bluuebunny/crossref_metadata_2025 huggingface dataset:
Reproducibility of lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with locally advanced rectal cancer.
Authors: Gawiński Cieszymierz
Published: January 2022

166

Background: Rectal cancer constitutes over one-third of all colorectal cancers (CRC) and is one of the leading cause of cancer-related death in developed countries. Treatment modalities applied in locally advanced tumors differ substantially among research centers. In order to identify high-risk patients and better adjust the therapy new markers are needed. Systemic inflammatory response (SIR) markers such as LMR, NLR and PLR have been proved highly prognostic in many malignancies, including CRC; however, they lack proper validation. In our study we assessed the reproducibility of LMR, NLR and PLR. Methods: Sixty patients with locally advanced rectal cancer treated in Maria-Sklodowska Curie National Institute of Oncology in Warsaw, Poland between 08.2017 and 12.2020 were prospectively enrolled in the study. Three consecutive blood morphology tests of each patient within a median period of 21 days were obtained before start of the treatment. Results: LMR, NLR and PLR calculated at two time-points were correlated with the coefficient of 0.776, 0.696 and 0.751 (p < 0.005 in all measurements), respectively. Patients were divided into LMR, NLR, PLR-high and low groups. If LMR at the first test was out of the range of 2.2-3.0 (+/- 0.4 from the cut-off) the risk of misclassification in the second measurement defined as an affiliation to a different (high or low) group than initially was 5.0% (95% CI 1.0-13.9%). In case of NLR, when outside of the range of 2.5-3.5 (+/- 0.5) it was 8.3% (95% CI 2.8-18.4%) and PLR outside of the range of 125-175 (+/- 25) 10.0% (95% CI 3.8-20.5%). Mean percentage change between the third and the first measurement of lymphocytes, monocytes, neutrophils and platelets count ranged from -5.59% to 4.76% and the standard error from 2.0 to 3.9. Conclusions: In conclusion SIR markers are reproducible, easily obtained biomarkers with potential application in clinical practice.
Age-associated mutations in RAS-mutated versus RAS-nonmutated metastatic colorectal cancer.
Authors: Kundranda Madappa N. , Kemkes Ariane C. , Routh Josh , De La O Jean-Paul , Evans Mark C. , Flannery Cynthia A. , Hall David W. , Therala Nishitha , Turner Michelle , Thakkar Snehal Govind
Published: January 2022

171

Background: Mutational profiling is recommended for selecting targeted therapy for metastatic colorectal cancer (mCRC). Evidence suggests that among patients with mutations in one of three RAS genes who underwent resection of liver metastasis, those with early onset mCRC had worse outcomes compared to those with late onset mCRC. The goal of this study was to explore whether other mutated genes in mCRC exhibit an association between age and wild type versus mutant RAS status. Methods: Between October 2018 and October 2020, 974 tumor samples from patients with mCRC were identified. Samples meeting requirements were profiled with the Oncotype MAP Pan-Cancer Tissue test, which sequences 257 genes from tumor tissue, including all 3 RAS genes ( HRAS, KRAS, NRAS). Using the Oncotype MAP assay, single base variants, indels, copy number alterations and structural variants/fusions were identified. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also determined. To identify genes for which there was an association between age group (patients ≤50 years vs >50 years) and RAS status we used Fisher’s Exact Test. Results: Of the 974 samples, 840 met minimum tumor tissue requirements for DNA sequencing (3mm2 and 15% tumor cellularity). Of these, 759 samples were successfully sequenced for NGS. Median turnaround time from the date of sample accessioning to the date of laboratory report was 5 days (interquartile range, IQR, 4-6 days). TMB varied from 0-227 mutations per megabase (median 6, IQR 4-8), and was high (≥10 mut/Mb) in 117 samples (15%). Of 775 specimens processed for MSI, 714 could be measured and approximately 7% were MSI-high. A total of 496 RAS variants were identified, of which 391 were pathogenic, likely pathogenic, or variants of unknown significance (349 KRAS, 34 NRAS, 8 HRAS). Of the 27 genes with at least 78 mutations in the data set, there was an association between RAS status and patient age for mutations at SMAD4, ABCC1, and RICTOR (Fisher’s Exact test, P < 0.05). For all three, mutations at these genes are relatively more prevalent in samples from young RAS wild type patients compared to young RAS mutant patients (Table). Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified numerous genomic changes in mCRC samples. There appears to be an association between age group and RAS status for three mutated genes, SMAD4, ABCC1, and RICTOR. The clinical implication is unclear and warrants further investigation with outcomes data.[Table: see text]
Rapid point of care NGS in colorectal cancer.
Authors: Raskin William , Cheema Parneet , Perdrizet Kirstin , Iafolla Marco , Dudani Shaan , Sheffield Brandon
Published: January 2022

172

Background: Next generation sequencing (NGS) is the laboratory cornerstone of precision oncology treatment. In advanced colorectal cancer (CRC), current guidelines recommend testing RAS, BRAF and MMR biomarkers as standard of care. The added value of comprehensive genomic profiling is so far unclear. Traditional NGS operations are complicated, requiring specialized equipment and personnel. In many jurisdictions, cancer patients are treated in publicly-funded community hospitals, where NGS is not typically utilized and access to testing via send-out services is associated with lengthy turnaround times. Here, we have validated and implemented one of the world's first "point of care" NGS services. Our early experience on NGS implementation and impact in CRC patients is described. Methods: All NGS studies were performed using the Oncomine Precision Assay (OPA) on the genexus integrated sequencer. NGS was performed at the request of the treating physician. All NGS was performed in a local community pathology lab by histotechnologists, simultaneously responsible for IHC testing (such as MMR) and interpreted by anatomic pathologists in conjunction with routine diagnostic pathology services. Retrospective chart review was performed for all patients undergoing sequencing studies and key data, including turnaround time and NGS findings were extracted from the electronic medical record for analysis. Results: A total of 51 cases with CRC were tested using point of care NGS from November 2020-August 2021, initiated by treating physicians. The median turnaround time for results was 3 days. Oncogenic driver events were identified in 46 (90%) cases, including canonical mutations in KRAS, NRAS and BRAF (Table). Actionable mutations were identified in 13 (25%) samples that would not have been identified with single-gene testing. Conclusions: Here, we show that comprehensive NGS can reveal occult resistance mechanisms to standard therapy and identify actionable biomarkers in a substantial proportion of patients with CRC. NGS added valuable information compared to guideline-recommended testing standards. Our study demonstrates that local testing can have rapid turnaround times. To our knowledge, this is the first report of “point of care” NGS in CRC. Further follow up is needed to explore the utility of these expanded roles for NGS testing. [Table: see text]
Metastatic bulk to predict subclonal heterogeneity by ctDNA in RAS/RAF-wildtype colorectal cancer.
Authors: Kratz Jeremy D. , Lubner Sam Joseph , LoConte Noelle K. , Patel Monica Arun , Uboha Nataliya Volodymyrivna , Lesnik Dyan M. , Ahmed Sara , Kelley Michael J. , Lemmon Kayla , Bassetti Michael Frederick , Sanger Cristina , Deming Dustin A.
Published: January 2022

186

Background: Distinct molecular subgroups of colorectal cancer (CRC) have been afforded with use of next-generation sequencing (NGS) as standard in clinical practice for advanced disease. We have previously demonstrated that disease bulk predicts clinical resistance to EGFR inhibition in RAS/RAF-wildtype (WT) CRC. We hypothesized bulky disease would predict advanced subclonal heterogeneity by circulating tumor DNA (ctDNA) in RAS/RAFWT CRC. Methods: Following IRB-approval, a retrospective review of molecular profiles in advanced CRC (n = 965) were compiled from the Veteran Administration’s (VA) National Precision Oncology Program (NPOP) and University of Wisconsin Precision Medicine Molecular Tumor Board (MTB). Disease bulk was defined as the longest diameter of metastatic disease or short axis for advanced lymphadenopathy. Molecular profiling was performed using commercially available platforms including Strata Oncology (MTB) and FoundationOne (NPOP). Bulky was compared as categorical (> 35 cm) and continuous variable against the count of pathologic variants. Results: The population was largely representative of advanced CRC with alterations in TP53 (80.5%), KRAS (44.8%), PIK3CA (22.0%) and BRAF (12.8%). Veterans had increased frequency of alterations in PIK3CA (22.7% v. 13.0%, p < 0.02) and BRAF (13.3% v. 6.9%, p < 0.05). There was no difference in metastatic bulk at the time of NGS for tissue biopsy between MTB and NPOP populations (t = 0.80). Disease bulk did not predict the number of pathologic variants from tissue sampling in RAS/RAFWT CRC (n = 96, t = 0.24). RAS/RAFMT cancers had increased frequency of subclonal alterations by ctDNA (9.1±4.0) v. RAS/RAFWT (4.5±3.4, p < 0.0001). Using ctDNA, bulky disease in RAS/RAFMT CRC was not predictive of increased pathologic variants (8.8±3.5 v. 9.5±4.8, t = 0.62). Bulky disease (> 35mm) in RAS/RAFWT CRC predicted increased subclonal variants (6.2±3.6 v. 3.5±2.9, p < 0.02). As a continuous variable, disease bulk predicted the number of pathologic variants in RAS/RAFWT CRC (R = 0.51). Conclusions: These data indicate that metastatic bulk is a predictor of subclonal heterogeneity by ctDNA in RAS/RAFWT CRC. Molecular profiling of tissue alone did not predict differences in subclonal heterogeneity when stratified by disease bulk in RAS/RAFWT CRC. Limited subclonal heterogeneity in non-bulky cancers support ongoing prospective investigations to select non-bulky cancers for early incorporation of anti-EGFR inhibition (NCT04587128).
Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity.
Authors: Hecht J. Randolph Randolph , Kopetz Scott , Patel Sandip Pravin , Welling Theodore , Morelli Maria Pia , Borad Mitesh J. , Molina Julian R. , Kirtane Kedar , Lin Yi , Fan-Port Michelle , Mardiros Armen , Beutner Karl , Lozac'hmeur Ariane , Lau Denise , Liechty Kirstin B. , Vong Judy , Ng Eric , Maloney David G. , Go William Y. , Simeone Diane M.
Published: January 2022

190

Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer–related mortality (5-yr survival rate, 14%, 3% and ̃5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA- or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy. Methods: The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with ≥ stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH. Results: HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers ( KRAS, BRAF and MSI status) were not associated with HLA-LOH. Conclusions: The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. [Table: see text]
Prognostic effect of RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Abid Haisam , Szabo Aniko , Taylor Bradley W. , Shreenivas Aditya V. , Chakrabarti Sakti , Kamgar Mandana , Thomas James P. , George Ben
Published: January 2022

191

Background: Somatic alterations in KRAS and BRAF have prognostic as well as predictive impact in pts with mCRC; however, the differential impact of various somatic alterations in these genes need further characterization. We analyzed the prognostic impact of specific somatic mutations in K RAS and BRAF in mCRC pts. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. Prevalence of genetic alterations was estimated using proportions and compared between groups using a chi-squared test. Patients were followed for survival from metastatic diagnosis until death or last follow-up, with left truncation at the time of CGP. Kaplan-Meier estimates were used to estimate overall survival, and groups were compared using a Cox-regression based likelihood ratio test. Results: 192 pts were identified - median age at diagnosis was 55 years, 62% (119/192) presented with metachronous metastatic disease, and 28% (54/192) had a rectal primary. Somatic mutations in KRAS were found in 49% (95/192) pts, and 53% (50/95) had a left sided primary (p = 0.3). Majority of the KRAS mutations localized to codon 12 (72/95 -76%), KRAS G12C comprised 12% (11/95). Median Overall Survival (mOS) of KRAS mutated pts was 3.0 years compared to 3.5 years for KRAS wild type (WT) pts (p = 0.5). Median OS of pts with different KRAS mutations were as follows: codon 12 mutations (excluding G12C) - 2.7 years; KRAS G12C – 5.2 years; non-codon 12 KRAS mutations - 4.8 years. BRAF mutations were identified in 7.8% (15/192) pts, and 67% (10/15) had a right sided primary (p = 0.062). BRAF V600E represented the most common alteration in BRAF – 87% (13/15). Patients with BRAF mutation had a mOS of 1.8 years compared to 3.1 years for BRAF WT pts (p = 0.2). Median OS of pts with different BRAF mutations were as follows: BRAF V600E – 1.8 years and BRAF non V600E - 2.1 years (p = 0.4). Conclusions: The numerically higher mOS in pts with KRAS G12C and non-codon 12 KRAS mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.
Clinical outcomes of neoadjuvant treatment strategies in localized mismatch repair-deficient rectal cancer.
Authors: Soderberg Leah C , Wookey Vanessa , Mitchell Jessica L. , Jochum Jacob A. , Tran Nguyen H. , Halfdanarson Thorvardur Ragnar , Hubbard Joleen M. , Graham Rondell P. , Mathis Kellie Leanne , Mahipal Amit , Jin Zhaohui
Published: January 2022

192

Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]
Characteristics and outcomes of patients with multiple synchronous colon cancer primaries.
Authors: Diab Maria , Goyal Subir , Switchenko Jeffrey M. , Alese Olatunji B. , Shaib Walid Labib , Akce Mehmet , Wu Christina , El-Rayes Bassel F.
Published: January 2022

194

Background: Patients (pts) with multiple synchronous colon cancer primaries (MCPs) constitute a unique subset of pts with colon cancer. However, there are limited published studies about these pts. The objective of this study is to compare the characteristics and outcomes of pts with MCPs to those with single colon cancer primaries (SCPs) using the largest study population to date. Methods: Data was obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Pts with synchronous MCPs were included and were matched 1:3 with pts with SCPs based on the Coarsened Exact Matching method for age, gender, and race. Only patients with multiple synchronous primaries were included (time since index = 0 months). We excluded pts with a lag time since diagnosis of index primary of 1 month or more. Univariate (UNA) and multivariable (MVA) analyses were performed to identify factors associated with patient outcomes. Kaplan-Meier analyses and Cox proportional hazards models were used to assess the association between tumor/patient characteristics and overall survival (OS). Results: A total of 3322 pts with MCPs and 9966 pts with SCPs were identified. Median age was 71 years. Majority were male (51.5%) and White (80.1%). 73.4% and 69.6% of pts had 12 or more lymph nodes examined for the MCPs and SCPs cohorts, respectively. The SCPs cohort included more T4 stage and more well- and moderately-differentiated histology. OS was significantly shorter in MCPs compared to SCPs (HR 1.29; 1.22-1.36; p < 0.001), with a 5- and 10-year OS rate of 47.8% and 28.2% for the MCPs and 56.4% and 41.6% for the SCPs, respectively, for all stages combined. In the MCPs cohort, the use of adjuvant chemotherapy was associated with an improved survival in AJCC stages II, III, and IV but not stage I. Conclusions: This is the largest study evaluating the impact of MCPs on outcomes. Across stages II to IV, pts with MCPs have a shorter survival than those with SCPs. Pts with stage II MCPs who receive adjuvant chemotherapy derive a survival benefit. Current guidelines do not list multiple synchronous primaries as a high-risk feature for stage II.
Effect of primary tumor location on second- or later-line treatment with anti-epidermal growth factor receptor antibodies in patients with metastatic colorectal cancer: A retrospective multicenter study.
Authors: Korphaisarn Krittiya , Archwamety Anita , Sintawichai Nattaya , Siripoon Teerada , Poungvarin Naravat , Tanasanvimon Suebpong , Sirachainan Ekaphop , Akewanlop Charuwan
Published: January 2022

195

Background: Currently, there are no guideline recommendations of anti-EGFR Ab specific to tumor sidedness in subsequent-line treatment in patients with metastatic colorectal cancer (mCRC). We previously reported the effect of primary tumor location on subsequent-line treatment with anti-EGFR Ab from a single center. Here we presented the outcome from a multi-center study. Methods: Medical records of patients diagnosed with mCRC at 3 academic centers in Thailand (Siriraj, Chulalongkorn, and Ramathibodi hospital) between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt mCRC 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 Kaplan-Meier method, and those results were compared using log-rank test. Results: Among the 2,102 patients who had KRAS analysis data, 1,130 (54%) patients had KRASwt. Of those, 413 patients received anti-EGFR Ab in second- or later-line treatment. One hundred and sixty-two of 413 (39%) patients had extended RAS analysis. Seventy (17%) patients had right-sided tumors. Two hundred and thirty-eight (58%) patients received anti-EGFR Ab in the third line, and 132 (32%) patients and 43 (10%) patients were treated in the second and more than third line, respectively. Single-agent irinotecan was the most commonly used backbone chemotherapy (303/413, 73%). Patients with right-sided tumors had non-significantly inferior PFS compared to patients with left-sided tumors (median PFS: 5.7 months (mo), 95% confidence interval [CI]: 3.9-7.5 vs. 7.5 mo, 95% CI 6.5-8.5; p =0.17). Subgroup analysis showed no difference in PFS when stratified by treatment lines. Patient with right-sided tumors had significantly inferior OS compared to patients with left-sided tumors (median OS: 23.3 mo vs. 29.9 mo; p =0.005). Conclusions: To date, this is the largest real world data of the effect of primary tumor location on anti-EGFR Ab which demonstrated that tumor sidedness has no significant impact on treatment outcomes in KRASwt mCRC patients receiving second- or later-line therapy. Our findings do not support the utility of tumor sidedness for treatment selection in these settings. We confirmed that patients with right-sided tumors had significantly worse survival.
Adverse event management costs for first-line treatment with cetuximab or panitumumab of RAS wild-type metastatic colorectal cancer patients in Latin America.
Authors: Pescott Chris , Kasle Adam , Esteso Federico , Stefani Stephen , Brust Leandro , Pinto Jose , Tilli Malena , Massello Matthew
Published: January 2022

203

Background: Anti-EGFR treatment of RAS wild-type metastatic colorectal cancer (mCRC) in Latin America includes cetuximab or panitumumab, added to chemotherapy (cet+CT and pan+CT, respectively). Adverse event (AE) profiles for each regimen may influence the treatment decision. This study aimed to estimate the associated financial impact of AE management in three countries: Argentina (AR), Brazil (BR) and Panama (PA) from a healthcare payer perspective. Methods: We revised a published Microsoft Excel-based economic model to calculate average patient- and population-level costs from a payer perspective of mCRC AE management for first-line cet+CT and pan+CT treatment, using AE frequency and severity data derived from the authorization relevant FDA prescribing information (PI), multiplied by the country-specific unit costs of managing AEs. Costs of AE management were obtained from publicly available sources in each country and converted to US dollars (USD). Country-specific market research data were applied to calculate costs at the eligible mCRC population level. The model structure and input parameters were endorsed by local practising oncologists. Results: A 17.5% (all-grade) and 31.6% (grade 3-4) lower average per patient AE frequency were estimated from the PI, for cet+CT vs pan+CT. Cost results are presented in the table. Projected AE management costs of cet+CT for the eligible mCRC population are $297,643 (AR), $124,981 (BR) and $65,895 (PA), annually, reducing current annual estimated AE costs by $42,181 (AR), $8,548 (BR) and $4,691 (PA). Conclusions: According to the average estimated AE frequencies, patients treated with cet+CT are expected to experience fewer AEs than with pan+CT. According to our analyses, the lower frequency rates could result in lower overall and severe AEs’ management costs, resulting in 12.4% (AR), 6.4% (BR) and 6.6% (PA) lower costs of AE management for cet+CT versus pan+CT.[Table: see text]
Survival of stage III colon cancer patients with adjuvant chemotherapy: Experience from a specialized cancer institute in Latinoamerica - Peru.
Authors: Veramendi Cabana Eder Christian , Cotito Izquierdo Jorge Antonio , Macetas Jackeline , Serrano Mariana , Pacheco Cristian , Castro Victor , Araujo Jhajaira M , Montenegro Paola Catherine
Published: January 2022

204

Background: In Peru, colon cancer is the 5th most common cause of cancer and the sixth most deadly. Currently, surgery remains as the only curative therapy, however, there is risk of recurrence. Adjuvant chemotherapy has become a useful tool to improve progression-free survival (PFS) and overall survival (OS). In this study, we determine the current survival of our stage III colon cancer patients, submitted to adjuvant chemotherapy, and if this is similar to the evidence seen in large international studies; also, we analyze if delay of adjuvant chemotherapy has impact on survival. Methods: This descriptive cross-sectional study involved 162 patients with stage III colon cancer who underwent a resection surgery and received adjuvant fluoropyrimidine-based chemotherapy. They were evaluated, according to the TNM classification (tumor, nodule), as low risk (T1-T3, N1) and high risk (T4, N2). We also classified patients, according to the weeks of delay from surgery to adjuvant chemotherapy, into subgroups of 6, 8 and 10 weeks. Results: The mean age was 63.7 years, 63 patients were women (38.9%), 99 patients (61.1%) were men. Only 38.3% of patients started adjuvant chemotherapy in the first 6 weeks after surgery, and 85.8% of patients, in the first 10 weeks; the median time from surgery to initiation of adjuvant chemotherapy was 7.0 weeks. We estimated that, at 3 years, the median PFS is 73.5% (95% CI: 65.8-82.1). The 3-year PFS in the low-risk group was 82.9% (95% CI: 72.3-95.0) and 67.3% (95% CI: 57.2-79.2) in the high-risk group. It was estimated that at 3 years, the median OS is 81.1% (95% CI: 75.2-87.5). The 3-year OS in the low-risk group was 87.9% (95% CI: 80.4-96.2) and 76.0% (95% CI: 67.8-85.3) in the high-risk group. Conclusions: The PFS and OS in Peruvian population is similar to data evidenced in international historical studies such as the IDEA trial. This study, also, suggests that starting adjuvant treatment within 10 weeks does not present an impact on OS and PFS in our population.
A glimpse into the future of esophageal carcinoma in the United States: Predicting the future incidence based on the current epidemiological data.
Authors: Tella Sri Harsha , Mara Kristin , Kommalapati Anuhya , Chakrabarti Sakti , Desai Aakash , McGarrah Patrick Walsh , Jin Zhaohui , Mahipal Amit
Published: January 2022

248

Background: Esophageal carcinoma is the 6th most common cause of death worldwide. While squamous cell carcinoma (SCC) was the most common among the histologic subtypes in the 20th century, recent reports have demonstrated an increased incidence of adenocarcinoma in both Eastern and Western world. With this changing paradigm of esophageal carcinoma, it is important to estimate the future burden of esophageal carcinoma by histology, age, sex, and race, that could help plan prevention, control, and treatment strategies for this cancer. Methods: We used Surveillance, Epidemiology, and End Results (SEER) 14 registries to obtain incidence data from 2000 to 2016. We applied age-period-cohort models to estimate future esophageal carcinoma incidence rates and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: Our estimate suggests that the incidence (per 100,000 persons) of esophageal adenocarcinoma is increasing in people within the age group of 40-65 years. Our prediction showed that the incidence will increase from 2.12 in 2021 to 2.82 in 2030 (3.2% per year, 95% CI –2.3% to 9.1%, p=0.26). Notably, we noticed a similar marginal increase in incidence among Asians, Black, and Whites in the 40-65 years age group (3.1%, 3.2%, and 4.2%, per year, respectively). White males aged >65 years had the highest incidence of esophageal adenocarcinoma (17.34 in 2021), and incidence decreased 1.3% per year. We noticed a marginally decreased incidence in Black male (-1.1% per year, p=0.71) and Asian male (-3.9% per year, p=0.17) population aged >65 years. Interestingly, we found a decrease in the incidence of SCC in the current age groups 40-65 (-2.7% per year, p=0.31) and >65 years (-4.6% per year, p=0.081). We observed that Asians had the greatest decrease in incidence (-4.3% per year) as compared to that of Blacks (-4.2% per year) and Whites (-2.9% per year), although there was no statistically significant difference in the annual decrease among races. Conclusions: In our study of esophageal cancer, we predict an increased incidence of adenocarcinoma histology subtype in the younger age group (40-65 years) while the SCC subtype will have a decreased trend. Strategies to prevention esophageal adenocarcinoma, including dietary changes, should preferentially target patients <65 years of age.[Table: see text]
STLA101 assay for the detection of cancerous progression in Barrett’s esophagus: A multi-institutional study.
Authors: Hartley Christopher , Hagen Catherine E. , Mittal Sumeet K. , Abdo Joe , Thyparambil Sheeno P. , Bansal Ajay
Published: January 2022

249

Background: Since 1975, Esophageal adenocarcinoma (EAC) incidence has increased more than any other cancer (̃700%). Pre-malignant metaplastic tissue, or Barrett's Esophagus (BE), is the only known precursor for EAC. Periodic histological assessment of endoscopic biopsy along dysplasia-carcinoma sequence is used to assess progression risk. Current surveillance protocols have clinical limitations as 80% of patients still present with stage II-IV EAC. The aim of this study is to compare novel proteomic expression patterns to distinguish stable BE patients from those who developed EAC using the STLA101 assay. Methods: After Institutional Review Board approval patients with BE/GERD were identified. Two cohorts were selected: progressors (progressed to EAC at subsequent interval of 0.5-3 years) and non–progressors (̃10 yrs of f/u surveillance without progression along dysplasia/carcinoma path). 24 normal esophageal mucosa samples with no h/o of BE were also retrieved for baseline expression levels. Tissue sections were microdissected to isolate pure BE cells from surrounding stromal cells. BE cells underwent a multi-step process where tissue was heated and digested to produce a liquid biopsy for mass spec. Isotopically labeled control peptides representing the STLA101 panel were spiked in with digested tissue samples to quantify all of the markers simultaneously using a Triple-quad mass spectrometer. Results: A total of 95 tissues were analyzed. 29 BE biopsies progressed to EAC within a mean of 380 days while the remaining 28 BE and 14 GERD specimens did not progress over a 10-yr period. All 8 biomarkers were expressed at a higher level in BE tissue that progressed to cancer when compared to BE/GERD tissue that remained stable over 10 years. The assay had a 100% technical success rate as no samples yielded “non-detectable” data points. Conclusions: The differential overexpression of the STLA101 panel on progressive and non-progressive BE tissues demonstrates the clinical utility of STLA101 as a predictive biomarker panel for early detection of esophageal carcinogenesis. Non-progressive BE tissues were similar to normal mucosa, therefore, patients whose BE tissue samples resemble this profile may receive a reduced screening cadence. On the other hand, patients with overexpression of the STLA101 panel may be eligible to receive more frequent screening or therapeutic intervention.
Geriatric-8 (G8) screening tool stratified the efficacy of S-1 plus ramucirumab in elderly patients with advanced/recurrent gastric cancer: A post-hoc analysis of the KSCC1701 trial.
Authors: Hu Qingjiang , Suyama Koichi , Kobayashi Kazuma , Katsuya Hiroo , Izawa Naoki , Uenosono Yoshikazu , 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: January 2022

256

Background: KSCC1701 trial showed the efficacy and safety of S-1 plus ramucirumab as a first-line treatment for elderly patients with advanced/recurrent gastric cancer. However, some frail patients may not benefit from S-1 plus ramucirumab. We aimed to clarify the usefulness of G8 screening tool for stratifying the efficacy and safety of S-1 plus ramucirumab therapy to elderly patients with advanced/recurrent gastric cancer. Methods: Patients aged 70 and older with previously untreated unresectable or recurrent gastric cancer were included from 23 institutes in Japan. They received S-1 (40-60 mg twice daily for 28 days, every 6 weeks) plus ramucirumab (8 mg/kg, every 2 weeks) until disease progression. The primary endpoint was the one-year survival rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The exploratory endpoint was detection of differences in treatment response by G8 screening tool. Results: Between September 2017 and November 2019, 48 patients were enrolled in this study. The cut-off value of G8 was determined as 11 by time-dependent ROC curve analysis for OS. Patients of G8 high (> = 11) and low (< 11) were 31 and 15, respectively. The characteristics of patients with G8 high/low were male: 21 (65.6%)/13 (81.3%), median age: 77/78 years, and PS (0): 16 (50.0%)/4 (25.0%). The one-year survival rate (total/G8-high/G8-low) was 65.2%/82.6%/26.7%. The median OS and PFS (total/G8-high/G8-low) were 16.4/20.7/6.9 months and 5.8/7.2/3.9 months, respectively. On Cox proportional hazards regression analysis for OS and PFS, the hazard ratio of G8-high was 0.156 [95%CI:0.066-0.367 (p < 0.0001)] and 0.391 [95%CI:0.202-0.755 (p = 0.0038)], respectively. The best RR (total/G8-high/G8-low) was 41.9%/55.6%/23.1%. The frequent grade 3 adverse events (total/G8-high/G8-low) was 78.7%/77.4%/81.3%. The frequent grade 4 adverse events (total/G8-high/G8-low) was 14.9%/16.1%/12.5%. Conclusions: Based on the results, G8 screening tool is useful for selecting elderly patients with advanced/recurrent gastric cancer in whom S-1 plus ramucirumab treatment shows a longer survival and a higher RR. Further examination including adverse events is therefore warranted. Clinical trial information: UMIN000028309.
Health-related quality of life (HRQoL) in patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) treated with nivolumab (N) plus chemotherapy (CT) or nivo plus ipilimumab (I) versus chemo: Results from CheckMate 648.
Authors: Bridgewater John A. , Chau Ian , Gricar Joseph , Blum Steven I. , Taylor Fiona , Lawrance Rachael , Padilla Brad , Yip Christine , Wyrwicz Lucjan
Published: January 2022

262

Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]
Risk of metabolic syndrome and fatty liver in gastric cancer survivors: A propensity score-matched analysis.
Authors: Park Hyojin
Published: January 2022

266

Background: With the recent development in cancer treatments, the number of cancer survivors is rapidly increasing. The aim of this study was to investigate the prevalence and risk of metabolic syndrome and fatty liver in GC survivors compared with that in non-cancer (NC) subjects. We also analysed the risk for metabolic dysfunction-associated fatty liver disease (MAFLD)8 in GC survivors compared with that in NC subjects. Methods: In this cross-sectional study, participants who visited Gangnam Severance Hospital from 2014 to 2019 for health check-ups were enrolled. After age- and sex-matched 1:4 propensity score matching, 119 GC survivors and 476 NC subjects were included. GC survivors were divided into operated gastric cancer survivors (OpGC) (n = 95) and non-operated survivors (non-OpGC) (n = 24). MetS was diagnosed by metabolic components and FL was assessed by ultrasonography. Results: MetS was observed in 21.0% of GC survivors and 30.5% of NC subjects, and in 13.7% of OpGC survivors and 50.0% of non-OpGC survivors. FL was observed in 25.2% of GC survivors and 37.6% of NC subjects, and in 21.1% of OpGC survivors and 41.7% of non-OpGC survivors. After adjusting for age, sex, MetS risk was significantly lower in OpGC survivors (odds ratio [OR] = 0.377, 95% confidence interval [CI]: 0.200-0.711, P = 0.003). FL risk was significantly lower in OpGC survivors (OR = 0.467, 95% CI: 0.267–0.816, P = 0.007), but not in non-OpGC survivors, compared with NC subjects. Risk of metabolic dysfunction-associated fatty liver disease was significantly lower in OpGC survivors (OR = 0.412, 95% CI: 0.233–0.729, P = 0.002) compared with NC subjects. Conclusions: OpGC survivors showed a lower risk of MetS and FL compared with NC subjects. These associations can be explored to ensure timely medical intervention in GC survivors.
Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC, RATIONALE 302): Impact on health-related quality of life (HRQoL).
Authors: Van Cutsem Eric , Kato Ken , Ajani Jaffer A. , Shen Lin , Xia Tianyu , Ding Ningning , Zhan Lin , Barnes Gisoo , Kim Sung-Bae
Published: January 2022

268

Background: RATIONALE 302 was a global phase 3 study (NCT03430843) that investigated tislelizumab (TIS) compared with investigator-chosen chemotherapy (ICC) as second-line treatment for patients (pts) with advanced or metastatic ESCC, in which TIS demonstrated a significant and clinically meaningful improvement in overall survival hazard ratio (HR = 0.70 [95% CI 0.57–0.85], P=0.0001), and a favorable safety profile compared with ICC. Here we assess the HRQoL of pts receiving TIS vs ICC in a pt population that usually experiences HRQoL deterioration. Methods: Adults with advanced or metastatic ESCC whose disease progressed following prior systemic therapy were randomized 1:1 to either TIS 200 mg IV every 3 weeks or ICC (paclitaxel, docetaxel, or irinotecan). HRQoL was measured using the global health status/quality of life (GHS/QoL), physical functioning, and fatigue scores from EORTC QLQ-C30 and the dysphagia, reflux, eating, and pain scores from the EORTC QLQ-OES18 from screening through Cycle 6 or until treatment discontinuation (whichever occurs first) Least-squares mean score change from baseline to Cycles 4 and 6 in HRQoL scores was assessed using a mixed model for repeated measurements. Time to deterioration (TTD) for the GHS/QoL score and the symptom scales of the QLQ-OES18 was examined using the Kaplan-Meier method. Results: Overall, 512 pts (median age 62) were randomized to TIS (n=256) or ICC (n=256). Compared with ICC, TIS-treated pts had stable GHS/QoL and fatigue scores as well as less decline in physical functioning at Cycles 4 and 6 (table). Except for pain, the TIS arm experienced less OES18 symptoms relative to baseline than the ICC arm. TTD analysis showed pts in TIS arm were at lower risk of worsening dysphagia (HR = 0.76 [95% CI 0.53, 1.07], P=0.0562) compared with ICC. Conclusions: The analysis showed that ESCC pts treated with TIS in the second line had a longer maintenance of HRQoL compared to pts treated with ICC. These results, along with improved survival and favorable safety profile, suggest TIS represents a potential new second-line treatment option for pts with advanced or metastatic ESCC. Clinical trial information: NCT03430843.[Table: see text]
Correlation of surgical volume and outcomes with gastrectomy.
Authors: Schuster Cassandra , Glasser Jamie , Huston Jamie , Shridhar Ravi , Meredith Kenneth Lee
Published: January 2022

272

Background: Gastric cancer(GC) is associated with significant mortality worldwide. Radical gastrectomy with lymphadenectomy is considered the only curative option for GC. Traditionally, these operations are associated with significant morbidity. However, a significant proportion of gastric resections are performed at low volume centers. We sought to compare oncologic outcomes of gastrectomy by surgical volume. Methods: Utilizing the National Cancer Database we identified patients with gastric cancer who underwent gastrectomy. We then stratified based upon volume of institution. Low volume(LV) < 10 gastric resections per year, and high volume(HV) > 10 gastric resections per year. Mann-Whitney U and Kruskal were used to compare continuous variables and Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. Multivariate analysis (MVA) was performed to identify predictors of survival. All statistical tests were two-sided and p < 0.05 was considered significant. Results: We identified 29,216 patients who underwent gastrectomy with a median age of 66.5 (18-90) years. There were 21,166 (72%) gastric resections performed at LV centers and 8,050 at HV centers, p < 0.001. Neoadjuvant therapy was most often utilized in the HV centers at 41.7% vs 24.1% in the LV centers, p < 0.001. The median number of lymph nodes removed were 19 (13-28) in the HV and 14 (8-21) in the LV groups respectively, p < 0.001. The R0 resection rates were 91.1% in high volume centers and 84.6% in the low volume centers p < 0.001. The length of hospitalization did not differ between groups (median 8 (6-12) days), p = 0.33. The 30-day readmission rates however, were higher in the low volume centers at 6.5% compared to 5.8% in the high volume centers. The 30 and 90-day mortality was 1.7% and 4.1% in the HV and 4.9% and 9.2% in the LV groups, p < 0.001 and p < 0.001 respectively. The median and overall 5-year survival was 83.8mo and 56% in the HV and 49.4mo and 46% in the LV cohorts, p = 0.001. Multivariate analysis revealed that age, sex, Charlson/Deyo score, tumor location, histology, grade, stage, facility volume, and neoadjuvant therapy were all predictors of survival. Conclusions: While the majority of gastric resections are performed at LV centers, oncologic outcomes, survival and mortality rates are worse compared to patients who undergo gastric resection at high volume centers. Gastric resections should be regionalized to high volume centers to ensure the best surgical and oncologic outcomes.