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Background: Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known. Objective: We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups. Methods: This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein–Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction. Results: Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%). Conclusions: Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is one of the most disabling disorders with significant comorbidity and mortality. Incidence and prevalence of CKD in cancer survivors are remarkably high in both adults and pediatric patients. The reasons for this high incidence/prevalence are multifold but kidney damage by cancer itself and cancer treatment (pharmacotherapy/surgery/radiation) are the main reasons. Since cancer survivors commonly have significant comorbidities, risk of cancer recurrence, limited physical function or life expectancy, special attentions should be paid when considering the treatment of CKD and its complications. Especially, shared decision-making should be considered when selecting the renal replacement therapies with as much information/facts/evidence as possible. [ABSTRACT FROM AUTHOR]

Summary: Background. Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients. Methods. Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m2 on days 1 and 15) and FTD/TPI (35 mg/m2/dose, twice daily, on days 1–5 and 8–12 [Level A] or on days 1–5 and days 15–19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR). Results. Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively. Conclusion. The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary. [ABSTRACT FROM AUTHOR]

Background: Primary tumor site and genomic status are utilized for regimen selection in metastatic colorectal cancer; however, the impact on clinical practice is not well known. Objective: We aimed to clarify the impact of primary tumor site and genomic status on clinical practice in metastatic colorectal cancer. Methods: The relationship between primary tumor site, genomic alterations, and clinical outcomes was evaluated in patients with untreated metastatic colorectal cancer using real-world data of a prospective observational study, SCRUM-Japan GI-SCREEN with clinical and genomic data set in 1011 patients enrolled from February 2015 to March 2017. Results: Five hundred and sixty-one patients were eligible for this study. Patients with right-sided tumors had a significantly worse survival, left-sided tumors with wild-type RAS had favorable outcomes when treated with anti-epidermal growth factor receptor monoclonal antibodies, and cecum tumors had poor prognosis when treated with bevacizumab. The rate of gene alterations varied considerably depending on the primary site. In addition, gene alterations of KRAS, BRAF, SMAD4, or TP53 had individually different contributions to survival from site to site. KRAS, BRAF, PTEN, or SMAD4 mutations were associated with efficacy of bevacizumab or anti-epidermal growth factor receptor monoclonal antibodies. Conclusions: Primary tumor site is a clinically useful biomarker to predict survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. Moreover, the prognostic or predictive value of several gene alterations by primary tumor site should be considered in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased availability of targeted therapies. However, in patients with gastrointestinal (GI) cancers, the utility of genomic profiling is unclear because of common non-druggable alterations and rapid disease progression that prevent a sufficient time period to seek targets. Objective: The aim of this study was to determine the utility of genomic profiling tests in patients with GI cancers. Methods: The subjects of this retrospective study were patients with GI cancers and patients with non-GI cancers who underwent tissue-based genomic profiling at a single institution from April 2017 to October 2020. The profile of gene alterations, frequency of tumor mutational burden-high (≥ 10 Muts/Mb), and accessibility of recommended molecular targeted therapy were compared between patients with GI cancers and patients with non-GI cancers. Results: In all, 133 patients with GI cancers and 63 patients with non-GI cancers were included. The genomic profiles of GI cancers showed the highest frequencies of TP53, KRAS, and APC mutations and a significantly lower frequency of PIK3CA mutations than those of non-GI cancers. Tumor mutational burden-high was significantly less prevalent in GI cancers (4% vs 20%, p = 0.008). Twenty-nine patients with GI cancers (40%) and 35 patients with non-GI cancers (56%) were recommended for targeted therapies based on the findings. Among them, seven patients each with GI cancers and non-GI cancers received the recommended therapy on their genomic findings, which showed similar treatment accessibility between the GI and non-GI cancer groups (10% vs 11%, p = 0.791). HER2-targeted and BRAF-targeted therapies were the primary treatments administered to patients with GI cancers. Conclusions: Although their genomic profiles revealed fewer druggable sites, patients with GI cancers accessed targeted therapies similarly to patients with non-GI cancers. The utility of genomic profile testing in patients with GI cancers was highlighted to determine if patients can receive specific treatments, such as HER2-targeted and BRAF-targeted therapies. [ABSTRACT FROM AUTHOR]

Summary: KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determined in the 1st stage, followed by evaluation of efficacy at the RD level in the 2nd-stage. Cetu was given at a loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m2 followed by biweekly infusions of 16 mg/m2 in level 1 and 16–12 mg/m2 in level 0. Twenty-two patients were enrolled. No dose-limiting toxicities were observed among three patients in level 1 in the first stage, which was determined as RD. Grade 3 or higher adverse events occurred in 59.1%; those in ≥5% of patients were anemia, γ-GTP elevation, and acneiform rash. Overall response rate was 0.0% [95% confidence interval (CI): 0.0%–15.4%] and disease control was achieved in 17 patients (77.3%, 95% CI: 54.6%–92.2%). Median progression-free survival time was 85.0 days (95% CI: 54.0–91.0) and median survival time was 196 days (95% CI: 113.0–306.0). RD was determined as level 1. The efficacy of this combination therapy after progression on Cetu/Pani was negligible. Trial Registration: UMIN000013006. [ABSTRACT FROM AUTHOR]

Background and aim: Fistula is one of the known complications of T4 esophageal cancer (T4-EC). The standard treatment for T4-EC is chemoradiotherapy, but detailed data about fistula resulting from chemoradiotherapy in this condition are limited. In particular, radiographic findings of T4-EC with fistula have not been reported. This study assessed the risk factors of fistula based on clinical information on patients with chemoradiotherapy for T4-EC. Methods: We retrospectively reviewed the clinical data of 59 T4-EC patients who had squamous cell carcinoma without any fistula before receiving definitive or palliative chemoradiotherapy. Results: A fistula was observed in 18 patients (31%) throughout their clinical course. The overall survival in the fistula group was significantly shorter than that in the non-fistula group (259 vs. 346 days; p = 0.0341). The axial tumor size on computed tomography (CT) was confirmed as an independent risk factor for esophageal fistula in multivariate analysis of stepwise methods [OR 1.226; 95% CI 1.109–1.411; p < 0.0001]. Twelve out of 14 patients with an axial tumor size of 50 mm or greater had developed a fistula. Conclusions: A large tumor size on the axial plane on CT is a risk factor for fistula formation. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) and RAS/RAF signaling pathway plays pivotal roles in tumor progression via proliferation, survival, invasion, and immune evasion. Two anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have become essential components in the treatment of patients with metastatic colorectal cancer (mCRC). Treatment with these anti-EGFR antibodies has shown definite benefits when administered in all treatment lines and is strongly recommended as the preferred regimen to prolong survival, especially when administered in the first- and third-lines. Recent efforts have revealed not only mechanisms responsible for resistance to anti-EGFR antibodies, including expanded RAS mutations as a negative predictive biomarker, but also the possibility of continuing anti-EGFR antibody treatment in combination with chemotherapy. Furthermore, the challenges associated with the pharmaceutical development of treatments for patients with mutant-type BRAF mCRC are ongoing. In this review, we provide an overview of the EGFR and RAS/RAF signaling pathway and antitumor activity, focusing on practical aspects such as established treatments including patient selection, treatment strategies, and future perspectives for drug development targeting the EGFR and RAS/RAF signaling pathway. [ABSTRACT FROM AUTHOR]

Oxaliplatin, a chemotherapeutic agent for colorectal cancer, has been associated with pathological evidence of sinusoidal endothelial injury in the liver. However, esophagogastric varices are a poorly recognized outcome of oxaliplatin-based chemotherapy. We report a 78-year-old man, whose past history of colon cancer was resection and treatment with mFOLFOX6 for 20 weeks, as adjuvant chemotherapy. After 3.5-year follow-up of the oxaliplatin-based chemotherapy, he was diagnosed with esophageal varices without liver dysfunction, indicating that the hepatotoxicity caused by oxaliplatin could be prolonged after its administration. Patients who have received oxaliplatin-based chemotherapy should be followed up carefully over the long term. [ABSTRACT FROM AUTHOR]

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application. [ABSTRACT FROM AUTHOR]