélie , Hammel Pascal
Published: June 2022

4007

Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences > 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]
Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial.
Authors: Fietkau Rainer , Ghadimi Michael , Grützmann Robert , Wittel Uwe A , Jacobasch Lutz , Uhl Waldemar , Croner Roland S. , Bechstein Wolf Otto , Neumann Ulf Peter , Waldschmidt Dirk , Boeck Stefan Hubert , Moosmann Nicolas , Reinacher-Schick Anke C. , Golcher Henriette , Adler Werner , Semrau Sabine , Kallies Annett , Hecht Markus , Tannapfel Andrea , Oettle Helmut
Published: June 2022

4008

Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p<0.01) than for CRM+ R0 surgery with 66.7 ± 0.15% (1y) and 41.2 ± 0.1% (2y) as well as for patients without or incomplete surgery with 68.5 ± 0.03% (1y) and 26.4 ± 0.03% (2y). Conclusions: The addition of radiotherapy after IC improves the R0 CRM - resection and pCR rate without significant change in R0 resection rate (primary endpoint). Pts with R0 CRM - resections had a better prognosis compared to patients with either R0 CRM+ or incomplete or without surgery. However, this effect on resectability did not translate into a statistically significant PFS or OS benefit in the whole cohort. Clinical trial information: NCT01827553. [Table: see text]
Effect of neutrophil extracellular traps on tumor lymph nodes.
Authors: SU Xin , Brassard Ariane , Dhoparee-Doomah Iqraa , Rohanizadeh Ramin , Giannias Betty , Bourdeau France , Sangwan Veena , Rayes Roni , Spicer Jonathan , Ferri Lorenzo , Cools-Lartigue Jonathan
Published: June 2022

4033

Background: In most human cancers, regional lymph nodes (LNs) are the first sites of metastasis. In addition to being an important part of the tumor staging system, with the advent of novel therapies, lymph node metastasis has become a crucial clinical intervention point before distant metastasis, the leading cause of cancer-associated deaths. To initiate metastasis, the conditions of LNs need to be optimized for tumor cell deposition and growth. This process is believed to be mediated by the activation of immune cells including polymorphonuclear neutrophils (PMNs). However, the cellular mechanism is not well defined. Our early observations suggest that PMNs and neutrophil extracellular traps (NETs), DNA comprising structures that are extruded in response to inflammatory cues, are associated with adverse oncologic outcomes. Thus, one potential mechanism of increased LN metastasis is that tEVs recruit PMNs and propend NETs formation. Methods: Human tissue micro-arrays (TMAs) of gastroesophageal (GEA) cancer patients were stained with PMN and NETs markers and quantified by HALO software. C57BL/6 or pad4-/- mice were injected with B16F10 or H59 cells alone or treated with neutrophil elastase inhibitor (NEi) or PMN depletion antibody. LN sections were stained with NETs markers and quantified by ImageJ (NIH). Results: In the study of 175 GEA cancer patients, lymphatic NET deposition was observed in both tumor infiltrated lymph nodes and tumor negative lymph nodes. We also demonstrated high LN NETs deposition was associated with reduced survival, even in the absence of overt metastasis ( p=0.03). Next, we sought to investigate the dynamic and the consequence of LN NETs deposition using animal models. We found that LN Neutrophil Recruitment and NET deposition happens in a pre-metastatic manner. Moreover, LN metastasis was abrogated through different kinds of NETs inhibition (neutrophil depletion, pad4 knockout and NEi treatment, n=10, p<0.001), demonstrating the consequences of LN NETs deposition and its potential as a treatment target. Finally, we showed that the LN PMN recruitment and NETs formation was mediated by increased production of IL-8 by Lymphatic Endothelial Cells (LEC). Conclusions: Together, we demonstrated that NETs can contribute to LN metastasis, and can serve as a potential therapeutic targets. By further investigating the detailed mechanism, this project will lead to major advances in the management of cancer patients.
Perioperative chemotherapy with LP002, an anti-PD-L1 antibody, in patients with resectable gastric and gastroesophageal junction cancer: A prospective, open-label, phase Ib trial.
Authors: Tang Jialin , Huang Jing , Zhang Bo , Qi Ling , Dao Xin , Wang Lin , Li Yong , Tian Yantao
Published: June 2022

4041

Background: Immune checkpoint inhibitors were effective, either alone or in combination with chemotherapy, in pts with metastatic gastric or gastroesophageal junction (GEJ) cancers, but their role for resectable disease remained unknown. We report the safety and pathological response of gastric/GEJ cancer pts receiving LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in a phase Ib trial. Methods: We enrolled pts with previously untreated, PD-L1 positive, resectable (cT2-4a, any N, M0) gastric/GEJ cancer. Eligible pts received three preoperative and six postoperative 2-week cycles of intravenous LP002 900mg on day 1, intravenous cisplatin 50 mg/m2 on day 1, and 2000 mg/m2 5-fluorouracil as 48-h infusion starting on day 1. The standard surgery was scheduled 4-6 weeks after completion of 3 cycles of preoperative treatment. The primary endpoint was safety. Secondary endpoints included proportion of pts with R0 resection and pathological complete response (pCR), disease-free survival, and overall survival. With pre- and post-treatment samples, we also characterized genomic changes in tumor tissue with next generation sequencing (NGS), and alterations in the tumor immune microenvironment (TIME) using multiplex immunofluorescence staining. Results: From September 2020 to July 2021, 30 pts were enrolled into this study. The median age was 64.5 years (range, 50-74). Most primary tumors were in the GEJ (N=28, 93.3%). 29 pts (96.7%) had adenocarcinoma, and 1 had small cell neuroendocrine tumor. The median follow-up duration was 7.9 months (range: 5.1-10.6) as of data cut-off (November 1, 2021). All pts completed the planned preoperative treatment, and 27 pts (90.0%) proceeded to surgery. Reasons for surgery not being performed were metastatic disease in 1 patient, and patient request in 2 cases. 24 pts had R0 resection, while 3 underwent R1 resection. 1 patient achieved pCR (TRG 1 per the Mandard’s tumor regression grading system) and 5 pts (18.5%) reached TRG 2-3. Treatment-related adverse events (TRAEs) were observed in 27 pts during perioperative treatment. Most of the TRAEs were of grade 1 to 2. The most common grade 3 toxicities were nausea (23.3%), neutrophil count decreased (16.7%) and anorexia (6.7%). 11 pts had immune-related adverse events, mostly grade 1 hyperthyroidism (45.5%). There were no grade 4-5 TRAEs. NGS analysis revealed that the mutation frequencies of the 733 genes in the sequencing panel decreased after preoperative treatment in pts with TRG 2-3. The analysis of TIME is undergoing. Conclusions: LP002 plus cisplatin and 5-fluorouracil was safe in pts with resectable gastric or GEJ cancer, and could be a new perioperative treatment option for PD-L1 positive disease. Pts are followed-up for survival outcomes. Clinical trial information: NCT04755543.
Cellworks singula therapy response index (TRI) predicts clinical outcomes for esophageal adenocarcinoma: MyCare-004.
Authors: Smyth Elizabeth Catherine , Watson Drew , Nutzinger Barbara , Castro Michael P , Kapoor Shweta , Prasad Samiksha Avinash , Rajagopalan Swaminathan , Cheah Calvin , Nair Prashant Ramachandran , Alam Aftab , Devonshire Ginny , Grehan Nicola , Suseela Rakhi Purushothaman , Tyagi Anuj , Agrawal Ashish Kumar , Azam Humera , Sauban Mohammed , Pampana Anusha , Macpherson Michele Dundas , Fitzgerald Rebecca C.
Published: June 2022

4064

Background: Computational biological modeling reveals many dysregulated signaling pathways responsible for hallmark behaviors of cancer and variable drug response in the population. A mechanistic model created for each patient using comprehensive genomic inputs can biosimulate downstream molecular effects of cell signaling and drugs for each patient’s personalized in silico virtual disease model. Singula TRI is designed to predict the outcome of specific therapies with a continuous TRI Score, 0 to 100, for each patient’s unique genomic network. Methods: TRI’s ability to predict Overall Survival (OS), Disease Free Survival (DFS) and Mandard – tumor regression grade (TRG) was prospectively evaluated in a retrospective cohort of gastroesophageal adenocarcinoma (GEA) from UK OCCAMS consortium. Random sampling stratified by clinical factors was used to split the data into independent training (N = 140) and validation (N = 131) subsets. Multivariate Cox Proportional Hazard (PH) and Proportional Odds models were used to predict survival and pathological response as a function of the pre-defined TRI and clinical thresholds compared with standard clinical factors. Results: 271 GEA patients were selected who had pre-chemo treated biopsies with 50x whole genome sequencing from the OCCAMS International Cancer Genome Consortium study. The median age was 65.6 years, 234 male and 30 female, with deceased median OS of 21.9 months and living of 49.9 months. There were 35 T2, 215 T3, 70 N0, 126 N1, 62 N2 and 266 M0. Patients were treated with physician prescribed chemotherapy treatments (PPT) according to UK clinical guidelines (SC). Biosimulation revealed that 99% of these tumors had deficiency in DNA repair genes. Other pathways included amplification of multi-drug resistance pumps, TP53 mutations and aberrations of the PI3K/AKT pathway genes. The table shows that TRI provides additional predictive information for OS and DFS beyond PPT and standard clinical factors. TRI was also predictive of TRG in univariate analysis. TRI scores were also generated for 82 alternate therapies for each patient enabling selection of optimal therapies with estimates of improvements in median OS and DFS compared to SC. Conclusions: In this cohort of patients, Cellworks Singula TRI was predictive of survival and TRG beyond clinical factors. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA and validation in prospective clinical studies is warranted.[Table: see text]
Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): A prospective, single-arm phase II trial.
Authors: Liu Dongming , Mu Han , Liu Changfu , Zhang Weihao , Cui Yunlong , Wu Qiang , Zhu Xiaolin , Fang Feng , Zhang Wei , Xing Wenge , Li Qiang , Song Tianqiang , Lu Wei , Li Huikai
Published: June 2022

4073

Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.
Organ-specific responses to atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma.
Authors: Cheon Jaekyung , Jung Sanghoon , Kang Beodeul , Kim Hyeyeong , Kim Chan , Chon Hongjae
Published: June 2022

4076

Background: Anti-PD-1 monotherapy elicits various organ-specific immune responses. Although advanced hepatocellular carcinoma (aHCC) showed 20–40% objective response rates (ORR) for cases of extrahepatic lesions in sites such as the lungs or lymph nodes (LNs), only 10% of intrahepatic lesions responded to the monotherapy. The organ-specific responses were due to tumor heterogeneity and differential microenvironments, and may have contributed to the failure of the phase III trials of anti-PD-1 monotherapy for aHCC. Recently, the combination of atezolizumab and bevacizumab (Ate/Bev) as first-line systemic treatment has resulted in survival benefits for patients with aHCC. However, the organ-specific response for this treatment has not been explored. We aimed to evaluate the organ-specific response to Ate/Bev combination therapy in patients with aHCC. Methods: We enrolled patients who received first-line Ate/Bev treatment for aHCC. Eligible patients included those with Child-Pugh A liver function, measurable tumor lesions, and serial image studies available for response evaluation. An independent radiologist reviewed the tumors located in the liver, lungs, LNs, and other sites. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used. Results: Between May 2020 and June 2021, 124 patients from two Korean cancer referral institutions received first-line Ate/Bev treatment for aHCC. The patient baseline characteristics included: hepatitis B (n = 85, 68.5%), hepatitis C (n = 6, 4.8%), non-viral (n = 33, 26.7%); BCLC stage A/B/C (n = 2, 1.6%/n = 19, 15.3%/n = 103, 83.1%); macrovascular invasion (n = 39, 31.5%); extrahepatic metastasis (n = 75, 60.5%); and AFP >400 ng/ml (n = 39, 31.5%). The median age was 62 years (range: 34–90). With median follow-up duration of 10.1 months, median progression-free survival was 6.8 months (95% CI, 3.6–10.0) and median overall survival was 16.9 months (95% CI, range not available). The ORR was 29.8%. For 260 individual tumor lesions, the liver was the most commonly involved organ (n = 152, 58.5%), followed by the LNs (n = 42, 16.2%) and lungs (n = 24, 9.2%). Ate/Bev treatment induced potent tumor shrinkage in both intrahepatic and extrahepatic lesions: ORR for hepatic lesions was 28.3%; LN lesions, 40.5%; lung lesions, 29.1%; and other metastatic lesions, 19.0%. Further, the organ-specific response rate for intrahepatic tumors decreased as the tumor size increased (36.7%: ≤50 mm, 13.0%: >50 mm). Conclusions: Unlike anti-PD-1 monotherapy, Ate/Bev combination therapy showed favorable responses even in intrahepatic lesions, which are comparable to those in extrahepatic lesions. As such, Ate/Bev may overcome an immune-tolerant hepatic microenvironment in patients with aHCC. (NCT04862949).
Targeting HER2 mutation–positive advanced biliary tract cancers with neratinib: Final results from the phase 2 SUMMIT basket trial.
Authors: Harding James J. , Piha-Paul Sarina Anne , Shah Ronak H. , Cleary James M. , Quinn David I. , Brana Irene , Moreno Victor , Borad Mitesh J. , Loi Sherene , Spanggaard Iben , Ford James M. , DiPrimeo Daniel , Berger Michael F. , Eli Lisa DeFazio , Meric-Bernstam Funda , Solit David B. , Abou-Alfa Ghassan K.
Published: June 2022

4079

Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.
The potential use of blood-based tumor fibrosis markers as diagnostic and prognostic biomarkers in patients with biliary tract cancer.
Authors: Christensen Troels Dreier , Jensen Christina , Willumsen Nicholas , Larsen Ole , Leerhøy Bonna , Hansen Carsten Palnaes , Madsen Kasper , Nielsen Dorte , Johansen Julia S.
Published: June 2022

4082

Background: Patients with biliary tract cancer (BTC) have a very poor prognosis. A better understanding of the disease and potential novel biomarkers are needed. BTC is characterized by a collagen-rich desmoplastic extracellular matrix (ECM), and tumor fibrosis is linked to cancer progression and treatment resistance. We tested the diagnostic and prognostic use of seven circulating biomarkers associated with ECM remodeling. We evaluated both pro-peptides (pro-peptide of collagen type III (Pro-C3), VI (PRO-C6), XI (PRO-C11)) and degradation fragments (matrix metalloproteinase (MMP) degraded collagen type III (C3M) and IV (C4M), granzyme B degraded collagen type IV (C4G), citrullinated and MMP degraded vimentin fragment (VICM)). Methods: The study included 269 patients with all stages of BTC (intrahepatic cholangiocarcinoma (CC) (n=124), extrahepatic CC (n=89), and gall bladder cancer (n=56)), and 49 patients with benign biliary tract disease. Serum samples were collected from the patients with BTC before surgery (n=36), 1st line (n=199), and 2nd line (n=56) treatment. A total of 22 patients had samples collected at two timepoints. The seven ECM markers and carbohydrate antigen 19-9 (CA19-9) were analyzed using enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay. Results: The levels of C3M, C4M, PRO-C3, PRO-C6, PRO-C11, and VICM were significantly elevated in patients with BTC compared to patients with benign disease (Wilcoxon test, adjusted p-value < 0.05). Area under receiver operating characteristics curve (AUC) identified PRO-C3 (AUC=0.87) as the ECM marker that best discriminated between patients with BTC and controls. A model combining PRO-C3 and CA19-9 further improved the diagnostic accuracy (AUC=0.97). Elevated levels of four markers (C3M, C4M, PRO-C3 and PRO-C6) before 1st line treatment for BTC were associated with short overall survival (OS) in separate multivariate cox regression analyses adjusting for CA19-9, performance status, and stage. Similarly, elevated levels of PRO-C3 and PRO-C6 before 2nd line treatment were associated with short OS (Table). Conclusions: We identified specific blood-based collagen fragments as potential novel biomarkers for BTC. Our results indicate that patients with BTC have an elevated collagen remodeling, and that increased collagen turnover is associated with a poor prognosis for these patients. [Table: see text]
Efficacy and safety of low-dose apatinib in advanced hepatocellular carcinoma.
Authors: Meng Lingbin , Zheng Zhuangzhuang , Ji Rui , Xu Xiaochun , Xin Ying , Jiang Xin
Published: June 2022

4104

Background: Apatinib, a tyrosine kinase inhibitor, has shown promising effects on advanced hepatocellular carcinoma (HCC) recently. However, studies on its efficacy and safety are limited with controversial findings. Therefore, this study aimed to reveal the efficacy and safety of low-dose apatinib for the treatment of advanced HCC in the real world. Methods: Between January 2017 and August 2020, 178 patients with advanced HCC treated with apatinib at three different institutions were included for the present study. 174 patients received oral apatinib 250 mg daily and 4 received 500 mg daily until disease progression. 25 and 103 patients were also treated with immunotherapy and transcatheter arterial chemoembolization (TACE) at least once, respectively. Tumor response and adverse reactions were evaluated according to RECIST 1.1 and CTCAE 5.0 respectively. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of variables in a univariate and multivariate setting. Results: During the 24-month follow-up period, 0 (0%), 28 (15.73%), 103 (57.87%) and 47 (26.40%) patients achieved a compete response (CR), partial response (PR), stable disease (SD), and progressive disease (PR), respectively. The overall response rate (ORR) and disease control rate (DCR) were 15.73% and 73.60% respectively. Interestingly, among the 28 patients with PR, 27 received apatinib as the first or second line treatment and 21 received immunotherapy or TACE as a combined treatment, indicating early application of apatinib and combination treatment could provide better efficacy. Kaplan-Meier analysis revealed the median overall survival (OS) and progressive-free survival (PFS) were 16.0 and 7.0 months respectively, which are significantly higher than previously reported survival of sorafenib in advanced HCC. Univariate Cox analysis indicated medication lines, distant metastasis, aplpha fetoprotein (AFP) level, portal vein tumor thrombus (PVTT) and combination therapy significantly affected OS and PFS. Multivariate Cox analysis confirmed third-line treatment (HR = 3.21; 95%CI = 1.54–6.68; p= 0.002), and PVTT (HR = 1.75; 95%CI = 1.13–2.70; p= 0.011) were independently associated with worse PFS. In contrast, apatinib combined with immunotherapy (HR = 0.52; 95%CI = 0.32–0.83; p= 0.008) or TACE (HR = 0.27; 95%CI = 0.18–0.40; p< 0.001) were independently associated with better PFS. Similar findings were also present on OS. The most common treatment-related adverse events were hypertension (29.21%), fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). No severe (grade ≥3) adverse events were observed. Conclusions: Low-dose apatinib is able to provide effective and safe treatment for advanced HCC. Early application of apatinib and combination treatment could provide even better efficacy.
Clinical and genomic characterization of ERBB2-altered gallbladder cancer.
Authors: Mondaca Sebastian , Schultz Nikolaus , Roa Juan Carlos , Walch Henry S. , Sepulveda Santiago , Harding James J. , Yaqubie Amin , Garcia Patricia , Aguayo Gloria , Nervi Bruno , Li Bob T. , Abou-Alfa Ghassan K.
Published: June 2022

4114

Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.
Analysis of molecular characterization: Pancreatic ductal adenocarcinoma with hepatic metastases.
Authors: He Yonggang , Huang Xiaobing , Li Jing , Tang Yichen , Du Pengyao , Zhang Yaxuan , Liu Chuang , Li Ling
Published: June 2022

4129

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Distant metastasis is the leading cause of cancer death. Approximately 50% of PDAC patients are discovered to have distant metastases, mainly in the liver. Chemotherapy is the main recommended treatment for metastatic PDACs, with a median survival time of only 4-6 months and the 5-year survival of 1%. Therefore, deciphering the molecular mechanisms of metastatic PDAC is urgently for exploring effective therapeutic targets. Methods: 93 normal-paired samples from patients with PDAC were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: A total 93 patients with PDAC were analyzed, including hepatic metastases (15/93), lymph node metastases (1/93), colon metastases (1/93), pelvic metastases (1/93), and no distant metastasis (75/93). In PDAC patients without distant metastasis, the most frequent mutated gene was KRAS (72%), followed by TP53 (60%), CDKN2A (21%), SMAD4 (17%), ARID1A (11%), RNF43 (9%), and RBM10 (8%). In PDAC patients with hepatic metastases, we found that the most frequent one was KRAS (100%), followed by TP53 (87%), CDKN2A (40%), SMAD4 (40%), RNF43 (13%), and RBM10 (6%). Furthermore, four PDAC patients occurred KRAS copy number amplification, including 2 cases of hepatic metastases. And a hepatic metastases PDAC patient had ERBB2 and MET copy number amplification. We also found that seven no-metastasis patients carried pathogenic or likely pathogenic germline variants, including BRIP1, PALB2, RECQL, ATM, RAD50, FANCM and BRCA1. Conclusions: High frequency mutation genes in PDAC patients with hepatic metastases were highly consistent with those of no-metastasis patients. KRAS and TP53 gene co-mutations were extensively mutated in hepatic metastases patients. Our results revealed the molecular mechanisms driving PDAC hepatic metastases should be considered in further study.
The impact of HRD in patients with pancreatic adenocarcinoma undergoing surgical resection: An updated analysis.
Authors: Jonsdottir Gudbjorg , Masson Asgeir Thor , Jacobus Laura S. , Churchman Michelle L. , Edge Stephen B. , Noonan Anne M. , Cavnar Michael J. , Ulahannan Susanna Varkey , Sahin Ibrahim Halil , Chan Carlos Hou Fai
Published: June 2022

4132

Background: Limited data is available regarding which mutations in the homologous recombination repair (HRR) pathway beyond BRCA can be targeted with platinum-based chemotherapy in the perioperative setting in patients with pancreatic ductal adenocarcinoma (PDAC). In this updated analysis, we assess the outcome of patients with homologous recombination deficiency (HRD) in response to platinum vs. non-platinum based perioperative chemotherapy in resected PDAC and have included additional variants linked to HRD. Methods: Patients with resectable PDAC, diagnosed between 1999-2020 from the participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Patient’s germline and somatic whole exome sequencing (WES) data were analyzed for known pathogenic and likely pathogenic variants according to ClinVar for the following HRR pathway genes: BRCA1, BRCA2, PALB2, BRIP1, BRAD1, BLM, BAP1, ATM, RAD51C, RAD51, RAD50, RAD54B, CHECK2, NBN, FANCA/B/C/D2/E/F/G, ARID1A, MRE11 and XRCC2. The Kaplan Meier method was used to compare median overall survival (mOS) between patients with and without HRR pathway mutations in response to perioperative platinum vs non-platinum-based chemotherapy. Multivariate cox proportional hazard model was used to calculate HR and 95% CIs adjusting for age, sex and pathologic stage. Results: The ORIEN cohort included 311 patients with resectable PDAC and available WES data. A total of 22 patients (7%) had an HRR pathway mutation. Of these, 8 (36%) received perioperative platinum-based chemotherapy and 9 (41%) a non-platinum based regimen, 4 patients (23%) received no perioperative systemic treatment. Frequency of HRR variants detected: BRCA2 n=8 (2.6%), BRCA1 n=3 (1%), ATM n=2 (0.6%), ARID1A n=1 (0.3%), BRIP1 n=1 (0.3%), CHECK2 n=1 (0.3%), FANCG n=1 (0.3%), PALPB2 n=1 (0.3%), RAD50 n=4 (1.3%), RAD51C n=1 (0.3%). The mOS for patients with HRR mutations exposed to perioperative platinum-based chemotherapy was 3.5 years (95% CI 3.4-NA), patients with HRR mutation but no platinum exposure had a mOS of 1.2 years (CI 0.9-NA). In patients with no HRR mutation exposed to platinum-based chemotherapy mOS was 2.7 years (CI 2.3-3.9) and in those without exposure mOS was 2.9 years, p=0.43. Comparison of risk of death between the 4 groups is demonstrated in the table. Conclusions: There was a trend towards improved survival in patients with PDAC who harbored a HRR pathway mutation and were treated with perioperative platinum-based chemotherapy compared to those with no platinum exposure. Our results highlight the importance of identifying patients with HRD beyond BRCA and the need for large prospective studies in the perioperative setting to further assess their predictive role. [Table: see text]
Evaluation of stage IV pancreatic adenocarcinomas based on mutational profiling of tumors.
Authors: Poruk Katherine E , Moran Amber , Doctor Vicki , Elvin Julia Andrea , Radhi Saba , Loaiza-Bonilla Arturo , Schink Julian C. , Markman Maurie
Published: June 2022

4139

Background: Curative treatment of pancreatic adenocarcinoma (PDAC) remains a challenge, as most patients present with advanced disease that has spread to other organs. The main opportunity for cure for these individuals remains systemic therapy. An improved understanding of the tumor biology is needed to appropriately target therapies for individual patients. We present cohort of Stage IV PDAC patients who underwent prospective comprehensive genomic profiling (CGP) in a national cancer network to evaluate genomic mutations, treatment patterns and survival. Methods: Between 2013 and 2021, 458 patients with Stage IV PDAC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue for treatment decision-making. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Patient demographics and outcomes were retrospectively reviewed with IRB approval. Results: Median patient age at presentation was 59 years (range, 26-84) and a majority were male (55%). Median overall survival was 15 months. Most patients were treated with first line chemotherapy, predominantly gemcitabine or FOLFIRINOX. GA were identified in 98% (n = 447) of PDAC patients. The most common genomic alterations were in KRAS (85%), TP53 (75%), CDKN2A (52%), SMAD4 (21%), ARID1A (9%), BRCA2 (5%), RNF43 (4%), and BRCA1 (1%). A mutation in one of the four commonly mutated genes ( KRAS, TP53, CDKN2A, or SMAD4) was identified in 94% (n = 426). Median overall survival was significantly worse for patients with mutations in KRAS or TP53 (both, P < 0.05). 185 patients (40%) had an actionable mutation based on the Know Your Tumor registry trial, including mutations in BRCA1, BRCA2, BRAF, CHEK2, ATM, ATK and STK11. MSI status was noted for 226 patients; only one patient was MSI-high. Tumor Mutational Burden (TMB) was known for 228 patients and was split as follows: 199 TMB-low (87%), 27 TMB-intermediate (12%), and 2 TMB-high (1%). TMB status was not associated with OS (P = 0.21). PD-L1 status was obtained in 20 patients, with 9 PD-L1 positive (45%); this was not associated with OS (P = 0.66). Of the 38 patients with a BRCA1 or BRCA2 mutation, 31 (82%) were treated with Olaparib. Other commonly utilized therapies included Niraparib (n = 56), Regorafenib (n = 8), Everolimus (n = 34), Erlotinib (n = 8), and Cetuximab (n = 6). Conclusions: In a large series of Stage IV PDAC patients assayed with CGP, GA were identified in 98% of tumors but only 40% had an actionable mutation. Most patients continue to be treated with conventional chemotherapy despite a sizeable group with targetable mutations. Further work is needed to identify targeted therapies for the more common mutations in PDAC given their impact on overall survival.