Fluoropyrimidine Chemotherapy Research Articles

Cost-effectiveness of extended DPYD testing before fluoropyrimidine chemotherapy in metastatic breast cancer in the UK.

The aim of this study was to evaluate the cost-effectiveness of ToxNav©, a multivariant genetic test, to screen for DPYD followed by personalized chemotherapy dosing for metastatic breast cancer in the UK compared with no testing followed by standard dose, standard of care. In the main analysis, ToxNav© was dominant over standard of care, producing 0.19 additional quality-adjusted life yearsand savings of £78,000 per patient over a lifetime. The mean additional quality-adjusted life years per person from 1000 simulations was 0.23savings(95% CI: 0.22-0.24) at £99,000 (95% CI: £95-102,000). Varying input parameters independently by range of 20% was unlikely to change the results in the main analysis. The probabilistic sensitivity analysis showed ~97% probability of the ToxNav©strategy to be dominant.

Risk of severe toxicity from topical fluoropyrimidine treatment in patients carrying DPYD variant alleles.

12123 Background: Patients carrying variant alleles of DPYD that reduce activity of dihydropyrimidine dehydrogenase have unacceptably high risk of severe toxicity from systemic fluoropyrimidine chemotherapy. DPYD testing prior to systemic fluoropyrimidine treatment is standard of care across Europe and is increasingly used in USA. There is a published case report of fatal toxicity from topical fluoropyridine chemotherapy in a DPYD variant carrier, but the risk of severe toxicity in these patients is unknown. This information is critical to determine whether patients receiving topical fluoropyrimidine treatment should also undergo DPYD genetic testing. The objective of this retrospective cohort study was to determine whether patients carrying DPYD variant alleles have increased risk of severe toxicity from topical fluoropyrimidine treatment. Methods: Individuals who received topical fluoropyrimidine treatment at Michigan Medicine and had available DPYD genotype data, due to participation in the Michigan Genomics Initiative institutional genetic data repository, were eligible for this analysis. Clinical data for the first cycle of topical fluoropyrimidine treatment was abstracted from the electronic medical record by an investigator blinded to genetic data. Toxicities were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The primary endpoint was grade 3+ toxicity. The secondary endpoint was grade 1+ toxicity. Genotypes for five validated decreased- or null-activity DPYD variant alleles were included: DPYD*2A (rs3918290), DPYD*13 (rs55886062), DPYD p.D949V (rs67376798) DPYD HapB3 (rs56038477) and DPYD p.Y186C (rs115232898). Toxicity rates in DPYD variant carriers vs. wild-type were compared using Fisher’s Exact tests. Results: 201 patients receiving topical fluoropyrimidine therapy who had available DPYD genotype data were included in the analysis. Most patients were self-reported white (97%), male (71%), and received topical fluoropyrimidine for a diagnosis of actinic keratosis (79%). As expected in a US patient cohort, 7.0% (14/201) of patients carried a DPYD variant. No patients experienced grade 3+ toxicity. Patients carrying a DPYD variant allele had nominally higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40 (95% Confidence Interval: 0.10-2.53), p = 0.19). Conclusions: Patients carrying DPYD variant alleles may have increased risk of non-severe toxicity from topical fluoropyrimidines, but the risk of severe toxicity is minimal regardless of genotype. DPYD genetic testing to prevent severe and fatal fluoropyrimidine toxicity should be reserved for patients receiving systemic treatment and need not include patients receiving topical treatment, in whom risk of severe toxicity is minimal.

Confirmatory DPYD Testing in Patients Receiving Fluoropyrimidines Who are Suspected DPYD Variant Carriers Based on a Genetic Data Repository.

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx-relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx-informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research-only genetic data repositories to expand the number of patients who benefit from PGx-informed treatment while we continue to work toward wide-scale adoption of PGx testing and implementation.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. Characteristics of patients receiving FOLFOX (n=195) and CAPOX (n=62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p<0.01) and oxaliplatin (72% vs. 66%, p=0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR=0.53, p=0.068) and similar OS (89% vs. 89%, HR=0.53, p=0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR=0.41, p=0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p=0.017) and hand-foot syndrome (p<0.001) but not peripheral neuropathy or myelosuppression. In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Phase 2 study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.

Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins. A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events. Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia. Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer.

Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre

BackgroundDihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom.MethodsPatients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers.ResultsBetween 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for DPYD heterozygous carriers and 93.2% (42.9–100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924).ConclusionsOur study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

The success of anti-PD-1 with chemotherapy for esophageal squamous cell carcinoma

In the ASTRUM-007 randomized double-blind phase III study, Song etal.1 showed that the combination of PD-1 inhibitors with first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas.

A novel outpatient regimen in management of fluoropyrimidine-induced cardiotoxicity.

Fluoropyrimidines (FP) are cornerstone drugs in the treatment of gastrointestinal (GI) malignancies. Cardiotoxicity secondary to an FP chemotherapy is a serious complication. There are no standardized guidelines on the treatment of FP induced cardiotoxicity which may result in interruption and even discontinuation of life saving treatment. We present our experience in FP rechallenge using a novel outpatient regimen based on our "up-front" triple agent antianginal protocol. We report the retrospective study of the patients with suspected FP induced cardiotoxicity. Patients meeting the criteria were selected by C3OD (curated cancer clinical outcomes database) at Kansas University Medical Center (KUMC). We identified all patients with gastrointestinal malignancies who had suspected FP induced cardiotoxicity from January 2015 to March 2022. We then included the patients who were rechallenged with planned fluoropyrimidine regimen utilizing the three drug KU-protocol. We utilized a novel regimen by repurposing the already FDA-approved anti-anginal drugs in a manner that minimizes the risk of hypotension and bradycardia. In this retrospective study, 10 patients with suspected fluoropyrimidine induced cardiotoxicity were included from January-2015 to March-2022 at KUMC. Out of 10 patients who were rechallenged utilizing KU-protocol, eight patients (80%) were able to complete the previously planned fluoropyrimidine regimen. None of the patients required ER visits or hospital admission due to cardiac symptoms during the rechallenge utilizing the KU-protocol. Utilizing our novel outpatient regimen, we have successfully and safely allowed re-challenge of FP chemotherapy with good tolerability and completion of the intended course of chemotherapy without recurrent morbidity.

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells.

Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions can have local and systemic influence on drug activity.

Prognostic value of mismatch repair deficiency in patients receiving first-line fluoropyrimidine plus platinum chemotherapy for metastatic, recurrent, or locally advanced unresectable gastric cancer.

461 Background: In localized gastric cancer (GC), deficient mismatch repair (dMMR) tumors reportedly have a favorable prognosis. However, a potentially detrimental effect of the dMMR status was suggested in patients treated with adjuvant chemotherapy. It remains unclear whether the mismatch repair (MMR) status can impact clinical outcomes in patients with metastatic GC (mGC) receiving palliative chemotherapy. We examined the impact of the MMR status on survival outcomes of patients with HER2-negative mGC receiving first-line fluoropyrimidine plus platinum (FP) chemotherapy. Methods: We reviewed patients with histologically confirmed metastatic, recurrent, or locally advanced unresectable adenocarcinoma of the stomach or gastroesophageal junction receiving first-line FP chemotherapy between January 2015 and August 2018 at Asan Medical Center, Korea. MMR status was correlated with clinical characteristics and survival outcomes for patients with available MMR immunohistochemistry results. Results: Of 895 patients, we analyzed 543 with available MMR protein expression results, and dMMR was detected in 4.4% (n=24). Patients with dMMR exhibited a significantly higher median age than those with proficient MMR (pMMR) (64 vs. 58 years, p=0.044). No signet ring cell carcinoma (SRCC) was detected among dMMR tumors, whereas SRCC was found in 17.5% of pMMR tumors. Based on our prognostic model (Koo DH et al, 2011), only 4.2% of patients with dMMR were classified as the poor-risk group (vs. 16.8% of patients with pMMR, p=0.097). No significant difference in progression-free survival (PFS) was noted between patients with dMMR and pMMR tumors (median, 5.6 vs. 5.8 months, p=0.266). Patients with dMMR tumors tended to have better overall survival than those with pMMR tumors; this difference was not statistically significant (median, 17.9 vs. 12.2 months, p=0.183). In the good-risk subgroup, patients with dMMR tumors had a significantly worse PFS than those with pMMR tumors (median, 5.6 vs. 9.2 months, p=0.009); multivariate analysis revealed that MMR status was an independent factor for poor PFS in this subgroup. Conclusions: Survival outcomes of dMMR mGC did not differ from pMMR in patients who received first-line FP chemotherapy. However, in the good-risk subgroup, patients with dMMR tumors had a significantly shorter PFS than those with pMMR, suggesting a potentially reduced efficacy of cytotoxic chemotherapy in these patients.

Analysis of the role of tumor microenvironment on clinical outcomes of chemotherapy in patients with advanced gastric cancer using high plex digital spatial profiling.

456 Background: Tumor consists of not only cancer cells but also various immune cells or stromal cells. And tumor microenvironment (TME) is known to be associated with response and resistance to treatment. However, the role of TME in the response to chemotherapy in advanced gastric cancer (AGC) remains unclear. We evaluated whether TME can affect the survival in patients with AGC who received first-line chemotherapy using high plex digital spatial profiling (DSP). Methods: Patients with AGC who received first-line chemotherapy were registered. Archival tumor tissue before first-line chemotherapy were obtained and tissue microarrays (TMAs) were made. Regions of interest (ROIs) were selected on each TMA and high plex DSP including RNA transcript was performed in all ROIs using GeoMx DSP (Whole Transcriptome Atlas) after masking by cytokeratin (CK) immunofluorescence. Differentially expressed gene (DEG), geneset enrichment analysis (GSEA), gene ontology (GO) and cell subsets were analyzed separately in CK-positive and CK-negative areas, using EdgeR, mSigDb, DAVID and CIBERSORT. Results: Thirty-three tumor tissues from 33 patients and 5 normal tissues were analyzed. All patients received fluoropyrimidine and platinum doublet chemotherapy. HER2+ was 15.2% and all with HER2+ AGC received trastuzumab plus chemotherapy. Five received nivolumab plus chemotherapy. Response rate was 48.5% and progression-free survival (PFS) was 9.8 months (95% CI, 6.85-NA). In CK-positive area, high expression of PIGR (polymeric Immunoglobulin receptor gene) (FDR q=0.013) and low expression of IFNE (FDR q=0.027) were associated with long PFS. Response to interferon beta (FDR q=0.044), cytokine-cytokine receptor interaction (FDR q=0.014) and antigen processing and presentation pathway (FDR q=0.015) were less activated in patients with long PFS in GO and GSEA. Although the density of CD8+ T cell did not affect PFS (6.9 vs. 10.8, p=0.25), high density of CX3CR1+memory CD8+T cells (Tmem) showed longer PFS (18.3 vs. 6.6 months, p=0.01), compared with low density of CX3CR1+CD8+Tmem. In CK-negative area, low density of CD8+ T cells were associated with longer PFS (6.3 vs. 18.3 months, p= 0.008). Conclusions: TME particularly in CK-positive area might affect survival for chemotherapy in AGC. PIGR and CX3CR1+CD8+Tmem were suggested as good candidate markers for predicting clinical outcomes of chemotherapy, indicating further analysis of TME will be needed especially in patients with AGC who received immune checkpoint inhibitors.

Nivolumab Combination Therapy for the Treatment of Unresectable Advanced or Metastatic Oesophageal Squamous Cell Carcinoma

Oesophageal cancer (OC) is the seventh most common malignancy worldwide, and there are few effective treatment options for advanced OC. Fluoropyrimidine and platinum-based chemotherapy has been the standard first-line treatment for advanced oesophageal squamous cell carcinoma (OSCC) but the survival outcomes are poor. Therefore, there is a need to develop new, more effective drugs. Immune checkpoint inhibitors (ICIs) have emerged as a new standard treatment for several malignancies. Nivolumab, a human monoclonal immunoglobulin G4 antibody that inhibits programmed cell death protein-1, has been developed for the treatment of advanced OSCC. Nivolumab monotherapy demonstrated clinical efficacy and safety in patients with OSCC in the ATTRACTION-3 trial, and was approved by the United States Food and Drug Administration as later-line treatment for patients with previously treated OSCC, regardless of programmed cell death protein-1 ligand expression status. Recently, the CheckMate 648 trial demonstrated the efficacy and safety of both an ICI in combination with chemotherapy, and a dual ICI combination, as first-line treatment for patients with advanced OSCC. This review discusses the current status of nivolumab combination therapy for patients with advanced OSCC, and future perspectives.

DPYD genotyping and predicting fluoropyrimidine toxicity: where do we stand?

Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.

Low intensity treatment in metastatic colorectal cancer

The optimal choice of first-line systemic therapy in initially unresectable metastatic colorectal cancer is becoming increasingly complex. Treatment selection and intensity should consider several factors including molecular status, primary tumour location, disease sites and burden, performance status and, importantly, patient preference. Although doublet chemotherapy backbone (a fluoropyrimidine [fluorouracil or capecitabine] and oxaliplatin, or a fluoropyrimidine and irinotecan) is typically recommended for first-line therapy in patients with unresectable metastatic colorectal cancer, the role of both higher intensity triplet chemotherapy (fluorouracil, oxaliplatin, and irinotecan) and lower intensity single-agent fluoropyrimidine chemotherapy have been explored in selected patient populations.

A Comparison of Standard Neoadjuvant Long-Course Chemoradiotherapy and Near-Total Neoadjuvant Therapy in Rectal Cancer: A Matched Pair Analysis at Equal Time Interval

<h3>Purpose/Objective(s)</h3> To investigate the efficacy of neoadjuvant chemotherapy administration following standard long-course chemoradiotherapy (LCCRT) before surgery (near-TNT), and to compare the outcomes with standard LCCRT in locally-advanced rectal cancer. <h3>Materials/Methods</h3> A total of 156 patients with cT3-4, cN0-2 rectal adenocarcinoma were included in this retrospective analysis, comprised of 79 patients treated with near-TNT, and 77 patients treated with LCCRT. Near-TNT defined as the incorporation of fluoropyrimidine plus oxaliplatin-based chemotherapy into the 12 weeks period between LCCRT and surgery. The patients treated with near-TNT and LCCRT were matched for cTNM stage at the same institution. The primary aim was to compare the pathologic complete response (pCR), and the secondary end-points were to compare the sphincter preservation and toxicity and safety of the treatments. <h3>Results</h3> A pCR was achieved in 40 of 156 patients (25.6 %) in the total population. The pCR were 24,1 % and 27,3 % with near-TNT and LCCRT, respectively (p=0,781). There was also no significant difference between near-TNT and LCCRT in term of sphincter preservation rate (65.8 % with near-TNT and 71.4 with LCCRT, p=0.561). The median tumor size was 2.5 cm (range: 0.2-10) after LCCRT, and 1.5 cm (range: 0.1-8) after near-TNT (p<0,001). Although near-TNT resulted in increased chemotherapy-related toxicity (p<0001), the treatment did not lead increased postoperative complications. When the groups compared with the Clavien-Dindo score, near-TNT group showed better postoperative complication rates (p=0,008). Additionally, near-TNT group exhibited better postoperative duration of hospitalization (p=0.002). <h3>Conclusion</h3> Though the addition of chemotherapy between the time interval of LCCRT and definitive surgery did not lead pCR rates, it might induce better tumor downsizing together with a cost of treatment-related toxicities. Besides downsizing effects, a positive postoperative complication rates make near-TNT as a potential treatment-approach in locally-advanced rectal cancer.

DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

Assessment of the Clinical Utility of Pretreatment DPYD Testing for Patients Receiving Fluoropyrimidine Chemotherapy.

Patients who carry pathogenic variants in DPYD have higher systemic fluoropyrimidine (FP) concentrations and greater risk of severe and fatal FP toxicity. Pretreatment DPYD testing and DPYD-guided FP dosing to reduce toxicity and health care costs is recommended by European clinical oncology guidelines and has been adopted across Europe, but has not been recommended or adopted in the United States. The cochairs of the National Comprehensive Cancer Network Guidelines for colon cancer treatment explained their concerns with recommending pretreatment DPYD testing, particularly the risk that reduced FP doses in DPYD carriers may reduce treatment efficacy. This special article uses previously published frameworks for assessing the clinical utility of cancer biomarker tests, including for germline indicators of toxicity risk, to assess the clinical utility of pretreatment DPYD testing, with a particular focus on the risk of reducing treatment efficacy. There is no direct evidence of efficacy reduction, and the available indirect evidence demonstrates that DPYD-guided FP dosing results in similar systemic FP exposure and toxicity compared with standard dosing in noncarriers, and is well calibrated to the maximum tolerated dose, strongly suggesting there is minimal risk of efficacy reduction. This article should serve as a call to action for clinicians and clinical guidelines committees in the United States to re-evaluate the clinical utility of pretreatment DPYD testing. If clinical utility has not been demonstrated, further dialogue is needed to clarify what additional evidence is needed and which of the available study designs, also described within this article, would be appropriate. Clinical guideline recommendations for pretreatment DPYD testing would increase clinical adoption and ensure that all patients receive maximally safe and effective FP treatment.

ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial

BackgroundFor patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act.MethodsELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life.DiscussionELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials.Trial registrationsEudraCT Number: 2020-004771-41(issued 01 October 2020); ISCRTN11398887(registered 14 July 2021).

343P DPYD gene sequencing and in silico functionality prediction of polymorphisms in 3,471 colorectal cancer patients treated with fluoropyrimidine (FP)

FP pharmacodynamics potentially depends on polymorphisms of genes related to its catabolism, anabolism, folate pathways, targets and transporters. EMA, CPIC and DPWG recommend DPYD testing (consensual variants *2A/*13/D949V/HapB3 of the DPYD gene coding for dihydropyrimidine dehydrogenase (DPD)) before starting FP chemotherapy. The main objective of this study is to identify a multigenic signature improving current recommendation to identify patients at risk of severe FP-induced toxicities. We herein present genetic results of DPYD sequencing.

Immunotherapy-Based Neoadjuvant Treatment of Advanced Microsatellite Instability-High Gastric Cancer: A Case Series.

Despite the use of first-line therapies like fluoropyrimidine and platinum-based cytotoxic chemotherapy, gastric cancer (GC) continues to carry a poor prognosis. Recent subgroup analyses of first-line phase III trials have demonstrated that patients with microsatellite instability-high (MSI-H) metastatic GC derive significant improvement in survival rates when immune checkpoint inhibitors (ICIs) are combined with chemotherapy compared with chemotherapy alone. However, it remains to be seen whether the success of ICIs in the metastatic setting can be translated into earlier stages of GC with resectable disease. We report 6 cases of locally advanced, nonmetastatic MSI-H GC that all demonstrated favorable response following treatment with pembrolizumab in addition to neoadjuvant chemotherapy. With the exception of immune-related colitis in one patient, pembrolizumab was well-tolerated. To our knowledge, this is the first reported US case series of patients treated with an ICI in combination with neoadjuvant chemotherapy for advanced, nonmetastatic, resectable or unresectable MSI-H GC.