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To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the implementation of a multidisciplinary circuit at three months from its implementation.This is a descriptive, observational and retrospective study, which included adult patients with gastrointestinal cancer treated at a tertiary university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity developed during the first three cycles. The genotyped variants were rs3918290 (c.1905+1Ggt;A), rs55886062 (c.1679Tgt;G), rs67376798 (c.2846Agt;T) and rs75017182 (c.1129-5923Cgt;G).A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6% (11 patients). The most frequently identified variant was rs75017182 (6 patients). The second most common variant was rs67376798 (3 patients), followed by rs3918290 (2 patients). No patients presented with the rs55886062 variant. Two of the dihydropyrimidine dehydrogenase carriers developed grade 3-5 toxicity after the first cycle of a regimen that included fluoropyrimidines. Both received full doses of fluoropyrimidine, since their dihydropyrimidine dehydrogenase genotype was unknown before treatment initiation. None of the dihydropyrimidine dehydrogenase carriers who began treatment with a reduced dose of fluoropyrimidine experienced grade 3-5 toxicity. Since the creation in October 2020 of a multidisciplinary team, with the active participation of hospital pharmacists, the monthly average of dihydropyrimidine dehydrogenase genotyping studies has increased from 6.4 (January-October) to 17.5 (November-December).The present study shows a relatively high prevalence of loss-of- function variants in the dihydropyrimidine dehydrogenase gene as well as the importance of genotyping such variants before starting a treatment with fluoropyrimidines. Hospital pharmacists can contribute to the implementation of pharmacogenetics in daily clinical practice in a tertiary hospital.Determinar la prevalencia de variantes de pérdida de función en el gen de la dihidropirimidina deshidrogenasa (DPYD) en pacientes con tumores digestivos, valorar su relevancia clínica y evaluar la implementación de un circuito multidisciplinar tras tres meses de funcionamiento.Método: Estudio descriptivo, observacional y retrospectivo donde se incluyeron los pacientes adultos afectos de tumores digestivos, atendidos en un hospital universitario de tercer nivel, a los que se había afectuado el genotipado de DPYD entre septiembre de 2019 y diciembre de 2020. Las variables recogidas fueron sexo, edad, tipo de cáncer, localización, estadio, tratamiento recibido, indicación del tratamiento y grado de toxicidad desarrollado durante los tres primeros ciclos. Se genotiparon las variantes rs3918290 (c.1905+1Ggt;A), rs55886062 (c.1679Tgt;G), rs67376798 (c.2846Agt;T) y rs75017182 (c.1129-5923Cgt;G).Se incluyeron 115 pacientes. La frecuencia de portadores en heterocigosis de variantes del gen DPYD fue del 9,6% (11 pacientes). La variante más frecuentemente identificada fue el rs75017182 (6 pacientes). La segunda variante más frecuente fue el rs67376798 (3 pacientes), seguida del rs3918290 (2 pacientes). Ningún paciente presentó la variante rs55886062. Dos de los pacientes portadores desarrollaron toxicidad grados 3-5 tras el primer ciclo de un esquema que incluía fluoropirimidinas. Ambos recibieron dosis plenas de fluoropirimidina, puesto que no se conocía el genotipo de DPYD antes de iniciar el tratamiento. Ninguno de los pacientes portadores que tmpezó el tratamiento con una dosis reducida de fluoropirimidina experimentó toxicidad grados 3-5. Desde la creación en octubre de 2020 de un equipo multidisciplinar, con participación activa del farmacéutico hospitalario, se ha incrementado el número de estudios de genotipado de DPYD de una media de 6,4 estudios mensuales (enero-octubre) a 17,5 (noviembre-diciembre).Nuestro estudio muestra la relativamente elevada prevalencia de variantes de pérdida de función en el gen DPYD, así como la importancia de genotiparlas antes de empezar un esquema de tratamiento que contenga fluoropirimidinas. El farmacéutico hospitalario puede contribuir a la implementación de la farmacogenética en la práctica clínica diaria en un hospital de tercer nivel.

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.

Purpose Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). Methods In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). Results Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. Conclusions The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

[Background] Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients., [Methods] We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR)., [Results] We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib., [Conclusions] ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics., This research is supported by a Fero Fellowship Award (C.S.), Asociación Española Contra el Cáncer (J.P. Barcelona) (C.S.), and ISCIII PI16/01371 (C.S.). C.S. and A.V. acknowledge to the Cellex Foundation for providing facilities and equipment.

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.