bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of primary tumor location on second- or later-line treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer: A single-center cohort study.
Authors: Archwamety Anita , Poungvarin Naravat , Akewanlop Charuwan , Korphaisarn Krittiya
Published: June 2021

3541

Background: The guideline recommends anti-EGFR monoclonal antibodies (anti-EGFR Ab) as first-line treatment only for patients with left-sided RAS wild type (RASwt) metastatic colorectal cancer (mCRC). However, there are no recommendations on tumor sidedness in subsequent lines. This study aimed to evaluate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC. Methods: Medical records of patients diagnosed with mCRC at Siriraj Hospital between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using the Kaplan-Meier method and compared using the log-rank test. Results: Of 671 patients who had data on KRAS analysis, 396 patients (59%) had KRASwt. Of these, 210 patients received anti-EGFR Ab in second- or later-line treatment. Twenty-nine percent of patients (60 out of 210) had extended RAS analysis. Thirty patients (14%) had right-sided tumors, while 180 patients (86%) had left-sided tumors. Sixty-nine percent of patients (146 of 210) were treated in the third line, while 19% and 12% were treated in the second and the fourth line, respectively. Single-agent irinotecan was the most commonly used chemotherapy backbone (92%). Patients with right-sided tumors had non-significantly inferior PFS compared with patients with left-sided tumors (median PFS was 4.7 months, 95% CI 0.8–8.7 vs. 6 months, 95% CI 4.6–7.3; p = 0.55). Subgroup analysis on the impact of primary tumor location showed no difference in PFS when stratified by treatment lines. Conclusions: This study demonstrated that tumor sidedness has no impact on treatment outcomes in patients treated with anti-EGFR Ab in second- or later-line treatment. Therefore, there is not enough evidence to use tumor sidedness for treatment selection in these settings. A multi-center retrospective study is ongoing.
NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.
Authors: WANG Hui , Ou Qiuxiang , Wu Xue , Nagasaka Misako , Ou Sai-Hong Ignatius , Shao Yang
Published: June 2021

3544

Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( < 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.
Effect of Medicaid expansion on incidence of early-onset colorectal cancer incidence among Hispanics.
Authors: Rahman Shafia , Patel Riya Jayesh , Liu Jianyou , Acuna-Villaorduna Ana , Kim Mimi , Goel Sanjay
Published: June 2021

3547

Background: Early onset colorectal cancer (EO-CRC, age < 50 years) is an emerging public health crisis; especially in Hispanics. Access to healthcare is critical for timely detection and is tied to medical insurance. In 2010, the Affordable Care Act allowed for expansion of Medicaid eligibility across the country, however, states were permitted to opt out by the US Supreme Court ruling of 2012, which created an unintended experiment in the healthcare market. We evaluated the effects of Medicaid expansion on the incidence of EO-CRC among Hispanics with the hypothesis that it would lead to an increase in incidence and early detection EO-CRC. Methods: The National Cancer Data Base was used to collect data on newly diagnosed Hispanics with EO-CRC (40-49 years), across all stages, from 2010-2017. Data for 21 expansion states (ES) that expanded Medicaid in 2014, and 16 non expansion (NES) states was analyzed. The yearly state-wise Hispanic population was collected from U.S Census Bureau for 2010-17. Incidence was computed as number of new cases of CRC divided by size of the state’s Hispanic population. Segmented Poisson generalized linear mixed effects model was used to analyze rate of change in yearly incidence of EOCRC before and after 2014, in ES and NES. Results: Average annual incidence (AI) of EO-CRC in Hispanics was 6/100,000 and 8/100,000 pre and post expansion, in ES, and 8/100,000 and 9/100,000 pre and post 2014 in the NES, respectively. Increase in AI of EO-CRC was 3.6% per year (2010-14) (95% CI: -0.1% to 7.4%), and 9.8% (2014-17) (95% CI: 5.2% to 14.7%) for ES states; and 6.4% (2010-14) (95% CI: 2.1% to 10.8%), and 1% (2014-17) (95% CI: -3.8% to 6.1%) in NES. ES showed greater change in EO-CRC incidence post expansion (2014) vs. pre-expansion, as compared to NES (p=0.078) table. There was no difference in stage at diagnosis between pre- and pos- expansion periods between ES and NES. Conclusions: Increase in incidence of EO-CRC in ES is likely due to greater access to health care due to Medicaid coverage as compared to NES. Other potential factor is migration of Medicaid eligible persons from NES to ES. However we need data past 2017 to confirm the current trend.[Table: see text]
FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases: The PARLIM trial (AIO KRK 0314).
Authors: Modest Dominik Paul , Karthaus Meinolf , Kasper Stefan , Moosmann Nicolas , Keitel Verena , Kiani Alexander , Fischer von Weikersthal Ludwig , Uhlig Jens , Jacobasch Lutz , Fuchs Martin , Kaiser Florian , Lerchenmuller Christian A. , Junghanss Christian , Held Swantje , Heinrich Kathrin , Jung Andreas , Stahler Arndt , Stintzing Sebastian , Heinemann Volker
Published: June 2021

3553

Background: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/ folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomized, controlled, open label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. Methods: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 wks of biweekly mFOLFOX6 plus panitumumab followed by 12 wks of panitumumab alone) was considered active if the 2-year-PFS rate was ≥65%. Based on historical data, a 2-year-PFS rate of 50% was estimated in the control arm (12 wks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. Results: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The 2-year-PFS rate was 34.3% with FOLFOX plus panitumumab and failed to meet the primary endpoint. The 2-year-PFS rate in the control arm was 25%. In the experimental arm, a more favourable outcome was observed with regard to PFS (HR: 0.72, 95%CI 0.45-1.17; P = 0.18) and OS (HR: 0.76 (95% CI 0.34-1.71, P = 0.51) which did, however, not reach the level of significance. Updated data including toxicity and subgroup analyses might be presented at the meeting Conclusions: The PARLIM trial clearly failed to demonstrate a PFS rate of 65% after resection of colorectal liver metastases 2 years after randomisation, potentially indicating that the generally high frequency of recurrence and the choice of primary endpoint did not correspond in this study population. However, a trend for improved PFS and OS by the addition of panitumumab to 12 wks of FOLFOX followed by 12 wks panitumumab maintenance therapy may support future trials with ant-EGFR antibodies in this specific treatment setting. Clinical trial information: NCT01384994.
Concurrent BRAFV600E and BRCA mutations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Prevalence and case series of mCRC (pts) with prolonged overall survival (OS).
Authors: Cannon Timothy Lewis , Randall Jamie , Sokol Ethan , Alexander Sonja , Wadlow Raymond Couric , Barnett Daniel , Rayes Danny , Deeken John F. , Nimeiri Halla , McGregor Kimberly
Published: June 2021

3561

Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically <1 year. Despite use of multi-agent first-line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board database, we identified 3 consecutive mCRC pts with MSS/ BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had prolonged overall survival. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. Methods: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes ( BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis were BRAF V600E co-mutated with BRCA1 and BRCA2, separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation are described along with 3 consecutive cases of CRC patients, identified through the Inova Schar Cancer Institute (ISCI) molecular tumor board (MTB) registry, whom had prolonged OS. Results: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% having co-mutations of BRAF V600E and BRCA1/2. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of these occurred in MSS BRAF V600E. BRCA1 co-mutated was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001 ). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, one confirmed germline and 2 somatic in origin, and had average gLOH of 21.4% with overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. Conclusions: Co-existence of BRAF V600E/ BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. Larger prospective clinical validation trials in this subset is warranted.[Table: see text]
Neoadjuvant chemotherapy to improve colon cancer survival in resectable metastatic colon cancer: A real world NCDB data analysis.
Authors: Parasramka Saurabh , Jacob Aasems , Chen Quan , Huang Bin , Hao Zhonglin
Published: June 2021

3567

Background: According to the SEER database, approximately 21% of colon cancer patients have synchronous metastatic disease at presentation with a five-year survival of only 14%. Liver is by far the most common site of metastasis. For resectable and borderline resectable metastatic lesions after conversion to surgical resection, five-year survival ranges between 40-70% in different series. Survival advantage of neoadjuvant chemotherapy is not clear. We present here an updated analysis of effect of different variables on survival of 3,247 patients from the National Cancer Database (NCDB) treated from 2010-2015. Methods: Adults 20 years or older with primary colon cancer and single organ metastatic disease either in the liver and/or lung at diagnosis were identified. All patients had received surgery to the primary site, resection of the distant site and chemotherapy within 1 year of diagnosis. Patients were categorized into 2 cohorts based on whether they received chemotherapy in the pre-operative/peri-operative setting (neoadjuvant chemotherapy –NAC) or post-operative setting (adjuvant chemotherapy AC). Descriptive analysis, Kaplan-Meier plots, Log-Rank tests and Cox regression models for multivariate survival analyses were performed. To assess uncertainty of estimates, a sensitive analysis was also performed based on the intention to treat principle by including additional surgery only and chemotherapy only cases. Results: A total of 3,247 patients with colon cancer with liver or lung metastases were identified. A large majority 2,527 patients (77.8%) received AC. 54.5% were males and 45.5% females. On multivariate analysis, patients who received NAC had overall survival (OS) advantage with hazard ratio (HR) 0.86 (0.75-0.98). Clinical factors associated with worse survival included age > 75 HR 1.31; positive margin status with R1 HR 1.49 or R2 HR 2.33; Comorbidity index ≥ 2 HR 1.68; positive KRAS status HR 1.20; N2 disease HR1.95; ; having liver metastasis compared to lung HR 1.65 ;. Factors associated with improved survival were CEA less than 30 ng/ml at diagnosis and left sided tumor with HR of 0.64 (0.56-0.72) and 0.75(0.67-0.84) respectively. Conclusions: Metastatic colon cancer with single organ liver or lung lesions benefit from neoadjuvant chemotherapy based on our analysis of the real-world data. The survival advantage in this setting has not been shown before.
Mucinous colorectal cancer: Disease characteristics, treatment outcomes and the impact of metastasectomy.
Authors: Cowzer Darren , Harrold Emily , Sui Jane Sze Yin , Lucas Mairi , Fenlon Helen M , Redmond Karen C , Eaton Donna , Conneely John B , McEntee Gerry P , Brannigan Ann E , Shields Conor J , Mulsow Jurgen , Kelly Catherine Margaret , Greally Megan , McCaffrey John
Published: June 2021

3586

Background: Mucinous colorectal cancer (CRC) differs from adenocarcinoma with regard to clinical and histological features and is reported to have inferior outcomes when compared to non-mucinous CRC. This study aims to evaluate the clinical features and outcomes of patients with mucinous CRC at our institution. Methods: Medical records of patients with CRC that were referred to medical oncology between September 1999 and September 2018 were retrospectively reviewed. Mucinous histology was defined as those containing > 50% mucin identified on histology specimens. Statistical analysis was performed using Prism V9.0. Results: We identified 1,115 patients with CRC that were referred to medical oncology during this period. The tumours of 81 (7.3%) patients were classified as mucinous. Median age was 65 (28-94 years) and 45 (55.5%) were male. Forty-one patients (51%) had right sided tumours, 27 (33%) had left sided tumours and 13 (16%) had rectal tumours. Twenty-three (28.4%) had de novo metastatic disease. Eleven of 24 patients (46%) with stage II disease relapsed and 18 of 33 (55%) of those with stage III disease relapsed. Radiological surveillance identified 20/29 (69%) of relapsed disease, 5 (17%) were symptomatic and 4 (14%) had a rise in CEA. Median follow up for patients with stage II disease was 53 months and 3 year and 5-year disease free survival (DFS) was equal in both groups at 60.9%. For stage III disease 3- and 5-year DFS was 58.1% and 48.4% respectively with a median follow up of 43 months. In the metastatic setting, we observed no significant difference in overall survival (OS) between left and right sided tumours ( p = 0.550). Median OS for pts with stage IV mucinous CRC who received any treatment was 25 months. Metastasectomy was performed in 25/52 (48%) patients and was associated with a significant improvement in OS, 23 vs 51 months ( p < 0.005, HR 0.4). Conclusions: Mucinous CRC has been associated with inferior responses to treatment and worse overall outcomes compared to non-mucinous histologies. Survival in advanced-stage disease in our cohort is higher than what has been reported in the literature. With an effective multi-disciplinary approach and the increasing use of metastasectomy as a treatment option, survival in the advanced disease setting may be comparable to non-mucinous CRC.
Clinicopathological and molecular characteristics of early-onset stage III colon adenocarcinoma: An analysis of 25 studies with 35,713 patients in the Adjuvant Colon Cancer End Points (ACCENT) database.
Authors: Jin Zhaohui , Dixon Jesse G. , Parekh Hiral , Sinicrope Frank A. , Yothers Greg , Haller Daniel G. , Schmoll Hans , De Gramont Aimery , Kerr Rachel , Taieb Julien , Van Cutsem Eric , Twelves Chris , Saltz Leonard B. , Tomita Naohiro , Yoshino Takayuki , Andre Thierry , Mahipal Amit , Goldberg Richard M. , George Thomas J. , Shi Qian
Published: June 2021

3597

Background: Colon cancer (CC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years) is increasing. There are limited data suggesting that, as a group, patients with early onset CRC (eoCC) may have different phenotypic characteristics compared to those with late onset CRC (loCC, age ≥ 50 years). Methods: Individual patient data on 35,713 subjects with stage III CC from 25 randomized studies (recruiting between 1987 and 2009) in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for gender, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness and molecular markers. Results: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III eoCC (n = 6246) had similar distributions according to gender, race, PS, risk group, tumor sidedness and T/N stage compared to those with loCC (n = 29467). Patients with eoCC were significantly less likely to be overweight (30.2% vs 36.2%) but more commonly had ≥ 12 lymph nodes resected (69.5% vs 58.7%). The eoCC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%), and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher frequency of Lynch syndrome in eoCC. In univariate analysis, patients with stage III eoCC had significantly better OS, DFS, and SAR; the difference between 3-year DFS and RFR strongly suggests the OS/DFS difference between these the eoCC and loCC may be due to increased competing risks and comorbidities in patients with loCC. In multivariate analysis, age at onset lost its prognostic value when outcome was adjusted for molecular markers. The clear relation between age of onset and KRAS/BRAF status was confirmed in the interaction analysis. Conclusions: Tumor biology was an important determinant of prognosis regardless of patient age. In multivariate analysis age of onset was not a statistically significant determinant of outcome.[Table: see text]
Impact of radiotherapy for local control in T3 N0 rectal cancer managed with total mesorectal excision: A systematic review and meta-analysis.
Authors: Fabregas Jesus C. , Bang Andrew , Tjong Michael , Kucharczyk Michael
Published: June 2021

3604

Background: Total mesorectal excision (TME) significantly improved rectal cancer outcomes. Radiotherapy (RT) is recommended for T3N0 rectal cancers, though benefit has not been demonstrated in combination with TME for this specific population. This meta-analysis could provide evidence to ameliorate toxicities from treatment. Methods: Randomized clinical trials and observational studies published until October 18, 2020 were identified via PubMed and Embase. Objective: To determine whether RT decreased the risk of local recurrence (LR) in T3N0 rectal cancer managed with TME. Study Selection and Extraction: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were observed for literature search, extraction, and screening. Studies with LR data specific to T3N0M0 rectal cancer, treated with and without RT, were included. Reviews, non-English articles, and non-TME studies were excluded. Newcastle Ottawa Scale (NOS) evaluated quality. Meta-analysis was done with a random-effects model. Main outcome: Meta-analysis of the relative risk of LR was conducted. Results: 7,246 studies were screened, 134 full-text studies assessed for eligibility, 5 studies were included in the final analysis. No randomized data reported results specific to our study population. Five retrospective cohort studies involving 932 participants reported LR outcomes. The median follow-up ranged from 38.4 months up to 71 months. Four studies took place in Asia (797 participants) and one in North America (135 participants) (Table). Quality according to NOS ranged from 7–9. The estimated average relative risk for LR at 5 years was 0.63 (95% CI 0.31–1.29; I2=41.8%) when RT was used. Conclusions: This meta-analysis’ supports that there is no clear benefit to LR with the addition of RT in T3N0 patients with rectal adenocarcinoma undergoing TME. As meta-analysis was limited to retrospective cohort studies, there is concern for bias. Registration Prospero number CRD42020216058 .[Table: see text]
The prognostic value of tumor markers in patients (pts) with resectable gastric cancer (GC) receiving perioperative therapy in the CRITICS trial.
Authors: Slagter Astrid E. , Vollebergh Marieke A. , Caspers Irene A , van Sandick Johanna W. , Sikorska Karolina , Lind Pehr A. , Nordsmark Marianne , Putter Hein , Braak Jeffrey P.B.M. , Meershoek – Klein Kranenbarg Elma , Van De Velde Cornelis J.H. , Jansen Edwin PM , Cats Annemieke , Van Laarhoven Hanneke W.M. , van Grieken Nicole C.T. , Verheij Marcel
Published: June 2021

4024

Background: Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are well-known tumor markers. Most studies on CEA and CA 19-9 in pts with GC were performed in Asia, and/or in the metastatic setting. The aim of this study was to investigate the prognostic value of blood derived laboratory parameters in a cohort of European pts with resectable non-metastatic GC. Methods: In the CRITICS trial, 788 pts with resectable GC underwent perioperative therapy (preoperative chemotherapy plus either postoperative chemotherapy or postoperative chemoradiotherapy). Blood levels of CEA, CA 19-9, alkaline phosphatase (AP), creatinine, neutrophils, hemoglobin (Hb) and lactate dehydrogenase (LDH) were determined prior to treatment. Data for these variables were available for at least 89% of the pts. Factors significant on univariable cox regression analysis were further explored in multivariable analysis. Probabilities to undergo potentially curative surgery was investigated for factors significant on multivariable analysis. The relationship between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 pts with available ctDNA data. Results: CEA and CA 19-9 were identified as independent prognostic factors for survival (Table). Probabilities to undergo potentially curative surgery were 86%, 77% and 60% for pts with no elevated tumor makers versus those with elevated CEA or elevated CA 19-9 versus those with both tumor markers elevated, respectively (p<0.001). No relationship was found between elevated tumor marker(s) and the presence of ctDNA neither pretreatment nor preoperatively. Conclusions: Pretreatment blood levels of CEA and CA 19-9 were identified as prognostic factors for overall survival in a large cohort of European GC pts with potentially curable disease. These factors may guide treatment choices at an early phase and should be included in future trials to determine their role in clinical decision making.[Table: see text]
Frequency of homologous recombination-related (HRR) genes mutations in gastric cancer.
Authors: Wang Wei , Huaiming Wang , Chen Yuhong , Liu Huanhuan , Zhang Yanrui , Liang Xiayuan , Zhang Yun , Lou Feng , Cao Shanbo , Wang Huina
Published: June 2021

4031

Background: Homologous recombination deficiency (HRD) might contribute to predict response of immunotherapy and Chemotherapy response and PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. We aimed to analyze the mutational pattern of HRR genes and the relationship between HRR-related genes and clinical outcomes in gastric cancer. Methods: We prospectively sequenced 386 Chinese patients with gastric cancer using next-generation sequencing techniques with 808 cancer-related genes. 440 patients with WES data from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. Correlations between HRR genes and clinical outcomes were identified via bioinformatic analysis using TCGA datasets. Results: In the Chinese cohort, 10.4% (40/386) patients exhibited genomic alterations in HRR genes. The frequently mutated genes were BRCA2 (2.3%), ATM (1.8%), CDK12 (1.8%), BRCA1 (1.0%), CHEK2(1.0%), PALB2(0.8%), BARD1 (0.5%), RAD51B (0.5%), and RAD54L (0.3%). 8.3% patients had at least one somatic HRR genes mutation. Pathogenic germline variants were identified in 2.1% (8/386) patients. No participants carried both germline and somatic HRR gene mutations. In TCGA cohort, 19.1% (841/440) patients had at least one somatic mutation in an HRR gene. The frequently mutated genes were BRCA2 (6.4%), ATM (6.4%), CDK12 (3.2%), BRCA1 (3.2%), BARD1 (2.3%), PALB2 (2.3%), HEK2 (1.6%), CHEK1 (1.4%), BROP1 (1.1%), RAD54L (1.1%), FANCL (0.9%), RAD51D (0.9%), RAD51C (0.7%), PPP2R2A (0.5%), and RAD51B (0.5%). Chinese cohort had lower frequently somatic mutation of HRR genes compared to that in TCGA cohort (8.3% vs 19.1%, p < 0.001). Interestingly, in the TCGA cohort, patients with HRR-mut had significantly elevated tumor mutational burden, microsatellite instability status and enhanced immune activity than patients with HRR-wt. In the MSK-IMPACT cohort comprising 49 patients treated with ICIs, patients with HRR-mut had significantly better overall survival compared to those in patients with HRR-wt (p = 0.027). Conclusions: Our data suggest that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments, such as immunotherapeutic combine PARP inhibitor (PARPi) therapy. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in GC is necessary.
A multicenter phase II study of S-1 plus ramucirumab as first-line treatment in elderly patients with advanced/recurrent gastric cancer (KSCC1701).
Authors: Katsuya Hiroo , Suyama Koichi , Kobayashi Kazuma , Izawa Naoki , Uenosono Yoshikazu , Hu Qingjiang , Kusumoto Tetsuya , Otsu Hajime , Orita Hiroyuki , Kawanaka Hirofumi , Shibao Kazunori , Koga Satoshi , Shimokawa Mototsugu , Makiyama Akitaka , Saeki Hiroshi , Oki Eiji , Baba Hideo , Mori Masaki
Published: June 2021

4043

Background: Elderly patients are often intolerable in the combination with cytotoxic agents. Therapy with S-1 alone is a key option for initial chemotherapy for Japanese elderly patients with unresectable gastric cancer in clinical practice. However, there are some cases in which the antitumor effects with S-1 alone are insufficient. We aimed to investigate the efficacy and safety of S-1 plus ramucirumab therapy to elderly patients with advanced/recurrent gastric cancer. Methods: Patients aged 70 years and older with previously untreated unresectable or recurrent gastric cancer patients were included in Japan. They received S-1 therapy (40-60 mg twice daily for 28 days, every 6 weeks) plus ramucirumab therapy (8 mg/kg, every 2 weeks) until disease progression. The primary endpoint was the one-year survival rate and null hypothesis of one-year survival was set as 40%, which is the lower bound of the 95% confidence interval in previously reported studies on S-1 therapy. The secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. Results: Between September 2017 and November 2019, 48 patients were enrolled in this study. The characteristics of patients were male/female: 34/14, median age: 77.5 years (range: 71-87), and PS (0/1): 20/28. The one-year survival rate was 65.2% (95% confidence interval 49.8-78.6%), which means this trial met the primary endpoint. The median OS and PFS were 16.4 months (95%CI:12.0–20.7) and 5.8 months (95%CI:4.0–7.2), respectively. The best RR (CR+PR) was 60.9%. The frequent grade 3 or grade 4 adverse events were neutropenia (27.7%), anorexia (23.4%), anemia (19.1%), hypertension (14.9%), leucopenia (12.8%) and hypoalbuminemia (12.8%). Conclusions: Based on the observed efficacy and safety, S-1 plus ramucirumab is an appropriate first-line treatment for elderly patients with advanced/recurrent gastric cancer. Clinical trial information: UMIN000028309.
Risk factors of metachronous peritoneal carcinomatosis after potentially curative gastric cancer resection in the CRITICS trial.
Authors: Caspers Irene A , Sikorska Karolina , Slagter Astrid E. , Meershoek – Klein Kranenbarg Elma , Van De Velde Cornelis J.H. , Lind Pehr A. , Nordsmark Marianne , Jansen Edwin PM , Verheij Marcel , van Sandick Johanna W. , Cats Annemieke , van Grieken Nicole C.T.
Published: June 2021

4053

Background: Peritoneal carcinomatosis (PC) is accountable for over 50% of metastatic spread in gastric cancer (GC). Little is known about factors contributing to the risk of metachronous PC as a single site of metastases after preoperative chemotherapy and potentially curative resection. An accurate prediction model of risk factors identifying high risk populations may pave the way for new treatment strategies, such as intraperitoneal chemotherapy. In this analysis, risk factors for the development of isolated metachronous PC after preoperative chemotherapy and surgical resection were investigated. Methods: In the CRITICS trial, 788 patients with resectable GC were randomized for preoperative chemotherapy and gastrectomy followed by either chemotherapy or chemoradiotherapy. Patients who underwent a potentially curative resection without peritoneal metastases at time of surgery were included in this analysis. Univariate and multivariate analyses were performed using a competing risk model. Results: In total, 617 patients met the inclusion criteria. Overall, 97 of 617 (16%) patients developed metachronous PC. The peritoneum was the first site of recurrence in 64 of 617 (10%) patients. Diffuse or mixed type GC, ypT4 stage and ypN3 stage or a lymph node ratio (LNR) with >20% tumor positivity were independent predictors of isolated PC in both univariate and multivariate analyses with hazard ratios (HR) of 2.90, 2.63 and 2.31, respectively (Table). ypT4 and ypN3 stage or a LNR >20% were also independent predictors of distant recurrence or death with HR of 1.46 and 2.34, respectively. Patients in whom all predictors were present had the highest 2 year cumulative incidences of both isolated PC development and other events of 39.6% and 48.8%, respectively. Conclusions: Diffuse or mixed tumor type, ypT4 and ypN3 or a LNR >20% were identified as independent risk factors for metachronous PC as a single site of metastases in a large cohort of patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors might identify a subgroup that could benefit from preventive treatment strategies.[Table: see text]
A phase II study of neoadjuvant immunotherapy combined with chemotherapy (camrelizumab plus albumin paclitaxel and carboplatin) in resectable thoracic esophageal squamous cell cancer (NICE study): Interim results.
Authors: Li Zhigang , Liu Jun , Zhang Ming , Shao Jinchen , Yang Yang , Li Hongxuan , Liu Zhichao , Zhang Renquan , Yu Bentong , Chen Hezhong
Published: June 2021

4060

Background: We conducted a phase II trial of preoperative chemotherapy with albumin paclitaxel and carboplatin combined with camrelizumab (NICE regimen), in patients with locally advanced esophageal squamous cell carcinoma (ESCC) with multiple lymph nodes metastasis. Initial results were analyzed to assess the efficacy and safety of this strategy. Methods: This was a prospective, multicenter, open, single arm, phase II trial. Eligible patients were histologically confirmed thoracic ESCC, staged as T1b-4a, N2-3 (≥ 3 stations), and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes) according to the 8th edition of American Joint Committee on Cancer. Patients received neoadjuvant treatment (NICE regimen) with intravenous camrelizumab (200 mg, day 1) plus albumin paclitaxel (100 mg/m2, day 1, 8, 15) and carboplatin (area under curve 5, day 1) of each 21-day cycle, for two cycles before surgery. The primary endpoint is pathological complete response (pCR) rate in the per-protocol population, which included all patients who had tumor resection and received at least one cycle of neoadjuvant treatment. Secondary endpoints include R0 resection rate, adverse events and disease-free survival. Safety was assessed in the modified intention-to-treat population. Results: Of the planned 60 patients enrolled, 55 (91.7%) patients have received the full two-cycles NICE regimen successfully, 4 patients didn’t receive the complete neoadjuvant therapy due to intolerance (3 patients) and drop out (1 patient), 1 patient died due to pneumonia on the second cycle of neoadjuvant therapy. Grade 3-5 treatment-related adverse events (TRAEs) rate was 53.3% and TRAEs resulting in discontinuation rate was 6.7%. The common grade 3-5 TRAEs included lymphopenia (50%), thrombocytopenia (10%), pneumonia (5%) and thyroid dysfunction (3.3%). At the time of writing, 47 patients underwent surgery within 27-85 days (median 36 days) after NICE treatment, in which 7 patients had delays to surgery due to TRAEs. All patients achieved radical (R0) resection. There was no in-hospital and postoperative 30-day mortality. pCR (ypT0N0) was identified in 20 (42.5%) of 47 patients and 5 (10.6%) patients had complete pathological response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). Conclusions: Preoperative NICE regimen has achieved satisfatory initial results of disease response in locally advanced thoracic ESCC. A phase III randomized controlled trial is required to demonstarate the possible survival improvement. Trial registration: ChiCTR1900026240 Clinical trial information: ChiCTR1900026240.
Health-related quality of life (HRQOL) in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC): Interim results of nivolumab plus chemotherapy (N+C) versus (C) from CheckMate 649.
Authors: Wyrwicz Lucjan , Elimova Elena , Blum Steven I. , Xiao Hong , Davenport Eric , Wang Jinyi , Hunter Shannon , Li Mingshun , Kondo Kaoru , Moehler Markus H.
Published: June 2021

4066

Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) GC/GEJC/EAC. Prespecified interim results showed statistically significant improvement in overall survival (OS) and progression-free survival (PFS) for N+C vs C in all randomized pts and pts whose tumors expressed programmed death-ligand 1 combined positive score (CPS) ≥ 5. We present interim HRQOL results for CPS ≥ 5 pts, included as exploratory in the study. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment, and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1,581 pts were randomized to N+C (n = 789) and C (n = 792); of those, 955 pts had CPS ≥ 5 (N+C [n = 473] and C [n = 482]). Among 821 pts with BL and post BL PROs (N+C [n = 421] and C [n = 400]), BL scores for FACT-Ga total were similar for N+C and C. Least-squares mean differences from BL favored N+C at most visits for EQ-5D and FACT-Ga total and GaCS, and were comparable for other FACT subscales (data not shown). TTI largely favored N+C (most hazard ratios (HR) > 1) but was not significantly different between treatments. For TTSD, pts treated with N+C had decreased risk of deterioration (HR < 1) in EQ-5D UI, FACT-Ga total, and GaCS. TuDD showed statistically significant delays in deterioration (HR with confidence intervals [CI] < 1) for all scores. Conclusions: Pts with 1L GC/GEJC/EAC experienced better HRQOL with N+C compared with C alone. Change from BL in EQ-5D and FACT-Ga total and GaCS favored N+C at most visits. N+C decreased deterioration risk compared to C with OS and PFS improvement, suggesting favorable benefits in 1L GC/GEJC/EAC pts with CPS ≥ 5. Clinical trial information: NCT02872116. [Table: see text]
Preliminary results of molecular screening for FGFR alterations (alts) in the RAGNAR histology-agnostic study with the FGFR-inhibitor (FGFRi) erdafitinib.
Authors: Massard Christophe , Pant Shubham , Iyer Gopa , Schuler Martin H. , Witt Olaf , Qin Shukui , Tabernero Josep , Doi Toshihiko , Hargrave Darren R. , Hammond Constance , Little Shonda Marie , Xia Qi , Cao Jing , Santiago-Walker Ademi E. , Sweiti Hussein
Published: June 2021

4081

Background: FGFR alts (mutations and fusions) have been reported in multiple advanced solid tumors at varying frequencies. These alts may function as oncogenic drivers of disease independent of the underlying tumor type. RAGNAR is an ongoing phase 2, histology-agnostic trial investigating the efficacy and safety of erdafitinib, a selective pan-FGFRi, in patients (pts) with advanced solid tumors and FGFR alts. Little is known about the incidence, diversity or predominant FGFR alts across solid tumors in the clinical setting. Here, we provide an update on molecular screening and enrollment in the primary analysis population. Methods: Pts with advanced solid tumors were molecularly screened for eligible FGFR alts via central next generation sequencing (NGS) or review of local NGS reports. Underlying tumor type, FGFR alts, demographics and key disease characteristics were collected at baseline. Results: From Nov 2019 to Jan 2021, 5758 pts were molecularly screened (central or local) in 15 countries. 191 pts (3.3%) fulfilled primary analysis molecular eligibility criteria; 110 pts were enrolled. Among pts enrolled, 14 (12.7%) had central screening and 96 (87.3%) had local NGS reports. Eligible FGFR alts were identified in 19 tumor types, including rare cancers and ones (eg, pancreatic) with a very low prevalence of FGFR alts in genomic databases (Table). Median age was 57 y, and 19 pts (17.3%) were < 40 y. Gender distribution was even. Conclusions: Findings from molecular screening in the RAGNAR study indicate a wide range of FGFR-altered tumor types, including a notable number of cancers where eligible FGFR alts were considered exceedingly rare (eg, pancreatic). These results demonstrate the feasibility of conducting clinical trials on pts with rare genetic alts by adopting a histology-agnostic design and using both central testing and local NGS reports for molecular screening. This approach also helps investigate rare tumors, where histology-specific trials are challenging. Efficacy and safety results from the RAGNAR study will help define the benefit of erdafitinib in FGFR-altered advanced solid tumors. Clinical trial information: NCT04083976. [Table: see text]
Treatment-related toxicity and improved outcomes with immune checkpoint inhibitors in patients with hepatocellular carcinoma.
Authors: Cortellini Alessio , Marron Thomas Urban , Mishra-Kalyani Pallavi Shruti , Gong Yutao , Saeed Anwaar , Jun Tomi , Dharmapuri Sirish , Naqash Abdul Rafeh , Khan Uqba , Kaseb Ahmed Omar , Huang Yi-Hsiang , Ang Celina , Schneider Julie A. , Pillai Anjana , Rimassa Lorenza , Pazdur Richard , Theoret Marc Robert , Lemery Steven , Pelosof Lorraine Cheryl , Pinato David James
Published: June 2021

4085

Background: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI), however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). This retrospective multi-center study aimed to examine whether trAEs are prognostic in HCC. Methods: We established an international consortium of 10 tertiary-care referral centers located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to test whether the development of clinically significant trAE (i.e. graded >2, trAE2) predicted for improved overall (OS), progression-free survival (PFS), and overall response rates (ORR) following ICI, and subsequently validated this association in a separate cohort of 406 HCC patients receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. Results: In a multi-institutional cohort of 357 patients, 274 (77%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 304, 85%), trAE were reported in 146 patients (41%). Development of trAE2 were associated with longer OS (23.3 versus 12.2 months) and PFS (8.6 months versus 3.7 months). After adjusting for viral aetiology, gender, presence of cirrhosis, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy, trAE2 were confirmed predictors of improved OS (HR 0.55; 95%CI:0.34-0.88) and PFS (HR 0.51; 95%CI: 0.35-0.74). TrAE2 were associated with higher ORR (27% versus 16%) from ICI. The association between trAE2 and patients’ OS (HR 0.49; 95%CI:0.34-0.70) and PFS (HR 0.43; 95%CI:0.32-0.59) was also observed in the FDA dataset. After a 6-weeks landmark selection, trAE2 were confirmed to be associated with improved PFS (HR 0.59; 95%CI:0.39-0.87); the additional analysis adjusted for tumour response and duration of treatment within the FDA cohort further confirmed the association with longer PFS (HR 0.67; 95%CI: 0.47-0.94). Conclusions: Development of trAE2 may correlate with response and survival in patients with HCC receiving ICI, a clinical setting where the lack of biomarkers still represents an unmet need. Prospective studies aimed at understanding the underlying immunologic foundations of such relationship are warranted to identify predictive biomarkers of toxicity and response.
ARID1A mutation to predict disease progression during first-line chemotherapy in biliary tract cancer patients.
Authors: Lee Sung Hwan , Cheon Jaekyung , Lee Seoyoung , Choi Hye Jin , Kang Beodeul , Im Hyeon-Su , Kim Chan , Choi Sung Hoon , Lee Choong-kun , Chon Hongjae
Published: June 2021

4105

Background: Biliary tract cancer (BTC) is a retractable disease showing a dismal prognosis with therapeutic resistance. There are clinical unmet needs on predicting therapeutic response and precise strategy for the patient classification according to clinically relevant tumor biology in the patients with BTC. We aimed to identify clinically detectable genomic alteration predicting therapeutic response after first-line chemotherapy in BTC using real-world data. Methods: A comprehensive genomic analysis of multi-institutional cohorts of BTC cases was performed using next-generation sequencing (NGS) with targeted DNA panel and patients’ clinicopathologic data. Results: A total of 200 BTC patients with NGS panel tests from three cancer centers were included in this study. The genomic alteration of TP53 (55.5%), KRAS (23%), ARID1A (10%), and ERBB2 amplification (10%) were the most frequent alteration events in the BTC. Pathologically-proved BTC including extrahepatic (n = 52), ampulla of Vater (n = 4), gallbladder (n = 56), intrahepatic (n = 88) cancers showed a distinct pattern of genomic alterations in terms of ARID1A for extrahepatic BTC and ERBB2 amplification, RB1, ARID2 for GB cancer, and KRAS, IDH1, PBRM1, BAP1 for intrahepatic BTC respectively (chi-square test, P < 0.05). The oncologic outcomes for progression-free and overall survival were significantly stratified according to the best response after the first-line chemotherapy (log-rank test, P < 0.001). The logistic regression test revealed that ARID1A, BRCA2, and STK11 could significantly predict disease progression during first-line chemotherapy. ARID1A, especially, was the only independent predictive marker in the multivariate regression model in total BTC (OR 3.91, 95%CI 1.25-11.66, P = 0.015) and extrahepatic BTC (OR 5.71, 95%CI 1.23-28.98, P = 0.027). The predictive performance of significant genomic alteration was enhanced with the tumor marker CA19-9 (DeLong’s test, Z = 1.933, P = 0.053, AUC 0.73, 95%CI 0.623-0.837). Conclusions: Clinically available NGS test showed distinct genomic alterations in terms of different deterioration patterns for oncogenic molecular pathways according to the anatomic locations of BTC. Integrative analysis using the data for genomic alteration and therapeutic response for the first-line chemotherapy uncover that the patients with ARID1A mutation show a significant disease progression rate during initial treatment for BTC, especially in the extrahepatic BTC. Prospective translational studies revealing underlying biology and precision strategy should be followed to improve the therapeutic response of BTC.